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Paolo VENTURA
Professore Associato
Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell'Adulto
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Pubblicazioni
2023
- A Fatal Case of Pseudomonas aeruginosa Community-Acquired Pneumonia in an Immunocompetent Patient: Clinical and Molecular Characterization and Literature Review
[Articolo su rivista]
Barp, Nicole; Marcacci, Matteo; Biagioni, Emanuela; Serio, Lucia; Busani, Stefano; Ventura, Paolo; Franceschini, Erica; Orlando, Gabriella; Venturelli, Claudia; Menozzi, Ilaria; Tambassi, Martina; Scaltriti, Erika; Pongolini, Stefano; Sarti, Mario; Pietrangelo, Antonello; Girardis, Massimo; Mussini, Cristina; Meschiari, Marianna
abstract
Rare cases of Pseudomonas aeruginosa community-acquired pneumonia (PA-CAP) were
reported in non-immunocompromised patients. We describe a case of Pseudomonas aeruginosa
(PA) necrotizing cavitary CAP with a fatal outcome in a 53-year-old man previously infected with
SARS-CoV-2, who was admitted for dyspnea, fever, cough, hemoptysis, acute respiratory failure
and a right upper lobe opacification. Six hours after admission, despite effective antibiotic therapy,
he experienced multi-organ failure and died. Autopsy confirmed necrotizing pneumonia with
alveolar hemorrhage. Blood and bronchoalveolar lavage cultures were positive for PA serotype
O:9 belonging to ST1184. The strain shares the same virulence factor profile with reference genome
PA01. With the aim to better investigate the clinical and molecular characteristics of PA-CAP, we
considered the literature of the last 13 years concerning this topic. The prevalence of hospitalized
PA-CAP is about 4% and has a mortality rate of 33–66%. Smoking, alcohol abuse and contaminated
fluid exposure were the recognized risk factors; most cases presented the same symptoms described
above and needed intensive care. Co-infection of PA-influenza A is described, which is possibly
caused by influenza-inducing respiratory epithelial cell dysfunction: the same pathophysiological
mechanism could be assumed with SARS-CoV-2 infection. Considering the high rate of fatal
outcomes, additional studies are needed to identify sources of infections and new risk factors, along
with genetic and immunological features. Current CAP guidelines should be revised in light of
these results.
2023
- Clinical application of NGS in the diagnosis of iron overload disorders or hyperferritinemia of genetic origin
[Abstract in Rivista]
Ricci, A.; Bergamini, E.; Scarlini, S.; Buzzetti, E.; Caleffi, A.; Rabacchi, C.; Ventura, P.; Artuso, L.; Tenedini, E.; Tagliafico, E.; Pietrangelo, A.; Corradini, E.
abstract
2023
- Efficacy and safety of givosiran for acute hepatic porphyria: Final results of the
randomized phase III ENVISION trial
[Articolo su rivista]
Kuter, David J.; Bonkovsky, Herbert L.; Monroy, Susana; Ross, Gayle; Guillén-Navarro, Encarna; Cappellini, MARIA DOMENICA; Minder, Anna-Elisabeth; Hother-Nielsen, Ole; Ventura, Paolo; Jia, Gang; Sweetser, Marianne T.; Thapar, Manish
abstract
Background & Aims: Acute hepatic porphyria (AHP) is caused by defects in hepatic
heme biosynthesis, leading to disabling acute neurovisceral attacks and chronic
symptoms. In ENVISION (NCT03338816), givosiran treatment for 6 months reduced
attacks and other disease manifestations, compared with placebo. Here we report data
from the 36-month final analysis of ENVISION.
Methods: Ninety-four patients with AHP (age ≥12 years) and recurrent attacks were
randomized 1:1 to monthly double-blind subcutaneous givosiran 2.5 mg/kg (N=48) or
placebo (N=46) for 6 months. In the open-label extension (OLE) period, 93 patients
received givosiran 2.5 or 1.25 mg/kg for 6 months or more before transitioning to 2.5
mg/kg. Endpoints were exploratory unless otherwise noted.
Results: During givosiran treatment, median annualized attack rate (AAR) was 0.4.
Through Month 36, annualized days of hemin use remained low in the continuous
givosiran group (median, 0.0 to 0.4) and decreased in the placebo crossover group
(16.2 to 0.4). At end of OLE, in the continuous givosiran and placebo crossover groups,
86% and 92%, respectively, had 0 attacks. AAR was lower than historical AAR in 98%
and 100%, respectively (post hoc analysis), and there were 0 days of hemin use in 88%
and 90%, respectively. The 12-item Short Form Health Survey physical and mental
component scores increased by 8.6 and 8.1, respectively (continuous givosiran) and 9.4
and 3.2, respectively (placebo crossover). EQ-5D health-related questionnaire scores
increased by 18.9 (continuous givosiran) and 9.9 (placebo crossover). Lowering of
urinary delta-aminolevulinic acid and porphobilinogen levels was sustained. Safety
findings demonstrated a continued positive risk/benefit profile for givosiran.
2023
- Key Terms and Definitions in Acute Porphyrias: Results of an International Delphi Consensus Led by the European Porphyria Network
[Articolo su rivista]
Stein, Penelope E; Edel, Yonatan; Mansour, Razan; Mustafa, Reem A; Sandberg, Sverre; Aarsand, Aasne; Anderson, K. E; Badminton, M; Balwani, M; Bonkovsky, H; Cappellini, M. D; Cassiman, D; Deybach, Jc; Gill, G; Gouya, L; Harper, P; Hift, R; Ivanova, A; Langendonk, J; Naik, H; Marcacci, M; Pischik, E; Rees, D; Sardh, E; Schmitt, C; Sonderup, M; Stolzel, U; To-Figueroas, J; Ventura, P; Wang, B; Weiler-Normann, C; Whatley, S; Wilson, P
abstract
Background: Acute porphyrias are a group of rare inherited disorders causing acute neurovisceral attacks. Many terms used frequently in the literature and in clinical practice are ambiguous, which can lead to confusion in the way patients are managed, studied, and reported in clinical studies. Agreed definitions are a necessary first step in developing management guidelines and will facilitate communication of results of future clinical research. Methods: The Delphi method was used to generate consensus on key terms and definitions in acute porphyria. The process started with a brainstorming phase offered to all members of the European Porphyria Network followed by 2 Delphi rounds among international experts in the field of porphyria (the Acute Porphyria Expert Panel). A consensus of 75% or more was defined as the agreement threshold. Results: 63 respondents from 26 countries participated in the brainstorming phase, leading to the choice of 9 terms and definitions. 34 experts were invited to take part in the Delphi rounds. 7 of the initial 9 terms and definitions which entered the first Delphi round achieved the threshold for agreement. Following a second Delphi round, all 9 definitions achieved agreement. Conclusion: Agreement on the definitions for 9 important terms describing acute porphyrias represents a significant step forward for the porphyria community. It will facilitate more accurate comparison of outcomes among porphyria centres and in clinical trials and provide a strong framework for developing evidence based clinical guidelines.
2023
- Labile plasma iron and echocardiographic parameters are associated to cardiac events in beta-thalassemic patients
[Articolo su rivista]
Ferrara, F; Coppi, F; Riva, R; Ventura, P; Ricci, A; Mattioli, Av; Talarico, M; Garuti, C; Bevini, M; Rochira, V; Buzzetti, E; Pietrangelo, A; Corradini, E
abstract
Background and aim: Notwithstanding the improvement in therapies, patients
affected by thalassemia major (TM) and intermedia (TI) are still at
high risk of cardiac complications. This study aimed at evaluating the incidence
and predictive factors for developing cardiac events in adult β-TM
and TI patients.
Population andmethods: Data on diagnosis and clinical historywere
collected retrospectively; prospective data on new-onset cardiac failure
and arrhythmias, echocardiographic parameters, biochemical variables
including non-transferrin-bound iron (NTBI) and labile plasma iron (LPI),
magnetic resonance imaging (MRI) T2* measurement of hepatic and cardiac
iron deposits, and iron chelation therapy were recorded during a 6
year follow-up.
Results: Thirty-seven patients, 29 TM and 8 TI, were included. At
baseline, 8 TM patients and 1 TI patient had previously experienced a
cardiac event (mainly heart failure). All patients were on chelation therapy
and only 3 TM patients had mild-to-severe cardiac siderosis. During
follow-up, 11 patients (29.7%) experienced a new cardiac event. The occurrence
of cardiac events was correlated to high LPI levels (OR 12.0,
95% CI 1.56-92.3, p 0.017), low mean pre-transfusion hemoglobin (OR
0.21, 95% C.I. 0.051-0.761, p 0.21), and echocardiographic parameters
suggestive of myocardial hypertrophy. Multivariate analysis disclosed
high LPI and left ventricle mass index (LVMI) as independent variables
significantly associated with cardiac events. Cardiac iron deposits measured
by MRI T2* failed to predict cardiac events.
Conclusion: LPI, Hb levels, and echocardiographic parameters assessing
cardiac remodeling are associated to cardiac events in adult TM
and TI patients. LPI might represent both a prognostic marker and a
potential target for novel treatment strategies. Further studies are warranted to confirm our findings on larger populations
2022
- Acute Hepatic Porphyrias: “Purple Flags”—Clinical Features that should Prompt Specific Diagnostic Testing
[Articolo su rivista]
Anderson, Karl E.; Desnick, Robert J.; Felicitystewart, M.; Ventura, Paolo; Bonkovsky, Herbert L.
abstract
Background
Porphyrias are a group of rare diseases leading to dysregulation in heme biosynthesis and the accumulation of heme precursors, including porphyrinogens, which in their oxidized states [porphyrins] are reddish or purple. Acute hepatic porphyrias (AHP) comprise four diseases that cause acute debilitating neurovisceral attacks. Despite diagnostic advances, AHP is often undiagnosed or misdiagnosed due to a lack of disease awareness, low clinical suspicion, variable presentation, and nonspecific symptoms that mimic more common diseases. Delays in diagnosis and treatment increase the risk of serious acute and chronic complications.
Aim
In order to assess whether symptoms alone or in combination might be utilized as important indicators or “purple flags” that, when present, should alert clinicians to suspect AHP and pursue specific diagnostic testing, we conducted a comprehensive review of the literature on AHP, including cohort studies and case reports over two epochs, from 1980 to 2006 and from 2012 to 2018.
Results
We found that severe abdominal pain, with or without acute central nervous system manifestations and peripheral neuropathy, continues to be recognized the most frequent symptom. Hyponatremia, change in urine color, and certain chronic symptoms were also identified as features that should raise suspicion of AHP. To improve diagnosis of AHP, clinicians need to take a broad perspective, including demographic data and medical history, into consideration.
Conclusions
The clinical features of AHP continue to be severe pain, especially pain in the abdomen. Other features that should raise suspicion are autonomic, peripheral, or central neuropathies, hyponatremia, and red-purple urine color.
2022
- Ataxia-myoclonus syndrome in patients with SARS-CoV2 infection
[Articolo su rivista]
Guerra, A. F.; Martinelli, I.; Rispoli, V.; Marcacci, M.; Cavallieri, F.; Nizzoli, S.; Valzania, F.; Ventura, P.; Meletti, S.; Pietrangelo, A.
abstract
2022
- Challenges in diagnosis and management of acute hepatic porphyrias: from an uncommon pediatric onset to innovative treatments and perspectives
[Articolo su rivista]
Marcacci, Matteo; Ricci, Andrea; Cuoghi, Chiara; Marchini, Stefano; Pietrangelo, Antonello; Ventura, Paolo
abstract
Acute hepatic porphyrias (AHPs) are a family of four rare genetic diseases resulting from a deficiency in one of the
enzymes involved in heme biosynthesis. AHP patients can experience potentially life-threatening acute attacks,
characterized by severe abdominal pain, along with other signs and symptoms including nausea, mental confusion,
hyponatraemia, hypertension, tachycardia and muscle weakness. Some patients also experience chronic manifestations
and long-term complications, such as chronic pain syndrome, neuropathy and porphyria-associated kidney
disease. Most symptomatic patients have only a few attacks in their lifetime; nevertheless, some experience frequent
attacks that result in ongoing symptoms and a significant negative impact on their quality of life (QoL). Initial diagnosis
of AHP can be made with a test for urinary porphobilinogen, -aminolaevulinic acid and porphyrins using a
single random (spot) sample. However, diagnosis is frequently missed or delayed, often for years, because the clinical
symptoms of AHP are non-specific and mimic other more common disorders. Delayed diagnosis is of concern as
some commonly used medications can trigger or exacerbate acute attacks, and untreated attacks can become severe,
potentially leading to permanent neurological damage or fatality. Other attack triggers include hormonal fluctuations
in women, stress, alcohol and low-calorie diets, which should be avoided in patients where possible. For the management
of attacks, intravenous hemin is approved, whereas new therapeutic approaches are currently being investigated
as a baseline therapy for prevention of attacks and improvement of QoL. Among these, a novel siRNA-based
agent, givosiran, has shown very promising results in a recently concluded Phase III trial and has been approved for
the management of AHPs. Here, we propose a challenging case study-with a very unusual pediatric onset of variegate
porphyria-as a starting point to summarize the main clinical aspects (namely, clinical manifestations, diagnostic challenges,
and therapeutic management) of AHPs, with a focus on the latest therapeutic innovations.
2022
- Disease burden in patients with acute hepatic porphyria: experience from the phase 3 ENVISION study
[Articolo su rivista]
Wang, Bruce; Ventura, Paolo; Takase, Kei‑ichiro; Thapar, Manish; Cassiman, David; Kubisch, Ilja; Liu, Shangbin; Sweetser, Marianne T.; Balwani, Manisha
abstract
Background: Acute hepatic porphyria (AHP) is a family of four rare genetic diseases, each involving deficiency in
a hepatic heme biosynthetic enzyme. Resultant overproduction of the neurotoxic intermediates δ-aminolevulinic
acid (ALA) and porphobilinogen (PBG) leads to disabling acute neurovisceral attacks and progressive neuropathy.
We evaluated the AHP disease burden in patients aged ≥ 12 years in a post hoc analysis of the Phase 3, randomized,
double-blind, placebo-controlled ENVISION trial of givosiran (NCT03338816), an RNA interference (RNAi) therapeutic
that targets the enzyme ALAS1 to decrease ALA and PBG production. We analyzed baseline AHP severity via chronic
symptoms between attacks, comorbidities, concomitant medications, hemin-associated complications, and quality
of life (QOL) and evaluated givosiran (2.5 mg/kg monthly) in patients with and without prior hemin prophylaxis on
number and severity of attacks and pain scores during and between attacks.
Results: Participants (placebo, n = 46; givosiran, n = 48) included patients with low and high annualized attack rates
(AARs; range 0–46). At baseline, patients reported chronic symptoms (52%), including nausea, fatigue, and pain;
comorbidities, including neuropathy (38%) and psychiatric disorders (47%); concomitant medications, including
chronic opioids (29%); hemin-associated complications (eg, iron overload); and poor QOL (low SF-12 and EuroQol
visual analog scale scores). A linear relationship between time since diagnosis and AAR with placebo suggested worsening
of disease over time without effective treatment. Givosiran reduced the number and severity of attacks, days
with worst pain scores above baseline, and opioid use versus placebo.
Conclusions: Patients with AHP, regardless of annualized attack rates, have considerable disease burden that may partly be alleviated with givosiran.
2022
- Endothelial Dysfunction in Acute Hepatic Porphyrias
[Articolo su rivista]
Ricci, Andrea; Sandri, Gilda; Marcacci, Matteo; Di Pierro, Elena; Granata, Francesca; Cuoghi, Chiara; Marchini, Stefano; Pietrangelo, Antonello; Ventura, Paolo
abstract
Background Acute hepatic porphyrias (AHPs) are a group of rare diseases caused by
dysfunctions in the pathway of heme biosynthesis. Although acute neurovisceral attacks are the
most dramatic manifestations, patients are at risk of developing long-term complications, several of
which are of a vascular nature. The accumulation of non-porphyrin heme precursors is deemed to
cause most clinical symptoms. AimWe measured the serum levels of endothelin-1 (ET-1) and nitric
oxide (NO) to assess the presence of endothelial dysfunction (ED) in patients with AHPs. Forty-six
patients were classified, according to their clinical phenotype, as symptomatic (AP-SP), asymptomatic
with biochemical alterations (AP-BA), and asymptomatic without biochemical alterations (AP-AC).
Results Even excluding those under hemin treatment, AP-SP patients had the lowest NO and highest
ET-1 levels, whereas no significant differences were found between AP-BA and AP-AC patients.
AP-SP patients had significantly more often abnormal levels of ED markers. Patients with the highest
heme precursor urinary levels had the greatest alterations in ED markers, although no significant
correlation was detected. Conclusions ED is more closely related to the clinical phenotype of AHPs
than to their classical biochemical alterations. Some still undefined disease modifiers may possibly
determine the clinical picture of AHPs through an effect on endothelial functions.
2022
- Givosiran for the treatment of acute hepatic porphyria
[Articolo su rivista]
Ventura, Paolo; Ricci, Andrea
abstract
Introduction: Acute hepatic porphyrias (AHPs) are a family of rare inherited disorders characterized by
enzyme dysfunctions in the hepatic pathway of heme biosynthesis. In AHPs, accumulation of the
neurotoxic porphyrin precursors delta-aminolevulinic acid and porphobilinogen, caused by enhanced
activity of hepatic aminolevulinate synthase 1 (ALAS1), is associated with acute, potentially lifethreatening
neurovisceral attacks. Symptoms during and between attacks dramatically reduce patients’
quality of life (QoL). Givosiran is the first mRNA-targeted treatment for AHPs, silencing ALAS1
expression.
Areas covered: For givosiran, this review summarizes its chemistry, mechanism of action, pharmacokinetics,
pharmacodynamics, safety, preclinical and clinical data in AHP, postmarketing surveillance, and
regulatory status. A literature search of public and internal databases was performed, bibliographies of
retrieved articles were manually searched to identify additional studies of relevance, and information
was also provided by Alnylam Pharmaceuticals.
Expert opinion: Givosiran is a small interfering RNA (siRNA) therapeutic that reduces hepatic activity of
ALAS1 and decreases accumulation of neurotoxic porphyrin precursors in patients with AHPs, ultimately
reducing the number of acute attacks and improving symptoms and QoL between attacks. As AHPs are
lifelong diseases, long-term safety data are needed for givosiran as an siRNA-based therapy.
2022
- Hyperhomocysteinemia in acute hepatic porphyria (AHP) and implications for treatment with givosiran
[Articolo su rivista]
Ventura, Paolo; Sardh, Eliane; Longo, Nicola; Balwani, Manisha; Plutzky, Jorge; Gouya, Laurent; Phillips, John; Rhyee, Sean; Fanelli, Mary-Jean; Sweetser, Marianne T.; Petrides, Petro E.
abstract
Introduction: Homocysteine is a sulfur-containing amino acid formed in the intermediary metabolism of methionine. Amino acid metabolism and heme biosynthesis pathways are complexly intertwined. Plasma homocysteine elevation, hyperhomocysteinemia (HHcy), has been reported in patients with acute hepatic porphyria (AHP), a family of rare genetic disorders caused by defects in hepatic heme biosynthesis.
Areas covered
: This article summarizes published case series in which givosiran, a subcutaneously administered small interfering RNA approved for AHP treatment, appeared to exacerbate dysregulated homocysteine metabolism in patients with AHP. A comprehensive exploratory analysis of ENVISION trial data demonstrated that on a population level, givosiran increased homocysteine, but with wide interpatient variations, and there is no proof of correlations between HHcy and changes in efficacy or safety of givosiran.
Expert opinion
: The strong correlation and co-increase of homocysteine and methionine suggest HHcy associated with givosiran is likely attributable to the impaired trans-sulfuration pathway catalyzed by cystathionine β-synthase, which uses vitamin B6 as a cofactor. Data-based consensus supports monitoring total plasma homocysteine and vitamin B6, B12, and folate levels before and during givosiran treatment; supplementing with pyridoxine/vitamin B6 in patients with homocysteine levels >100 μmol/L; and involving patients with homocysteine levels >30 μmol/L in decisions to supplement.
2022
- Iron Metabolism in the Disorders of Heme Biosynthesis
[Articolo su rivista]
Ricci, Andrea; Di Betto, Giada; Bergamini, Elisa; Buzzetti, Elena; Corradini, Elena; Ventura, Paolo
abstract
Given its remarkable property to easily switch between different oxidative states, iron is
essential in countless cellular functions which involve redox reactions. At the same time, uncon-
trolled interactions between iron and its surrounding milieu may be damaging to cells and tissues.
Heme—the iron-chelated form of protoporphyrin IX—is a macrocyclic tetrapyrrole and a coordina-
tion complex for diatomic gases, accurately engineered by evolution to exploit the catalytic, oxygen-
binding, and oxidoreductive properties of iron while minimizing its damaging effects on tissues.
The majority of the body production of heme is ultimately incorporated into hemoglobin within
mature erythrocytes; thus, regulation of heme biosynthesis by iron is central in erythropoiesis.
Additionally, heme is a cofactor in several metabolic pathways, which can be modulated by iron-
dependent signals as well. Impairment in some steps of the pathway of heme biosynthesis is the main
pathogenetic mechanism of two groups of diseases collectively known as porphyrias and congenital
sideroblastic anemias. In porphyrias, according to the specific enzyme involved, heme precursors
accumulate up to the enzyme stop in disease-specific patterns and organs. Therefore, different por-
phyrias manifest themselves under strikingly different clinical pictures. In congenital sideroblastic
anemias, instead, an altered utilization of mitochondrial iron by erythroid precursors leads to mito-
chondrial iron overload and an accumulation of ring sideroblasts in the bone marrow. In line with
the complexity of the processes involved, the role of iron in these conditions is then multifarious.
This review aims to summarise the most important lines of evidence concerning the interplay be-
tween iron and heme metabolism, as well as the clinical and experimental aspects of the role of iron
in inherited conditions of altered heme biosynthesis.
2022
- Iron in Porphyrias: Friend or Foe?
[Articolo su rivista]
Buzzetti, Elena; Ventura, Paolo; Corradini, Elena
abstract
Iron is a trace element that is important for many vital processes, including oxygen
transport, oxidative metabolism, cellular proliferation, and catalytic reactions. Iron supports these
functions mainly as part of the heme molecule. Heme synthesis is an eight-step process which, when
defective at the level of one of the eight enzymes involved, can cause the development of a group
of diseases, either inherited or acquired, called porphyrias. Despite the strict link between iron and
heme, the role of iron in the different types of porphyrias, particularly as a risk factor for disease
development/progression or as a potential therapeutic target or molecule, is still being debated, since
contrasting results have emerged from clinical observations, in vitro studies and animal models. In
this review we aim to deepen such aspects by drawing attention to the current evidence on the role of
iron in porphyrias and its potential implication. Testing for iron status and its metabolic pathways
through blood tests, imaging techniques or genetic studies on patients affected by porphyrias can
provide additional diagnostic and prognostic value to the clinical care, leading to a more tailored and
effective management.
2022
- Recognized and Emerging Features of Erythropoietic and
X-Linked Protoporphyria
[Articolo su rivista]
Di Pierro, Elena; Granata, Francesca; De Canio, Michele; Rossi, Mariateresa; Ricci, Andrea; Marcacci, Matteo; De Luca, Giacomo; Sarno, Luisa; Barbieri, Luca; Ventura, Paolo; Graziadei, Giovanna
abstract
Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are inherited
disorders resulting from defects in two different enzymes of the heme biosynthetic pathway, i.e.,
ferrochelatase (FECH) and delta-aminolevulinic acid synthase-2 (ALAS2), respectively. The
ubiquitous FECH catalyzes the insertion of iron into the protoporphyrin ring to generate the final
product, heme. After hemoglobinization, FECH can utilize other metals like zinc to bind the
remainder of the protoporphyrin molecules, leading to the formation of zinc protoporphyrin.
Therefore, FECH deficiency in EPP limits the formation of both heme and zinc protoporphyrin
molecules. The erythroid-specific ALAS2 catalyses the synthesis of delta-aminolevulinic acid
(ALA), from the union of glycine and succinyl-coenzyme A, in the first step of the pathway in the
erythron. In XLP, ALAS2 activity increases, resulting in the amplified formation of ALA, and iron
becomes the rate-limiting factor for heme synthesis in the erythroid tissue. Both EPP and XLP lead
to the systemic accumulation of protoporphyrin IX (PPIX) in blood, erythrocytes, and tissues
causing the major symptom of cutaneous photosensitivity and several other less recognized signs
that need to be considered. Although significant advances have been made in our understanding of
EPP and XLP in recent years, a complete understanding of the factors governing the variability in
clinical expression and the severity (progression) of the disease remains elusive. The present review
provides an overview of both well-established facts and the latest findings regarding these rare
diseases.
2022
- Serum HBsAg and ddPCR HBV-DNA as predictive parameters of
HBsAg loss after nucleo(s)tide analogue (NA) treatment discontinuation
in non-cirrhotic patients with Chronic Hepatitis B
[Poster]
Guerra, A. F.; Tomassoli, G.; Piermatteo, L.; D’Anna, S.; Salpini, R.; Svicher, V.; Abbati, G.; Pietrangelo, A.; Ventura, P.
abstract
Introduction: Stopping nucleo(s)tide analogue (NA) treatment in
selected non-cirrhotic Chronic Hepatitis B (CHB) often leads to
virus-induced flares, which may result to life-threatening liver failure.
Aim: to identify predictive parameters of off-NAs response at the
end of treatment and their association with HBsAg loss or HBsAg
< 100IU/ml, for a safe discontinuation of treatment.
Materials and Methods: 38 non-cirrhotic CHB patients, with complete
virological suppression ( > 4 years), were prospectively monitored
after suspending NA treatment for a median (IQR) time of
16 (10-19) months. Plasma samples at suspension date (baseline,
BL) were collected and used to quantify serum HBV-DNA by highly
sensitive droplet digital PCR (ddPCR). HBsAg was quantified by the
ARCHITECT HBsAg assay at BL, every 2 weeks from suspension in
the first month, followed by every month until the sixth month,
then every 3 months.
Results: At BL, 28 (73.7%) pts had detectable serum HBV-DNA (median[
IQR] 5[2-11] IU/mL), while 10 (26.3%) were completely negative
to HBV-DNA. After NA suspension, 7 (18.4%) achieved HBsAg
< 100IU/mL (median [IQR]: 43 [35-53]IU/ml) and 8 (21.1%)
lost HBsAg at last follow-up. Patients achieving HBsAg loss had
lower HBsAg levels at BL (140 [70-480]IU/ml with vs 1162 [439-
3135] without HBsAg loss, p = 0.014). The negativity to HBV-DNA
by ddPCR at BL strongly correlated with the achievement of HBsAg
< 100IU/mL or HBsAg loss after NA suspension (70% [7/10] with vs
28.6% [8/28] without negative BL HBV-DNA; OR [95%CI]: 5.8 [1.3-
23.6], p = 0.03).The combination of HBsAg < 500IU/mL + negativity
HBV-DNA by ddPCR at BL was the best predictor for achieving
HBsAg < 100IU/mL or HBsAg loss (85.7% with vs 27.6% without
this combination; OR [95%CI]: 15.8 (1.6-152.2; p = 0.008; PPV = 86%;
NPV = 72%).
Conclusions: Residual HBV replicative activity at NA suspension,
measured by highly sensitive assays, provides an added value in
identifying patients more prone to achieve HBV functional cure.
2021
- Ceruloplasmin gene variants are associated with hyperferritinemia and increased liver iron in patients with {NAFLD}
[Articolo su rivista]
Corradini, Elena; Buzzetti, Elena; Dongiovanni, Paola; Scarlini, Stefania; Caleffi, Angela; Pelusi, Serena; Bernardis, Isabella; Ventura, Paolo; Rametta, Raffaela; Tenedini, Elena; Tagliafico, Enrico; Ludovica Fracanzani, Anna; Fargion, Silvia; Pietrangelo, Antonello; Vittorio Valenti, Luca
abstract
Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disorder resulting from genetic and environmental factors. Hyperferritinemia has been associated with increased hepatic iron stores and worse outcomes in patients with NAFLD. The aim of this study was to evaluate the prevalence of variants of iron-related genes and their association with hyperferritinemia, hepatic iron stores and liver disease severity in patients with NAFLD.
2021
- Clinical factors associated with death in 3044 COVID-19 patients managed in internal medicine wards in Italy: results from the SIMI-COVID-19 study of the Italian Society of Internal Medicine (SIMI)
[Articolo su rivista]
Corradini, Elena; Ventura, Paolo; Ageno, Walter; Cogliati, Chiara Beatrice; Muiesan, Maria Lorenza; Girelli, Domenico; Pirisi, Mario; Gasbarrini, Antonio; Angeli, Paolo; Querini, Patrizia Rovere; Bosi, Emanuele; Tresoldi, Moreno; Vettor, Roberto; Cattaneo, Marco; Piscaglia, Fabio; Brucato, Antonio Luca; Perlini, Stefano; Martelletti, Paolo; Pontremoli, Roberto; Porta, Massimo; Minuz, Pietro; Olivieri, Oliviero; Sesti, Giorgio; Biolo, Gianni; Rizzoni, Damiano; Serviddio, Gaetano; Cipollone, Francesco; Grassi, Davide; Manfredini, Roberto; Moreo, Guido Luigi; Pietrangelo, Antonello
abstract
During the COVID-19 2020 outbreak, a large body of data has been provided on general management and outcomes of hospitalized COVID-19 patients. Yet, relatively little is known on characteristics and outcome of patients managed in Internal Medicine Units (IMU). To address this gap, the Italian Society of Internal Medicine has conducted a nationwide cohort multicentre study on death outcome in adult COVID-19 patients admitted and managed in IMU. This study assessed 3044 COVID-19 patients at 41 referral hospitals across Italy from February 3rd to May 8th 2020. Demographics, comorbidities, organ dysfunction, treatment, and outcomes including death were assessed. During the study period, 697 patients (22.9%) were transferred to intensive care units, and 351 died in IMU (death rate 14.9%). At admission, factors independently associated with in-hospital mortality were age (OR 2.46, p = 0.000), productive cough (OR 2.04, p = 0.000), pre-existing chronic heart failure (OR 1.58, p = 0.017) and chronic obstructive pulmonary disease (OR 1.17, p = 0.048), the number of comorbidities (OR 1.34, p = 0.000) and polypharmacy (OR 1.20, p = 0.000). Of note, up to 40% of elderly patients did not report fever at admission. Decreasing PaO2/FiO2 ratio at admission was strongly inversely associated with survival. The use of conventional oxygen supplementation increased with the number of pre-existing comorbidities, but it did not associate with better survival in patients with PaO2/FiO2 ratio < 100. The latter, significantly benefited by the early use of non-invasive mechanical ventilation. Our study identified PaO2/FiO2 ratio at admission and comorbidity as the main alert signs to inform clinical decisions and resource allocation in non-critically ill COVID-19 patients admitted to IMU.
2021
- Disease Burden in Patients With Acute Hepatic Porphyria: Experience From the Phase 3 ENVISION Study
[Abstract in Atti di Convegno]
Wang, Bruce; Ventura, Paolo; Takase, Kei-ichiro; Thapar, Manish; Cassiman, David M.; Kubisch, Ilja; Hua, Zhaowei; Sweetser, Marianne T.; Balwani, Manisha
abstract
Introduction:
Acute hepatic porphyria (AHP) is a family of rare genetic diseases caused by defects in hepatic heme biosynthesis. Intravenous (IV) hemin is the standard of care for acute attacks and is at times used off label prophylactically, but can have acute (e.g. phlebitis) and chronic (e.g. iron overload) complications. The phase 3 ENVISION study (NCT03338816) showed givosiran reduced annualized attack rate (AAR) by 73% versus placebo in the double-blind (DB) period. Open-label extension data showed 85% of patients continuing givosiran were attack free at >15–18 months. Here we summarize data from ENVISION to assess the spectrum of disease burden associated with AHP.
Methods:
Patients (N=94) enrolled in ENVISION had experienced ≥2 attacks requiring hospitalization, urgent care, or IV hemin at home in the 6 months before the study. This analysis assessed AAR, daily worst pain (eDiary), comorbidity, concomitant medication, and quality of life (12-Item Short Form Health Survey [SF-12]).
Results:
Patients had severe disease burden at study entry, consistent with AHP burden shown in natural history studies. Patients reported a median of 4 (range, 0–46) attacks during the previous 6 months, despite 40% being on prophylactic hemin. Of all patients, 34% did not have attacks requiring hospitalization. Chronic symptoms, including pain, were experienced by 52% of patients daily or on most days between attacks. Baseline median SF-12 bodily pain score was 40 (scale 0–100), suggesting interference with normal functioning. Overall, 29% of patients used opioids daily or on most days between attacks. Most patients had comorbidities at baseline (47% had psychiatric disorders) (Table 1) and were taking concomitant medications. The median (Q1–Q3) ferritin level was 209 (48–719) µg/L (normal: female, 13–150 µg/L; male, 30–400 µg/L). A moderate linear correlation between longer time since AHP diagnosis and higher AAR with placebo during the 6-month DB period (r=0.403) suggests patients may experience worsening disease and complications over time. Givosiran provided clinical benefit, including reduction of daily worst pain and analgesics use.
Conclusion:
AHP disease burden, including the number of attacks, comorbidities, and concomitant medication use, has negative impacts on daily functioning. Earlier initiation of treatments, such as givosiran, that prevent attacks and reduce chronic manifestations of AHP may lead to improved prognosis for patients.
2021
- Efficacy and safety of givosiran for acute hepatic porphyria: 24-month interim analysis of the randomized phase 3 ENVISION study
[Articolo su rivista]
Ventura, Paolo; Bonkovsky, Herbert L.; Gouya, Laurent; Aguilera-Peiró, Paula; Montgomery Bissell, D.; Stein, Penelope E.; Balwani, Manisha; Anderson, D. Karl E.; Parker, Charles; Kuter, David J.; Monroy, Susana; Oh, Jeeyoung; Ritchie, Bruce; Ko, John J.; Hua, Zhaowei; Sweetser, Marianne T.; Sardh, Eliane
abstract
Background & Aims
Upregulation of hepatic delta-aminolevulinic acid synthase 1 with accumulation of potentially toxic heme precursors delta-aminolevulinic acid and porphobilinogen is fundamental to the pathogenesis of acute hepatic porphyria. Aims: evaluate long-term efficacy and safety of givosiran in acute hepatic porphyria.
Methods
Interim analysis of ongoing ENVISION study (NCT03338816), after all active patients completed their Month 24 visit. Patients with acute hepatic porphyria (≥12 years) with recurrent attacks received givosiran (2.5 mg/kg monthly) (n=48) or placebo (n=46) for 6 months (double-blind period); 93 received givosiran (2.5 mg or 1.25 mg/kg monthly) in the open-label extension (continuous givosiran, n=47/48; placebo crossover, n=46/46). Endpoints included annualized attack rate, urinary delta-aminolevulinic acid and porphobilinogen levels, hemin use, daily worst pain, quality of life, and adverse events.
Results
Patients receiving continuous givosiran had sustained annualized attack rate reduction (median 1.0 in double-blind period, 0.0 in open-label extension); in placebo crossover patients, median annualized attack rate decreased from 10.7 to 1.4. Median annualized days of hemin use were 0.0 (double-blind period) and 0.0 (open-label extension) for continuous givosiran patients and reduced from 14.98 to 0.71 for placebo crossover patients. Long-term givosiran led to sustained lowering of delta-aminolevulinic acid and porphobilinogen and improvements in daily worst pain and quality of life. Safety findings were consistent with the double-blind period.
Conclusions
Long-term givosiran has an acceptable safety profile and significantly benefits acute hepatic porphyria patients with recurrent attacks by reducing attack frequency, hemin use, and severity of daily worst pain while improving quality of life.
2021
- Hyperhomocysteinemia in patients with acute porphyrias: a possible effect of ALAS1 modulation by siRNAm therapy and its control by vitamin supplementation
[Articolo su rivista]
Ricci, A.; Marcacci, M.; Cuoghi, C.; Pietrangelo, A.; Ventura, P.
abstract
2021
- Kidney Involvement in Acute Hepatic Porphyrias:
Pathophysiology and Diagnostic Implications
[Articolo su rivista]
Ricci, Andrea; Carmine Guida, Caludio; Manzini, Paola; Cuoghi, Chiara; Ventura, Paolo
abstract
Porphyrias are a group of rare disorders originating from an enzyme dysfunction in the
pathway of heme biosynthesis. Depending on the specific enzyme involved, porphyrias manifest
under drastically different clinical pictures. The most dramatic presentation of the four congenital
acute hepatic porphyrias (AHPs: acute intermittent porphyria—AIP, ALAD deficiency, hereditary
coproporphyria—HCP, and porphyria variegata—VP) consists of potentially life-threatening neurovisceral
attacks, for which givosiran, a novel and effective siRNA-based therapeutic, has recently
been licensed. Nonetheless, the clinical manifestations of acute porphyrias are multifaceted and do
not limit themselves to acute attacks. In particular, porphyria-associated kidney disease (PAKD) is a
distinct, long-term degenerating condition with specific pathological and clinical features, for which a
satisfactory treatment is not available yet. In PAKD, chronic tubule-interstitial damage has been most
commonly reported, though other pathologic features (e.g., chronic fibrous intimal hyperplasia) are
consistent findings. Given the relevant role of the kidney in porphyrin metabolism, the mechanisms
possibly intervening in causing renal damage in AHPs are different: among others, d-aminolevulinic
acid (ALA)-induced oxidative damage on mitochondria, intracellular toxic aggregation of porphyrins
in proximal tubular cells, and derangements in the delicate microcirculatory balances of the kidney
might be implicated. The presence of a variant of the human peptide transporter 2 (PEPT2), with
a greater affinity to its substrates (including ALA), might confer a greater susceptibility to kidney
damage in patients with AHPs. Furthermore, a possible effect of givosiran in worsening kidney
function has been observed. In sum, the diagnostic workup of AHPs should always include a baseline
evaluation of renal function, and periodic monitoring of the progression of kidney disease in patients
with AHPs is strongly recommended. This review outlines the role of the kidney in porphyrin
metabolism, the available evidence in support of the current etiologic and pathogenetic hypotheses,
and the known clinical features of renal involvement in acute hepatic porphyrias.
2021
- Liver Transplantation for Acute Intermittent Porphyria
[Articolo su rivista]
Lissing, Mattias; Nowak, Greg; Adam, René; Karam, Vincent; Boyd, Alexander; Gouya, Laurent; Meersseman, Wouter; Melum, Espen; Ołdakowska‐Jedynak, Urszula; Reiter, Florian P.; Colmenero, Jordi; Sanchez, Rosario; Herden, Uta; Langendonk, Janneke; Ventura, Paolo; Isoniemi, Helena; Boillot, Olivier; Braun, Felix; Perrodin, Stéphanie; Mowlem, Elizabeth; Wahlin, Staffan
abstract
Recurrent attacks of acute intermittent porphyria (AIP) result in poor quality of life and significant risks of morbidity and mortality. Liver transplantation (LT) offers cure but published data on outcome after LT are limited. We aimed to assess the pre‐transplant characteristics, complications and outcomes for patients transplanted for AIP. Data was collected retrospectively from the European Liver Transplant Registry (ELTR) and from questionnaires sent to identified transplant and porphyria centers.
We studied 38 patients transplanted in 12 countries 2002–2019. Median age at LT was 37 years (range 18‐58) and 34 (89%) were female. Two patients were re‐transplanted and nine died during follow‐up. The 1‐year and 5‐year overall survival was 92% and 82%, which is comparable to other metabolic diseases transplanted during the same period. Advanced pretransplant neurological impairment was identified as a risk factor for mortality. The 5‐year survival was 94% among 19 patients with moderate or no neuropathy at LT, and 83% among 10 patients with severe neuropathy (p=0.04). Pretransplant renal impairment had no significant effect on survival with a 5‐year survival of 81% among 18 patients with a pretransplant GFR >60ml/min, and 71% among 14 patients with a pretransplant GFR <60ml/min (p=0.16). While few patients improved their renal function after LT, neurological impairments improved, and no worsening of neurological symptoms was recorded. No patient had AIP attacks after LT, except for a patient who received an auxiliary graft.
Liver transplantation is a curative treatment option for patients with recurrent attacks of AIP. Severe neuropathy and impaired renal function are common and increase the risk for poor outcome. If other treatment options fail, evaluation for liver transplantation should be performed early.
2021
- Mechanisms of Neuronal Damage in Acute Hepatic Porphyrias
[Articolo su rivista]
Ricci, Andrea; Di Pierro, Elena; Marcacci, Matteo; Ventura, Paolo
abstract
Porphyrias are a group of congenital and acquired diseases caused by an enzymatic
impairment in the biosynthesis of heme. Depending on the specific enzyme involved, different types
of porphyrias (i.e., chronic vs. acute, cutaneous vs. neurovisceral, hepatic vs. erythropoietic) are
described, with different clinical presentations. Acute hepatic porphyrias (AHPs) are characterized
by life-threatening acute neuro-visceral crises (acute porphyric attacks, APAs), featuring a wide
range of neuropathic (central, peripheral, autonomic) manifestations. APAs are usually unleashed by
external “porphyrinogenic” triggers, which are thought to cause an increased metabolic demand for
heme. During APAs, the heme precursors -aminolevulinic acid (ALA) and porphobilinogen (PBG)
accumulate in the bloodstream and urine. Even though several hypotheses have been developed to
explain the protean clinical picture of APAs, the exact mechanism of neuronal damage in AHPs is
still a matter of debate. In recent decades, a role has been proposed for oxidative damage caused by
ALA, mitochondrial and synaptic ALA toxicity, dysfunction induced by relative heme deficiency on
cytochromes and other hemeproteins (i.e., nitric oxide synthases), pyridoxal phosphate functional
deficiency, derangements in the metabolic pathways of tryptophan, and other factors. Since the
pathway leading to the biosynthesis of heme is inscribed into a complex network of interactions,
which also includes some fundamental processes of basal metabolism, a disruption in any of the steps
of this pathway is likely to have multiple pathogenic effects. Here, we aim to provide a comprehensive
review of the current evidence regarding the mechanisms of neuronal damage in AHPs.
2020
- Clinical and molecular epidemiology of erythropoietic protoporphyria in Italy
[Articolo su rivista]
Ventura, Paolo; Brancaleoni, Valentina; Di Pierro, Elena; Graziadei, Giovanna; Macrì, Annelise; Carmine Guida, Claudio; Nicolli, Annamaria; Teresa Rossi, Maria; Granata, Francesca; Fiorentino, Valeria.; Fustinoni, Silvia; Sala, Raffella; Calzavara Pinton, Piergiacomo; Trevisan, Andrea; Marchini, Stefano; Cuoghi, Chiara; Marcacci, Matteo; Corradini, Elena; Sorge, Fiammetta; Aurizi, Caterina; Grazia Savino, Maria; Cappellini, Maria Domenica; Pietrangelo, Antonello
abstract
Background: Erythropoietic protoporphyria (EPP) is a rare inherited disease associated with heme metabolism, characterized by severe life-long photosensitivity and liver involvement. Objectives: To provide epidemiological data of EPP in Italy. Materials and Methods: Prospective/retrospective data of EPP patients were collected by an Italian network of porphyria specialist centres (Gruppo Italiano Porfiria, GrIP) over a 20-year period (1996-2017). Results: In total, 179 patients (79 females) with a clinical and biochemical diagnosis of EPP were assessed, revealing a prevalence of 3.15 cases per million persons and an incidence of 0.13 cases per million persons/year. Incidence significantly increased after 2009 (due to the availability of alfa-melanotide, which effectively limits skin photosensitivity). Mean age at diagnosis was 28 years, with only 22 patients (12.2%) diagnosed ≤10 years old. Gene mutations were assessed in 173 (96.6%) patients; most (164; 91.3%) were FECH mutations on one allele in association with the hypomorphic variant, c.315-48C, on the other (classic EPP), and nine (5.2%) were ALAS2 mutations (X-linked EPP). Only one case of autosomal recessive EPP was observed. Of the 42 different FECH mutations, 15 are novel, three mutations collectively accounted for 45.9% (75/164) of the mutations (c.215dupT [27.2%], c.901_902delTG [11.5%] and c.67 + 5G > A [7.2%]), and frameshift mutations were prevalent (33.3%). A form of light protection was used by 109/179 (60.8%) patients, and 100 (56%) had at least one α-melanotide implant. Three cases of severe acute liver involvement, requiring OLT, were observed. Conclusions: These data define, for the first time, the clinical and molecular epidemiology of EPP in Italy.
2020
- EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks
[Articolo su rivista]
Gouya, L; Ventura, P; Balwani, M; Bissell, Dm; Rees, Dc; Stölzel, U; Phillips, Jd; Kauppinen, R; Langendonk, Jg; Desnick, Rj; Deybach, Jc; Bonkovsky, Hl; Parker, C; Naik, H; Badminton, M; Stein, Pe; Minder, E; Windyga, J; Bruha, R; Cappellini, Md; Sardh, E; Harper, P; Sandberg, S; Aarsand, Ak; Andersen, J; Alegre, F; Ivanova, A; Talbi, N; Chan, A; Querbes, W; Ko, J; Penz, C; Liu, S; Lin, T; Simon, A; Anderson, Ke.
abstract
BACKGROUND AND AIMS: Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. APPROACH AND RESULTS: EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization. CONCLUSIONS: Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies.
2020
- Hyperhomocysteinemia in patients with acute porphyrias: A potentially dangerous metabolic crossroad?
[Articolo su rivista]
Ventura, P.; Corradini, E.; Di Pierro, E.; Marchini, S.; Marcacci, M.; Cuoghi, C.; Buzzetti, E.; Pietrangelo, A.
abstract
Background: Acute porphyrias (AP) are characterized by heme deficiency and induction of hepatic 5-aminolevulinate synthase (ALAS1). Hyperhomocysteinemia (HHcy) is associated with endothelial damage, neurotoxicity and increased risk for vascular diseases. Interestingly, both heme biosynthesis and sulphur amino acid metabolism require vitamin B6, (Pyridoxal-phosphate, PLP) an important cofactor of ALAS1 and of cystathionine β-synthase (CBS) and cystathionine γ-lyase (CGL) enzymes that catabolize homocysteine (Hcy). Moreover, heme itself is an important cofactor for CBS. Aim: to assess plasma Hcy status and HHcy main determinants in patients with AP. Materials and methods: A total of 46 patients with AP (31 with Acute Intermittent Porphyria,15 with Variegate Porphyria) were assessed for clinical status (symptomatic vs. asymptomatic), serum Hcy, Cysteine (Cys), Vit.B6, Vit.B12, red blood cell folates and urinary delta-aminolevulinic acid (ALA) and porphobilinogen(PBG) levels (mean of six measurements). Results: Symptomatic AP patients had significantly higher urinary ALA and PBG levels, plasma Hcy, HHcy prevalence and Hcy/Cys ratio when compared to asymptomatic carriers of AP. Even though no significant correlation was observed between ALA/PBG urinary levels and serum Hcy levels, patients with higher levels of ALA and PBG had significantly higher levels of Hcy, a higher prevalence of moderate-to severe HHcy and serum PLP levels below the 25th percentile of a reference assessment with 300 healthy Italian subjects(<45nmol/L). Conclusions: Most patients with symptomatic AP present HHcy resulting from alterations in sulphur amino acid metabolism. HHcy may represent an indirect marker of ALAS1 induction and its prevalence may be suggestive of a role of HHcy in the pathogenesis and/or comorbidities of AP.
2020
- Phase 3 Trial of RNAi Therapeutic Givosiran for Acute
Intermittent Porphyria
[Articolo su rivista]
Balwani, M.; Sardh, E.; Ventura, P.; Peiró, P. A.; Rees, D. C.; Stölzel, U.; Bissell, D. M.; Bonkovsky, H. L.; Windyga, J.; Anderson, K. E.; Parker, C.; Silver, S. M.; Keel, S. B.; Wang, J. -D.; Stein, P. E.; Harper, P.; Vassiliou, D.; Wang, B.; Phillips, J.; Ivanova, A.; Langendonk, J. G.; Kauppinen, R.; Minder, E.; Horie, Y.; Penz, C.; Chen, J.; Liu, S.; Ko, J. J.; Sweetser, M. T.; Garg, P.; Vaishnaw, A.; Kim, J. B.; Simon, A. R.; Gouya, and L.
abstract
BACKGROUND
Up-regulation of hepatic delta-aminolevulinic acid synthase 1 (ALAS1), with resultant
accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen, is central
to the pathogenesis of acute attacks and chronic symptoms in acute hepatic
porphyria. Givosiran, an RNA interference therapy, inhibits ALAS1 expression.
METHODS
In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned
symptomatic patients with acute hepatic porphyria to receive either subcutaneous
givosiran (2.5 mg per kilogram of body weight) or placebo monthly for 6 months.
The primary end point was the annualized rate of composite porphyria attacks
among patients with acute intermittent porphyria, the most common subtype of
acute hepatic porphyria. (Composite porphyria attacks resulted in hospitalization,
an urgent health care visit, or intravenous administration of hemin at home.) Key
secondary end points were levels of ALA and porphobilinogen and the annualized
attack rate among patients with acute hepatic porphyria, along with hemin use
and daily worst pain scores in patients with acute intermittent porphyria.
RESULTS
A total of 94 patients underwent randomization (48 in the givosiran group and 46
in the placebo group). Among the 89 patients with acute intermittent porphyria, the
mean annualized attack rate was 3.2 in the givosiran group and 12.5 in the placebo
group, representing a 74% lower rate in the givosiran group (P<0.001); the results
were similar among the 94 patients with acute hepatic porphyria. Among the patients
with acute intermittent porphyria, givosiran led to lower levels of urinary ALA
and porphobilinogen, fewer days of hemin use, and better daily scores for pain than
placebo. Key adverse events that were observed more frequently in the givosiran
group were elevations in serum aminotransferase levels, changes in serum creatinine
levels and the estimated glomerular filtration rate, and injection-site reactions.
CONCLUSIONS
Among patients with acute intermittent porphyria, those who received givosiran
had a significantly lower rate of porphyria attacks and better results for multiple
other disease manifestations than those who received placebo. The increased efficacy
was accompanied by a higher frequency of hepatic and renal adverse events.
(Funded by Alnylam Pharmaceuticals; ENVISION ClinicalTrials.gov number,
NCT03338816.)
2020
- When awareness makes the difference:
diagnosing and treating the acute hepatic
porphyrias
[Articolo su rivista]
Ventura, P
abstract
2019
- Rhodococcus equi Pneumonia in Kidney Transplant Recipient Affected by Acute Intermittent Porphyria: A Case Report
[Articolo su rivista]
Alfano, G.; Ventura, P.; Fontana, F.; Marcacci, M.; Ligabue, G.; Scarlini, S.; Franceschini, E.; Codeluppi, M.; Guaraldi, G.; Mussini, C.; Cappelli, G.
abstract
Rhodococcus equi is a gram-positive coccobacillus responsible for severe infections in patients with weakened immune systems. R equi generally causes pnumonia that may evolve into fatal systemic infection if left untreated. Here, we present a case of a 67-year-old woman affected by acute intermittent porphyria (AIP) who developed R equi pneumonia 7 months after kidney transplant. Although clinical features at presentation were nonspecific, lung computed tomography showed right perihilar consolidation with a mass-like appearance causing bronchial obstruction. Appropriate antibiotic including intravenous meropenem and oral azithromycin that was then switched to oral levofloxacin and oral azithromycin along with reduction of immunosuppressive therapy resolved pneumonia without provoking an acute attack of porphyria. AIP limited the choice of antibiotics for the treatment of R equi infection because some potentially porphyrinogenic antibacterial agents were avoided. Based on this experience, azithromycin and meropenem can be safely administered for the treatment of R Equi infection in patients with AIP.
2019
- Safety and efficacy of sucrosomal iron in inflammatory bowel disease patients with iron deficiency anemia
[Articolo su rivista]
Abbati, G.; Incerti, F.; Boarini, C.; Bocchi, D.; Ventura, P.; Buzzetti, E.; Pietrangelo, A.
abstract
Iron deficiency anemia (IDA) is one of the most common complications of inflammatory bowel disease (IBD). We planned a prospective study to address tolerability and efficacy of sucrosomial iron, a new oral formulation of ferric pyrophosphate, in IBD patients. Thirty patients with a confirmed diagnosis of Crohn’s Disease (CD) or ulcerative colitis (UC) and mild IDA were enrolled. Patients with severe IBD were excluded. All patients underwent 12 weeks of oral treatment with 30 mg/day of sucrosomial iron. Treatment compliance and adverse events were investigated every 4 weeks. Iron status, hematological parameters and IBD activity scores were determined at baseline and at the end of treatment, as well as serum hepcidin and non-transferrin bound iron (NTBI) levels. Twenty-four (80%) patients took more than 90% of the prescribed regimen. Forty-four adverse events (AEs) were recorded, but none of them is considered certainly or probably related to the study treatment. Interestingly, only eleven gastrointestinal events were recorded in 9 (30%) patients. At the end of treatment, all iron parameters improved significantly and Hb increased in 86% of patients (from 11.67 to 12.37 g/dl, p = 0.001). Serum hepcidin showed a significant increase in 79% of patients and became positively correlated with C-reactive protein (CRP) at the end of the study, while NTBI remained below the detection threshold after iron supplementation. The IBD activity scores improved in both CD and UC. This pilot interventional study supports the therapeutic use of sucrosomial iron in IBD and paves the way for future studies in larger or more difficult IBD populations.
2019
- Serum Albumin Is Inversely Associated With Portal Vein Thrombosis in Cirrhosis
[Articolo su rivista]
Basili, Stefania; Carnevale, Roberto; Nocella, Cristina; Bartimoccia, Simona; Raparelli, Valeria; Talerico, Giovanni; Stefanini, Lucia; Romiti, Giulio F; Perticone, Francesco; Corazza, Gino R; Piscaglia, Fabio; Pietrangelo, Antonello; Violi, Francesco; and PRO-LIVER collaborators, : Ainora Maria Elena; Andreozzi, Paola; Andriulli, Angelo; Angelico, Francesco; Angelico, Mario; Figliomeni, Antonio; Anzaldi, Massimiliano; Arena, Umberto; Averna, Maurizio; Barone, Milena; Bazzini, Cristina; Bergamaschi, Gaetano; Bertoni, Michele; Bianchi Giovanni, Battista; Bianchi Paola, Ilaria; Boari, Benedetta; Bombonato, Giancarlo; Bracco, Christian; Brocco, Silvia; Buonauro, Agostino; Buttà, Carmelo; Buzzetti, Elena; Cacciola, Irene; Calabria, Stefano; Cangemi, Roberto; Capeci, William; Caradio, Federica; Carderi, Isabella; Carleo, Pietro; Caroleo, Benedetto; Carrabba Maria, Domenica; Castorani, Luigi; Cavallo, Maurizio; Cecchetto, Lara; Cesaro, Flavio; Cicco, Sebastiano; Cimini, Claudia; Colombo Barbara, Maria; Corradini, Elena; Corrao, Salvatore; Costantino, Giorgio; Costanzo, Filippo; Croce, Giuseppe; Cuoghi, Chiara; Curigliano, Valentina; D’Alitto, Felicia; D’Amico, Gennaro; De Franchis, Roberto; De Giorgi, Alfredo; De Vuono, Stefano; Debernardi Venon, Wilma; Del Ben, Maria; Del Corso, Lisette; Delitala, Giuseppe; Denegri, Andrea; Di Cesare, Valentina; Di Giosia, Paolo; Di Michele, Dario; Di Minno, Giovanni; Donnarumma, Emilia; Drenaggi, Davide; Durante-Mangoni, Emanuele; Falsetti, Lorenzo; Farcomeni, Alessio; Farinaro, Vincenza; Fasolato, Silvano; Ferrari, Giovanni; Fierro, Tiziana; Forgione, Alessandra; Frugiuele, Pierluigi; Galati, Giovanni; Gallo, Paolo; Garcovich, Matteo; Gargano, Ruggiero; Gasbarrini, Antonio; Gatta, Angelo; Giammanco, Antonina; Giannelli, Gianluigi; Giorgini, Paolo; Gobbi, Paolo; Granito, Alessandro; Grassi, Davide; Greco, Antonio; Grembiale, Alessandro; Gresele, Paolo; Hijazi, Daniel; Iacobellis, Angelo; Iamele, Luigi; Invernizzi, Pietro; Ippolito, Antonio; Laffi, Giacomo; Licata, Anna; Liguori Maria, Livia; Lorusso, Giusi; Maimone, Sergio; Manfredini, Roberto; Marcacci, Matteo; Marchese, Alessandra; Marinelli, Sara; Marra Alberto, Maria; Martino Giuseppe, Pio; Masala, Maristella; Masotti, Michela; Merla, Antonio; Miceli, Giuseppe; Montebianco Abenavoli, Ludovico; Morana, Ignazio; Morelli, Olivia; Murgia, Giuseppe; Naccarato, Paola; Neri, Sergio; Niro, Grazia; Nobili, Lorenzo; Padula, Donatella; Palasciano, Giuseppe; Palmieri Vincenzo, Ostilio; Pastori, Daniele; Pattoneri, Paolo; Perego, Francesca; Perticone, Maria; Pesce, Paola; Petramala, Luigi; Pettinari, Irene; Piano, Salvatore; Picardi, Antonio; Pignataro Francesca, Serena; Pignataro, Pietro; Pignatelli, Pasquale; Pinna, Miriam; Pinto, Antonio; Pinto, Daniela; Polimeni, Licia; Pretti, Vincenzo; Privitera, Graziella; Proietti, Marco; Pucci, Giacomo; Purrello, Francesco; Ragone, Enrico; Raimondo, Giovanni; Restuccia, Tea; Riccardi, Laura; Rizzetto, Mario; Rodríguez-Castro Kryssia, Isabel; Romanelli Roberto, Giulio; Ruscio, Eleonora; Sacerdoti, David; Salinaro, Francesco; Salvi, Aldo; Salzano, Andrea; Santangelo, Giuseppe; Santarossa, Claudia; Santilli, Francesca; Santovito, Daniela; Scarpini, Francesca; Schiavone, Cosima; Scicali, Roberto; Senzolo, Marco; Serra, Carla; Serviddio, Gaetano; Sirico, Domenico; Soresi, Maurizio; Sperduti, Nicolò; Staffolani, Silvia; Staltari, Orietta; Stasi, Cristina; Suppressa, Patrizia; Svegliati Baroni, Gianluca; Talia, Michela; Tana, Claudio; Tassone Eliezer, Joseph; Todisco, Tommaso; Toriello, Filippo; Torres, Daniele; Traversa, Matteo; Tripepi, Giovanni; Tufano, Antonella; Tuttolomondo, Antonino; Varvara, Doriana; Vazzana, Natale; Vecchio Claudia, Rita; Vendemiale, Gianluigi; Ventura, Paolo; Vespasiani-Gentilucci, Umberto; Vettore, Elia; Vidili, Gianpaolo; Villani, Rosanna; Vincenzo, Ronca; Visioli, Giacomo; Vitale, Francesco; Zocco Maria, Assunta.
abstract
We analyzed whether serum albumin is independently associated with portal vein thrombosis (PVT) in liver cirrhosis (LC) and if a biologic plausibility exists. This study was divided into three parts. In part 1 (retrospective analysis), 753 consecutive patients with LC with ultrasound-detected PVT were retrospectively analyzed. In part 2, 112 patients with LC and 56 matched controls were entered in the cross-sectional study. In part 3, 5 patients with cirrhosis were entered in the in vivo study and 4 healthy subjects (HSs) were entered in the in vitro study to explore if albumin may affect platelet activation by modulating oxidative stress. In the 753 patients with LC, the prevalence of PVT was 16.7%; logistic analysis showed that only age (odds ratio [OR], 1.024; P = 0.012) and serum albumin (OR, -0.422; P = 0.0001) significantly predicted patients with PVT. Analyzing the 112 patients with LC and controls, soluble clusters of differentiation (CD)40-ligand (P = 0.0238), soluble Nox2-derived peptide (sNox2-dp; P < 0.0001), and urinary excretion of isoprostanes (P = 0.0078) were higher in patients with LC. In LC, albumin was correlated with sCD4OL (Spearman's rank correlation coefficient [r(s)], -0.33; P < 0.001), sNox2-dp (r(s), -0.57; P < 0.0001), and urinary excretion of isoprostanes (r(s), -0.48; P < 0.0001) levels. The in vivo study showed a progressive decrease in platelet aggregation, sNox2-dp, and urinary 8-iso prostaglandin F2 alpha-III formation 2 hours and 3 days after albumin infusion. Finally, platelet aggregation, sNox2-dp, and isoprostane formation significantly decreased in platelets from HSs incubated with scalar concentrations of albumin. Conclusion: Low serum albumin in LC is associated with PVT, suggesting that albumin could be a modulator of the hemostatic system through interference with mechanisms regulating platelet activation.
2018
- Clinical impact of application of risk assessment models (Padua
Prediction Score and Improve Bleeding Score) on venous
thromboembolism, major hemorrhage and health expenditure
associated with pharmacologic VTE prophylaxis: a “real life”
prospective and retrospective observational study on patients
hospitalized in a Single Internal Medicine Unit (the STIME study)
[Articolo su rivista]
Depietri, Luca; Marietta, Marco; Scarlini, Stefania; Marcacci, Matteo; Corradini, Elena; Pietrangelo, Antonello; Ventura, Paolo
abstract
International guidelines recommend the use of pharmacological prophylaxis in hospitalized medical patients at high risk of
venous thromboembolism (VTE). The same international guidelines suggest the employment of standardized risk assessment
models (RAMs) when evaluating the administration of pharmacological prophylaxis in acutely ill medical patients.
The Padua Prediction Score and the Improve Bleeding Score have been indicated as the best available RAMs to predict
thrombotic and haemorrhagic risk in hospitalized medical patients, but it is still unknown whether their combined use may
lead to a significant reduction in thrombotic and haemorrhagic events. It is also unclear whether their extensive use can affect
to some extent health expenditure associated with pharmacological VTE prophylaxis. The purpose of this single-centre,
prospective and retrospective observational study is to investigate these unanswered questions. All patients admitted to our
Internal Medicine Department between May 2015 and August 2015, i.e., before the introduction and extensive use of RAMs,
were consecutively enrolled (retrospective group). Similarly, all patients admitted between November 2016 and February
2017—once RAMs clinical use became a consolidated practice—have also been consecutively recruited (prospective group).
Consecutively, 203 patients were enrolled in the retrospective group and 210 patients were enrolled in the prospective group.
Three events of major bleeding and one event of pulmonary embolism were observed in the prospective group; three events
of major hemorrhage and two events of pulmonary embolism were observed in the retrospective group (p = not significant).
A statistically significant decrease in pharmacological VTE prophylaxis among study groups was detected: 43.3% of prospective
group patients and 56.7% of retrospective group patients received pharmacological prophylaxis (p = .028). Overall, 299
drug doses for VTE prophylaxis have been spared after RAMs introduction (p = .0001) and health expenditure decreased by
27.2% (i.e., 1.67 € saved for each single patient). In conclusion, the extensive use of RAMs in our population of hospitalized
medical patients did not statistically affect VTE rate or incidence of major bleeding, but it resulted in a significant drop in
health expenditure related with pharmacological prophylaxis. Awaiting new clinical trials, a broad use of RAMs may be a
safe strategy for reducing health expenditure associated with VTE prophylaxis in hospitalized medical patients.
2018
- Fegato, pancreas e vie biliari.
[Capitolo/Saggio]
Pietrangelo, Antonello; Abbati, Gianluca; Corradini, Elena; Ventura, Paolo
abstract
-
2018
- Molecular characterization, by digital PCR analysis of four HMBS gene mutations affecting the ubiquitous isoform of Porphobilinogen Deaminase (PBGD) in patients with Acute Intermittent Porphyria (AIP)
[Articolo su rivista]
Granata, Francesca; Mendez, Manuel; Brancaleoni, Valentina; Castelbon, Francisco J.; Graziadei, Giovanna; Ventura, Paolo; Di Pierro, Elena
abstract
Genetic variants in promoters and alternative-splicing lesions require to be experimentally tested in order to validate them as causatives of a disease. The digital PCR (dPCR) approach, which is an alternative to the classical qPCR, is an innovative and a more sensitive method for the detection and quantification of nucleic acids. In the present study, we identified four HMBS gene mutations affecting the ubiquitous isoform of porphobilinogen deaminase (PBGD) and established a dPCR protocol which would be able to detect the different transcripts of this gene. With the application of this method, we were able to characterize the functional roles of these four genetic variants, demonstrating that all these mutations were causatives of the non-erythroid variant of the acute intermittent porphyria (AIP) disease.
2018
- Platelet count does not predict bleeding in cirrhotic patients: Results from the PRO-LIVER Study
[Articolo su rivista]
Basili, S. a; Raparelli V., B; Napoleone L., B; Talerico G., A; Corazza G. R., C; Perticone F., D; Sacerdoti D., E; Andriulli A., F; Licata A., G; Pietrangelo, A.; Picardi A., I; Raimondo G., J; Violi, F.; Palasciano, G.; D’Alitto, F.; Palmieri, V. O.; Santovito, D.; Di, Michele; D., Croce; G., Brocco; S., Fasolato; S., Cecchetto; L., Bombonato; G., Bertoni; M., Restuccia; T., Andreozzi; P., Liguori; M. L., Caroleo; B., Perticone; M., Staltari; O., Manfredini; De, Giorgi; A., Averna; M., Giammanco; A., Granito; A., Pettinari; I., Marinelli; S., Bolondi; L., Falsetti; L., Salvi; A., Durante-Mangoni; E., Cesaro; F., Farinaro; V., Ragone; E., Morana; I., Ippolito; A., Iacobellis; A., Niro; G., Merla; A., Maimone; S., Cacciola; I., Varvara; D., Drenaggi; D., Staffolani; S., Vespasiani-Gentilucci; U., Galati; G., Gallo; P., Davì; G., Schiavone; C., Santilli; F., Tana; C., Soresi; Bianchi, Giovanni; B., Carderi; I., Pinto; A., Tuttolomondo; A., Ferrari; G., Gresele; P., Fierro; T., Morelli; O., Laffi; G., Romanelli; R. G., Arena; U., Stasi; Gasbarrini, A.; Garcovich, M.; Zocco, M. A.; Riccardi, L.; Ainora, M. E.; Capeci, W.; Martino, Giuseppe; P., Nobili; L., Cavallo; M., Frugiuele; P., Greco; Ventura, P.; Cuoghi, C.; Marcacci, M.; Serviddio, G.; Vendemiale, G.; Villani, R.; Gargano, R.; Vidili, G.; Di, Cesare; V., Masala; M., Delitala; G., Invernizzi; P., Vincenzo; Di, Minno; G., Tufano; A., Purrello; F., Privitera; G., Forgione; A., Curigliano; V., Senzolo; M., Rodríguez-Castro; K. I., Giannelli; G., Serra; C., Neri; S., Pignataro; P., Rizzetto; M., Debernardi; V. W., Svegliati; B. G., Bergamaschi; G., Masotti; M., Costanzo; F., Antonio; F., Angelico; Del, Ben; M., Polimeni; L., Proietti; M., Cangemi; R., Romiti; G. F., Toriello; F., Sperduti; N., Santangelo; G., Visioli; G., Todisco; Vestri, Anna; R., Farcomeni; A., Corrao; S., Gobbi; Corradini, E.; Costantino, G.; Tripepi, G.; Angelico, M.; Bolondi, L.; Granito, A.; D’Amico, G.; Franchis, De; R., Gatta; A., Tassone; E. J., Anzaldi; M., Barone; M., Bazzini; C., Bianchi; P. I., Boari; B., Bracco; C., Buonauro; A., Buttà; Buzzetti, E.; Calabria, S.; Caradio, F.; Carleo, P.; Carrabba, Maria; D., Castorani; L., Cecchetto; L., Cicco; S., Cimini; C., Colombo; B., M.; De, Giorgi; De, Vuono; S., Denegri; Del, Corso; Di, Giosia; P., Donnarumma; E., Giorgini; P., Grassi; D., Grembiale; A., Hijazi; D., Iamele; L., Lorusso; G., Marchese; Marra, Alberto; M., Masala; M., Miceli; G., Montebianco; A. L., Murgia; G., Naccarato; P., Padula; D., Pattoneri; P., Perego; F., Pesce; P., Petramala; L., Piano; S., Pinto; D., Pinna; M., Pignataro; F. S., Pretti; V., Pucci; G., Salinaro; F., Salzano; A., Santarossa; C., Scarpini; F., Scicali; R., Sirico; D., Suppressa; P., Talia; M., Torres; D., Traversa; M., Vazzana; Vecchio, Claudia; R., Vettore; E., Vitale
abstract
OBJECTIVES: Thrombocytopenia is a hallmark for patients with cirrhosis and it is perceived as a risk factor for bleeding events. However, the relationship between platelet count and bleeding is still unclear. METHODS: We investigated the relationship between platelet count and major or clinical relevant nonmajor bleedings during a follow-up of ∼4 years. RESULTS: A total of 280 cirrhotic patients with different degrees of liver disease (67% males; age 64±37 years; 47% Child–Pugh B and C) were followed up for a median of 1,129 (interquartile range: 800–1,498) days yielding 953.12 patient-year of observation. The annual rate of any significant bleeding was 5.45%/year (3.57%/year and 1.89%/year for major and minor bleeding, respectively). Fifty-two (18.6%) patients experienced a major (n=34) or minor (n=18) bleeding event, predominantly from gastrointestinal origin. Platelet counts progressively decreased with the worsening of liver disease and were similar in patients with or without major or minor bleeding: a platelet count ≤50×103/μl was detected in 3 (6%) patients with and in 20 (9%) patients without any bleeding event. Conversely, prothrombin time-international normalized ratio was slightly higher in patients with overall or major bleeding. On Cox proportional hazard analysis, only a previous gastrointestinal bleeding (hazard ratio (HR): 1.96; 95% confidence interval: 1.11–3.47; P=0.020) and encephalopathy (HR: 2.05; 95% confidence interval: 1.16–3.62; P=0.013) independently predicted overall bleeding events. CONCLUSIONS: Platelet count does not predict unprovoked major or minor bleeding in cirrhotic patients.
2017
- Acute Intermittent Porphyria in a Child with Severe Neuropathy
[Articolo su rivista]
Di Pierro, Elena; Granata, Francesca; Rosafio, Cristiano; Marchini, Stefano; Guerra, Azzurra; Brancaleoni, Valentina; Iughetti, Lorenzo; Ventura, Paolo
abstract
Clinical presentation of acute intermittent porphyria before puberty is unusual. We diagnosed the non-erythroid
variant form of this disease in a male child, who first presented, at the age of 6 years, with unexplained neurological
symptoms and behavioural abnormalities. We also report the successful treatment, and the long-term clinical
management.
2017
- Oxford Manuale di Medicina Clinica
[Traduzione di Libro]
Ventura, Paolo; Cuoghi, Angela; De Ruvo, Nicola; Marcacci, Matteo; Piacentini, Federico
abstract
Traduzione della nona edizione del manuale tascabile di Medicina Clinica
2016
- EXPLORE: A prospective, multinational natural history study of acute hepatic porphyria patients with recurrent attacks
[Poster]
Anderson, Karl E.; Balwani, Manisha; Ventura, Paolo; Ivanova, Aneta; Bloomer, Joseph R.; Montgomery Bissell, D; Stölzel, Ulrich; Parker, Charles; Rees, David; Stein, Penny; Windyga, Jerzy; Kaupinnen, Raili; Langendonk, Janneke; Badminton, Michael; Minder, Elizabeth; Martasek, Pavel; Alegre, Felix; Cappellini, Maria; Bonkovsky, Herbert L.; Sandberg, Sverre; Kaarsand, Aasne K. Aarsand; Desnick, Robert J.; Deybach, Jean Charles; Phillips, John; Naik, Hetanshi; Sardh, Eliane; Harper, Pauline; Chan, Amy; Soh, Chang Heok; Mccarthy, Kirsten; Querbes, William; Penz, Craig; Simon, Amy; Gouya, Laurent
abstract
The acute hepatic porphyrias (AHP), including acute intermittent
porphyria (AIP), hereditary coproporphyria (HCP), and
variegate porphyria (VP), are due to a deficiency in the liver
of one of the eight enzymes required for heme biosynthesis.
Induction of the first enzyme 5-aminolevulinic acid synthase 1
(ALAS1) by triggers such as fasting or drug exposure can lead
to accumulation of neurotoxic heme intermediates that result
in acute life threatening neurovisceral attacks. Methods: We
are currently performing a prospective, multinational, observational
study to characterize the natural history and clinical
management of patients with AHP who experience recurrent
attacks (> 3 attacks per year) or receive prophylactic treatment
to prevent attacks. Patient porphyria disease activity questionnaires,
physical examinations, plasma and urinary porphyrin
precursors, circulating ALAS1 mRNA and health care utilization
data are collected at pre-specified intervals throughout the
6 month study. In addition, porphyria attack assessments and
porphyrin precursor levels are collected during attacks. Interim
Results: Enrollment is complete, but the study is ongoing. A
total of 112 patients have been enrolled from 20 centers in
13 countries. The mean patient age is 39 years old, with the
majority being female (99F; 13M) and having a diagnosis of
AIP (AIP=104; HCP=3; and VP=5) for a mean of 11.4 years.
Most patients (85%) reported being treated previously with
heme during an attack, while less than half (43%) reported taking
heme prophylactically to prevent attacks. Patients reported
a mean of 9.44 attacks (median 6; range 0-54) in the prior
year, of which approximately 70% required treatment in a
healthcare setting. The most common acute attack symptoms
included abdominal pain (92%), nausea or vomiting (80%)
and weakness (79%). Symptoms similar in character to those
occurring in attacks were reported chronically (i.e. all the time)
in 46% of the patients. The baseline urinary porphobilinogen
and aminolevulinic acid levels while patients were not having
an acute attack were elevated at 34.9 mmol/mol Cr and 26.7
mmol/mol Cr respectively (upper limit of normal: PBG < 1.2
mmol/mol Cr; ALA < 3.1 mmol/mol Cr). Summary: This ongoing
study should provide important information about the full
spectrum of disease in AHP patients with recurrent attacks, as
well as provide insights into AHP pathophysiology and disease
management. The fact that close to half the patients have porphyria
symptoms all the time, even when not in the setting of
an acute attack, suggests the disease is more chronic than previously
appreciated. Additional 6-month data from this study
will be reported.
2016
- HYPERHOMOCYSTEINEMIA AND MTHFR C677T POLYMORPHISM IN PATIENTS WITH PORTAL VEIN THROMBOSIS COMPLICATING LIVER CIRRHOSIS
[Articolo su rivista]
Ventura, Paolo; Venturelli, Giorgia; Marcacci, Matteo; Fiorini, Massimo; Marchini, Stefano; Cuoghi, Chiara; Pietrangelo, Antonello
abstract
Background: Portal vein thrombosis (PVT) is serious complication of liver cirrhosis (LC), especially in the presence
of hepatocellular carcinoma (HCC). The liver plays a key role in homocysteine (Hcy) metabolism: mild hyperhomocysteinemia
(HHcy) has been described in LC. HHcy is a risk factor for deep vein thrombosis. Methylentetrahydrofolate-
reductase (MTHFR) C677T polymorphism is the commonest determinant of mild HHcy and
has been involved also in cancer development.
Aim: To investigate a possible relation between HHcy, MTHFR status, HCC and PVT in patients affected by LC.
Materials and methods: 100 patients affected by LC, 38 with (PVT group, 24 with HCC) and 62 without PVT (LC
group, 14 with HCC) sex-, age-, liver disease stage and etiology-matched were assessed for thrombophilia,
smoking status, plasma Hcy, MTHFRC677T polymorphism and homocysteine-related vitamin status.
Results: A higher prevalence of HCC, HHcy and MTHFR TT status was observed in PVT group. No significant
difference in vitamin statuswas observed between groups. PatientswithHCC showed significantly higher plasma
Hcy and higher prevalence of HHcy than patients without HCC. They had also higher prevalence of MTHFR TT
status. In patients with TT status (n = 11) and HCC, 10 had HHcy e 9 had PVT.
Conclusions: Mild HHcy is associated to LC may have a role in PVT development and assessment of plasma Hcy
may be suggested in patients with LC (especially if complicated by HCC). Association between HCC and
MTHFR TT status is intriguing, due the postulated role for this polymorphism in cancer: it may represent a
possible link between HCC and PVT.
2016
- Le porfirie: incroci pericolosi fra cute, fegato e midollo osseo
[Articolo su rivista]
Ventura, Paolo
abstract
Review sugli aspetti generali delle porfirie, malattie metaboliche da alterazioni del matebolismo dell'eme con particolare enfasi sugli aspetti dell'interessamento multiorgano
2016
- Portal vein thrombosis relevance on liver cirrhosis: Italina Venous Thrombotic Events Registry
[Articolo su rivista]
Violi, Francesco; Gino Corazza, Roberto; Hugh Caldwell, Stephen; Perticone, Francesco; Gatta, Angelo; Angelico, Mario; Farcomeni, Alessio; Masotti, Michela; Napoleone, Laura; Vestri, Annarita; Raparelli, Valeria; Basili, Stefania; Ventura, Paolo; Collaborators, PRO-LIVER
abstract
Portal vein thrombosis may occur in cirrhosis;
nevertheless, its prevalence, and predictors are still elusive.
To investigate this issue, the Italian Society of Internal
Medicine undertook the ‘‘Portal vein thrombosis Relevance
On Liver cirrhosis: Italian Venous thrombotic Events
Registry’’ (PRO-LIVER). This prospective multicenter
study includes consecutive cirrhotic patients undergoing
Doppler ultrasound examination of the portal area to
evaluate the prevalence and incidence of portal vein
thrombosis over a 2-year scheduled follow-up. Seven
hundred and fifty-three (68 % men; 64 ± 12 years)
patients were included in the present analysis. Fifty percent
of the cases were cirrhotic outpatients. Viral (44 %) etiology
was predominant. Around half of the patients had a
mild-severity disease according to the Child–Pugh score;
hepatocellular carcinoma was present in 20 %. The
prevalence of ultrasound-detected portal vein thrombosis
was 17 % (n = 126); it was asymptomatic in 43 % of the
cases. Notably, more than half of the portal vein thrombosis
patients (n = 81) were not treated with anticoagulant
therapy. Logistic step-forward multivariate analysis
demonstrated that previous portal vein thrombosis
(p\0.001), Child–Pugh Class B ? C (p\0.001), hepatocellular
carcinoma (p = 0.01), previous upper gastrointestinal
bleeding (p = 0.030) and older age (p = 0.012)
were independently associated with portal vein thrombosis.
Portal vein thrombosis is a frequent complication of cirrhosis,
particularly in patients with moderate–severe liver
failure. The apparent undertreatment of patients with portal
vein thrombosis is a matter of concern and debate, which
should be addressed by planning interventional trials
especially with newer oral anticoagulants
2015
- Improvement of survival in patients with intermediate stage (BCLC-B) hepatocellular acrcinoma complicating liver cirrhosis by combination therapy with radiofrequency ablation and transcatheter chemioembolization
[Abstract in Rivista]
Ventura, Paolo; Santis, Mario De; Venturelli, Giorgia; Gangi, Pietro Di; Marcacci, Matteo; Fiorini, Massimo; Cuoghi, Chiara; Famiglietti, Elena; Torricelli, Pietro; Pietrangelo, Antonello
abstract
Efficacia del trattamento combinato di radiofrequenza e chemioembolizzazione vs. chemioembolizzaione semplice in pazienti selezionati con HCC in stadio intermedio (BCLC score). Approccio con Propensity score matching
2015
- Markers of Endothelial Dysfunction in patients with liver cirrhosis with anh without portal hypertension
[Abstract in Rivista]
Marcacci, Matteo; Fiorini, Massimo; Marchini, Stefano; Cuoghi, Chiara; Pietrangelo, Antonello; Ventura, Paolo
abstract
Studio sulla determinazione qualitativa e quantitativa dei marcatori di disfunzione endoteliale in pazienti affetti da cirrosi epatica con senza ipertensione portale significativa
2015
- The Acute Porphyric Attack: A Difficult Diagnosis for a Potential Lethal Event in Emergency Medicine
[Articolo su rivista]
Cuoghi, Chiara; Marcacci, Matteo; Ventura, Paolo
abstract
The porphyrias are a heterogeneous group of metabolic
disorders due to an inherited (but in some forms the disturbance may
also be acquired) enzymatic deficiency in the metabolic pathway
of heme biosynthesis. The variable degree of block in the heme
biosynthetic pathway due to the enzyme deficiency results in
accumulation of different metabolic intermediates, whose toxicity is
responsible for the peculiar (cutaneous and/or neurovisceral) clinical
pictures observed in each of these diseases. According to the clinical
features, the porphyrias are classified as “acute” (or neuropsychic)
[characterized by acute neurovisceral crises (the acute porphyric
attack) involving the autonomic and/or central nervous system, but
also the liver and the kidney] and “on acute” (or dermatological)
(mostly presenting with cutaneous lesions, due to photosensitivity).
The acute porphyrias are often misdiagnosed diseases: the acute
porphyric attack may in fact mimic many other more common medical
and neuropsychiatric conditions; its delayed diagnosis and treatment
(or its inappropriate treatment) may result in a fatal outcome. For
these reasons, many different specialists, such as surgeons,
psychiatrists, gastroenterologists, neurologists, emergency
physicians and dermatologists may be variably involved in the
diagnostic process, especially in those cases presenting with
acute and life-threatening clinical features. An early and definitive
diagnosis is mandatory to improve outcomes and to assure that
potentially harmful drugs are avoided. To date, the availability of an
adequate treatment has significantly improved the outcome of the
acute porphyric attacks, so the knowledge about the management of
these events may be relevant for the physicians working in internal
and emergency medicine units.
2014
- A challenging diagnosis for potential fatal diseases: Recommendations for diagnosing acute porphyrias
[Articolo su rivista]
Ventura, Paolo; Maria Domenica, Cappellini; Gianfranco, Biolcati; Claudio Carmine, Guida; Rocchi, Emilio
abstract
Acute porphyrias are a heterogeneous group of metabolic disorders resulting from a variable catalytic defect of
four enzymes out of the eight involved in the haembiosynthesis pathway; they are rare andmostly inherited diseases,
but in some circumstances, the metabolic disturbance may be acquired. Many different environmental factors
or pathological conditions (such as drugs, calorie restriction, hormones, infections, or alcohol abuse) often
play a key role in triggering the clinical exacerbation (acute porphyric attack) of these diseases that may often
mimic many other more common acute medical and neuropsychiatric conditions and whose delayed diagnosis
and treatment may be fatal. In order to obtain an accurate diagnosis of acute porphyria, the knowledge and the
use of appropriate diagnostic tools are mandatory, even in order to provide as soon as possible themore effective
treatment and to prevent the use of potentially unsafe drugs, which can severely precipitate these diseases, especially
in the presence of life-threatening symptoms.
In this paper, we provide some recommendations for the diagnostic steps of acute porphyrias by reviewing literature
and referring to clinical experience of the board members of the Gruppo Italiano Porfiria (GrIP).
2014
- Drugs and acute porphyrias: reasons for a hazardous relationship
[Articolo su rivista]
Roveri, Giulia; Nascimbeni, Fabio; Rocchi, Emilio; Ventura, Paolo
abstract
The porphyrias are a group of metabolic diseases caused by inherited or acquired enzymatic deficiency in the metabolic pathway of heme biosynthesis. Simplistically, they can be considered as storage diseases, because the partial enzymatic defect gives rise to a metabolic "bottleneck" in the biosynthetic pathway and hence to an accumulation of different metabolic intermediates, potentially toxic and responsible for the various (cutaneous or neurovisceral) clinical manifestations observed in these diseases. In the acute porphyrias (acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and the very rare delta-aminolevulinic acid dehydratase ALAD-d porphyria), the characteristic severe neurovisceral involvement is mainly ascribed to a tissue accumulation of delta-aminolevulinic acid, a neurotoxic nonporphyrin precursor. Many different factors, both endogenous and exogenous, may favor the accumulation of this precursor in patients who are carriers of an enzymatic defect consistent with an acute porphyria, thus contributing to trigger the serious (and potentially fatal) clinical manifestations of the disease (acute porphyric attacks). To date, many different drugs are known to be able to precipitate an acute porphyric attack, so that the acute porphyrias are also considered as pharmacogenetic or toxygenetic diseases. This article reviews the different biochemical mechanisms underlying the capacity of many drugs to precipitate a porphyric acute attack (drug porphyrogenicity) in carriers of genetic mutations responsible for acute porphyrias, and addresses the issue of prescribing drugs for patients affected by these rare, but extremely complex, diseases.
2014
- Porfiria acuta intermittente: un caso "eccezionale"
[Articolo su rivista]
Rosafio, Cristiano; P., Bergonzini; S., Marchini; S., Leoni; C., Fusco; Colli, Serena; Pietrangelo, Antonello; Paolucci, Paolo; Ventura, Paolo; Iughetti, Lorenzo
abstract
Le porfirie, disordini metabolici ereditari ed eterogenei, comprendono 8 quadri clinici causati da mutazioni enzimatiche nella catena biosintetica dell’eme che esitano in un accumulo di precursori tossici e patogenetici. Si distinguono porfirie acute e porfirie cutanee. Le prime, tra le quali la più comune è la porfiria acuta intermittente (AIP), si manifestano con crisi neuroviscerali e a carico del SNP, anche letali, descritte in letteratura quasi esclusivamente in soggetti puberi.
2014
- Porfirie Epatiche (capitolo 59)
[Capitolo/Saggio]
Ventura, Paolo
abstract
Le porfirie sono malattie metaboliche conseguenti a un difetto enzimatico della biosintesi dell'eme; il tipo di intermedio metabolico che si accumula è responsabile della presentazione clinica (attacchi neuroviscerali acuti potenzilamente letali e/o dermopatie da fotosensibilità); le porfirie epatiche sono considerate malattie a presentazione eccezionale in età pediatrica, molti sintomi sono però indistinguibili da quelli di malattie più comuni: come suggerito anche dal numero di segnalazioni negli ultimi anni, la possibilità di una sottostima diagnostica in età pediatrica è reale.
2014
- Prevalence Of Subclinical Liver Fibrosis Among Patients With Idiopathic Pulmonary Fibrosis
[Abstract in Rivista]
Cocconcelli, Elisabetta; Cerri, Stefania; Spagnolo, Paolo; Tonelli, Roberto; Ventura, Paolo; Abbati, Gianluca; Vegetti, Alberto; Pileri, Francesca; DEL GIOVANE, Cinzia; Balduzzi, Sara; Pietrangelo, Antonello; Richeldi, Luca; Luppi, Fabrizio
abstract
Rationale
Idiopathic pulmonary fibrosis (IPF) is a specific form of progressive fibrosing interstitial pneumonia of unknown cause. Common pathogenic mechanisms with chronic fibrotic disorders involving other organs are likely. Yet, data on the co-existence of subclinical fibrotic disease across multiple organs in patients with IPF are lacking. The present study aimed to investigate the prevalence of subclinical liver fibrosis among patients with IPF.
Methods
Patients referred to the Center for Rare Lung Disease of the University Hospital of Modena, with a diagnosis of IPF according to recent guidelines and without previous history of liver diseases underwent hepatic transient elastography (FibroScan®), a non-invasive technique measuring liver stiffness, which routinely used for the assessment of hepatic fibrosis in patients with chronic liver diseases. Hepatic fibrotic status is expressed in a scale from 0 (absence of hepatic fibrosis) to 4 (severe liver fibrosis / cirrhosis). Patients with body mass index (BMI) ≥29 (confidence limit of the instrument) were excluded. Patients, in which any degree of hepatic fibrosis was detected, underwent screening for possible secondary causes of liver fibrosis.
Results
Among 48 IPF patients (34 males, mean age 69 years), 11 (23%) were excluded because of high BMI. In 8 out 37 patients (22%) it was not possible to obtain successful measurements due to the excess of subcutaneous adipose tissue in the chest wall, or narrow intercostal spaces. Thirteen of 37 patients (35%) had abnormal hepatic transient elastography results: 4 patients fell within the range F1-F2 (6.1-7.6 kPa), 6 in F2 (7.4-8.4 kPa), one in F2-F3 (9.5 kPa), 1 in F4 (14.3 kPa) and 1 was identified as probable fibrosis not otherwise classifiable. In all cases, secondary causes of hepatic fibrosis were excluded. Minor impairment of markers of liver injury was found in a minority of patients with liver fibrosis, with AST and ALT values exceeding the threshold value respectively in 2 and 3 patients with liver fibrosis, detected on elastography.
Conclusions
Over one third of patients in this IPF cohort had a concomitant fibrosing subclinical process in the liver. These preliminary data prompt the need for a large prospective study aimed at clarifying the correlation between the fibrosing processes in the lung and in the liver and the possibility of shared pathogenic mechanisms.
2013
- Flow-mediated dilatation (FMD) assessment as a marker of endothelial
dysfunction in liver cirrhosis
[Abstract in Rivista]
Marcacci, Matteo; Fiorini, Massimo; A., Lattanzi; Venturelli, Giorgia; G., Roveri; C., Boni; F., Zappia; Pietrangelo, Antonello; Rossi, Rosario; Ventura, Paolo; Mario Coppo Liver Research, Group; Cardiology Unit, University of Modena; Reggio, Emilia; Modena, Italy
abstract
Background/aims: Portal hypertension (PH) complications are leading causes of death in patients with liver cirrhosis (LC). PH development in chronic liver disease depends on increased vascular intra-hepatic resistance and on hyperdynamic splanchnic circulation. Disturbances in “Endothelium-dependent” vasodilation, a condition known as “endothelial dysfunction” (ED), has been claimed as an important factor responsible for increased vascular hepatic resistance and PH development in LC. Aims of this study were to assess in LC patients: (1) the presence of ED and its correlation with disease stage and (2) correlation between of ED serum markers (MED) and flow-mediated dilatation (FMD), the gold standard test for evaluating ED.
Material and methods: 60 consecutive LC patients (mean age 65±10 years, 17 female) without portal thrombosis (40 with compensated and 20 with
decompensated disease) underwent a complete clinical, radiological and biochemical evaluation in order to assess the stage of disease and drug history; all subjects were assessed for MED [P-selectin, von Willebrand factor (vWF), endothelin-1 (ET-1), thrombomodulin (TM) and nitric oxide (NO)] serum levels and FMD (measured by ultrasound at brachial artery according to guidelines). MED and FMD were also assessed in 11 healthy subjects (mean age 26±6.6 female; controls).
Results: MED plasma levels increased with the degree of liver dysfunction (p for trend <0.001 in all cases); accordingly, FMD values decreased with
worsening of the stage of liver cirrhosis [controls (9.9±1.1%), compensated cirrhosis (6.1±1.8%), decompensated cirrhosis (5±1.3%), p for trend <0.01].
In LC patients a statistically significant correlation between MED markers and FMD was observed for ET-1: r= –0.4427 (p=0.0004) and P-selectin: r=
–0.477 (p=0.0001), vWF (r= –0.166, p=0.05), but not for TM (r= –0.245, p=0.05951) and NO (p=0.961). At multivariate analysis, ET-1 and P-selectin
remained significantly associated to FMD.
Conclusions: Our data confirm the presence of ED in LC patients, as indicated by the significant increase in serum MED and by FMD reduction observed in LC patients. All these parameters show also a significant correlation with the severity of liver disease. Significant correlation and association of FMD with serum MED values also suggest that FMD may be a reliable marker of ED in patients with LC.
2013
- IS FLOW-MEDIATED DILATATION (FMD) ASSESSMENT A RELIABLE MARKER OF ENDOTHELIAL DYSFUNCTION IN LIVER CIRRHOSIS?
[Abstract in Atti di Convegno]
Marcacci, Matteo; Fiorini, Massimo; Lattanzi, Antonella; Venturelli, Giorgia; Roveri, Giulia; Boni, Chiara; Zappia, Federica; Pietrangelo, Antonello; Rossi, Rosario; Ventura, Paolo
abstract
-
2013
- MARKERS OF ENDOTHELIAL DYSFUNCTION AS PREDICTORS OF ASCITIC DECOMPENSATION IN PATIENTS WITH LIVER CIRRHOSIS.
[Abstract in Rivista]
Fiorini, Massimo; Marcacci, Matteo; C., Boni; F., Zappia; G., Roveri; Venturelli, Giorgia; Pietrangelo, Antonello; Ventura, Paolo
abstract
-
2013
- Personality features of obese women in relation to binge eating and night eating
[Articolo su rivista]
Dalle Grave, Riccardo; Calugi, Simona; Marchesini, Giulio; BECK-PECCOZ, PAOLO LUIGI; Bosello, Ottavio; Compare, Angelo; Cuzzolaro, Massimo; Grossi, Enzo; Mannucci, Edoardo; Molinari, Enrico; Tomasi, Franco; Melchionda, Nazario; Ventura, Paolo; the QUOVADIS Study Group, For
abstract
Personality traits can affect eating behaviors, the development of obesity, and obesity treatment failure.
We investigated the personality characteristics and their relation with disordered eating in 586 obese
women consecutively seeking treatment at eight Italian medical centers (age, 47.779.8 years) and 185
age-matched, normal weight women without symptoms of eating disorders (Eating Attitude Testo20).
The assessment included anthropometry, the Temperament and Character Inventory (TCI), the Binge
Eating Scale (BES) and the Night Eating Questionnaire (NEQ). Logistic regression analyses were carried
out in different models with BES scoreZ27 and NEQZ30 as dependent variables and TCI scores as
independent factors. Personality traits of obese individuals included significantly lower selfdirectedness
and cooperativeness on TCI. BES and NEQ scores were higher in obese women, and values
above the defined cut-offs were present in 77 and 18 cases (14 with high BES), respectively. After
controlling for age and BMI, high BES values were associated with high novelty seeking and harm
avoidance and low self-directedness, the last two scales being also associated with high NEQ.
We conclude that personality traits differ between obese patients seeking treatment and controls,
and the presence of disordered eating is associated with specific personality characteristics.
2013
- Serum endothelin-1 as predictor of ascitic decompensation in patients with liver cirrhosis
[Abstract in Rivista]
Fiorini, Massimo; Marcacci, Matteo; C., Boni; F., Zappia; G., Roveri; Venturelli, Giorgia; Pietrangelo, Antonello; Ventura, Paolo
abstract
Background and aims: Intra- and extrahepatic endothelial dysfunction (ED) is considered to have a pivotal role in the development of portal hypertension
(PH) in liver cirrhosis (LC). Serum levels of markers of ED (MED) are increased in LC patients; they correlate with the stage of liver disease. Aims of
the present study were to assess 1) differences between MED in patients with compensated and decompensated LC; 2) possible prognostic role of MED in ascites development in compensated LC patients.
Methods: 90 consecutive LC patients (mean age 65±9 years, 24 female) underwent a complete clinical, radiological and biochemical evaluation in
order to assess stage and characteritics of disease; all subjects were assessed for MED [P-selectin, von Willebrand factor (vWF), endothelin-1 (ET-1),
thrombomodulin (TM) and nitric oxide (NO)]. The 70 patients (mean age 65±9 years,19 female) with compensated LC (no ascites, cLC) underwent
a 2 years-follow-up; their data were also compared with those of 20 (mean age 63±10 years, 5 female) LC patients with decompensated LC (presence of ascites, dLC) and those of 11 healthy controls (mean age 26±6.6 female).
Results: ET-1, P-selectin and TM serum levels were significantly higher in LC and in dLC patients with respect to controls. NO and vWF serum levels
were higher in dLC patients, whereas no difference was observed in cLC with respect to controls. 33/70 (47.1%) of cLC patients developed ascites
at follow-up. At univariate analysis, predictors of ascites development in cLC patients were serum concentrations of ET-1 (OR=3.56, p=0.000), TM
(OR=1.95, p=0.000) and P-selectin (OR=1.033, p=0.004) and Child-Pugh score (OR=1.05, p=0.041). At multivariate analysis (Cox regression), serum
ET-1 and diabetes were independent predictors of early development of ascites during the follow-up (HR=2.631, p=0.004) in cLC patients. Efficiency (ROC method) of high levels (cut-off value=6 pg/ml) of ET-1 in predicting ascites development was good (AUC=0.803).
2012
- Combination of radiofrequency ablation and transcatheter arterial
chemoembolization improves survival in advanced hepatocellular
carcinoma complicating liver cirrhosis
[Poster]
Ventura, Paolo; M., De Santis; Bonetti, Francesco; Venturelli, Giorgia; P., Di Gangi; M., Marcacci; Torricelli, Pietro; Pietrangelo, Antonello
abstract
Background: Treatment of hepatocellular carcinoma (HCC) still remains a
controversial issue. In particular, for patients with HCC status exceeding the
criteria for “curative” options (advanced HCC) there is no defined standard of
therapy.
Aim: To evaluate efficacy of combined treatment with radiofrequency ablation
(RFA) and transcatether arterial chemio-embolization (TACE) in advanced
HCC.
Materials and Methods: We performed a retrospective study to compare
the cumulative survival rate of patients with advanced HCC treated with
combined therapy (simultaneous application of TACE and RFA) [RFA-TACE
group, n=35] vs. those treated only by TACE [TACE group, n=36] or those
treated only by conservative option [Control group, n=36]. HCC was confirmed
by imaging and/or histology. All patients were monitored at one-three
months after treatment and every six months by imaging to check for treatment
success and/or HCC recurrence. In order to minimize possible bias due to the
retrospective design, a propensity score approach was used in analysing the
results.
Results: The median survival time were 31 months for TACE-RFA group,
21 months for patients in TACE group and 10 months in control group, respectively.
The 6-month survival rate was 96%, 90% and 78% in TACE-RFA
group, TACE group and control group, respectively; the 1-year survival rate
was 89%, 75% and 20.3%. At 3 years from HCC diagnosis, 6% of control
group patients were alive, versus 34% and 45% of TACE and TACE-RFA
group, respectively. Survival rates difference between groups were significant
(p=0.011 and p<0.001 TACE and Controls with respect to TACE-RFA group).
Treatment allocation (HR 2.14, p=0.022), and complete treatment response
were important independent predictors (HR 3.25, p=0.018) of survival.
Conclusion: Based on the results of this study we conclude that the combination
of RFA and TACE may represent a promising approach for the
treatment of advanced HCC complicating liver cirrhosis. nevertheless, a better
definition of patient’s characteristics and technical approaches together with
larger scale-randomized trials are needed.
2012
- Efficacy and safety of combination therapy with pegylated interferon
and ribavirin in aged patients with chronic hepatitis C
[Poster]
G., Abbati; Ventura, Paolo; Sardini, Carla; A., Vegetti; Pileri, Francesca; Cagnacci, Sara; Venturelli, Giorgia; Incerti, Federica; Pietrangelo, Antonello
abstract
Background & Aims: Combination therapy with pegylated interferon (PEGIFN)
and ribavirin has significantly improved virus eradication rate in patients
affected by HCV-related chronic hepatitis (C-HC). However, only few data are
available with respect to efficacy and safety of this therapy in aged patients.
This study aimed at investigating efficacy and tolerability of combination
therapy in aged patients with CH-C.
Methods: 473 patients [319 (67.4%) naive, 195 (41,2% female) with CH-C
(genotype 1, n=266; genotype 2, n=112, genotype 3, n=72, genotype 4, n=23),
of whom 68 (14.4%) over 65 years old (mean age 69±2 years), were treated
with Peg-IFN (alpha-2a or alpha-2b) plus ribavirin according to international
guidelines from January 2007 to July 2011. These patients were assessed for
sustained viral response (SVR) rate and for all known main predictors of SVR
in CH-C.
Results: The overall SVR rate resulted similar in both age groups [270/405
(66.6%) in subjects <65 years vs. 41/68 (60.3%) in subjects ≥65 years,
respectively, p=0.334)]. Overall, therapy discontinuance rate was low, with no
significant difference between patients over or under age 65 (4.4% vs. 4.9%,
respectively), the most common reason for discontinuance being anemia in
both groups.For patients over 65, at multivariate analysis, non-naïve status,
EVR and use of hematological growth factors were independent predictors
of SVR. Factors independently related to EVR at multivariate analysis were
non-naive, staging, genotype 2-3 vs. genotype1-4 and use of hematological
growth factors
Conclusions: Aged patients can be candidates for Peg-IFN plus ribavirin
therapy. The appropriate use of hematological factors in these patients may
be useful to achieve a significant reduction in the rate of therapy discontinuation
due to hematological side-effects. The response-guided therapy may be
applied in predicting therapy efficacy in this patient group
2012
- Weight loss and clinical characteristics of young adults patients seeking treatment at medical centers: Data from the QUOVADIS Study
[Articolo su rivista]
Calugi, S.; Dalle Grave, R.; Compare, A.; Dall’Aglio, E.; Petroni, M. L.; Marchesini, G.; Ventura, P.; QUOVADIS Study Group, The
abstract
OBJECTIVE: To compare clinical characteristics, attrition, weight loss, and psychological
changes of obese young adults and obese adults seeking treatment. MATERIALS
AND METHODS: 1530 individuals seeking treatment in 18 Italian medical centers were evaluated.
382 cases (25%) were classified as young adults (age≤35 years), 1148 (75%) as adults (>35
years). Psychological distress, binge eating, body uneasiness, and attitude towards eating were
evaluated, at baseline and after a 12-month weight-loss program, together with BMI
changes. Weight-loss expectations and primary motivation for seeking treatment were also
recorded. RESULTS: At baseline, young adults reported significantly higher BMI at age 20,
weight loss expectations and body uneasiness scores than adults. A significantly higher percentage
of young adults also reported improving appearance as primary reason for seeking
treatment. The attrition rate was significantly larger in young adults. Among completers, the
mean percent weight loss at 12 months and improvement of psychosocial variables were significantly
higher in young adults than in adults. By intention to treat, BMI changes were no
longer significant between groups. DISCUSSION: Obese young adults lose more weight
and considerably improve psychological distress, but show a higher attrition rate after 12
months of continuous care in a real world medical setting.
2011
- Capitolo 146 - Malattie Eredometaboliche del Fegato
[Capitolo/Saggio]
Ventura, Paolo; E., Ventura
abstract
Trattazione dettagliata delle malattie eredo-metaboliche del fegatoi, con particolare riferimento alle malattie da disordine del metabolsimo dell'EME (Porfirie) e da dosrdine del metabolsimo del rame (m. di Wilson)
2011
- Hepatocellular Carcinoma in HIV-infected Patients: Check Ealy, Treat Hard
[Articolo su rivista]
M., Berretta; Garlassi, Elisa; B., Cacopardo; A., Cappellani; Guaraldi, Giovanni; S., Cocchi; P., de Paoli; A., Lleshi; I., Izzi; A., Torresin; P., Di Gangi; Pietrangelo, Antonello; M. C., Ferrari; A., Beraz; S., Berretta; G., Nasti; DI BENEDETTO, Fabrizio; L., Balestreri; U., Tirelli; Ventura, Paolo
abstract
Purpose. Hepatocellular carcinoma (HCC) is an increasingcause of mortality in HIV-infected patients inthe highly active antiretroviral therapy (HAART) era.The aims of this study were to describe HCC tumorcharacteristics and different therapeutic approaches, toevaluate patient survival time from HCC diagnosis, andto identify clinical prognostic predictors in patients withand without HIV infection.Patients and Methods. A multicenter observationalretrospective comparison of 104 HIV-infected patientsand 484 uninfected patients was performed in four Italiancenters. HCC was staged according to the BarcelonaClinic Liver Cancer (BCLC) criteria.Results. Tumor characteristics of patients with andwithout HIV were significantly different for age, EasternCooperative Oncology Group performance status(PS) score <1, and etiology of chronic liver disease. Despitethe similar potentially curative option rate and better BCLC stage at diagnosis, the median survivaltime was significantly shorter in HIV patients. HIVpatients were less frequently retreated at relapse.Independent predictors of survival were: BCLC stage,potentially effective HCC therapy, tumor dimension <3cm, HCC diagnosis under a screening program, HCC recurrence,and portal vein thrombosis. Restricting the analysisto HIV patients only, all positive prognostic factorswere confirmed together with HAART exposure.Conclusion. This study confirms a significantlyshorter survival time in HIV HCC patients. The lessaggressive retreatment at recurrence approach does notbalance the benefit of younger age and better BCLCstage and PS score of HIV patients. Thus, consideringthe prognosis of HIV HCC patients, effective screeningtechniques, programs, and specific managementguidelines are urgently needed.
2011
- Le Porfirie (capitolo 23)
[Capitolo/Saggio]
Ventura, Paolo
abstract
Trattazione approfondita delle malattie da disturbo del metabolismo dell'eme (Porfirie)
2011
- Serum and Liver Iron Differently Regulate the Bone Morphogenetic Protein 6 (BMP6)-SMAD Signaling Pathway in Mice
[Articolo su rivista]
Corradini, Elena; Meynard, D; Wu, Qf; Chen, S; Ventura, Paolo; Pietrangelo, Antonello; Babitt, J. L.
abstract
The bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway is a central regulator of hepcidin expression and systemic iron balance. However, the molecular mechanisms by which iron is sensed to regulate BMP6-SMAD signaling and hepcidin expression are unknown. Here we examined the effects of circulating and tissue iron on Bmp6-Smad pathway activation and hepcidin expression in vivo after acute and chronic enteral iron administration in mice. We demonstrated that both transferrin saturation and liver iron content independently influence hepcidin expression. Although liver iron content is independently positively correlated with hepatic Bmp6 messenger RNA (mRNA) expression and overall activation of the Smad1/5/8 signaling pathway, transferrin saturation activates the downstream Smad1/5/8 signaling cascade, but does not induce Bmp6 mRNA expression in the liver. Hepatic inhibitory Smad7 mRNA expression is increased by both acute and chronic iron administration and mirrors overall activation of the Smad1/5/8 signaling cascade. In contrast to the Smad pathway, the extracellular signal-regulated kinase 1 and 2 (Erk1/2) mitogen-activated protein kinase (Mapk) signaling pathway in the liver is not activated by acute or chronic iron administration in mice. Conclusion: Our data demonstrate that the hepatic Bmp6-Smad signaling pathway is differentially activated by circulating and tissue iron to induce hepcidin expression, whereas the hepatic Erk1/2 signaling pathway is not activated by iron in vivo.
2011
- THE MOLECULAR BASIS FOR THE HEPATIC REGULATION OF HEPCIDIN, THE IRON HORMONE, BY BONE MORPHOGENETIC PROTEINS.
[Abstract in Rivista]
Corradini, Elena; Meynard, D; Montosi, Giuliana; Garuti, Cinzia; Wu, Q; Ventura, Paolo; Babitt, Jl; Lin, Hy; Pietrangelo, Antonello
abstract
-
2011
- Treatment of chronic hepatitis C by pegylated interferon plus ribavirin combination therapy in aged patients : why not ?
[Abstract in Rivista]
A., Vegetti; G., Abbati; C., Sardini; Venturelli, Giorgia; Cagnacci, Sara; Incerti, Federica; Pietrangelo, Antonello; Ventura, Paolo
abstract
Background & Aims: Pegylated interferon (PEG-IFN) plus ribavirin combination therapy has significantly improved the successful rate in virus eradication in patients affected by chronic hepatitis C. However, only few data are available with respect to antiviral effect and safety in aged patients. This study aimed at investigating the efficacy and tolerability of pegylated interferon (Peg-IFN) plus ribavirin therapy in aged patients with chronic hepatitis C (CH-C).
Methods: A total of 473 patients [319 (67.4%) naive, 195 (41,2% female) with CH-C (genotype 1, n = 266; genotype 2, n = 112, genotype 3 = 72, genotype 4=23), of whom 68 (14.4%) over 65 years old (y.o.) (mean age 69±2 years) , were treated with Peg-IFN (alfa-2a or alfa-2b) plus ribavirin according to international guidelines. These patients were assessed for sustained viral response (SVR) rate and for all known main predictors of SVR in CH-C.
Results: The overall SVR rate resulted similar in both age groups (270/405 (66.6%) in subjects <65 y.o vs. 41/68 (60.3%) in subjects ≥ 65 y.o, respectively, p=0.334). No significant difference in therapy discontinuance rate was observed between patients over and under 65 y.o. (4.4% vs. 4.9%, respectively), the most common reason being anemia in both groups. The table resumes the distribution of main known SVR predictors in the two considered groups
< 65 years (n=405) ≥ 65 years (n=68) p
Genotype (1-4/2-3) 252/153 37/31 0.229
High viral load (cut off 500.000 UI/ml) (yes/no) 154/251 16/52 0.028
PegIFN alfa 2a / PegIFN alfa 2b use 244/161 59/9 <.001
Rapid Viral Response (RVR) (yes/no)* 106/107 28/28 1.000
Early Viral Response (EVR) (yes/no) 308/97 50/18 0.76
Naive (yes/no) 275/130 44/24 0.675
Sex (male/female) 248/157 30/38 0.011
Grading (Ishak score) 4.89±2.13 5.77±1.88 0.022
Staging (Ishak score) 2.08±1.49 2.73±1.51 0.029
Liver cirrhosis (yes/no) 42/363 13/55 0.043
Therapy reduction (yes/no) 123/282 20/48 0.888
Ribavirin reduction (yes/no) 87/318 18/50 0.430
Use of erythropoietic fatctors (yes/no) 43/362 26/42 <.001
*data not available for all patients
For patients over 65 y.o., at multivariate analysis, genotype 2/3 (OR, 2.56,95% CI 1.89-5.65 p = 0.026) and EVR (OR, 45.5,95% CI 26.2-125.3 p <0.001) were significant predictors of SVR. Factors related to EVR at multivariate analysis were naive status (OR 2.58, 95%CI 1.26-3.69, p=.001), therapy with PEGIFNalfa 2a (OR 3.56, 95% CI 1.68-5.65, p=.014) and ribavirin reduction (OR 0.789, 95% CI 0.568-0.895, p=.015).
Conclusions: Aged patients can be candidates for Peg-IFN plus ribavirin therapy.The appropriate use of erythropietic factors in these patients may be useful to achieve a significant reduction in the rate of therapy discontinuation due to hematological side-effects. The response-guided therapy may be applied in predicting therapy efficay in these patients.
2010
- ANTIALDOSTERONE THERAPY IN LIVER CIRRHOSIS: A ROLE FOR PREVENTION OF CIRROTHIC CARDIOMIOPATHY?
[Abstract in Rivista]
Ventura, Paolo; Ferrari, Mariachiara; Nuzzo, Anna Chiara; Nascimbeni, Fabio; Romagnoli, Elisa; Rossi, Rosario; Moriondo, V; Vegetti, Alberto; Modena, Maria Grazia; Pietrangelo, Antonello
abstract
-
2010
- Antialdosterone therapy in liver cirrhosis: a role for prevention of cirrhitc cardiomiopathy ?
[Abstract in Rivista]
Ventura, Paolo; Ferrari, Mariachiara; Nuzzo, Anna Chiara; Nascimbeni, Fabio; Romagnoli, Elisa; Rossi, Rosario; Moriondo, Valeria; Vegetti, Alberto; Modena, Maria Grazia; Pietrangelo, Antonello
abstract
Background and aims: Cirrhotic cardiomiopathy (CC) comprises a constellation of cardiac abnormalities associated with liver cirrhosis (LC) progression and due to multiple pathogenetic mechanisms; even if not responsible of overt heart failure, CC plays a major role in cardiac dysfunction complicating OLT or TIPPS placement. Our work aims at assessing the prevalence of CC and the different role of possible CC-associated factors.
Materials and methods: 50 patients (17 f) affected by LC and 17 (6f) by chronic hepatitis were studied. Hemochromatosis, cardiopulmonary or alcohol-related diseases were excluded. All subjects were assessed for cardiac parameters (EF, Ea, TAPSE, E/A ratio and Deceleration time (DT), QTc interval); Child-Pugh score; ANF ,BNF, Epinephrine (E), Norepinephrine (NE), PRA, Aldosterone (A), nitric oxide (NO), IL-6 and TNF-a, PIIINP plasma levels; APRI, Fibroscore, 4-parameter scores; drugs history (type and exposition time).
Results: We observed a significant prevalence of diastolic dysfunction in LC group (50% of patients had abnormal E/A ratio and 62% abnormal DT) with a higher prevalence in advanced disease (100% and 92 % of Child C patients had abnormal E/A ratio and DT, respectively). Prolonged QT (pQT) was present in 19 LC patients (38%) vs. 1 (6.25%) in ECA subjects (p<.001). At univariate analysis, diastolic dysfunction indices (abnormal DT and E/A ratio) resulted significantly related to NO, TNF-alfa, NE, E , A , PRA, ANP and BNP plasma levels; they both were also significantly related to plasma PIIINP levels , Fibroscore and 4-parameters fibrosis scores. A significant correlation between pQT interval and Child score, duration of disease (years), plasma levels of TNF-a, A, ANP, BNP, PIIINP and Fibroscore and 4-parameters scores was also present. E/A ratio, DT and pQT resulted significantly inversely related to antialdosterone therapy exposition (measured as AUC of time x dose). The table resumes the multivariate analysis’ results (stepwise multiple logistic regression) using E/A ratio <1 as dependent variable. Similar result were obtained when using pQT as dependent variable.
SE OR 95% CI p
Antialdosterone exposition -.539 .137 0.66 0.43-0.78 .011
Child Score .621 .292 1.35 1.26-2.13 .019
Aldosterone .728 .325 1.26 1.15-3.58 .026
PIIINP .345 .121 1.06 1.02-1.18 .042
Conclusions: Antialdosterone exposition results inversely and independentely related to CC abnormalities, this suggesting a role for optimized (in terms of dose and timing) antialdosterone therapy in prevention of CC development.
2010
- CLINICAL OUTCOMES AND SURVIVAL IN PATIENTS WITH HEPATOCELLULAR CARCINOMA AND HIV INFECTION
[Abstract in Rivista]
Berretta, M; Garlassi, E; Ventura, Paolo; Cacopardo, B; Lleshi, A; Cocchi, S; Guaraldi, Giovanni; Pietrangelo, Antonello; Tirelli, U.
abstract
-
2010
- Clinical and psychological correlates of health related quality of life in obese patients
[Articolo su rivista]
Mannucci, Edoardo; L Petroni, Maria; Villanova, Nicola; M Rotella, Carlo; Apolone, Giovanni; Marchesini, Giulio; Ventura, Paolo; QUOVADIS Study Group, The
abstract
Background: Health-related quality of life (HRQL) is poor in obese subjects and is a relevant outcome in
intervention studies. We aimed to determine factors associated with poor HRQL in obese patients seeking weight
loss in medical units, outside specific research projects.
Methods: HRQL, together with a number of demographic and clinical parameters, was studied with generic (SF-36,
PGWB) and disease-specific (ORWELL-97) questionnaires in an unselected sample of 1,886 (1,494 women; 392 men)
obese (BMI > 30 kg/m2) patients aged 20-65 years attending 25 medical units scattered throughout Italy. The
clinics provide weight loss treatment using different programs. General psychopathology (SCL-90 questionnaire),
the presence of binge eating (Binge Eating scale), previous weight cycling and somatic comorbidity (Charlson’s
index) were also determined. Scores on SF-36 and PGWB were compared with Italian population norms, and their
association with putative determinants of HRQL after adjustment for confounders was assessed through logistic
regression analysis.
Results: HRQL scores were significantly lower in women than in men. A greater impairment of quality of life was
observed in relation to increasing BMI class, concurrent psychopathology, associated somatic diseases, binge eating,
and weight cycling. In multivariate analysis, psychopathology (presence of previously-diagnosed mental disorders
and/or elevated scores on SCL-90) was associated with lower HRQL scores on both psychosocial and somatic
domains; somatic diseases and higher BMI, after adjustment for confounders, were associated with impairment of
physical domains, while binge eating and weight cycling appeared to affect psychosocial domains only.
Conclusions: Psychopathological disturbances are the most relevant factors associated with poor HRQL in obese
patients, affecting not only psychosocial, but also physical domains, largely independent of the severity of obesity.
Psychological/psychiatric interventions are essential for a comprehensive treatment of obesity, and to improve
treatment outcome and to reduce the burden of disease.
2010
- HIV INFECTION AND SURVIVAL IN PATIENTS WITH HCCAND LIVER CIRRHOSIS
[Abstract in Rivista]
Ventura, Paolo; Garlassi, Elisa; B., Cacopardo; P., Di Gangi; Ferrari, Maria Chiara; Venturelli, Giorgia; U., Tirelli; Guaraldi, Giovanni; Pietrangelo, Antonello; M., Berretta
abstract
Background and Aims: HCC is an emerging problem for HIVpatients, particularly if HCV and/or HBV co-infected. At the present,few data are available on the effect of HCC treatment receipt in HIV+patients. Our data aim to retrospectively compare survival rates inpatients with and without HIV infection affected by liver cirrhosisand HCC (HCC-LC).Materials and Methods: 65 HIV positive (HIV+) (54 on HAART;34 A1-A3, 17 B1-B3 and 9 C1-C3 stage; 12 with CD4 lowerthan 200) and 267 HIV negative (HIV−) HCC-LC subjects werecompared in terms of survival rates considering age, tumor andliver disease characteristics at the diagnosis (etiology, BCLC stage,number of lesions, vascular invasion, progression), treatment receipt(no treatment, palliative or curative, treatment at the progression),HIV status. All subjects were male and had at least three-months ofdisease follow up.Results: The Table resumes median survival rates according todifferent treatment strategies in the considered groups.Median survival (months) pHIV+ HIV−Overall 31.3±4.91 (n = 65) 59.7±7.07 (n = 267) .010Untreated 4.52±1.83 (n = 6) 36.1±15.2 (n = 48) .000Treated (all treatment) 35.0±11.3 (n = 59) 65.0±7.23 (n = 219) .042Treated (curative) 35.1±11.9 (n = 25) 67.8±14.7 (n = 75) .000Treated (palliative) 31.1±10.2 (n = 34) 53.1±11.1 (n = 144) .052Factors independently related to survival (Cox regression) were:HIVab pos (HR = .567, 95% CI 0.317–0.912, p = 0.046), HCCTreatment (HR = 1.506, 95%–CI 1.154–2.549, p = 0.035), tumor size>5 cm (HR = 1.257, 95% CI 1.106–1.636, p = 0.025) BCLC 0−1(HR = 1.247, 95% CI 1.100–1.576, P = 0.034), such as HAARTtherapy (HR = 2.25, 95% CI 1.01–5.048, p = .048) and treatment atprogression (TaP) (HR = 2.801, 95% CI 1.78–4.56, p = 0.000). HIV−patients had a higher frequency of TaP (88.6% vs. 67.3%, p = 0.001).Conclusions: HIV infection negatively influences HCC outcome,even in treated patients. The role of reduced re-treatment rate in caseof HCC progression in these patients needs be evaluated.
2010
- Hepatocellular carcinoma in HIV infected patients: check early, treat hard.
[Abstract in Rivista]
E., Garlassi; Ventura, Paolo; M., Beretta; S., Cocchi; B., Cacopardo; C., Stentarelli; P., Di Gangi; Pietrangelo, Antonello; U., Tirelli; Guaraldi, Giovanni
abstract
Hepatocellular carcinoma (HCC) is an emerging problem for HIV patients, particularly if HCV and/or HBV co-infected. The aim of the study was to evaluate the impact of early diagnosis and effective treatment on survival of HIV infected patients with HCC.
2010
- Hepcidin expression does not rescue the iron-poor phenotype of Kupffer cells in Hfe-null mice after liver transplantation.
[Articolo su rivista]
Garuti, Cinzia; Tian, Y; Montosi, Giuliana; Sabelli, Manuela; Corradini, Elena; Graf, R; Ventura, Paolo; Vegetti, Alberto; Clavien, Pa; Pietrangelo, Antonello
abstract
BACKGROUND & AIMS: Hemochromatosis is a common hereditary disease caused by mutations in HFE and characterized by increased absorption of iron in the intestine. However, the intestine does not appear to be the site of mutant HFE activity in the disease; we investigated the role of the liver-the source of the iron regulatory hormone hepcidin-in pathogenesis in mice. METHODS: We exchanged livers between Hfe wild-type (+/+) and Hfe null (-/-) mice by orthotopic liver transplantation (OLT) and assessed histopathology, serum and tissue iron parameters, and hepatic hepcidin messenger RNA expression. RESULTS: At 6-8 months after OLT, Hfe(-/-) mice that received Hfe(-/-) livers maintained the hemochromatosis phenotype: iron accumulation in hepatocytes but not Kupffer cells (KC), increased transferrin levels, and low levels of iron in the spleen. Hfe(+/+) mice that received Hfe(-/-) livers had increased levels of iron in serum and liver and low levels of iron in spleen. However, they did not develop the iron-poor KCs that characterize hemochromatosis: KCs appeared iron rich, although hepatic hepcidin expression was low. Transplantation of Hfe(+/+) livers into Hfe(-/-) mice prevented hepatic iron accumulation but did not return spleen and plasma levels of iron to normal; KCs still appeared to be iron poor, despite normal hepcidin expression. CONCLUSIONS: In Hfe(-/-) mice, transplantation of livers from Hfe(+/+) mice reversed the iron-loading phenotype associated with hemochromatosis (regardless of Hfe expression in intestine). However, KCs still had low levels of iron that were not affected by hepatic hepcidin expression. These findings indicate an independent, iron-modifying effect of HFE in KCs.
2010
- La relazione tra i livelli di folati, vitamina B12 e omocisteina e la densità minerale ossea a livello vertebrale e femorale
[Altro]
Xholli, A; Ventura, Paolo; Petrella, E; Romani, C; Palma, F; Volpe, Annibale; Cagnacci, Angelo
abstract
-
2010
- Malattie Metaboliche Ereditarie con Interessamento Epatico: Porfirie e Difetto di alfa1-antitripsina
[Capitolo/Saggio]
Ventura, Ezio; Ventura, Paolo
abstract
Il capitolo contiene una approfondita revisione delle malattie derivanti da difetti del metabolismo dell'eme (le Porfirie) e da difetto congenito di alfa 1 - antitripsina
2010
- Novel human pathological mutations. Gene symbol: UROD. Disease: porphyria, cutanea tarda
[Articolo su rivista]
V., Brancaleoni; E., Di Pierro; V., Moriondo; A., Borghi; C., Sardini; Ventura, Paolo; M. D., Cappellini
abstract
A new mutation of Uro-dercaboxylase gene, responsable for clinical PCT, is described
2010
- Weight management, psychological distress and binge eating in obesity.
A reappraisal of the problem
[Articolo su rivista]
Dalle Grave, R; Calugi, S; Petroni, Ml; Di Domizio, S; Marchesini, G; Ventura, P; The QUOVADIS, Group
abstract
The psychological effects of dieting and weight loss have been an area of controversy in obesity. As part of
a large multicenter study involving 1944 obese subjects seeking treatment at Italian medical centers, we
investigated the effects of weight loss on psychological distress and binge eating in 500 subjects
remaining in continuous treatment at different centers with slightly different strategies (78.8% females;
age: M = 46.2 years, SD = 10.8; BMI: M = 37.3 kg/m2, SD = 5.6). At baseline and after 12 months all
subjects were evaluated by the SymptomCheckList-90 Global Severity Index (SCL-GSI) and by the Binge
Eating Scale (BES). In both males and females, weight loss was associated with improved psychometric
testing. Changes in SCL-GSI were associated with changes in BMI (b = 0.13; t = 2.85; p < 0.005), after
adjustment for age, gender, initial BMI and center variability. Similarly, BES changes were associated
with BMI change (b = 0.15; t = 3.21; p < 0.001). We conclude that in subjects compliant to follow-up a
successful management of obesity, not directly addressing psychological distress, is associated with a
significant improvement of both psychological distress and binge eating, linearly related to the amount
of weight loss, independently of treatment procedures.
2009
- Bone Morphogenetic Protein Signaling Is Impaired in an Hfe Knockout Mouse Model of Hemochromatosis.
[Articolo su rivista]
Corradini, Elena; Garuti, Cinzia; Montosi, Giuliana; Ventura, Paolo; Andriopoulos, B; Lin, Hy; Pietrangelo, Antonello; Babitt, Jl
abstract
Mutations in HFE are the most common cause of the iron-overload disorder hereditary hemochromatosis. Levels of the main iron regulatory hormone, hepcidin, are inappropriately low in hereditary hemochromatosis mouse models and patients with HFE mutations, indicating that HFE regulates hepcidin. The bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway is an important endogenous regulator of hepcidin expression. We investigated whether HFE is involved in BMP6-SMAD regulation of hepcidin expression. METHODS: The BMP6-SMAD pathway was examined in Hfe knockout (KO) mice and in wild-type (WT) mice as controls. Mice were placed on diets of varying iron content. Hepcidin induction by BMP6 was examined in primary hepatocytes from Hfe KO mice; data were compared with those of WT mice. RESULTS: Liver levels of Bmp6 messenger RNA (mRNA) were higher in Hfe KO mice; these were appropriate for the increased hepatic levels of iron in these mice, compared with WT mice. However, levels of hepatic phosphorylated Smad 1/5/8 protein (an intracellular mediator of Bmp6 signaling) and Id1 mRNA (a target gene of Bmp6) were inappropriately low for the body iron burden and Bmp6 mRNA levels in Hfe KO, compared with WT mice. BMP6 induction of hepcidin expression was reduced in Hfe KO hepatocytes compared with WT hepatocytes. CONCLUSIONS: HFE is not involved in regulation of BMP6 by iron, but does regulate the downstream signals of BMP6 that are triggered by iron.
2009
- Clinical, biochemical and genetic characteristics of Variegate Porphyria in Italy
[Articolo su rivista]
E., Di Pierro; Ventura, Paolo; V., Brancaleoni; Moriondo, Valeria; Marchini, Stefano; D., Tavazzi; Nascimbeni, Fabio; Ferrari, Mariachiara; Rocchi, Emilio; M. D., Cappellini
abstract
Variegate Porphyria (VP) is an autosomal dominant disorder found worldwide but is rare in Italy. In this study we provide an overview of clinical, biochemical and genetic background of 33 Italian VP patients diagnosed in the last fifteen years. About 70% of patients had experienced clinical symptoms: 43.4% had photosensivity, 8.7% acute attacks and 47.8% both. Among the 33 patients, 14 different mutations were identified. Of these only 6 defects have been previously described in other countries and 8 are unique having been identified for the first time in Italy. Two of these, the c.851G>T and the c.1013C>G, were found in two and four unrelated families respectively. No mutation has been found in homozygosis and no significant correlation has been observed between specific clinical and biochemical manifestations and the type of mutation. In contrast, normal faecal protoporphyrin excretion was high predictive of silent phenotype. Normal urinary excretion of PBG and ALA, predicted absence of neurovisceral symptoms. This paper represents the first compilation of data on genotype-phenotype relation in Italian patients with VP.
2009
- Hyperhomocysteinaemia in HIV-infected patients: determinants of variability and correlations with predictors of cardiovascular disease.
[Articolo su rivista]
Guaraldi, Giovanni; Ventura, Paolo; Garlassi, E.; Orlando, G.; Squillace, N.; Nardini, Giulia; Stentarelli, C.; Zona, S.; Marchini, S.; Moriondo, V.; Tebas, P.
abstract
OBJECTIVE: We evaluated hyperhomocysteinaemia (HHcy) in a cohort of HIV-infected patients in order to assess its relation to cardiovascular risk (CVR) and identify determinants of HHcy variability. METHODS: Cross-sectional observational study. HIV-infected patients on stable highly active antiretroviral therapy (ART) were evaluated for the presence of the metabolic syndrome, lipodystrophy and traditional CVR factors. Plasma homocysteine levels were measured using high-performance liquid chromatography. RESULTS: Five hundred and sixty-seven patients (38% female) with a median age of 44 years were included in the study. Homocysteine (Hcy) was significantly higher in patients with the metabolic syndrome and lipodystrophy. No significant association was found between Hcy levels and the use of ART. However, Hcy was associated with higher blood pressure, waist circumference and waist-to-hip ratio, total lean body mass, visceral adipose tissue (VAT), VAT/total adipose tissue, homeostasis model assessment of insulin resistance (HOMA-IR), triglycerides, high-density lipoprotein cholesterol, apolipoprotein A1, B, and creatinine. All 10-year CVR assessment scores were significantly associated with Hcy. In a multivariate regression model, systolic blood pressure, vitamin supplementation and HOMA-IR were significantly and independently related to Hcy. CONCLUSIONS: Hcy is elevated in HIV-infected patients and is significantly associated with increased CVR. Measurement of Hcy might be useful in identifying particularly high-risk populations at whom therapeutic interventions could be targeted.
2009
- MTHFR C677T polymorhism and hyperhomocysteinemia in patients with liver cirrhosis complicated by portal vein thrombosis and hepatocellular carcinoma
[Abstract in Rivista]
Nascimbeni, Fabio; Ventura, Paolo; Moriondo, Valeria; Marchini, Stefano; M. C., Rosa; Ferrari, Mariachiara; G., Abbati; Romagnoli, Elisa; Pietrangelo, Antonello
abstract
BACKGROUND: Mild hyperhomocysteinemia (HHcy) is an independent risk factor for deep vein thrombosis; the liver plays a key role in homocysteine (Hcy) metabolism, being the sole tissue provided with the whole enzymatic set of transsulfuration and remethylation pathways; the liver has also a key-role in storage and metabolism of vitamins needed as cofactor in sulphur aminocid metabolism. Among different determinants of HHcy, the methylen-tetrahydrofolate reductase (MTHFR) C677T polymorphism has an high prevalence in general population (the homozygous state (TT) have been estimated in about 18% of italians). MTHFR gene anomalies have been also involved in cancer development, through a mechanism involving the impairment of folate metabolism and hence inducing alterations in DNA repair and methylation. Liver cirrhosis (LC) is by far the most important risk factor of portal vein thrombosis (PVT) especially if complicated by hepatocellular carcinoma (HCC). AIM: Considering the complex interaction between HHcy, MTHFR status and liver function impairment , aim of our study was to investigate a possible relation between HHcy, MTHFR status, HCC and PVT in patients with liver cirrhosisMATERIALS and METHODS: To these purposes, we have studied 86 patients (35 f, mean age 65±10 years) affected by LC, 53 without portal thrombosis (LC group) and 33 with portal thrombosis (doppler ultrasonography, angio-CT or angiography dcumented) (PVT group) . Patients in the two groups were age- ,Child Pugh score- , etiology- and sex–matched. All patients were assessed for plasma homocysteine (HPLC) , MTHFR C677T and vitamin (reb blood cell folate, serum B12 and B6) status. RESULTS: The table resumes the results regarding HCC presence and homocysteine parameters in the two studied groups.PVT (n=33)LC (n=53)pOR (95% CI)HCC presence (y/n)21/12 (63.6 %)12/41 (22.6%).0073.26 (1.31÷8.12)Mean plasma Hcy16.4 ± 6.112.1 ± 6.1.0151.07 (1.01÷1.15)HHcy prevalence (y/n)§21/12 (63.6%)15/38 (28.3%).0023.08 (1.61÷7.41)MTHFR status (CC/CT/TT)8/12/1335/14/4.001* .013***TT prevalence; **CT plus TT status vs. CC prevalence; §= >15 nmol/mlNo significant differences in vitamin status (red blood cell folate, and serum B12 and B6) were observed between groups. Patients with HCC (n=33) showed significant higher levels of plasma Hcy (17.7±5.9 vs. 13.5±5.8, p.039) and significant higher prevalence of HHcy (19/33, 57.5% vs.17/53, 32.1%, p=.025, OR 1.79, 95% CI 1.12÷2.99) than patients without HCC(n=53). Patients with HCC had also a significant higher prevalence of MTHFR TT status (10/33, 30.3% vs. 7/53, 13.2 %, p=.044, OR 2.67, 95% CI 1.07÷6.67). Interestingly, all patients with MTHFR TT status had HHcy and all patients MTHFR TT and HCC had PVT.CONCLUSION: Mild HHcy associated to liver cirrhosis may play a possible role for PVT development. Even if confirmations by larger and prospective studies are needed, assessment of homocysteine (simple and cheap) may be suggested in patients with liver cirrhosis (especially in case of advanced liver disease or in the presence of HCC).Our data concerning the association between HCC and MTHFR TT status is intriguing, due the postulated role for this polymorphism in cancerogenesis: it may represent a further link between HCC and PVT
2009
- Novel human pathological mutations. Gene symbol: PPOX. Disease: porphyria, variegate
[Articolo su rivista]
S., Ausenda; V., Moriondo; Marchini, Stefano; V., Besana; E., Di Pierro; V., Brancaleoni; Ventura, Paolo; Rocchi, Emilio; M. D., Cappellini
abstract
New mutation in protopoprhyrinogen-oxidase gene responsable for overt clinical form of Porphyria Variegata is described
2009
- Role of Multidrug-Resistance Protein 2 in coproporphyrin transport: results from experimental studies in bile fistula rat models
[Articolo su rivista]
Moriondo, Valeria; Marchini, Stefano; P., Di Gangi; Ferrari, Mariachiara; Nascimbeni, Fabio; Rocchi, Emilio; Ventura, Paolo
abstract
Coproporphyrin (CP) is one of the main by-products of heme biosynthesis and its abnormal accumulation is associated with different forms of porphyria. Indirect data obtained from animal and human models have suggested a possible role for Multidrug Resistance-associated Protein 2 (MRP2) and other MRPs in hepatocyte excretion of CP. Using normal, MRP2-deficient and a cholestatic rat model, we have assessed the role of MRPs in CP disposition. MRP levels were assayed using immunofluorescence. Biliary and urinary excretion patterns of CP and conjugate bilirubin were measured during equimolar infusions of CP isomers with and without phenoldibromopthalein sulfonate (BSP), a well-known MRP2 substrate. Our results suggest a role for the MRP system as a possible regulator of CP traffic and accumulation in normal and pathological conditions. Alteration in this systems (as observed in cholestatic disease) may play an important role in triggering clinical expression of porphyria in individuals with underlying mutations leading to porphyrin accumulation and may help explain the phenotypic heterogeneity in patients affected by different forms of porphyrias.
2009
- Serum ferritin as a predictor of treatment outcome in patients with chronic hepatitis C
[Articolo su rivista]
F., Ferrara; Ventura, Paolo; Vegetti, Alberto; M., Guido; G., Abbati; Corradini, Elena; G., Fattovich; C., Ferrari; M., Tagliazucchi; A., Carbonieri; A., Orlandini; S., Fagiuoli; S., Boninsegna; E., Minola; G., Rizzo; F., Belussi; M., Felder; M., Massari; G., Pozzato; S., Bonetto; P., Rovere; C., Sardini; A., Borghi; M. L., Zeneroli; P., Toniutto; E., Rossi; Pietrangelo, Antonello
abstract
OBJECTIVES: Antiviral treatment in chronic hepatitis C (CHC) involves ribavirin, a hemolytic agent. We planned a prospective study to evaluate whether drug-induced iron perturbation is clinically relevant as it relates to therapeutic outcome. METHODS: Iron variables were sequentially assessed in 206 CHC patients undergoing antiviral therapy and were correlated with pretreatment iron status and histology, hemolysis, and therapeutic outcome. RESULTS: At week 1 of therapy, serum iron (SI), transferrin saturation (TS), and serum ferritin (SF) increased markedly in all patients. All iron parameters correlated with hemolysis up to week 4; this correlation was lost for SF at later time points. SF rise during treatment was inversely related to baseline SF and iron deposits in hepatic mesenchymal/Kupffer cells. Both baseline SF and mesenchymal iron significantly correlated with fibrosis at multivariate analysis (P=0.015 and 0.008, respectively). Interestingly, baseline SF, despite good specificity (89%), had low sensitivity in predicting siderosis (25%). During therapy, SI, TS, and hemolysis parameters did not correlate with sustained virological response (SVR), whereas SF rise became an independent predictor of therapeutic response: a 2.5-fold increase of SF at week 12 associated with higher likelihood of SVR (odds ratio 1.91, P=0.032). Accordingly, lack of mesenchymal iron deposits at the baseline biopsy correlated with SVR (odds ratio 3.02, P=0.043). CONCLUSIONS: In CHC, SF is a useful marker for assessing disease duration and progression before starting treatment and for predicting therapeutic response while on therapy. SF rise during antiviral therapy is largely independent of hemolysis and likely indicates activation of macrophages in response to antivirals.
2009
- Terapia antialadosteronica e prevenzione della cardiomiopatia cirrotica
[Abstract in Rivista]
Ferrari, Mariachiara; Ventura, Paolo; A., Nuzzo; Nascimbeni, Fabio; Romagnoli, Elisa; Vegetti, Alberto; Rossi, Rosario; Moriondo, Valeria; Marchini, Stefano; Modena, Maria Grazia; Pietrangelo, Antonello
abstract
BACKGROUND: La “cardiomiopatia cirrotica” [CC] comprende una serie di alterazioni funzionali (disfunzione sistolica ma soprattutto diastolica; presenza di alterazioni strutturali e morfologiche a carico degli atri e dei ventricoli; allungamento del tratto QT all’elettrocardiogramma; presenza di markers sierici suggestivi di sofferenza e/o fibrosi cardiaca) che si instaurano a livello miocardico col progredire della malattia epatica. Poiché la CC è indipendente dall’eziologia dell’epatopatia, diversi fattori bioumorali cirrosi-associati sono stati considerati responsabili del suo sviluppo.SCOPO DEL LAVORO: (1) valutare la prevalenza di CC nei pazienti ricoverati presso un centro epatologico specialistico (2) valutare il grado di correlazione e importanza relativa dei vari fattori bioumorali CC-associati (3) costruire un algoritmo predittivo della presenza di coinvolgimento miocardico nel paziente con cirrosi.MATERIALI E METODI : Abbiamo studiato 50 pazienti (17 donne, età media 65 ± 9 anni) affetti da cirrosi epatica. Abbiamo escluso dallo studio pazienti affetti da cirrosi con storia o evidenza clinica di cardiopatia, pneumopatia, anemia grave, o altra patologia sistemica infiammatoria. Lo studio ha incluso anche un secondo gruppo di 17 pazienti (6 donne, età media 63 ± 7 anni) affetti da epatite cronica attiva (ECA) non cirrotica (biopsia con stadio ISHAK ≤ 4) non in trattamento attivo con terapia antivirale (interferone e/o antivirali) al momento dell’inclusione nello studio e senza storia clinica di cardiopatia, pneumopatia o altra patologia sistemica infiammatoria. Tutti i pazienti arruolati sono stati sottoposti a (1) determinazione della pressione arteriosa (2) ECG per valutazione del QT e QT corretto; (3) valutazione dello stadio di malattia (score Child-Pugh Turcotte e MELD); (4) determinazione dei livelli plasmatici di diverse sostanze coinvolte nella patogenesi della CC e/o considerate come marcatori bioumorali di insufficienza cardiaca [Fattori natriuretici (ANF e BNF), Epinefrina (E), Norepinefrina (NE), attività reninica plasmatica (PRA), Aldosterone (A), Ossido nitrico (NO), Interleuchina 6 (IL-6) e Tumor necrosis factor alfa (TNF-)]; (5) determinazione plasmatica di indici diretti [determinazione del pro peptide n-terminale del pro collagene di tipo III (PIIINP)] e indiretti di fibrosi (score non invasivi di fibrosi APRI, 4-parametrs e Fibroscore). (6) anamnesi farmacologica. Tutti i pazienti sono inoltre stati sottoposti a ecocardiogramma mono e bidimensionale per la determinazione degli indici di funzionalità sistolica e diastolica [FE, Ea, TAPSE, E/A ratio, Deceleration time (DT)].RISULTATI : La prevalenza di deficit diastolico nella nostra popolazione di cirrotici è risultata elevata (il 50% dei pazienti con cirrosi epatica presenta un E/A ratio patologico e il 62% presenta un DT patologico); per entrambi i parametri la prevalenza tende ad aumentare col peggiorare dello stadio di malattia (il 100% dei soggetti in Child C hanno un E/A ratio patologico e il 92% dei pazienti un DT patologico). QT allungato era presente in 19 pazienti con cirrosi epatica (38%) rispetto a 1/16 soggetti con ECA (6.25%) (p<.001). All’analisi univariata gli indici di funzione diastolica (DT e E/A ratio) apparivano significativamente correlati coi livelli di NO r=.414, p=.000 e r=.395, p=.001), TNF-alfa r=-514, p=.000, r=.481, p=.000) , NE r=-.615, p=.000, r=.-569, p=.000), E(r= -.605, p=.000, r= -.569,p=.000) Aldosterone (r= -.476,p=.000; r=.587, p=.000) PRA, (r= -.512, p= .012; r=-656, p=.001), ANP (r= - 521, p=.000; r=.560, p=.000) e BNP (r=-574, p=.001; r=669, p=.000); apparivano inoltre entrambi correlati agli indici di fibrosi diretti (PIIINP) (r=-546, p=.000; r=.524, p=.000) e al punteggio ottenuto con gli scores Fibroscore (r=-.490, p=.000) e 4-parameters (r= - .490, p=.000; r= .583, p=.002). Abbiamo osservato una associazione significativa fra presenza di QT lungo e pun
2009
- The Acute Porphyrias: a diagnostic and theraputic challenge in internal and emergency medicine
[Articolo su rivista]
Ventura, Paolo; M. D., Cappellini; Rocchi, Emilio
abstract
The porphyrias are a heterogeneous group ofmetabolic diseases resulting from a variable catalytic defectof one of the eight enzymes involved in the heme biosynthesispathway; they are mostly inherited diseases, but insome circumstances the metabolic disturbance may beacquired. The specific patterns of tissue overproduction (andhence accumulation and excretion) of toxic heme precursors,associated with each enzymatic deficiency, are responsiblefor the characteristic biochemical and clinical features ofeach of these diseases. Moreover, even in the presence of aspecific inherited enzymatic defect, many different environmentalfactors (such as drugs, calorie restriction, hormones,sunlight exposition, infections, etc.) often play a keyrole in triggering the clinical expression of the various formsof porphyrias. The porphyrias are often misdiagnosed diseases,due their multiform clinical manifestations, able tomimic many other more common diseases. For this reason,many different specialists, such as surgeons, psychiatrists,gastroenterologists, neurologists, emergency physicians anddermatologists may be variably involved in the diagnosticprocess, especially for the forms presenting with acute andlife-threatening clinical features. According to the clinicalfeatures, the porphyrias can be classified into neuropsychiatric(characterized by neurovisceral crises involving autonomicand central nervous system but also the liver and thekidney with possible consequences in terms of neurological,psychic, cardiac, respiratory, liver and kidney functions),dermatological (mostly presenting with cutaneous lesionsdue to photosensitivity), and mixed forms. From a strictlyclinical point of view, porphyrias presenting with neurovisceralattacks are also referred as acute porphyrias: they arethe object of the present review. An accurate diagnosis ofacute porphyria requires knowledge and the use of correctdiagnostic tools, and it is mandatory to provide a moreappropriate therapeutic approach and prevent the use ofpotentially unsafe drugs, able to severely precipitate thesediseases, especially in the presence of life-threateningsymptoms. To date, availability of a relatively stable haempreparation (haem arginate) has significantly improved thetreatment outcome of acute porphyric attacks, so theknowledge about the diagnosis and the management of thesediseases may be relevant for physicians working in internalmedicine, neurology and emergency units.
2008
- Correlazione tra i livelli di omocisteina e densità minerale ossea in donne in postmenopausa. Uno studio longitudinale
[Altro]
Petrella, E.; Ventura, Paolo; Caretto, S.; Cannoletta, Marianna; Zanin, R.; Generali, M.; Xholli, Anjeza; Volpe, Annibale; Cagnacci, Angelo
abstract
-
2008
- Hemolysis and hyperhomocysteinemia caused by cobalamin deficiency: three case reports and review of the literature
[Articolo su rivista]
Ventura, Paolo
abstract
Concurrent hemolysis in patients with vitamin B12 deficiency is a well-recognized phenomenon and has been attributed to intramedullary destruction of erythrocytes (ineffective erythropoiesis). Recent studies revealed that homocysteine increased the risk of hemolysis in vitamin B12 deficiency in vitro and there is a high frequency (30%) of vitamin B12 deficiency in asymptomatic patients with homozygous methylene tetrahydrofolate reductase (MTHFR) C677T mutation, a known cause of hyperhomocysteinemia. Here we report three patients with MTHFR mutations and vitamin B12 deficiency presenting with hemolytic anemia and severely elevated homocysteine levels. Patients demonstrated complete resolution of hemolysis with simultaneous normalization of serum homocysteine levels after vitamin B12 treatments. We reviewed pertinent literature, and hypothesized that hemolytic anemia may be more prevalent in patients who have a coexisting MTHFR gene mutation and vitamin B12 deficiency possibly related to severely elevated homocysteine levels. The hemolysis in these cases occurred predominantly in peripheral blood likely due to the combined effects of structurally defective erythrocytes and homocysteine-induced endothelial damage with microangiopathy.
2008
- Insulin resistance in advanced liver cirrhosis : the role of liver dysfunction and the “dissociated” effect on glucose versus lipid and amino acid metabolism
[Abstract in Rivista]
Ventura, Paolo; Romagnoli, Elisa; Nascimbeni, Fabio; Ferrari, Mariachiara; Moriondo, Valeria; Marchini, Stefano; G., Pacini; E., Ventura; M. L., Zeneroli
abstract
Background: Chronic liver failure is characterized by the progression of multiple important metabolic derangements, simultaneously interesting all main metabolic pathways. In liver cirrhosis, an impaired glucose tolerance with insulin resistance is frequently observed (20% of these patients may develop overt diabetes mellitus during the disease progression). Aim: to evaluate (1) the role of liver dysfunction in inducing the alteration of insulin sensitivity in patients with advanced stage of liver cirrhosis and (2) the effect of this metabolic derangement on amino acid and lipid metabolism in patients with liver cirrhosis with respect to healthy controls and to patients with type II diabetes mellitus.Materials and methods: To this purpose 23 subjects with documented advanced liver cirrhosis (LC), 14 age and sex-matched healthy subjects (controls) and 10 patients with type II diabetes mellitus without liver disease (DM) were studied. A FSIVGTT test (Frequently Sample Intravenous Glucose Tolerance Test) with simultaneous evaluation of glucose, lipid and amino acid metabolism parameters was performed and the results for glucose, Insulin and C-peptide were analyzed by the MINMOD program, able to adapt data to three different mathematical models, generating predictions of kinetic of glucose disappearance and insulin and C-peptide production; FSIVGTT lipid metabolism parameters (NEFA levels) were measured by colorimetric kit and FSIVGTT amino acid metabolism parameters [Branched Chain Amino Acid, (BCAA) and Aromatic Amino Acid, (AAA) profile], by Amino Acid Analyzer. Results: The MINMOD integration of data concerning secretion and kinetics of C-peptide with those of insulin, confirm that advanced-stage liver cirrhosis is characterised by significant insulin-resistance with hyperinsulinemia and suggest the main role of reduction of insulin liver extraction (h) in insulin-resistance syndrome of liver cirrhosis. The effects of this liver-failure inducted insulin-resistance seem to have some peculiarities concerning lipid and amino acid metabolism, consisting in a relative conservation (greater effect than that observed in DM subjects) of insulin effect in peripheral tissues: in LC patients insulin seems to maintain a relative greater capacity to promote both BCAA and NEFA utilization by muscle and fat tissue (“dissociated effect”) with respect to patients with type II diabetes mellitus. Conclusion: The relative preservation of insulin sensibility by peripheral tissues represents an important and a positive fact, as rationalizes the use, for example, of BCAA solutions for nutritional purposes in presence of starvation or negative azoth balance, all conditions known to negatively influencing some neuropsychological complications of liver cirrhosis.
2008
- Metabolic syndrome, psychological status and quality of life in obesity: the QUOVADIS Study
[Articolo su rivista]
Corica, F; Corsonello, A; Apolone, G; Mannucci, E; Lucchetti, M; Bonfiglio, C; Melchionda, N; Marchesini, G; Ventura, P; Study Group, Quovadis
abstract
Objective: We aimed to investigate the association of the clinical variables of the metabolic syndrome (MS) and psychological
parameters on health-related quality of life (HRQL) in obesity. In particular, our aim was to investigate the relative impact
of physical symptoms, somatic diseases and psychological distress on both the physical and the mental domains of HRQL.
Design: Cross-sectional study.
Subjects: A cohort of 1822 obese outpatients seeking treatment in medical centers.
Measurements: HRQL was measured by the standardized summary scores for physical (PCS) and mental (MCS) components of
the Short Form 36 Health Survey (SF-36). Patients were grouped according to tertiles of PCS and MCS. Metabolic and
psychological profiles of PCS and MCS tertiles were compared by discriminant analysis.
Results: The profile of metabolic and psychological variables was tertile-specific in 62.4 and 68.3% of patients in the lowest and
highest tertiles of PCS, respectively, while concordance was low in the mid-tertile (32.8%). Concordance was very high in the
lowest (74.4%) and in the highest (75.5%) tertiles of MCS, and was fair in the mid-tertile (53.2%). The main correlates of PCS
were obesity-specific and general psychological well-being, BMI, body uneasiness, binge eating, gender and psychiatric distress.
Only hypertension and hyperglycemia qualified as correlates among the components of MS. The components of MS did not
define MCS.
Conclusions: Psychological well-being is the most important correlate of HRQL in obesity, both in the physical and in the mental
domains, whereas the features of MS correlate only to some extent with the physical domain of HRQL.
2008
- Portal vein thrombosis and thrombophilia in liver cirrhosis: a role for hyperhomocysteinemia ?
[Abstract in Rivista]
Ventura, Paolo; M. C., Rosa; Romagnoli, Elisa; Tremosini, Silvia; Marchini, Stefano; E., Grandone; Moriondo, Valeria; P., Vergura; Zeneroli, Maria Luisa
abstract
Background: Hyperhomocysteinemia (HHcy) is a risk factor of venous thrombosis. Liver plays a key role in homocysteine (Hcy) metabolism. Portal vein thrombosis (PVT) is a serious complication of liver cirrhosis (LC). Different prothrombotic conditions have been considered as risks factors of PVT in LC; a few data are available about HHcy. Materials and Methods: we studied consecutively 86 cirrhotic patients [33 with PVT (PVT, mean age 64±11, 13 females) and 53 without PVT (LC, mean age 66±9, 22 females), no differences in cirrhosis aetiology among groups]; disease stage (Child-Pugh score), HCC presence, smoking, natural anticoagulants (protein C, S and ATIII) and other thrombophilic factors (Factor VIIIc, LAC , FVL, PTHR A20210), plasma Hcy, Hcy-related vitamin status and MTHFR C677T mutation prevalence were assessed in all patients (table 1). Results: A progressive increase in plasma Hcy levels, an higher prevalence of HHcy with the worsening of liver function; an high prevalence of HHcy in PVT group vs. LC group (63.6% vs.28.3%, p=.002) and a significant association of HHcy with PVT [OR=3.26 (95% CI 1.3 ÷ 8.1, p=.003) were observed.PVT (n=33)CC (n=53)pFVL4 (12.1 %)6 (11.3 %).983°PTHR A2021012 (36.4%)5 (9.4%).004°MTHFR C677→T§25 [13] (75.7%)18 [4] (33.9%).013°High Factor VIIIc**19 (57.5%)19 (35.8%).048°LAC3 (9.1 %)4 (7.5%).893°HCC presence (Y/N)12 (57.1%)17 (47.2%).815°Smokers (Y/N)11 (33 %)18 (33.9%).921°Protein S (%)69.5 ± 21.572.8 ± 23.8.565*Protein C (%)54.5 ± 20.5 56.4 ± 25.1.744*AT III (%)62.8 ± 18.865.3 ± 25.2.662*Factor VIIIc (IU/dl)203 ± 59176 ± 65.062*Homocysteine (mol/L)16.4 ± 6.112.0 ± 6.1.015*§Between square brackets is indicated the prevalence of homozygosis; ** High Factor VIIIc = > 170 IU/dl *** HHcy = > 12 mol/L; °test ; *T-testConclusion: According to our data, HHcy, similarly to other thrombosis risk factors, may play a role in the pathogenesis of TVP in patients affected by liver cirrhosis. Identification of this risk group may be essential to plan clinical prevention strategies especially in patients candidates for surgery or other intervention at risk of PVT.
2008
- Radiofrequency ablation combined with transcatheter arterial chemioembolization in the treatment of advanced hepatocellular carcinoma
[Abstract in Rivista]
Ventura, Paolo; M., De Santis; Romagnoli, Elisa; Tremosini, Silvia; Zaldini, Piera; E., Boldrini; P., Ballesini; A., Borghi; A., Cristani; Gandolfo, Marco; C., Sardini; I., Venturini; Torricelli, Pietro; M. L., Zeneroli
abstract
Background : Treatment of HCC complicating liver cirrhosis still remains a controversial issue, due to both the characteristics of the malignant disease per se and to the problems of underlying associated chronic liver disease. In particular, for patients with HCC not elegible for “curative” options (advanced HCC) (who, despite of surveillance programs, still remain a relevant amount in the clinical practice) there is no standard therapy. Aim: to evaluate efficacy of combined treatment with radiofrequency ablation (RFA) and transcatether arterial chemio-embolization (TACE) in the treatment of advanced hepatocellular carcinoma.Materials and Methods: We compared the treatment efficacy (cumulative survival rate after treatment) in 30 HCC-confirmed (imaging and/or histological proven) patients treated with combined therapy (simultaneous application of TACE and RFA; RFA was performed on to the greatest node in case of multiple nodes) [RFA-TACE group] with HCC-confirmed patients treated only by TACE [TACE group] or by conservative option [Control group]. Patients in TACE and Control groups were chosen as matching more as possible with patients in RFA-TACE group with regard to all possible factors influencing survival. Patients in TACE group could not undergo RFA due to technical (site of tumour, lesion undetectable at ultrasound, etc) and/or refuse of treatment. Control group could not undergo TACE due to portal complete or partial thrombosis or site of tumour. All patients were monitored at one-three months after treatment and every six months by imaging to control for treatment success and neoplasm relapse.Results: Characteristics of the considered groups are resumed in the table below. No patients were lost at follow-up. Survival rates were better in TACE-RFA group than TACE and control group. The median survival time was 16.1 months for TACE-RFA, 12.1 for TACE and 8.4 for Controls. The 6-month, 1-year and 2-years survival rate was 78%, 71% and 47% TACE-RFA group vs. 72%, 66% and 40% and 65%, 55% and 39% in TACE and Control group (p=.025 and p=.002 with respect to TACE-RFA group, i.e significant after Bonferroni correction for multiple comparisons).RFA-TACE (n=30)TACE (n=34)Controls (n=35)Age67±764±868±10Sex (males)22 (73.3%)25 (73.5%)26 (74.3%)Child score6.8±1.56.8±1.37.1±1.9Child group A/B11/1911/2310/25Nodes (mean)3.1±1.23.2 ±1.13.4±1.6Major node dimension3.9±1.53.8±1.63.9±1.8Single / Multiple node8/209/269/26BCLC stage ( B/C)16/1416/1815/20Milan criteria1 2/ 3 17/1315/1915/20Duration of Liver Disease (years) 8.4±4.48.7±3.58.6±3.5Etiology : Viral vs. Nonviral22/828/628/71 2= Single node > 3 and < 5 cm or multiple nodes (max 3) with the greatest ≤ 3 cm; 3= Single node > 5 cm or multiple nodes (more than 3 or up to 3 with the greatest > 3 cm)Conclusion: The combination of RFA and TACE is a promising approach for the treatment of advanced HCC complicating liver cirrhosis, nevertheless a better definition of patient’s characteristics and technical approaches are needed together with large scale-randomized trial for confirmation of results.
2007
- Anti- and pro-oxidant factors and endothelial dysfunction in chronic cigarette smokers with coronary heart disease
[Articolo su rivista]
Rocchi, E; Bursi, F; Ventura, Paolo; Ronzoni, A; Gozzi, C; Casalgrandi, G; Marri, L; Rossi, Rosario; Modena, Maria Grazia
abstract
BACKGROUND: Endothelial dysfunction in cigarette smokers has been ascribed to increased oxidative damage. The aims of the present study were to compare the endothelial function of normotensive smokers with that of non-smokers and to examine its relation to some parameters representative of oxidative damage and of antioxidant capacity. METHODS: We investigated 32 chronic smokers (15-30 cigarettes daily) affected by coronary heart disease, ranging from acute myocardial infarction to instable angina pectoris, and 28 matched non-smokers without any definite risk factors. All subjects underwent assessment of nitric oxide (NO)-dependent endothelial function, measured as brachial artery vasodilatation in response to reactive ischemia, using a standardized echographic method. Plasma and urinary levels of NO were also measured in all subjects, as were urinary 15-isoprostane F(2t), plasma serum lipids, homocysteine (Hcy), ascorbic acid, retinol, tocopherol, and alpha- and beta-carotene (by high-performance liquid chromatography). RESULTS: Smokers showed a significantly lower NO-mediated vasodilatation response (3.50% vs. 6.18%, p<0.001) and higher levels of urinary NO metabolites and 15-isoprostane F(2t). They also had higher levels of Hcy (p<0.001); these values were significantly and inversely related to NO serum levels (r=-0.512, p<0.001). Moreover, smokers had a significant and corresponding reduction in circulating levels of ascorbic acid, tocopherol, and alpha- and beta-carotene. CONCLUSIONS: The present study shows a clear relation between endothelial dysfunction (NO production impairment) and cigarette smoking, especially in the presence of high levels of LDL-cholesterol. It also defines some markers of both oxidative damage and antioxidant protective capacity in this condition. The monitoring of these factors may be advisable in order to assess the amount of endothelial damage
2007
- Antiviral treatment profoundly affects iron status in HCV patients: Implications for management and treatment outcome
[Abstract in Atti di Convegno]
Ferrara, F; Guido, M; Ventura, Paolo; Vegetti, A; Abbati, G; Corradmi, E; Ferrari, C; Fattovich, G; Pietrangelo, Antonello
abstract
No abstract available
2007
- Psychological Distress in Morbid Obesity in Relation to Weight History
[Articolo su rivista]
Letizia Petroni, Maria; Villanova, Nicola; Avagnina, Sebastiano; Antonia Fusco, Maria; Fatati, Giuseppe; Compare, Angelo; Marchesini, Giulio; Ventura, Paolo; QUOVADIS Study Group, The
abstract
Background: Very few data are available on psychological
distress in morbidly obese subjects in relation
to the history of their weight. In subjects with childhood
obesity, psychological distress might be better
than in adult-onset obesity, because of progressive
adaptation to the social stigma.
Methods: Psychological distress was tested in relation
to BMI at age 20 years (BMI-20), weight history
and somatic co-morbidities in 632 treatment-seeking,
morbidly obese participants from the QUOVADIS
cohort (130 men, 502 women; mean age 45.5 years).
The number of dieting attempts/year, BMI increase
and cumulative BMI loss since age 20 were calculated
as weight cycling parameters.The Symptom Check
List-90 (SCL-90), the Psychological General Well-
Being (PGWB), the Binge-Eating Scale, and the
ORWELL-97 questionnaire were used to score psychometry
and health-related quality of life (HRQL).
Complications were quantitatively assessed by a
modified Charlson’s score.
Results: BMI-20 was normal in 35% of cases and >35
kg/m2 in only 14%. Psychometric scores were not different
in relation to BMI-20, when corrected for age,
with the exception of the General Health scale of
PGWB, showing a greater distress in subjects with
normal BMI-20. In most cases, the prevalence of
pathological results of questionnaires showed a Jshaped
curve, with participants with normal BMI-20 or
those with Class II-III obesity in early adulthood having
the highest prevalence of psychological/psychiatric
distress and poor HRQL.Weight cycling was a risk factor
for binge-eating, depression and interpersonal
sensitivity in SCL-90, whereas somatic co-morbidities
adversely affected most SCL-90 and all PGWB scales.
Conclusion: Weight cycling and somatic co-morbidities,
but not age of onset of obesity, are the main
factors negatively influencing psychological health in
treatment-seeking, morbidly obese subjects.
2007
- Sarcoma primitivo del cuore. Descrizione di un caso
[Articolo su rivista]
Tremosini, Silvia; Vegetti, Alberto; D., Arioli; Ventura, Paolo; G., Rossi; Modena, Maria Grazia; M. L., Zeneroli
abstract
Primary cardiac tumors are rare events. We describe here a case of undifferentiated pleomorphic sarcoma (so-called pleomorphic malignant fibrous histiocytoma) obliterating mostly the left side and the anterior wall of pericardium in a 84-year-old man admitted for mild dyspnea at rest. The diagnosis was suspected after excluding the lung origin of the mass (observed by plain chest radiography) by thorax computed tomography but it was confirmed only by cardiac-gated magnetic resonance imaging and transthoracic biopsy. Considering both patient's age and comorbidity, and local extension of the lesion, after counseling with cardiac surgeons and oncologists, the patient was treated only by conservative medical therapy. The patient died 6 months after the diagnosis due to a superior vena cava syndrome as an effect of infiltration and obstruction of superior vena cava by the tumor at the site of vein entry in the right atrium. This case is an example of a primary cardiac tumor that causes relative myocardial sufferance both by infiltration and by limitation of normal heart diastolic function.
2007
- The Effect of Obesity Management on Body Image in Patients Seeking Treatment at Medical Centers
[Articolo su rivista]
Dalle Grave, Riccardo; Cuzzolaro, Massimo; Calugi, Simona; Tomasi, Franco; Temperilli, Flavia; Marchesini, Giulio; Ventura, Paolo; QUOVADIS Study Group, The
abstract
treatment-
seeking patients with obesity. We aimed to investigate
the effects of obesity management on body image in patients
with obesity attending Italian medical centers for
weight loss programs.
Research Methods and Procedures: A total of 473 obese
patients seeking treatment in 13 Italian medical centers
(80% females; age, 45.9 standard deviation 11.0 years;
BMI, 36.8 5.7 kg/m2) were evaluated at baseline and after
a 6-month weight loss treatment. Body uneasiness, psychiatric
distress, and binge eating were tested by Body Uneasiness
Test (BUT, Part A), Symptom CheckList-90 (SCL-
90), and Binge Eating Scale (BES), respectively.
Results: At 6-month follow-up, the percentage weight loss
was significantly higher in men (9.0 6.3%) than in
women (6.8 7.3%; p 0.010). Both men and women had
a significant improvement in BUT Global Severity Index
and in all of the BUT subscales with the exception of the
Compulsive Self-Monitoring subscale. Linear regression
analysis selected baseline psychological and behavioral
measures (global score of BUT and SCL-90) and improved
psychiatric distress and binge eating as independent predictors
of changes in basal body dissatisfaction in females,
whereas in males, changes were associated only with baseline
BUT-Global Severity Index score, binge eating, and its
treatment-associated improvement. Pre-treatment BMI and
BMI changes did not enter the regression.
Discussion: Obesity treatment, even with a modest degree
of weight loss, is associated with a significant improvement
of body image, in both females and males. This effect
depends mainly on psychological factors, not on the amount
of weight loss.
2007
- Tumour markers in internal medicine: a low-cost test or an unnecessary expense? A retrospective study based on appropriateness
[Articolo su rivista]
D., Arioli; M., Pipino; E., Boldrini; E., Amateis; A., Cristani; Ventura, Paolo; Romagnoli, Elisa; M. C., De Santis; M. L., Zeneroli
abstract
In the last 35 years tumour markers (TM) have gained currency in clinical practice. However, in the light of indications by international guidelines, their use is often unjustified. Our aim was to quantify the use of some of the most common TM, assessing their appropriateness and their efficacy in an Internal Medicine Unit. METHODS: In the three Internal Medicine Units of the Department of Internal Medicine of Policlinico of Modena we have carried out a retrospective analysis of the assessment of the main TM (CEA, CA19.9, CA 125, CA 15.3, NSE). The analysis was divided into two distinct phases: (I) quantitative phase, in order to assess the scale of the problem in economical terms; (II) qualitative phase, in order to assess the efficacy of the tests and the appropriateness of their use. RESULTS: (I) At last one of the considered TM was requested in 5102 out of the 8253 admitted patients (62%) (period 2001-2003). The trend was similar in all three units examined. (II) The qualitative analyses revealed: (1) the most common motivation for their use (79%) was diagnostic, mostly prior to any other test; (2) a mere 5% of the requests were appropriate according to the international literature; and (3) TM showed a low positive predictive value when used for diagnosis in an unselected population such as that of an Internal Medicine unit. CONCLUSIONS: The results of our study showed that TM determination represents an overall cost for Internal Medicine units and that there is a high inappropriateness in their use compared to what it is suggested by international guidelines. Though the TM is a low-cost test when used correctly, it seems an unnecessary expense if not adequately incorporated into the decision making process.
2007
- Urinary coproporhyrin isomers during therapy with IFn-RIBA in patients with chronic hepatitis due to HCV infection
[Abstract in Rivista]
Ventura, Paolo; C., Sardini; Romagnoli, Elisa; Moriondo, Valeria; Marchini, Stefano; Tremosini, Silvia; A., Borghi; M. L., Zeneroli; Rocchi, Emilio
abstract
Background : MRP2 transporter has a proven role in biliary export of many different products of hepatocytic metabolism. Particularly, human and animal models have demonstrated MRP2 role in biliary excretion of coproporhyrins: its preference for isomer I (CPI) export with respect to isomer III (CPIII) is responsable for the biliary CPI/CPIII ratio about 2-3:1 and the plasma and urinary CPI/CPIII ratio about 1:2-3. A significant reduction of MRP2 expression has been described in many different acquired cholestatic liver diseases and in patients with chronic hepatitis (CH) due to HCV infection. Aim of our study was to evaluate quantitative and qualitative (CPI/CPIII ratio) urinary CP excretion in patients with CH due to HCV before (T0), at 3 months (T3) and at the end of antiviral therapy (ET) (peg-IFN + Ribavirin)Materials and Methods: 60 patients (18 females, aged 46±11 years, genotype: 1 (31); 2(10); 3(15); 4(4); 51 naive) with istologically proven HCV-inducted CH were consecutively enrolled; 5 (8.4%) did not conclude the study. 10 healthy subjects sex- and age-matched were also considered for comparing the basal values. None of considered subjects had overt laboratory [i.e. serum alkaline phosphatase (AP) over the normal range] or clinical signs of cholestasis. All patients underwent a urinary evaluation (HPLC) of CPI excretion at T0, T3 and ET. SVR (n=34) was defined as serum HCV-RNA undetectable after 6 months of follow-up. Results: Basal serum FA levels resulted significantly related both to basal urinary total CPI (r=.405, p=.001), and basal CPI/CPIII ratio (r=.692, p=.000). Table I show Total urinary CPI e urinary CPI/CPIII ratio in controls and in HCV patients with respect to serum PA percentile.Table IPA ≥ 75°percentile(≥ 232 u/L) (n=16)(group A)PA < 75° percentile (<232 U/L) (n=44)(group B)Controls(n=10)Urinary CPI (g/g urinary creatinine)66.6 ± 29.4142.4±21.2232.6±12.3CPI/CPIII ratio1.71±0.610.75±0.510.38±0.121p<.012p<.05 with respect to controlsDuring IFN therapy, patients in group A significantly reduce both urinary CPI excretion (45±21 at T3 and 38±18 g/g urinary creatinine at ET, p<.05 and <.01 vs. T0, respectively) and CPI/CPIII ratio (1.1±0.4 at T3 and 0.55±0.32 at ET p<.05 and <.01 vs. T0, respectively) in case of SVR (n=10), whereas no significant effect was observed in subjects non responders to antiviral therapy (NR, n=6) . Patients of group B show a similar trend for normalization of CPI/CPII ratio and CPI/CPIII ratio (0.60 ±0.3 at T3 and 0.41±0.22 at ET, p<.05 and <.05 vs. T0, respectively) and reduction of CPI (39±12 at T3 and 36±11 g/g cretinine at ET, p<.07 and <.06 vs. T0, respectively) in case of SVR (n=24). Also in group B no significant modification of total CPI urinary excretion nor of CPI/CPIII ratio was observed in NR. Overall, a reduction of CPI/CPIII ratio >60% at T3 showed a 88% PPV for SVR, reaching 95% if considering only patients in group A.Our data indirectly confirm the effect of liver chronic infection due to HCV on MRP2 expression, whose alteration may be considered as the main responsible for the observed urinary CPI modifications (greater excretion with CPI/CPIII ratio inversion). Even if more confirmative data are needed, monitoring of urinary CPI excretion (especially CPI/CPIII ratio) may be a useful, cheap and simple tool in early prediction of the response to antiviral therapy in subjects affected by HCV CH, especially in the presence of mild laboratory signs of cholestasis.
2007
- Validating the Body Uneasiness Test (BUT) in obese patients
[Articolo su rivista]
Marano, G.; Cuzzolaro, M.; Vetrone, G.; Garfinkel, P. E.; Temperilli, F.; Spera, G.; Dalle Grave, R.; Calugi, S.; Marchesini, G.; Ventura, P.; QUOVADIS Study Group1, The
abstract
OBJECTIVE: To investigate the psychometric properties of the Body
Uneasiness Test (BUT) in a large sample of subjects with obesity seeking treatment. BUT is a
71-item self-report questionnaire in two parts: BUT-A which measures weight phobia, body
image concerns, avoidance, compulsive self-monitoring, detachment and estrangement feelings
towards one’s own body (depersonalization); and BUT-B, which looks at specific worries
about particular body parts or functions. METHODS: We recruited a clinical sample of
1,812 adult subjects (age range 18-65 years, females 1,411, males 401) with obesity (Body
Mass Index, BMI ≥30 kg/m2) and a normal weight (BMI value between 18.5 and 25 kg/m2)
non-clinical sample of 457 adult subjects (females 248, males 209) with an Eating Attitudes
Test-26 (EAT-26) score under the cut-off point 20 (scores ≥20 indicate possible cases of eating
disorders). RESULTS: The exploratory and confirmatory analyses confirmed a structural
five-factor model for BUT-A and an eight-factor model for BUT-B. Internal consistency was
satisfactory. Concurrent validity with Binge Eating Scale (BES) and Three-Factor Eating
Questionnaire (TFEQ) was evaluated. The authors calculated mean values for BUT scores in
adult (18-65 years) patients with obesity, and evaluated the influence of gender, age and BMI.
Females obtained statistically significant higher scores than males in all age groups and in all
classes of obesity; patients with obesity, compared with normal weight subjects, generally
obtained statistically significant higher scores, but few differences could be attributed to the
influence of BMI. CONCLUSION: The BUT can be a valuable multidimensional tool for the
clinical assessment of body uneasiness in obesity; the scores of its sub-scales do not show a
linear correlation with BMI values.
2006
- A large deletion on chromosome 11 in acute intermittent porphyria
[Articolo su rivista]
E., Di Pierro; V., Besana; V., Moriondo; V., Brancaleoni; D., Tavazzi; G., Casalgrandi; Ventura, Paolo; Rocchi, Emilio; M. D., Cappellini
abstract
Acute intermittent porphyria (AIP) is an autosomal disorder caused by molecular abnormalities in the gene coding for hydroxymethylbilane synthase (HMBS), the third enzyme in the heme biosynthetic pathway. So far, more than 242 different mutations responsible for All? have been identified in this gene. In an Italian family with typical clinical and biochemical signs of AIP, no mutation was found by direct sequencing of the entire hydroxymethylbilane synthase gene (HMBS). All the symptomatic patients showed apparent homozygosity and absence of mendelian segregation for eleven common polymorphisms along the gene. Excluding interference of polymorphisms in the primer sites, we assumed the presence of a complete HMBS gene deletion. In order to identify the size of this deletion, single nucleotide polymorphisms (SNPs) analysis was extended to flanking genes, H2A Histone Family member X (H2AFX) and Dolichyl-Phosphate N-Acetylglucosarnine Phosphotransferase 1 (DPAGT1), downstream and Vacuolar protein sorting 11 (VPS11), upstream. Heterozygous polymorphisms in the VPS11 and DPAGT1 genes were found. Thus, we performed a Long-PCR with primers situated in regions outside the homozygous polymorphisins and we identified a double deletion with inversion on chromosome 11 (g22516974-22524062del7088, g22524062-22524278inv216, g22524278_22531093del6815). Even if the deletions include the entire HMBS and H2AFX genes and 1463 bp of the final portion of DPAGT1 gene, our patients had no other symptoms than AIP.
2006
- Construct Validity of the Short Form-36 Health Survey and Its Relationship with BMI in Obese Outpatients
[Articolo su rivista]
Corica, Francesco; Corsonello, Andrea; Apolone, Giovanni; Lucchetti, Maria; Melchionda, Nazario; Marchesini, Giulio; Ventura, Paolo; QUOVADIS Study Group, The
abstract
Objective: To investigate the construct validity of the Short
Form-36 (SF-36) Health Survey questionnaire in obese patients.
Research Methods and Procedures: Our series consisted of
1735 obese patients (age, 44.7 11.0 years; 1346 women)
consecutively enrolled in the QUOVADIS study, an observational
multicenter study of obese treatment-seeking outpatients.
The construct validity of the SF-36 was assessed
by main component analysis. Age-, gender-, and educationadjusted
general linear models were used to investigate the
relationship between BMI and SF-36 domains or factors
identified by main component analysis.
Results: BMI was significantly associated with poor healthrelated
quality of life in all eight SF-36 domains, and the
strongest association was observed with physical activity.
Main components analysis generated a six-factor solution
explaining 59% of the observed variance. BMI was strongly
associated with factors based on the loading of items regarding
the physical activity domain and factors based on
role-physical and role-emotional items or general health and
bodily pain items. In contrast, mental health-, vitality-, and
social functioning-based factors were not related to BMI.
Discussion: In obese treatment-seeking outpatients, the
clustering of SF-36 items in main components is not significantly
different from the domain-based approach generally
used, thus confirming the robustness of such a generic
questionnaire in this specific condition. However, the peculiar
clustering of some SF-36 items and their relationship
with BMI suggest that the health-related quality of life
profile of subjects belonging to that population may be
better described with alternative aggregations of the SF-36
items or with disease-tailored questionnaires.
2005
- Hyperhomocysteinaemia in chronic liver diseases: role of disease stage, vitamin status and methylenetetrahydrofolate reductase genetics
[Articolo su rivista]
Ventura, Paolo; Rosa, Maria Cristina; G., Abbati; Marchini, Stefano; E., Grandone; P., Vergura; Tremosini, Silvia; Zeneroli, Maria Luisa
abstract
Background/Aims: The liver plays a key role in sulphur aminoacid metabolism hence, homocysteine metabolism may be impaired in chronic liver diseases. The aim of this study was to investigate, in patients affected by chronic liver diseases, (1) the prevalence of hyperhomocysteinaemia and (2) the role of its determinants such as the stage and the aetiology of disease, vitamin status, genetic documented alterations (methylenetetrahydrofolate reductase deficiency) and presence/absence of documented malignant evolution (hepatocellular carcinoma). Materials and methods: One hundred and thirty patients with chronic liver disease (34 with chronic active hepatitis, 12 with fatty liver and 88 with liver cirrhosis) and 50 healthy age-matched control subjects were included into the study. Results: Hyperhomocysteinaemia was defined as homocysteine plasma levels greater than 12.6 mumol/l. Hyperhomocysteinaemia prevalence in liver cirrhosis group was 40.9%, significantly higher (all P<0.01) with respect to controls (12%), chronic active hepatitis (14.7%) and fatty liver (25%) groups and increased with Child-Pugh stage [Child A: 22.2%, Child B (50%); Child C (58.3%)]. In chronic-active hepatitis and liver cirrhosis, the prevalence of subjects with methylenetetrahydrofolate reductase C677-->T mutation (both as CT and as TT) and hyperhomocysteinaemia results in significantly higher levels with respect to controls. Methylenetetrahydrofolate reductase C677-->T mutation and disease stage showed to be the most important predictive factors of hyperhomocysteinaemia in liver cirrhosis whereas the influence of homocysteine-related vitamin status seems to have a secondary role. Conclusions: In conclusion hyperhomocysteinaemia is highly prevalent in liver cirrhosis but not in other chronic liver diseases; it may contribute to fibrogenesis and vascular complication of liver cirrhosis.
2005
- Impiego dei marcatori di neoplasia (CEA, CA 19.9, CA 125, CA 16.3, NSE) in Medinina Interna: uno studio retrospettivo
[Abstract in Rivista]
D., Arioli; M., Pipino; E., Boldrini; E., Amateis; A., Cristani; Ventura, Paolo; M. L., Zeneroli
abstract
Premessa e scopi: Nella pratica clinica, l’utilizzo in ambito internistico dei marcatori neoplastici (MN) è frequente e spesso non giustificato dalle raccomandazioni presenti in letteratura. Scopo del presente lavoro è quantificare la modalità di utilizzo dei MN in ambito internistico valutandone l’appropriatezza. Materiali e metodi: Nel Dipartimento di Medicina Interna e Specialità Mediche del Policlinico di Modena e’ stata eseguita un’analisi retrospettiva sull’impiego dei principali MN (CEA, CA 19.9, CA 125, NSE, CA 15.3).L’analisi e’ stata divisa in due fasi distinte: (I) quantitativa (numero totale di richieste di MN in 4 distinte Unità Operative nel periodo 2001-2003), allo scopo di valutare l’entità del problema; (II) qualitativa, limitata ad un semestre (anno 2002) e ad una sola di tali UO (Medicina II) , con lo scopo di verificare il rapporto costo-beneficio e l’ appropriatezza delle richieste (ovvero corrispondenza fra motivazione dell’utilizzo del MN e raccomandazioni internazionali al suo utilizzo, sulla base della diagnosi di ammissione e di dimissione, sulla storia clinica del ricovero e del paziente). Risultati: Il numero di determinazioni dei MN nel periodo considerato è risultato elevato, pari a circa il 62% dei pazienti ricoverati (5102 su 8253), con valori sovrapponibili nei 3 reparti internistici considerati. Nell’ UO di medicina II, nel semestre campione considerato, l’appropriatezza dell’utilizzo dei MN nel loro complesso è risultata pari al 4.8% (12/248) [CEA= 9%, CA19.9= 3%, CA-125 = 2%, NSE= 9.6%, CA 15.3 = 19.3%): la motivazione più frequente (79%) del loro utilizzo è stata quella diagnostica, spesso precedente qualsiasi altra indagine. Nella figura sono riportati i valori di sensibilità , specificità e valore predittivo positivo (VPP) dei diversi MN studiati calcolati in base alla diagnosi di dimissione (presenza/assenza di patologia neoplastica accertata). Conclusioni: I risultati del nostro studio mostrano una elevata inappropriatezza nell’utilizzo dei MN in ambiente internistico, motivata probabilmente dalla consuetudine e da timori di “inadempienza diagnostica”. In accordo con quanto definito dalle più recenti raccomandazioni in campo oncologico, i MN, come confermato anche dallo scarso VPP da noi osservato (vedi figura), sono del tutto irrilevanti se usati a scopo diagnostico precoce in popolazioni non selezionate (nel nostro campione 1/284, pari al 0.4%). Essi risultano pertanto frutto di spesa non trascurabile (circa € 30.000/anno) nonostante siano test a basso costo (da euro 10.6 a euro 18.4) e dotati di buona sensibilità e specificità. Il loro utilizzo in popolazione selezionate di pazienti (ovvero follow-up e conferma diagnostica) rappresenta pertanto il solo uso avvalorato da un favorevole rapporto costo-beneficio nell’ambito di una divisione di medicina interna.
2005
- Isomeri urinari della Coproporfirina in pazienti con Epatopatie Colestatiche Acquisite e sindrome di Dubin-Johnson
[Abstract in Rivista]
Tremosini, Silvia; Ventura, Paolo; Casalgrandi, Giovanna; Marchini, Stefano; E., Ventura; Rocchi, Emilio
abstract
Argomento della nostra comunicazione è la valutazione dell’escrezione urinaria degli isomeri della coprorporfirina in pazienti affetti da diverse forme di epatopatia colestatica o da sindrome di Dubin-Johnson. Esistono diverse dimostrazioni (basate su studi di cinetica combinata di escrezione biliare, su modelli animali e umani) che suggeriscono che l’MRP2, l’unico trasportatore di membrana della famiglia dei trasportatori delle Multidrug Resistance Protein presente sul polo biliare dell’epatocita (gli altri sono normalmente ben rappresentai sul versante baso-laterale dell’epatocita) sia il trasportatore biliare più specifico per gli isomeri della CP. Tale trasportatore condivide la sua specificità anche con altre sostanze, come la BSF e la bilirubina coniugata. E’ oggi ben dimostrato che il suo deficit congenito è alla base della sindrome di Dubin-Johnson. Va inoltre ricordato che tutti gli MRPs hanno una notevole omologia strutturale pertanto non è sorprendente come in condizioni particolari ciò possa riflettere anche un certo grado di analogia funzionale (possono cioè condividere stessi substrati).Ci siamo chiesti se questi dati possano avere un utilizzo nella pratica clinica. Basandoci sulla dimostrazione delle reversibilità dell’espressione dell’espressione bilare dell’MRP2 in caso di eliminazione della causa scatenante, ci siamo focalizzati (XXIII) sui pazienti affetti da Epatite cronica attiva in terapia con IFN. Si tratta di dati preliminari e su pochi casi ma potete vedere che i soggetti con HCV-RNA negativizzato a tre mesi di terapia (e con alta probabilità di essere”responders”) vanno incontro a una progressiva normalizzazione nel tempo del rapporto CPI / CPIII urinario, cosa che non abbiamo osservato in coloro che a tre mesi sono risltati HCV RNA negativi (non repsonders).(XXIV) In conclusioneLa diversa regolazione sia a livello intracellulare che intraorgano dei sistemi di trasporto (MRP) può spiegare le caratteristiche alterazioni del profilo urinario della CP osservabili in corso di DJS a di epatopatie colestatiche acquisiteConsiderando il relativo basso costo e la semplicità della determinazioni quali-quantitativa degli isomeri delle CP nelle urine , unitamente alla dimostrazione della precoce alterazione (o normalizzazione) in seguito a induzione (o risoluzione) di colestasi, tale determinazione potrebbe avere un significato nella diagnosi, prognosi e monitoraggio di diverse forme di epatopatia colestatica.
2005
- Weight Loss Expectations in Obese Patients and Treatment Attrition: An Observational Multicenter Study
[Articolo su rivista]
Riccardo Dalle Grave, ; Simona, Calugi; Enrico, Molinari; Maria Letizia Petroni, ; Bondi, Mario; Angelo, Compare; Giulio, Marchesini; Ventura, Paolo; the QUOVADIS Study Group,
abstract
Objective: To investigate the influence of weight loss expectations
(expected 1-year BMI loss, dream and maximum
acceptable BMI) on attrition in obese patients seeking treatment.
Research Methods and Procedures: Obese subjects (1785;
1393 women; median age, 46 years; median BMI, 36.7
kg/m2) seeking treatment in 23 medical Italian centers were
evaluated. Baseline diet and weight history, weight loss
expectations, and primary motivation for seeking treatment
(health or improving appearance) were systematically recorded.
Psychiatric distress, binge eating, and body image
dissatisfaction were tested at baseline by self-administered
questionnaires (Symptom Check List-90, Binge Eating
Scale, and Body Uneasiness Test). Attrition and BMI
change at 12 months were prospectively recorded.
Results: At 12 months, 923 of 1785 patients (51.7%) had
discontinued treatment. Compared with continuers, dropouts
had a significantly lower age, a lower age at first
dieting, lower dream BMI, a higher expected 1-year BMI
loss, and a higher weight phobia. At logistic regression
analysis, the strongest predictors of attrition at 12 months
were lower age and higher expected 1-year BMI loss. The
risk of drop-out increased systematically for unit increase in
expected BMI loss at 12 months (hazard ratio, 1.12; 95%
confidence interval, 1.04 to 1.20; p 0.0018). The risk was
particularly elevated in the first 6 months.
Discussion: Baseline weight loss expectations are independent
cognitive predictors of attrition in obese patients entering
a weight-losing program; the higher the expectations,
the higher attrition at 12 months. Unrealistic weight goals
should be tackled at the very beginning of treatment.
2004
- A role for homocysteine increase in haemolysis of megaloblastic anaemias due to vitamin B-12 and folate deficiency: results from an in vitro experience
[Articolo su rivista]
Ventura, Paolo; R., Panini; S., Tremosini; Salvioli, Gianfranco
abstract
Megaloblastic anaemias (MA) are frequently associated with haemolysis. The pathogenesis of these finding is not clear, but it is thought depend on the greater destruction of abnormal and fragile megaloblastic erythrocytes. Vitamin B-12 and folate deficiencies are the ommonest cause of MA; these deficiencies may simultaneously induce a significant alteration in homocysteine metabolism leading to yperhomocysteinemia. Blood cells have enzymes involved in homocysteine metabolism. Considering the possible effects of yperhomocysteinemia in erythrocyte toxicity (due to oxidative damage and/or to interaction with sultbydryl residues of structural and tzymatic proteins), the aim of our study was to evaluate (1) the homocysteine blood cells production in patients with MA due to vitamin B-12 and folate deficiency and (2) the possible role and mechanism of hyperhomocysteinemia in MA haemolysis. After incubation at 37 C, blood samples from MA patients showed higher and significant levels of Hcy, LDH, lipid peroxidation parameters (MDA), and ghost protein-bound cy than controls. Haemolysis ( %) was higher in MA patients than controls and was significantly correlated with Hey accumulation in the medium, lipid peroxidation indices and ghost protein-bound Hey. No significant (or significantly lower) alterations through time in considered parameters were observed in the corresponding samples incubated at 4degreesC or in samples incubated with methionine-free medium lower Hey production). Our data, deriving from an in vitro experience, suggest a possible role of Hey accumulation due to vitamin B12 and)late deficiencies in haemolysis associated to MA due to vitamin deficiency.
2004
- Alendronate reduces bone resorption in HIV-associated osteopenia/osteoporosis
[Articolo su rivista]
Guaraldi, Giovanni; G., Orlando; G., Madeddu; F., Vescini; Ventura, Paolo; S., Campostrini; M. S., Mura; N., Parise; R., Caudarella; Esposito, Roberto
abstract
Purpose: To evaluate the effects of alendronate, vitamin D, and calcium supplementation on bone metabolism and bone mineral density (BMD) in both HIV-infected men and women treated with highly active antiretroviral therapy (HAART). Method: We performed a 52-week prospective, multicenter, randomized, open-label clinical trial. Eligible participants were on stable HAART and had BMD values at the femoral neck or lumbar spine that corresponded to a t score less than -1. Patients were randomized to receive alendronate 70 mg weekly or no alendronate; calcium 1000 mg daily and vitamin D 500 IU daily were provided to all study recipients. Primary endpoint of the study was the change in bone metabolism evaluated by N-telopeptide of type 1 collagen and bone-specific alkaline phosphatase; the secondary endpoint was BMD variation. Results: 18 patients were randomized to the alendronate and 23 to the no-alendronate group (controls). The alendronate-treatment group compared to controls had a significant decrease in serum N-telopeptides, 1914 +/- 1433.4 vs. 3967 +/- 1650.5 pM/L (p = .005) after 1 year. Lumbar spine BMD increased by 4% in the alendronate group (p = .004) vs. 3.7% (p = .062) in controls, compared to baseline values. Femoral neck BMD decreased by 0.5% in the alendronate group (p = .05) and by 3.5% in the control group (p = .04). No between-groups differences for BMD were found (Delta lumbar-BMD 0.0351 +/- 0.0406 in cases and 0.0356 +/- 0.073 in controls [p = .9771, Delta femoral-BMD -0.085 +/- 0.160 in cases and -0.100 +/- 0.165 in controls [p = .795]). Conclusion: Alendronate plus vitamin D and calcium was effective in reducing bone resorption. Alendronate improved lumbar BMD and minimized femoral BMD decrease after 52 weeks compared to treatment with vitamin D and calcium alone in patients on HAART with osteopenia/osteoporosis.
2004
- Alendronate reduces bone turnover in HIV-associated Osteopenia and Osteoporosis
[Abstract in Atti di Convegno]
Guaraldi, Giovanni; Orlando, G.; Maddeddu, G.; Vescini, F.; Ventura, Paolo; Campostrini, S.; Corradini, E.; Parise, N.; Solinas, P.; Calia, G. M.; Mura, M. S.; Nardini, Giulia; Beghetto, Barbara; Caudarella, R.; Esposito, Roberto
abstract
OOsteopenia and Osteoporosis are frequent complications of HIV infection and may be related with low trauma fractures. Gender differences, with an increased prevalence of osteoporosis in male patients, have been observed. We conducted a 104-week prospective, randomized, open-label study to evaluate the effects of alendronate, vitamin D, and calcium supplementation on bone metabolism and bone mineral density in patients with HIV infection. Interim analysis at 52 weeks is presented.
2004
- Hyperhomocysteinemia and other newly recognized inherited coagulation disorders (factor V Leiden and prothrombin gene mutation) in patients with idiopathic cerebral vein thrombosis
[Articolo su rivista]
Ventura, Paolo; M., Cobelli; M., Marietta; R., Panini; M. C., Rosa; Salvioli, Gianfranco
abstract
Background: Idiopathic cerebral vein thrombosis (iCVT) represents approximately 30% of the cases of cerebral vein thrombosis (CVT). New, inherited - factor V Leiden (FVL) and prothrombin gene mutation (PTHRA(20210)) and inherited/acquired - hyperhomocysteinemia (HHcy) - prothrombotic conditions have been detected recently. Methods: We assessed fasting plasma homocysteine (Hcy) levels and main Hcy determinants, FVL and PTHRA(20210) in 30 patients with documented iCVT and 40 age- and sex-matched healthy subjects. Results: A strong and significant association of PTHRA(20210) [ 30% (9/ 30) vs. 2.5% (1/40) iCVT vs. controls, respectively, p = 0.001; OR = 16.174, p = 0.002] and HHcy [13/30 (43.3%) vs. 4/40 (10%) iCVT vs. controls, respectively; p = 0.002, OR = 6.88, p = 0.002] with iCVT was found. Conclusions: PTHRA(20210) and HHcy should be considered when screening for thrombophilia and should be assessed in patients with a family or personal history of CVT. Copyright
2004
- I fattori di rischio cardiovascolare nell'anziano
[Articolo su rivista]
Ventura, Paolo; Mussi, Chiara; G., Salvioli
abstract
L'articolo approfondisce gli spetti e il significato nella popolazione anziana dei fattori di rischio cardiovascolare, con particolare riferimento alle differenze rigurado alla popolazione generale
2004
- La parete arteriosa durante l'invecchiamento: problemi anatomofisiologici e clinici
[Articolo su rivista]
Mussi, Chiara; Ventura, Paolo; Salvioli, Gianfranco
abstract
Il lavoro analizza le modificazioni della parete arteriosa durante l'invecchiamento e le conseguenze fisiopatologiche che ne derivano
2004
- La prevenzione cardiovascolare: come implementare le conoscenze e i comportamenti in una società che invecchia ?
[Articolo su rivista]
Mussi, Chiara; Ventura, Paolo; Salvioli, Gianfranco
abstract
IL lavoro affronta le problematiche relative ai8 fattori dei rischio cardiovascolare e alla prevenzione della malattia cardiovascolare con l'invecchiamento
2004
- Lìiperomocisteinemia nella popolazione anziana: non solo un fattore di rischio vascolare
[Articolo su rivista]
Ventura, Paolo; Salvioli, Gianfranco
abstract
L'articolo affronta il significato dell'iperomocisteinemia nell'anziano, non solo un fattore di rischio cardiovascolare di patologia aterotrombotica ma ance un indicatore di stato di malnutrizione e un fattore di rischio indipendente di patologia involutiva cerebrale
2004
- Plasma homocysteine after insulin infusion in type II diabetic patients with and without methionine intolerance
[Articolo su rivista]
Ventura, Paolo; R., Panini; S., Emiliani; Salvioli, Gianfranco
abstract
Background: A high prevalence of hyperhomocysteinemia has been reported in type II diabetic patients with documented vascular disease; hence the hypothesis that hyperhomocysteinemia may contribute to overall mortality in diabetic patients. The link between insulin and homocysteine metabolism has not been completely clarified yet; in particular, only few data are available on the effects of insulin in vivo on homocysteine metabolism in the presence of abnormalities of sulphur amino acid metabolism (methionine intolerance). Materials and Methods: To establish whether methionine intolerance and which of its determinants could influence total plasma homocysteine in response to insulin infusion in vivo in type II diabetic patients, we submitted 18 patients (Group A) with normal and 18 patients with abnormal (hyperhomocysteinemia) (Group B) response to oral methionine load to a glucose/clamp study. At time 0, and 30, 60 and 120 minutes after hyperinsulinemia, homocysteine and methionine plasma levels were assessed. In order to evaluate the cause of methionine intolerance, all patients were assayed for fasting homocysteine-cysteine ratio (as a marker of suspected heterozygosis for cystathionine-beta-synthase deficit), MTHFR C677T status and homocysteine-related vitamin status (serum vitamin B-6 [PLP], vitamin B-12 and folate). Results: After hyperinsulinemia, plasma methionine was reduced (by about - 30 % at 120 minutes vs. basal values) within both groups, whereas tHcy tend to decrease in group A following insulin administration (up to - 6.6 +/- 3.6% vs. basal values at 120 minutes) with a significantly higher variability, while in patients with methionine intolerance (group B) tHcy tended to increase (up to + 29.05 +/- 8.3 % vs. basal values at 120 min from the clamp). Serum folic acid (7.45 +/- 2.8 vs. 4.82 +/- 2.5 nmol/L, p < 0.05), Vit. B-12 (348 +/- 78 vs. 242 +/- 65 pmol/L, p < 0.05) and PLP (84.1 +/- 23.6 vs. 50.6 +/- 32.4 nmol/L; p < 0.01) were significantly higher in group A than in group 13; PLP levels significantly correlated with homocysteine after 4 h methionine load (n = 36; r = - 0.327, p < 0.05); group A showed also a significantly lower prevalence of suspected heterozygosis for cystathionine-beta-synthase deficit (1/18 [11.1 %] vs. 5/18 [33.3 %], p < 0.05) and MTHFR T allele presence (4/18 [22.2 %] vs. 11 /18 [61.1 %], p < 0.01). A stepwise regression analysis with tHcy plasma level variations (event A = reduction; event B = increase) as the dependent variable showed that low serum folate and PLP levels and presence of MTHFR T allele were the variables associated with insulin-induced tHcy increase. Conclusions: Methionine intolerance may influence the effect of insulin administration on plasma homocysteine in patients affected by type 2 diabetes. To prevent a possible acute (and repeated) hype rhomocysteinemia due to insulin administration in cases of methionine intolerance, it may be useful to assess the presence of methionine intolerance (tHcy after oral methionine loading) and Hcy-related vitamin status in all patients due to be subjected to insulin therapy.
2004
- Pro-oxidant and antioxidant factors in acute intermittent porphyria: Family studies
[Articolo su rivista]
Rocchi, Emilio; Ventura, Paolo; Ronzoni, Alessandro; Gozzi, Chiara; Casalgrandi, Giovanna; Rosa, M. C.; Marri, L.; Cappellini, M. D.
abstract
Given the crucial role of iron and porphyrins in oxidative cellular damage in the chronic porphyrias, we undertook an extensive study in families with acute porphyrias to evaluate the possible role of similar oxidative damage in these diseases, whose natural history is often also complicated by neoplastic evolution. Four unrelated patients with acute intermittent porphyria (AIP) were studied together with 37 members of four different families. Aminolevulinic acid and porphobilinogen were measured in urine, and porphyrins in urine, plasma and stools. The activity of the congenitally deficient enzyme, porphobilinogen deaminase, and the concentrations of plasma iron, transferrin, ferritin, and various antioxidants ( ascorbic acid, retinol, tocopherol, alpha- and beta-carotene, by a personal HPLC method) and the urinary and plasma metabolites of nitrous oxide were also assayed. The results showed no relationship between the observed increase of porphyrin metabolites and the presence of markers of oxidative damage or the decrease of circulating antioxidants: however, when such a decrease was registered, it depended on spontaneous or iatrogenic iron accumulation. We conclude that family screening, recommended for the identification of AIP carriers, must also include evaluation of iron stores with a view to preventing the oxidative damage and in order to forestall the neoplastic evolution of the disease.
2004
- Red wine consumption prevents vascular oxidative stress induced by a high-fat meal in healthy volunteers
[Articolo su rivista]
Ventura, Paolo; Bini, Anna; R., Panini; L., Marri; Tomasi, Aldo; Salvioli, Gianfranco
abstract
In order to investigate the effect of red wine on plasma lipid and oxidative stress parameters after a high-fat meal, fifteen healthy volunteers were studied: three days after a high-fat meal with 250 mL of water, they received the same meal with 250 mL of red wine. During both periods, serial blood samples were drawn before and 2, 4, and 8 hours after the meal to evaluate plasma lipids (cholesterol and triglycerides; retinyl palmitate), oxidative stress (D-ROM, and malondialdehyde) and antioxidant (total plasma antioxidant levels and uric acid) parameters. During the meal without wine, plasma lipid parameters increased significantly, whereas plasma total plasma antioxidant levels decreased, and a trend toward reduction of uric acid levels was seen). A similar trend in lipid parameters was observed after the meal with wine; no significant difference in individual lipid parameter trends after a meal with and without wine was observed. Wine ingestion induced higher total plasma antioxidant levels and uric acid; malondialdehyde levels remained constant after wine ingestion. Plasma D-ROM showed a significant postprandial increase in both experiments, but it was significantly lowered after wine ingestion. Our results give evidence of oxidative stress following a fat-rich meal in healthy subjects, suggesting that ingestion of red wine during a high-fat meal significantly reduces oxidative stress without inducing any significant modification in postprandial lipemia.
2004
- Snoring, hypertension and Type 2 diabetes in obesity. Protection by physical activity
[Articolo su rivista]
Marchesini, G.; Pontiroli, A.; Salvioli, G.; Novi, R. F.; Vitacolonna, E.; Taboga, C.; Ciccarone, A. M.; Grossi, E.; Ventura, P; QUOVADIS Study Group, The
abstract
Sleep-related breathing disorders are recognized as major health problems in obesity. They are involved in both hypertension and Type 2 diabetes, through mechanisms possibly related to increased sympathetic tone. We studied the association of habitual snoring with diabetes, hypertension, weight cycling and physical activity in a large Italian database of treatment-seeking obese subjects. Clinical and behavioral data were assessed by standardized questionnaires. Consecutive data of 1890 obese patients were analyzed [average body mass index (BMI), 38.2 kg/m(2), median age: 46 yr, 78% females], from 25 obesity Italian centers, with low prevalence of clinical manifestations of cardiovascular disease. Habitual snoring was reported in 56% of the cases, and was associated with day-time sleepiness. The prevalence increased with obesity class and waist circumference, and was positively associated with weight cycling and weight gain since the age of 20, and smoking. Regular physical activity had a protective effect. Snoring was associated with diabetes and hypertension at univariate analysis, but in multivariate analysis an independent effect was only observed for hypertension. After adjustment for age, gender and BMI, physical activity maintained an independent, protective effect on both snoring (odds ratio 0.65, 95% confidence interval 0.49-0.84; p = 0.001), diabetes (0.50, 0.30-0.86; p = 0.011) and hypertension (0.71, 0.53-0.95; p = 0.023). We conclude that in treatment-seeking, obese subjects with low prevalence of cardiovascular disease, snoring independently increases the risk of hypertension, whereas physical activity exerts a protection on both snoring and complications. These data underline the importance of lifestyle interventions to limit the burden of obesity and associated diseases.
2004
- The Metabolic Syndrome in Treatment-Seeking Obese Persons
[Articolo su rivista]
Marchesini, Giulio; Melchionda, Nazario; Apolone, Giovanni; Cuzzolaro, Massimo; Mannucci, Edoardo; Corica, Francesco; Grossi, Enzo; Ventura, Paolo; QUOVADIS Study Group, The
abstract
Obesity is a major risk factor for several metabolic diseases, frequently clustering to form the metabolic syndrome, carrying
a high risk of cardiovascular mortality. We aimed to assess the prevalence of the metabolic syndrome in treatment-seeking
obese subjects and the potential protective effect of physical activity. A cross-sectional analysis of data from a large Italian
database of treatment-seeking obese subjects was performed. The metabolic syndrome was defined according to the criteria
provisionally set by the National Cholesterol Education Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults, based on waist circumference, fasting glucose, triglyceride (TG) and high-density lipoprotein-cholesterol
(HDL-C) levels, and arterial pressure. Data were available in 1,889 Caucasian subjects, 78% females, from 25 obesity
centers. Minimum criteria for the metabolic syndrome were fulfilled in 53% of cases. The prevalence increased with age and
obesity class and was negatively associated with participation in a structured program of physical activity (odds ratio, 0.76;
0.58 to 0.99; P .041), after correction for age, sex, and body mass. The prevalence of cardiovascular disease was higher in
subjects with the metabolic syndrome. A subset of 12.8% of cases had no metabolic abnormalities. They had a lower
prevalence of abdominal obesity and cardiovascular disease. Isolated obesity was significantly associated with physical
activity (odds ratio, 1.86; 1.33 to 2.60; P .0003). Multiple metabolic disorders are present in most obese patients, and their
prevalence is lower in physically active subjects. It is time to move towards a more integrated approach and to reconsider
resource allocation to improve lifestyle changes for large-scale control of obesity.
2004
- Weight cycling in treatment-seeking obese persons: data from the QUOVADIS study
[Articolo su rivista]
Marchesini, G; Cuzzolaro, M; Mannucci, E; Dalle Grave, R; Gennaro, M; Tomasi, F; Barantani, Eg; Melchionda, N; Ventura, P; QUOVADIS Study Group8, The
abstract
OBJECTIVE: To determine parameters of weight history useful for the assessment of weight cycling and their association with
psychological distress and binge eating.
DESIGN: Cross-sectional.
SUBJECTS: A total of 1889 treatment-seeking obese subjects, enrolled by 25 Italian centers (78% female subject), aged 20–65 y
(median 45); 1691 reported previous efforts to lose weight (median age of first dieting, 30 y).
MEASUREMENTS: The number of yearly attempts to lose weight, weight gain since age 20 y, cumulative weight loss and
gain were checked by a predefined structured interview. Psychological distress was tested by means of Symptom Check-List 90
(SCL-90), Binge Eating Scale (BES) and Three Factor Eating Questionnaire (TFEQ).
RESULTS: Differences in anthropometric, clinical and psychological parameters were observed in relation to previous attempts
to lose weight. Patients in the upper quartile of parameters of weight history were considered weight cyclers. In multivariate
logistic regression analysis, after correction for age, sex and BMI, a high BES score was the only factor systematically associated
with a high frequency of dieting (OR, 1.70; 95% confidence interval, 1.22–2.36; P¼0.022), with higher cumulative weight loss
(1.42; 1.12–1.80; P¼0.003) and cumulative weight gain (1.38; 1.06–1.79; P¼0.017). However, the sensitivity, specificity and
positive predictive value of a high BES score were very low to detect cyclers. Weight cycling did not carry a higher risk of
complicating diseases.
CONCLUSIONS: Weight cycling is associated with psychological distress, and binge eating independently increases the risk, but
cannot be used to predict cycling. Also, obese patients who do not experience overeating as a loss of control discontinue
treatment or regain weight following therapy.
2003
- Effetti dell’insulina sui livelli di omocisteina plasmatica in pazienti con diabete mellito tipo ii con e senza intolleranza alla metionina
[Abstract in Atti di Convegno]
Ventura, Paolo; Panini, Rossana; M. C., Rosa; G., Salvioli
abstract
Premessa- Una elevata prevalenza di iperomocisteinemia (HHcy) è stata osservata in pazienti con diabete mellito tipo II e malattia vascolare documentata; da qui l’ipotesi che la iperomocisteinemia possa contribuire alla mortalità generale nei pazienti diabetici. Il legame fra insulina e metabolismo dell'omocisteina (Hcy) non è stato ancora chiarito; in particolare, sono disponibili soltanto pochi dati circa gli effetti in vivo dell’insulina sul metabolismo dell' Hcy in presenza di quelle alterazioni (congenite e/o acquisite) del metabolismo degli aminoacidi solforati in grado di condizionare una condizione di HHcy (intolleranza alla metionina). Scopo- valutare in che modo la presenza di una condizione di intolleranza della metionina possa influenzare i livelli plasmatici di Hcy in risposta all'infusione dell'insulina in vivo in pazienti con diabete tipo II.Materiali e metodi - Abbiamo sottoposto 18 pazienti (gruppo A) con normale e 18 pazienti con anormale (iperomocisteinemia dopo carico, intolleranza alla metionina) risposta (gruppo B) al carico orale con metionina ad uno studio di clamp euglicemico. A tempo 0 ed a 30, 60 e 120 minuti dall’induzione di iperinsulinemia, abbiamo valutato i livelli circolanti di omocisteina (tHcy) e metionina (Met) (HPLC). Per valutare la causa di intolleranza della metionina, tutti i pazienti sono stati sottoposti a valutazione del rapporto omocisteina-cisteina a digiuno (indicatore di sospetta eterozigosi per deficit di CS), a valutazione genetica della mutazione C677T della MTHFR e al dosaggio sierico delle vitamine necessarie al corretto metabolismo dell’omocisteina [ vitamina B 6 ( PLP), vitamina B 12 e folati ]. Risultati - Dopo iperinsulinemia, i livelli di Met sono risultati ridotti (circa –30% a 120 minuti rispetto ai valori basali) in entrambi i gruppi, mentre la tHcy è risultata ridursi nel gruppo A (fino a - 6.6 3.6 % rispetto ai valori basali), ed aumentare nel gruppo B (fino a +29.05 8.3 % rispetto ai valori basali) . I livelli sierici di folati (7.45 2.8 contro. 4.82 2.5 nmol/L, p<0.05), Vit. B 12 (348 78 contro. 242 65 pmol/L, p< 0.05) e PLP (84.1 23.6 contro 50.6 32.4 nmol/L; p<0.01) sono risultati più alti nel gruppo A che nel gruppo B; i livelli di PLP sono risultati correlare significativamente con quelli della tHcy dopo carico (n=36; r=-.327, p<0.05); il gruppo A presentava inoltre una prevalenza inferiore di sospetta eterozigosi per CS [ 1/18 (11.1 %) contro 5/18(33.3%), p<0.05 ] e una ridotta prevalenza dell'allele mutato T della MTHFR [ 4/18 (22.2%) contro 11/18 (61.1%), p<0.01 ]. L’analisi di regressione logistica multipla con la variazione di Hcy sotto stimolo insulinico (evento A = riduzione; evento B = aumento) come variabile dipendente, ha indicato la carenza di folati e di PLP e la presenza dell'allele di MTHFR T come le variabili più significativamente predittive del tipo di risposta dell’Hcy all’iperinsulinemia.Conclusioni - La presenza di intolleranza alla metionina può influenzare l'effetto dell'insulina sull' omocisteina plasmatica in pazienti con diabete tipo 2. Per prevenire la possibilità di episodi acuti, ripetuti e potenzialmente dannosi, di iperomocisteinemia in questi pazienti in seguito alla assunzione di insulina, potrebbe essere utile la valutazione della presenza di una condizione di intolleranza della metionina (test orale alla metionina) e uno studio dello stato vitaminico Hcy-relato in tutti i pazienti diabetici da sottoporre alla terapia insulinica.
2003
- Metodologia per l’adozione di linee guida cliniche in Medicina Interna.
[Abstract in Atti di Convegno]
Ballesini, P; Borghi, A; Corradini, Elena; Cristani, A; Ferrara, F; Gandolfo, Marco; Pipino, M; Polidoro, S; Rosa, C; Sardini, C; Vandelli, Carmen; Ventura, Paolo; Venturini, I; Zeneroli, Ml
abstract
Le linee guida definiscono raccomandazioni, elaborate a partire da un'analisi multidisciplinare e sistematica della letteratura scientifica disponibile, con l'obiettivo di assitere i professionisti sanitari nelle decisioni cliniche, individuando le modalità assistenziali più appropriate in specifiche circostanze. Anche la migliore linea guida disponibile può fallire i suoi obiettivi se non passa attraverso fasi di adattamento locale e di implemenatzione
2003
- Parametri predittivi e risposta sostenuta alla terapia antivirale combinata nell'epatite cronica attivva HCV correlata (ECA HCV)
[Abstract in Atti di Convegno]
P., Ballesini; E., Boldrini; A., Borghi; G., Cioni; Corradini, Elena; A., Cristani; F., Ferrara; Gandolfo, Marco; Pietrangelo, Antonello; M., Pipino; S., Polidoro; C., Rosa; C., Sardini; Vandelli, Carmen; E., Ventura; Ventura, Paolo; I., Venturini; M. L., Zeneroli
abstract
Introduzione: benché siano codificate le migliori terapie per l’ECA da HCV, rimangono relativamente controverse le scelte su quando cominciare la terapia e in quali pazienti. Il presente studio è una analisi retrospettiva che prende in considerazione la risposta virologica, i parametri istologici ed alcune altre caratteristiche (anagrafiche…) rilevanti dei pazienti.Soggetti e metodi: Abbiamo considerato 127 pazienti (età 47 ± 11, 47 f) con diagnosi istologica di ECA HCV-correlata; tutti i pazienti, trattati con associazione di IFN2b (di cui 37 nella forma pegilata) e ribavirina, sono stati valutati per genotipo virale (sfavorevole : 1 e 4; favorevole: 2 e 3), grading e staging istologici (sia considerando i valori continui che a due classi: per lo staging da 0 a 2 e da 3 a 6; per il grading da 0 a 4 e da 5 a 18) secondo Ishak et al., stato di naive o relapser e risposta alla terapia (sustained responders, SR: risposta sostenuta a oltre 6 mesi dal termine della terapia; non sustained responders, NSR: risposta assente o interruzione terapia per intolleranza o altro).Risultati: I due gruppi di pazienti, SR (n=63) e NSR (n=64) non differivano in modo significativo per età (45±11 vs. 48±10) [erano tuttavia più frequenti i soggetti di età uguale o inferiore a 40 anni : 28/63 (44.4%) vs. 15/64 (23.4%), p=0.012 ] e sesso ( m/f : 37/26 vs. 43/21), mentre nel gruppo SR erano più frequenti i naives [47/63 (74.6%) vs. 36/64 (56.2%), p= 0.024], i genotipi favorevoli [29/63 (46 %) vs. 19/64 (29.7 %), p= 0.001], i pazienti con basso valore di necro-infiammazione (grading=0-4) [36/63 (57.1%) vs. 17/64 (26.5%), p= 0.058] e fibrosi (staging=0-2) [47/63 (74.6%) vs. 37/64 (57.8%), p= 0.046]. L’associazione tra risposta favorevole e i suddetti parametri, misurata in termini di Odds Ratio è risultata significativa per la presenza di genotipo favorevole (OR= 2.15, IC 95%= 1.35÷3.4, p=0.000), stato naive (OR=1.34, IC 95%= 1.04÷1.74, p= 0.019), età giovane (OR= 1.9, IC 95% = 1.12 ÷ 3.19, p=0.001), basso valore di staging (OR= 1.29, IC 95%= 1.01÷ 1.66, p= 0.035), basso valore di grading (OR= 1.55, IC 95% = 0.977÷ 2.46, p=0.043). La tabella evidenzia il risultato dell’analisi di regressione logistica che considera come variabile dipendente il tipo di risposta (SR o NSR) alla terapia e come covariate la presenza di un’età maggiore o minore di 40 anni, il genotipo (favorevole o sfavorevole), la condizione naive o relapser, la presenza di bassi o alti livelli di necro-infiammazione (grading) o fibrosi (staging), parametri che nella nostra casistica hanno dimostrato singolarmente una associazione significativa con la risposta alla terapia. ParametroBE.S.WaldSig.Exp(B)Naive-,630,4202,246,134,533Genotipo 1,125,4067,699,0063,081Grading-,411,434,896,344,663Staging-,510,4381,352,245,601Età-,451,4331,086,297,637R2= 0.196Discussione: Come noto, la risposta alla terapia antivirale combinata per l’ECA HCV correlata dipende da numerosi fattori. I nostri dati confermano differenze significative nella risposta sostenuta per età inferiore a 40 anni, genotipo favorevole, basso grado di fibrosi e di necro-infiammazione; nessuno di tali parametri dimostra tuttavia un livello di associazione tale da guidare la scelta terapeutica nel singolo paziente. Il tentativo di costruire con tali parametri un modello predittivo della risposta mediante analisi di regressione logistica risulta insoddisfacente (solo circa il 20% di accuratezza predittiva).
2003
- Plasma nitric oxide production during acute hyperhomocysteinemia in atherosclerotic patients and controls
[Abstract in Rivista]
Ventura, Paolo; M., Turci; Marchini, Stefano; G., Casalgrandi; Salvioli, Gianfranco; Rocchi, Emilio
abstract
The work deals with the different production of nitric oxide by vascular endothelium during hyoerhomocysteinemia induced by oral methionine load in patiemts affected by diffuse atherosclerosis and in sex amd age -matched controls
2003
- Portal vein thrombosis and hyperhomocysteinemia in patients with liver cirrosis
[Abstract in Rivista]
Ventura, Paolo; M. C., Rosa; Marchini, Stefano; G., Abbati; A., Borghi; M. L., Zeneroli
abstract
Background: Portal vein thrombosis (PVT) is a severe complication of liver cirrhosis (LC), especially in presence of hepatocarcinoma (HCC). Liver is the main site of homocysteine (Hcy) metabolism and Hcy-related vitamins (folate, B12) storage. Aim: Assessment of possible association of moderate hyperhomocysteinemia (HHcy) (> 15 mol/L), risk factor for deep venous thrombosis, and TVP in different stage LC patients, with and without HCC.Methods: 16 (aged 60±12, 8 f) LC patients with documented (doppler ultrasonography) PVT and 32 (aged 64±11, 12f) without PT were studied [total plasma Hcy (HPLC), Hcy-related vitamin status (ELISA), stage of disease (Child-Pugh score), presence of HCC (radiological and/or histological diagnosis), ethiology (alcohol, viral, both, other)]. Results: Hcy levels significantly (corrected for vitamin status) increases with Child-Pugh score (A: 11.84±4.2, n=12; B=16.5±8.2, n=22; C=18.5±8.1, n=14, mol/L. p=0.021); HCC patients (n=18) showed higher Hcy than those without HCC (17.7±7.4vs.13.5±5.9,p=ns,after vitamin status correction). As expected, prevalence of HCC was higher in PVT group (10/16 (62.5%) vs. 8/32 (25%) ,p <0.01). TVP group presented lower serum folate (3.8±1.2 vs. 5.5±1.8 nmol/ml, p=0.017) and B12 levels (352±89 vs. 516±125, p=.038), with no differences for different ethiologies, and a higher prevalence of folate and B12 deficit. After correction for vitamin status, Child-Pugh score, and prevalence of HCC, TVP group showed higher Hcy (19.7±5.5 vs. 13.81±7.8 mol/L, p=0.015) and an higher prevalence of HHcy (10/16 (62.5%) vs 8/32 (25%), p<.011). Association of HHcy and TVP resulted significant (OR=5.0,95%CI:1.4-18.2, p=0.014). Conclusions: Our data suggest the possible importance of raised Hcy levels in development of TVP in cirrhotic patients, especially in higher stadium of disease or complicated by HCC. Studies about the role of treatment of HHcy in LC patients for the prevention of TVP are underway.
2003
- Relevance of different apolipoprotein content in binding of homocysteine to plasma lipoproteins
[Articolo su rivista]
Ventura, Paolo; R., Panini; Mc, Rosa; E., Gaetti; Salvioli, Gianfranco
abstract
Background and Aims: In plasma the atherogenic thiol homocysteine (Hcy) circulates either free or bound to proteins (Pb-Hcy). The present study sets out to evaluate the lipoprotein-Hcy (LP-Hcy) binding in vivo and the possible influence of different apolipoprotein content in this binding, being lipoprotein oxidation a possible mechanism of Hcy-induced damage. Methods and Results: In 34 healthy subjects we assayed fasting plasma lipoprotein and correspondent apolipoprotein (apo A-I, apo A-II, apo C-II, apo C-III, apo B, apo(a) and apo E content, and Hcy bound to different plasma protein fractions; moreover ten subjects underwent an oral methionine load in order to evaluate possible dynamic modifications of Pb-Hcy and LP-Hcy after induction of hyperhomocysteinemia. Pb-Hcy (mean values 9.22+/-1.7 mumol/L) represented about 78% of total plasma Hcy (mean values 11.8+/-1.8 mumol/L). Pb-Hcy distribution between the different fractions was as follows (mumol/L): VLDL = 0.25+/-0.08 (2.7%); LDL = 0.88+/-0.22 (9.5%);HDL = 1.40+/-0.36 (15.2%);fractions with density greater than 1.21 g/mL (Lipoprotein-Free Protein Fraction, LPDS) = 6.7+/-1.2 (72.6%). Hcy/protein ratios (nmol/mg of protein) in each protein fraction were: VLDL = 0.32+/-0.19, LDL = 0.43+/-0.37, HDL = 0.26+/-0.18, LPDS < 0.1, thus suggesting a higher binding capacity for Hcy by VLDL and LDL. These data were confirmed by the higher increase in Hcy content in LDL and VLDL (76 and 90%, respectively vs 36% and 3.1% for HDL and LPDS fractions) after hyperhomocysteinemia. Lp-Hcy binding significantly correlated with the apo B content of VLDL and LDL and Apo A-I content of HDL. Conclusions: An important fraction of plasma Hcy circulates bound to LP (about 27% of Pb-Hcy); VLDL and LDL show the highest binding capacity for Hcy, probably due to their content in Apo B, a possible high capacity binding site for Hcy. (C)2003, Medikal Press.
2003
- Relevance of different apolipoprtein content in homocysteine binding to plasma lipoproteins
[Abstract in Rivista]
Ventura, Paolo; Panini, Rossana; M. C., Rosa; E., Gaetti; Salvioli, Gianfranco
abstract
Background and aims: In plasma, homocysteine (Hcy) circulates free or bound to proteins (Pb-Hcy). Our study sets out to assess the lipoprotein-Hcy (LP-Hcy) binding in vivo and the possible influence of different apolipoprotein content in this binding. Methods: In 34 healthy subjects fasting plasma lipoprotein (Sequential ultra-centrifugation) and correspondent apolipoprotein (apo A-I, apo A-II, apo C-II, apo C-III, apo B, apo(a) and apo E) content (Immunoturbidimetric assay), and Hcy (HPLC) bound to different plasma protein fractions were assessed; ten subjects underwent a methionine oral load in order to evaluate Pb-Hcy and LP-Hcy modifications after induction of hyperhomocysteinemia (HHcy). Results: Pb-Hcy (mean values 9.22±1.7 mol/L) resulted 78% of total plasma Hcy (mean values 11.8±1.8 mol/L). Pb-Hcy distribution between the different fractions was as follows (mol/L): VLDL= 0.25 ± 0.08 (2.7 %); LDL= 0.88 ± 0.22 (9.5 %); HDL =1.40 ± 0.36 (15.2 %), Lipoprotein-Free Protein Fraction (LPDS) = 6.7 ± 1.2 (72.6 %). Hcy/protein ratios (mol / g of protein) of each protein fraction were: VLDL= 0.32 ± 0.19, LDL= 0.43 ± 0.37, HDL= 0.26 ± 0.18, LPDS < 0.1, this suggesting a higher binding capacity for Hcy of VLDL and LDL. This data was confirmed by the higher increase in Hcy content in LDL and VLDL (+76 and +90%, respectively vs. +36% and +3.1 % for HDL and LPDS fractions) after HHcy. Lp-Hcy binding significantly correlated with the apo B content of VLDL and LDL and Apo A-I content of HDL. Conclusions: An important fraction of Hcy circulates bound to LP (about 27% of Pb-Hcy); VLDL and LDL show the highest binding capacity for Hcy; this may be due to content in Apo B, a possible high capacity binding site for Hcy (great availability of free cysteine and lysine residuals).
2003
- Rilevanza del diverso contenuto apolipoproteico nel legame dell’omocisteina alle lipoproteine
[Abstract in Atti di Convegno]
Ventura, Paolo; Panini, Rossana; M. C., Rosa; E., Gaetti; Salvioli, Gianfranco
abstract
Premesse: Nel plasma l’omocisteina (Hcy) circola in forma libera e (per la maggior parte, circa il 70-80% del totale) legata alle proteine (Pb-Hcy). E’ ormai accettato il ruolo pro-aterogeno di moderatamente elevati livelli plasmatici di omocisteina; meno definita è la relazione esistente fra omocisteina e metabolismo lipidico, sebbene una relazione fra livelli di omocisteina (dotata di attività pro-ossidante) e ossidazione delle lipoproteine sia stata riportata da diversi autori.Scopo: valutare l’esistenza di un legame fra Hcy e lipoproteine (LP-Hcy) in vivo e la possibile influenza del differente contenuto apolipoproteico in tale legame.Materiali e metodi: 34 soggetti sani (età media 54 ± 8, 18 donne) sono stati sottoposti a determinazione del contenuto plasmatico delle principali lipoproteine (ultracentrifugazione sequenziale) e del loro corrispondente contenuto apoproteico (Apo A-I, apo A-II, apo C-II, apo C-III, apo-B, apo (a) e apo E) (immunoturbidimetria) e a dosaggio (HPLC con metodica fluorimetrica) dell’Hcy legata alle diverse frazioni lipoproteiche; inoltre, dieci soggetti sono stati sottoposti a carico orale con metionina (100 mg/kg in 200 cc di the), allo scopo di valutare variazioni “dinamiche” nel legame Pb-Hcy e LP-Hcy in seguito all’induzione di iperomocisteinemia (HHcy).Risultati: la quota di Hcy circolante legata a proteine (9.22 ± 1.7 mol/L) è risultata il 78% del totale (11.8 ± 1.8 mol/L). La distribuzione della quota di Hcy legata fra le diverse frazioni proteiche ottenute con ultracentrifugazione sequenziale è risultata la seguente (mol/L): VLDL= 0.25±0.08 (2.7%); LDL= 0.88± 0.22 (9.5%); HDL= 1.4 ± 0.36 (15.2%), Frazione plasmatica proteica senza lipoproteine (LPDS): 6.7± 1.2 (72.6%). Il rapporto fra Hcy legata e contenuto proteico di ciascuna frazione (mol Hcy / g di proteina) è risultato: VLDL =0.32± 0.19, LDL=0.43±0.37, HDL=0.26±0.18, LPDS <0.1: ciò suggerisce una maggiore capacità legante l’Hcy da parte di VLDL e LDL. Il dato è confermato dai risultati della prova “dinamica”: in corso di HHcy indotta da carico con metionina, l’aumento percentuale del contenuto in Hcy è risultato nettamente superiore nelle frazioni LDL e VLDL (rispettivamente del 90% e del 76% rispetto al contenuto di partenza) che in quelle HDL e LPDS (36% e 31%, rispettivamente). Il legame LP-Hcy correla in modo significativo, sia in condizioni basali che dopo carico con metionina con il contenuto in apo-B delle VLDL e delle LDL e di Apo A-I nelle HDL. Ciò può dipendere dalla peculiare struttura primaria di tali apoproteine (ricche di residui laterali liberi di cisteina e lisina, siti di legame preferenziale dell’omocisteina).Conclusioni: Una frazione significativa dell’omocisteina circola nel plasma legata a lipoproteine (circa il 27% della quota legata a proteine); fra queste le VLDL e le LDL mostrano la maggiore capacità legante per l’Hcy, probabilmente in relazione al loro contenuto in apo-B, proteina ricca in residui laterali sulfidrilici liberi e residui di lisina , possibili punti di reazione con gruppo sulfidrilico libero dell’Hcy.
2003
- The QUOVADIS Study: features of obese Italian patients seeking treatment at specialist centers
[Articolo su rivista]
Melchionda, N.; Marchesini, G.; Apolone, G.; Cuzzolaro, M.; Mannucci, E.; Grossi, E.; Ventura, P; Quovadis Study, Group
abstract
Obesity is a major risk factor for several chronic diseases, but the burden associated with it
also extends to psychosocial areas and to perceived health status. In 1999 an observational study on healthrelated
quality of life in obesity was planned. The study was entirely web-based. Case Report Forms and
the individual items of 7 self-administered questionnaires were directly implemented on a general database
via an extranet system from 25 Italian centers. By December 2001, after enrolment had stopped, the
database included anthropometric, socioeconomic and clinical data of 1944 patients (78% females). Weightcycling
was reported in over 80% of cases, overeating in 60-65%, structured physical activity in only 13-
15%. Several chronic illnesses were associated. Whereas the prevalence of diabetes and hypertension was
related to the degree of obesity, hyperlipidemia and coronary heart disease did not increase further with
increasing obesity. A disturbed psychological mood was twice more common in females. Concern for present
health was the main reason for seeking treatment in both genders; concern for body appearance was
more common in females. Male subjects were more frequently assigned to dietary counseling and physical
exercise, whereas in females psychotherapy was more frequently considered. Various forms of behavioral
approach were planned in approximately 50% of patients. Finally, very few patients were initially
considered for pharmacological intervention or bariatric surgery. The study provides a comprehensive
picture of Italian patients seeking treatment for obesity. Data on perceived health status, psychological
well being, body image awareness, eating behavior disorders and psychopathological distress will
provide clues to a comprehensive assessment of obesity, the effects of treatments and reasons for failure.
2003
- Trombosi portale e iperomocisteinemia in pazienti con cirrosi epatica
[Abstract in Atti di Convegno]
Ventura, Paolo; M. C., Rosa; Marchini, Stefano; G., Abbati; G., Cioni; A. Borghi e. M. . L., Zeneroli
abstract
Premesse: La trombosi portale (TP) è una grave complicanza della cirrosi epatica (CE), spesso associata alla presenza di epatocarcinoma (HCC). Il fegato è la sede principale del metabolismo degli aminoacidi solforati e soprattutto (transmetilazione e transulfurazione) dell’omocisteina (Hcy), il cui incremento plasmatico, anche a livelli moderati, rappresenta un fattore di rischio di malattia tromboembolica; il fegato è inoltre la sede di accumulo e utilizzo dei principali fattori vitaminici essenziali al corretto metabolismo dell’omocisteina.Scopo: valutare una possibile associazione fra iperomocisteinemia moderata (>12 mol/L) e TP in pazienti affetti da CE in diversi stadi di malattia, con e senza HCC.Materiali e metodi:48 pazienti (età media 60 ± 10, 20 f) affetti da CE, di cui 16 (8 f) con documentata TP (ultrasonografia doppler) sono stati sottoposti a determinazione dei livelli circolanti di Hcy (HPLC con detector fluorimetrico), a determinazione dei livelli circolanti dei fattori vitaminici Hcy-relati (folati eritrocitari e vitamina B12) (ELISA), a valutazione della funzionalità renale (creatinine clearance), dello stadio di malattia (Child-Pugh Score), a screening diagnostico per HCC (diagnosi radiologica e/o istologica), valutazione eziologia (esotossica, virale, entrambe, altro). Tutti i pazienti sono stati contestualmente sottoposti a screening per trombofilia (determinazione proteina C, S, antitrombina III, resistenza proteina C attivata, ricerca di lupus anticoagulante).Risultati: I livelli circolanti di Hcy risultano aumentare significativamente con l’aumentare della gravità della malattia (Stadio A, 11.8 ± 4.2 n=12; B= 16.5 ± 8.2, n=22; C= 18.5 ± 8.1, n=14, mol/L, p=0.021, corretti per stato vitaminico e funzionalità renale); i pazienti con HCC (n=18, 8 Child B e 10 Child C) presentavano livelli più alti di Hcy di quelli senza HCC (17.7± 7.4 vs. 13.5 ± 5.9 mol/L, p=ns, dopo correzione per stato vitaminico e funzionalità renale). Come atteso, la prevalenza di TP risultava più alta nel gruppo con HCC [10/16 (62.5%) vs. 8/32 (25%), p<0.01). I soggetti con TP presentavano una disponibilità inferiore di folati (3.8 ± 1.2 vs. 5.5 ± 1.8 nmol/ml, p= 0.017) e di vitamina B12 (352 ± 89 vs. 516 ± 125 pmol/L, p=0.038) rispetto ai soggetti senza TP; non vi era nè differenza dei livelli vitaminici né una maggiore prevalenza di deficit vitaminico fra le diverse eziologie. Dopo correzione per stato vitaminico, Child-Pugh score, funzionalità renale e presenza di HCC, il gruppo con TP mostrava livelli di Hcy più alti 19.7±5.5 vs. 13.8± 7.8 mol/L, p=0.015) e una maggiore prevalenza di iperomocisteinemia [10/16 (62.5%) vs 8/32 (25%) , p=0.011). L’associazione fra HHcy e TP è risultata significativa (OR= 5.0, 95% CI: 1.4-18.2, p=0.014).Non sono risultate differenze significative nei livelli degli altri fattori trombofilici fra il gruppo con TP e quello senza.Conclusioni: i dati suggeriscono il possibile ruolo dell’iperomocisteinemia nello sviluppo di TP nei pazienti affetti da CE, specialmente nelle fasi avanzate della malattia o complicate da HCC. Ulteriori studi di conferma su casistiche più ampie, come pure studi sui possibili effetti preventivi del trattamento dell’iperomocisteinemia, sono tuttavia necessari prima di trarre conclusioni definitive.
2003
- Urinary and plasma homocysteine and cysteine levels during prolonged oral N-acetylcysteine therapy
[Articolo su rivista]
Ventura, Paolo; R., Panini; G., Abbati; G., Marchetti; Salvioli, Gianfranco
abstract
Acute administration of N-acetylcysteine (NAC) may induce alterations in plasma and urinary levels of homocysteine (Hcy) and cysteine (Cys). We studied the effects of continuous oral NAC therapy on different Hcy and Cys plasma and urinary forms in 40 healthy subjects assigned to three groups (groups A: n = 13, no therapy; group B: n = 14, NAC 600 mg/day, and group C: n = 14, NAC 1,800 mg/day) for 1 month (T-1). After a 1-month washout period without therapy (T-2), all subjects were treated with oral NAC (1,800 mg/day) for 2 months and (T-3 and T-4) reassessed monthly for plasma and urinary thiols. The treated subjects showed a significant decrease in plasma total Hcy and a slight increase in total Cys levels; the alterations of different forms of plasma thiols suggested an NAC-induced increase in disulfide forms and an increase in urinary Hcy and Cys excretion as disulfide forms. The effects appeared to be dose dependent, being more marked in subjects treated with higher dosages. This approach may be important, as an association or alternative therapy in hyperhomocysteinemic conditions of poor responses to vitamins. Copyright
2003
- Weight Loss Expectations in Obese Patients Seeking Treatment at Medical Centers
[Articolo su rivista]
Dalle Grave, Riccardo; Calugi, Simona; Magri, Flavia; Cuzzolaro, Massimo; Dall’Aglio, Elisabetta; Lucchin, Lucio; Melchionda, Nazario; Marchesini, Giulio; Ventura, Paolo; QUOVADIS Study Group, The
abstract
Objective: To investigate weight loss expectations (expected
1-year BMI loss, dream BMI, and maximum acceptable
BMI) in obese patients seeking treatment and to examine
whether expectations differ by sex, weight, diet and
weight history, age, psychological factors, and primary motivations
for weight loss.
Research Methods and Procedures: 1891 obese patients
seeking treatment in 25 Italian medical centers (1473 women;
age, 44.7 11.0 years; BMI, 38.2 6.5 kg/m2) were
evaluated. Diet and weight history, weight loss expectations,
and primary motivation for seeking treatment (health
or improving appearance) were systematically recorded.
Psychiatric distress, binge eating, and body image dissatisfaction
were tested by self-administered questionnaires
(Symptom CheckList-90, Binge Eating Scale, and Body
Uneasiness Test).
Results: In 1011 cases (53.4%), 1-year expected BMI loss
was 9 kg/m2, dream BMI was 26.0 3.4 kg/m2 (corresponding
to a 32% loss), and maximum acceptable BMI was
29.3 4.4 kg/m2 (23%). BMI and age were the strongest
predictors of weight goals. Weight loss necessary to reach
the desired targets was largely in excess of weight loss
observed during previous dieting. Psychiatric distress, body
dissatisfaction, and binge eating did not predict weight loss
expectations. The primary motivation for weight loss was
concern for future or present health; women seeking treatment
to improve appearance had a lower grade of obesity,
were younger, and had first attempted weight loss at a
younger age.
Discussion: Obese Italian patients had unrealistic weight
loss expectations. There were significant disparities between
patients’ perceptions and physicians’ weight loss
recommendations of desirable treatment outcome.
2002
- Genetic polymorphisms of Fas (CD95) and FasL (CD178) in human longevity: studies on centenarians
[Articolo su rivista]
Pinti, Marcello; Troiano, Leonarda; Nasi, Milena; L., Moretti; E., Monterastelli; A., Mazzacani; Mussi, Chiara; Ventura, Paolo; F., Olivieri; C., Franceschi; Salvioli, Gianfranco; Cossarizza, Andrea
abstract
Apoptosis plays a crucial role in immunosenescence, as also evidenced by the increased expression of Fas in lymphocytes from aged people. However, little is known about the genetic regulation of Fas and its ligand, FasL. We have studied their polymorphisms in 50 centenarians and 86 young donors living in Northern Italy. The first Fas polymorphism; at position -670, has in Caucasian a heterozigosity of 51%; the second, at -1377 position, has the wild type allele (G) with a very high frequency (83%) respect to the mutant allele. Genotype and allele distribution for both polymorphisms were similar in controls and centenarians. Similar results were found as far as two FasL polymorphisms (IVS2nt-124 and IVS3nt169) are concerned. On the whole, our data suggest that Fas and FasL polymorphisms, as well as their haplotypes, are unlikely to be associated with successful human longevity.
2001
- Alendronate for the treatment of Osteoporosis in HIV-infected patients.
[Abstract in Atti di Convegno]
Guaraldi, Giovanni; Ventura, Paolo; Orlando, G.; Albuzza, M.; Borderi, M.; Bedini, A.; Della Loggia, P.; Esposito, Roberto
abstract
We report on a 51-year old man with AIDS who underwent a cycle of alendronate therapy for pathologic fracture of a lumbar vertebra, induced by antiretroviral therapy. The patient received 10mg of alendronate daily with calcium and vitamin D supplements, for 6 months.
2001
- Alendronate treatment for osteoporosis in patients infected with human immunodeficiency virus.
[Articolo su rivista]
Guaraldi, Giovanni; Ventura, Paolo; Albuzza, M.; Orlando, G.; Bedini, A.; Esposito, Roberto
abstract
Drug-induced osteoporosis is not rare and is mainly caused by treatment with glucocorticoids. Highly active antiretroviral therapy (HAART) has also been shown to accelerate bone mineral loss in HIV-infected patients and has been proven to be a potent inducer of osteoporosis in this (usually young) population [1]. We have recently described pathologic fractures in patients who have osteopenia and osteoporosis induced by antiretroviral therapy [2]. Here we report the result of alendronate therapy in a 51-year-old man with AIDS and severe osteoporosis.In February 2000, this patient suffered a trivial trauma while walking. A radiogram showed a fracture of the body of lumbar vertebra L1; soon thereafter, because of an anterior vertebral collapse, the patient developed severe disability and pain. At the time of the fracture, the patient's CD4 count was 522 cells/μL and virus load (as measured by branched-DNA level) was <50 copies/mL. He had been receiving a stable course of antiretroviral therapy with stavudine, lamivudine, and indinavir for 36 months. The patient was given 10 mg of alendronate daily with calcium (500 mg daily in the form of calcium carbonate) and vitamin D supplements (450 IU daily), for 6 months.Before and at the end of treatment, dual-energy x-ray absorptiometry scanning (DEXA) was performed to determine the bone mineral density (BMD) of the whole body and of the lumbar spine (vertebrae L1 through L5). Before treatment, DEXA documented that the median BMD of the lumbar spine was 0.691 g/cm2 (t score, −3.85; z score, −3.53). At the end of treatment, DEXA showed that the median BMD of the lumbar spine was 0.832 g/cm2 (t score, −2.35; z score, −1.34). A 20.4% increase in lumbar spine BMD was obtained by the end of treatment, and the patient's pain was almost completely relieved. A radiograph did not reveal any new fractures.After 6 months of treatment, the patient developed lactic acidosis and interrupted both antiretroviral therapy and alendronate therapy. Other authors have recently described the association of lactic acidemia with osteoporosis in HIV-infected men, which suggests that this is a real phenomenon and not a spurious association [3].The effect of alendronate on BMD in HIV-infected patients with osteoporosis has not been evaluated yet. On the other hand, no approved treatment exists for osteoporosis that develops secondary to antiretroviral therapy. This case report encourages the development of clinical trials to study the effect of alendronate in HIV-infected patients with metabolic bone disease. Information regarding the safety of this drug in combination with HAART is urgently needed.
2001
- Continuous combined hormone replacement therapy with oral 17-beta estradiol and norethisterone acetate improves homocysteine metabolism in postmenopausal women
[Articolo su rivista]
Ventura, Paolo; Cagnacci, Angelo; Malmusi, Stefania; Panini, Rossana; Baldassari, Francesco; Arangino, Serenella; Volpe, Annibale; Salvioli, Gianfranco
abstract
-
2001
- Continuous combined hormone replacement therapy with oral 17β-estradiol and norethisterone acetate improves homocysteine metabolism in postmenopausal women
[Articolo su rivista]
Ventura, Paolo; Cagnacci, Angelo; S., Malmusi; R., Panini; F., Baldassari; S., Arangino; Volpe, Annibale; Salvioli, Gianfranco
abstract
Objective: To evaluate the effect of a continuous combined oral hormone replacement therapy (HRT) on basal and post-methionine load homocysteine levels in postmenopausal women. Design: Twenty-two postmenopausal women (PMW) were randomly allocated to receive either continuous combined oral HRT (2 mg of estradiol plus 1 mg of norethisterone acetate; n = 11) or no treatment (controls, n = 11) for 6 months. A methionine oral load (0.1 g/kg body weight) was performed in each subject at time 0 and after 6 months. Serum homocysteine levels were measured by high-performance liquid chromatography in samples collected at time 0 and at 4, 8, and 24 h after the methionine load, while levels of vitamin B, (by high-performance liquid chromatography) and B,, and folate (both by ELISA) were assayed in samples collected at time 0. Results: Serum levels of glucose and body mass index increased in treated PMW, whereas folate decreased in controls. In treated PMW, basal homocysteine tended to decrease (10.6 +/- 3.3 mu mol/L vs. 9.62 +/- 2.8 mu mol/L, p = 0.062), whereas in controls it significantly increased (10.7 +/- 2.65 mu mol/L vs. 12.17 +/- 3.89 mu mol/L, p < 0.05). This increase was not significant after correction for vitamin status (p = 0.072). Homocysteine values 4 h (31.9 +/- 13.53 mu mol/L vs. 39.83 +/- 22.53 mu mol/L, p < 0.05) and 8 h (35.1 +/- 13.13 vs. 43.34 +/- 22.15 mu mol/L) after methionine, and integrated homocysteine response to methionine (392.5 +/- 133.8 mu mol/24 h vs. 458.8 +/- 104.8 mu mol/24 h; p < 0.05), were significantly reduced in HRT-treated, but not in untreated, PMW. Conclusions: Continuous combined oral HRT with 17 beta -estradiol plus norethisterone acetate reduces homocysteine levels, mainly after a methionine load. This effect seems to be independent of vitamin status and may have positive implications for the prevention of cardiovascular diseases in PMW.
2001
- Effect of N-acetylcysteine long term oral administration on plasma and urinary homocysteine and cysteine levels
[Abstract in Atti di Convegno]
Ventura, Paolo; Panini, Rossana; G., Marchetti; Salvioli, Gianfranco
abstract
Background: A decrease of plasma homocysteine (Hcy) may represent a therapeutic promise for reducing the impact of atherosclerosis. N-acetyl-cysteine (NAC) at high dosage seems able to interfere with endogenous thiols [cysteine (Cys) and Hcy] by forming mixed disulphides undergoing a more efficient renal clearance. Aim : to assess the effect of NAC oral chronic administration (different doses) on plasma and urine levels of different forms of plasma Cys and Hcy. Methods: In 40 healthy (44±15 years, 22 F) we assessed fasting total and free (= not protein bound) forms of plasma and urinary levels of Hcy and Cys. After informed consent subjects were randomly assigned to group A (n= 13, no therapy), group B (n= 14, NAC 600 mg once daily per os) and group C (n= 14, NAC once daily 1800 mg per os) for a month. Results: Group C showed a significant reduction of total Hcy (10.68 2.8 vs. 13.64 3.56 mmol/L, p= .001) a not significant reduction of free Hcy (3.48 0.72 vs. 3.55 0.74 mol/L, p=.702) a significant reduction of total Cys (320 93 vs. 377 122 mol/L, p=.013) a not significant reduction of free Cys (147 26.5 vs. 162 40.6 mol/L, p= .294), a significant increase of free/bound Hcy and Cys ratio (33.2 3.21 vs. 26.5 3.7 %, p= .000 and 48 7.6 vs. 42 6.0 %, p=.045, respectively).Group B showed a significant reduction of total plasma Hcy (11.6 3.7 vs. 12.88 3.9 mol/L, p=0.031) but not significant modification of other thiols forms levels.After NAC therapy Group C showed also significant higher daily Hcy and Cys urinary levels (11.73.5 vs. 9.13.1 mmol/ mg urinary creatinine , p<0.01, 24773 vs. 22074 mmol/ mg urinary creatinine, p=0.011).Also group B showed higher, but not significant, Hcy and Cys urinary levels (11.24.2 vs 10.513.3 mol/ mg urinary creatinine, p=0.056 and 23949 vs 22955 mol/ mg urinary creatinine, p=0.055). No significant variations in plasma and urinary thiols were noticed in group A.Conclusions: A chronic (one month) oral NAC administration induces a decrease of the main circulating plasma thiols (Cys and Hcy) by increasing their renal excretion. This effect seems dose-dependent, being significant only at higher NAC dosage; the modification of plasma thiols forms (reduction of total and free forms but increase of free/total ratio) support the hypothesis of displacement by NAC of thiols from their plasma protein binding sites to form mixed disulphides, which in turns may undergo a higher renal clearance, resulting in an increase of urinary excretion.
2001
- Homocysteine Production and membrane oxidative stress in erythrocytes
[Abstract in Atti di Convegno]
Ventura, Paolo; Panini, Rossana; Salvioli, Gianfranco
abstract
Background: Homocysteine (Hcy) seems to induce oxidative stress (H2O2 production). Hcy synthesis occurs in erythrocytes (RBC).Aims: To assess if Hcy production in RBC may contribute to membrane lipid peroxidation.Methods: 15 RBC samples from patients with normal plasma Hcy (7.8 ± 3.1 mol/L) (controls) and 15 from megaloblastic anemia patients, [with higher Hcy plasma levels (19.1 ± 6.3 mol/L , p<0.01 with respect to controls) and RBC folate and serum B12 levels significantly lower (145.6 ± 34.1 vs. 272.6 ± 61.3 g/L, p<0.01, and 152 ± 65.5vs.582.6±195.6 pmol/ml,p<0.01, respectively)] were incubated both at 4°C and at 37° C in a RPMI folate and B12-free medium, containing methionine 50 mol. In each sample supernatant we measured at 4, 8 and 24 h Hcy, malondialdehyde (MDA) (HPLC) (marker of lipid peroxidation) and LDH levels (marker of early membrane damage) Results: In 37°C incubation samples Hcy production resulted higher in samples from megaloblastic anemia, whereas a slight Hcy increase was observed during incubation at 4°C in both groups (see figure). Hcy production (incubation at 37°C) seems associated to an higher lipid peroxidation and membrane functional derangement (see table) and a significant correlation ( 4 h : r=.668, p<0.01; 8h : r=.774, p<0.01; 24h : r= .556, p<0.01) was found between RBC Hcy production and MDA levels in the supernatant from samples at 37° Conclusions: Hcy production by RBC contribute to oxidative stress of membrane lipids. Lipoperoxidation (higher MDA levels in the medium) and membrane damage (LDH levels) in vitamin-deficient RBC may account for higher frequency of haemolysis in patients with megaloblastic anemia.
2001
- Homocysteine erythrocyte production in patients affected by dementia
[Abstract in Atti di Convegno]
Ventura, Paolo; Panini, Rossana; M., Uneddu; M., Modugno; Neri, Mirco; Salvioli, Gianfranco
abstract
Background: Patients affected by dementia Alzheimer type (DAT) or vascular dementia (VD) often exhibit mild hyperhomocysteinemia (HHcy); HHcy may be important in neuron damage: it is an early marker of vitamin deficit, (folate and vit. B12), often associated with cognitive decline; HHcy itself seems to exert a neurotoxic effect (activation of NMDA receptors and induction of cell death; excitotoxic effect by some metabolites) and it is also an indipendent risk factor for (cerebro)vascular disease. Red blood cells (RBC) have enzymatic activities for Hcy synthesis (methionine demethylation) and (probably) metabolism (remethylation to methionine), representing a possible model for studying abnormalities of Hcy metabolism.Aim: to assess the possible difference in RBC production between healthy elderly and elderly affected by Dementia syndrome.Methods: In 105 subjects affected by dementia (DSM-IV criteria) [55 by DAT (30 f, mean age 78±8 years) and 50 by VD (38 f, 81±5 years); DAT and VD diagnosis was made by NINCDS-ARDRA and NINDS-AIREN criteria and Hachinsky score] and 40 healthyelderly (controls; 22 f; mean aged 77±10 years) we assessed fasting plasma Hcy (HPLC) and serum vit. B12 and RBC folates (RIA) . A RBC sample from all subjects was incubated at 37° for 8 h in RPMI vitamin-free (Ht=26%) medium. In these samples we measured at time 0 e after 4 and 8 hour Hcy concentration (supernatant and RBC cytoplasm).Results: RBC from AD patients produce more Hcy (p<0.05 for all parameters in DAT e VD vs. controls, ANOVA, Tukey post hoc); in RBC from VD patients Hcy production is higher than from DAT, but not significantly (p=0.055) (see figure). Data are corrected for Hcy-related vitamin status.Conclusions: Our data are suggestive that AD patients have higher prevalence of transmethylathion abnormalities with respect to controls. This may have both indirect (role of methylation in normal neuron trophism) and direct (toxicity due to Hcy accumulation) physiologic relevance.
2001
- Hyperhomocysteinemia and related factors in 600 hospitalized elderly subjects
[Articolo su rivista]
Ventura, Paolo; R., Panini; C., Verlato; G., Scarpetta; Salvioli, Gianfranco
abstract
Hyperhomocysteinemia (HHcy) is a metabolic disorder frequently occurring in the elderly population. Recently several reports have suggested abnormalities in homocysteine (tHcy) metabolism implicating HHcy as a metabolic link in the multifactorial processes characterizing many geriatric illnesses-with special emphasis on atherosclerotic vascular diseases and cognitive impairment. The present study was undertaken in a large sample of elderly hospitalized subjects to determine (1) the prevalence of HHcy, (2) the association of HHcy with vascular and cognitive disorders, and (3) the factors independently predicting Hhcy. Six hundred elderly subjects (264 men and 336 women; mean age, 79 +/-9 years) were randomly chosen from those admitted as inpatients over a period of 3 years. In all patients, body mass index (BMI), mid-upper arm muscle area (MUAMA), plasma cholesterol, triglycerides, total proteins, albumin, lymphocyte count, creatinine, homocysteine (fasting and 4 hours after methionine oral load), serum vitamin B-6, vitamin B-12, and folate concentrations were measured. The presence of disease or use of medications known to affect homocysteine plasma levels were also recorded. The mean fasting tHcy level was 16.8 +/- 12 mu mol/L in the whole sample, 18.18 +/- 13.25 mu mol/L in men, and 15.86 +/- 12.14 mu mol/L in women (P=.005 men v women). The mean Hcy level 4 hours after methionine load was 37.95 +/- 20.9 in the whole sample. Prevalence of hyperhomocysteinemia (fasting Hcy greater than or equal to 15 mu mol/L or 4 hours after methionine load greater than or equal to 35 mu mol/L) was 61% (365/600) (67% in men and 56% in women, P<.05). HHcy was rarely (8%) an isolated disorder; in addition to diabetes (20%), renal failure (48.2%), and malnutrition (20.2%), it was often associated with heart failure (30%), malignancies (20.5%), and the use of diuretics (56%) and anticonvulsant drugs (13%). Plasma homocysteine progressively increases across subjects from those with no diabetes, malnutrition, renal failure, obesity, inflammatory bowel disease, heart failure to those with 1, 2, or more concurrent diseases. Multiple stepwise regression analysis showed that 72% of plasma total fasting tHcy variability was explained by age, serum folate, plasma albumin, use of diuretics, and renal function (measured as plasma creatinine clearance). In conclusion, the present study documents that hyperhomocysteinemia, in elderly hospitalized patients is (1) a common finding, (2) frequently associated with vascular and cognitive disorders, and (3) probably a secondary phenomenon in most cases. The major predictor of high plasma homocysteine levels were age, serum folate, plasma albumin, plasma creatinine clearance, and use of diuretic drugs. These variables explain a large proportion of plasma Hcy variability. Copyright
2001
- Methionine intolerance and plasma homocysteine after insulin infusion in type II diabetic patients
[Abstract in Atti di Convegno]
Ventura, Paolo; Panini, Rossana; S., Emiliani; Salvioli, Gianfranco
abstract
Background-To establish whether transsulfuration impairment (methionine intolerance) may influence total plasma homocysteine (Hcy) in response to insulin infusion in type II diabetic patients (DB).Materials and Methods- DB with normal (group A, n=13) and abnormal (hyperhomocysteinemia, HHcy)) (Group B, n=17) response to oral methionine load underwent a glucose/clamp study. At time 0, and 30, 60 and 120 minutes after hyperinsulinemia, Hcy and methionine (Met) plasma levels were assessed. All patients were assayed for fasting Homocysteine-Cysteine ratio (as marker of suspected heterozygosis for cystathionine--synthase deficit) and vitamin status [serum vitamin B6 (PLP), vitamin B12 and folate]. Results- After hyperinsulinemia, plasma methionine reduced (about –30% at 120 minutes vs. basal values) within both groups, whereas Hcy decreased in group A (up to –15.2 8.9 % at 120 minutes) and increased in group B (up to +30.6 10.9 % at 120 minutes). (see figure) PLP was higher in group A than in group B (94.2 42.6 vs. 54.6 32.4 nmol/L; p<0.01); group A showed a lower prevalence of suspected heterozygosis for cystathionine--synthase deficit (1/13 (7,7%) vs.13/17 (76.5%), p=0.000). Conclusions-Methionine intolerance may influence insulin effect on plasma Hcy. To prevent a possible acute HHcy due to insulin administration in case of transsulfuration impairment, it may be suggested to assess transsulfuration capacity in all patients due to be subjected to insulin therapy.
2001
- Pathological fractures in AIDS patients with osteopenia and osteoporosis induced by antiretroviral therapy
[Articolo su rivista]
Guaraldi, Giovanni; Ventura, Paolo; M., Albuzza; G., Orlando; A., Bedini; G., Amorico; Esposito, Roberto
abstract
Osteopenia and osteoporosis have recently been included among the metabolic complications of antiretroviral therapy in HIV-infected patients. The pathogenesis and particularly the role of each individual medication are currently poorly understood. The prevalence and natural history of these conditions have been evaluated only in cross-sectional studies [1], so that their clinical evolution is still unclear. Avascular osteonecrosis has also been described among AIDS patients receiving or not receiving antiretroviral therapy, suggesting that this is a real phenomenon and not a spurious association [2-6]. However, pathological bone fractures have never been reported in patients with bone alterations induced by antiretroviral therapy.We report on two AIDS patients, one with osteopenia and the other with osteoporosis, who suffered fractures after trivial trauma. Both had moderate central and peripheral lipodystrophy, without any significant alterations in lipid metabolism. A dual energy X-ray absorptiometry (DEXA) scanner was used to determine the bone mineral density of the whole body, lumbar spine (L1-L5) and proximal femur.
2001
- Ursodeoxycholic acid complexation with 2-hydroxypropyl-beta-cyclodextrin increases ursodeoxycholic acid biliary excretion after single oral administration in rats
[Articolo su rivista]
Ventura, Paolo; R., Panini; G., Montosi; C., Garuti; Vandelli, Maria Angela; G., Brunetti; Hd, Tauschel; Pietrangelo, Antonello; Salvioli, Gianfranco
abstract
Complexation of ursodeoxycholic acid (UDCA) with 2-hydroxypropyl-beta -cyclodextrin (HP beta CD) improves the water solubility and the dissolution rate of UDCA and may therefore increase its bioavailability. We compared the amount and the rate of biliary excretion of UDCA and biliary lipid secretion after a single oral administration of UDCA in 3 different pharmaceutical formulations [UDCA-HP beta CD (´urso-beta -cyclodextrin´), UDCA suspension and UDCA capsule] at 3 different dosages each, in 11 groups (2 control groups) of bile fistula rats. UDCA excretion increased with an increase in dose, biliary UDCA recovery and peak secretion were significantly higher after administration of UDCA-HP beta CD than after UDCA in suspension or capsule. This enhancement of biliary excretion may achieve greater UDCA enrichment in the bile acid pool than conventional pharmaceutical UDCA formulations, this giving to UDCA-HP beta CD a considerable therapeutical potential, Copyright
2000
- Pathological fractures in patients with osteopenia and osteoporosis induced by antiretroviral therapy
[Abstract in Rivista]
Guaraldi, Giovanni; Ventura, Paolo; Albuzza, M.; Bedini, A.; Amorico, G.; Esposito, Roberto
abstract
Osteopenia and osteoporosis have recently been included among the metabolic complications of antiretroviral therapy. Its pathogenesis and particularly the role of each individual medication are poorly understood. Pathological bone fractureshave never been observed in patients with osteopenia and osteoporosis. Previously described case reports, in fact, refer to fractures due to avascular necrosis or osteonecrosis.
2000
- Peroxidation indices and total antioxidant capacity in plasma during hyperhomocysteinemia induced by methionine oral loading
[Articolo su rivista]
Ventura, Paolo; R., Panini; C., Verlato; G., Scarpetta; Salvioli, Gianfranco
abstract
Hyperhomocysteinemia is a risk factor for vascular disease, although its mechanism of action is not fully clear. Different experimental studies have suggested that homocysteine (Hcy) exerts a pro-oxidant effect in the presence of metal ions (Fe and Cu). To test for a similar effect in vivo, we studied plasma markers of lipid and protein oxidation du ring hyperhomocysteifiemia induced by an oral methionine load. Twenty-nine subjects (aged 61 +/- 25 years; 17 women), 25 of whom underwent oral methionine (100 mg/kg) loading, were studied; in every case, we measured total plasma Hey, malondialdehyde (MDA), conjugated dienes (DIE), and oxidized protein ([PTOX] carbonylic groups) in basal conditions and 4, 6, 8, and 24 hours after methionine loading. Four participants acted as controls. In every case, we also measured total plasma antioxidant capacity (ANTOX) in basal conditions and 8 hours after methionine loading. Eight hours after methionine loading, plasma Hey increased from 17.6 +/- 11.4 to 54.3 +/- 31.6 nmol/ml, PTOX from 0.33 +/- 0.18 to 0.71 +/- 0.33 nmol/mg protein, DIE from 493 +/- 163 to 590 +/- 202 optical density units, and MDA from 1.66 +/- 0.81 to 2.1 +/- 0.93 nmol/ml. There was a significant correlation (Spearman´s r) between Hey and both PTOX (r = .86, P = .01) and MDA (r = .47, P < .05) 8 hours after methionine loading. No significant modifications of the plasma parameters were found during the observation period in controls. ANTOX at 8 hours was significantly (paired ttest) reduced in probands (from 1.74 +/- 0.59 to 1.14 +/- 0.55 mmol/ml, P = .014); no significant difference was observed for plasma ANTOX in controls. Hyperhomocysteinemia due to oral methionine loading induced an increase in plasma oxidation markers. In the absence of hyperhomocysteinemia. no significant modifications were observed. These findings, together with the decrease in ANTOX and the corresponding increase in total plasma Hey, are consistent with a pro-oxidant effect of acute hyperhomocysteinemia in vivo. Copyright
1999
- Influences of continuous combined HRT on homysteine
[Altro]
Malmusi, S; Ventura, Paolo; Panini, R; Salvioli, Gf; Renzi, A; Cagnacci, Angelo; Volpe, Annibale
abstract
-
1999
- N-acetyl-cysteine reduces homocysteine plasma levels after single intravenous administration by increasing thiols urinary excretion
[Articolo su rivista]
Ventura, Paolo; R., Panini; Mc, Pasini; G., Scarpetta; Salvioli, Gianfranco
abstract
A decrease of plasma homocysteine (Hcy) may represent a therapeutic promise for reducing the impact of atherosclerosis. N-Acetyl-cysteine (NAC) is a thiol-containing compound interfering with endogenous thiols, cysteine (Cys) and Hey, by forming with them mixed disulphides with a possibly more efficient renal clearance. The aim of this work was to assess the effect of NAC intravenous infusion on plasma levels of different forms of Hey and particularly to verify the effect on Hey renal excretion. We collected basal blood samples at 0.5, 1, 2, 5, 8 and 24 h after the beginning of NAC infusion (50 mg kg-l body wt.) and also 24-h urine samples of the day of NAC infusion and of the day before and of the day after the infusion in ten healthy subjects (mean age 73 +/- 15). Urinary and plasma thiols (Hcy, Cys and NAG) were assayed by HPLC. Both total plasma Hey (approx. 69% vs basal values) and Cys (approx. 40% vs basal values) fell progressively, reaching a minimum 5 h after infusion start; total free (i.e. not bound to proteins) Hey (2.2 +/- 1.8 down from 4.4 +/- 4.2 nmol ml(-1)) and Cys (70.4 +/- 39.8 down from 113.3 +/- 61.2 nmol ml(-1)) decreased as well. Reduced (thiolic-free form) Hey and Cys decreased during infusion, though not as pronounced as for the other forms. Percentagewise, out of the total plasma levels, Hey and Cys total free form and reduced form tended to increase over infusion as well as their difference (i.e. the plasma mixed disulphide moiety), thus supporting the idea that excess NAC displaces thiols from their plasma binding sites forming mixed disulphides. Urinary total Cys and Hey excretion significantly increased at the end of the day of NAC infusion (tenfold for Cys and fivefold for Hey) and reduced appreciably on the following day. Also urinary excretion of the free form of Cys and Hey increased at the end of the day of NAC infusion, although in a lower amount with respect of total amounts, meaning a reduction of percentage Cys and Hey excreted as the free form; for none of the patients had proteinuria, the ´free´ form of urine thiols has to be identified in the ´reduced´ form, the difference between the total and free form reflecting the ´mixed disulphide´ moiety. NAC intravenous administration induces an efficient and rapid reduction of plasma thiols, particularly of Hey; our data support the hypothesis that NAC displaces thiols from their binding protein sites and forms, in excess of plasma NAG, mixed disulphides (NAC-Hcy) with an high renal clearance. This effect may represent the start of an alternative approach in the treatment of hyperhomocysteinaemic conditions.
1999
- Prevention of a first episode of variceal bleeding: role of duplex Doppler sonographic measurement of the acute response to beta-blockers.
[Articolo su rivista]
G., Cioni; F., Turrini; E., Tincani; P., D'Alimonte; A., Cristani; E., Boldrini; E., Baraldi; P. G., Pedrazzini; Ventura, Paolo; E., Ventura
abstract
The aim of our study was to assess whether acute variations in portal vein Doppler sonographic parameters induced by administration of a single beta-blocker agent are predictive of the long-term effects of these drugs in the prevention of a first episode of variceal bleeding. In 30 patients with liver cirrhosis at high risk for variceal bleeding, duplex Doppler sonographic parameters (maximal portal flow velocity, portal blood flow, and congestion index) were measured before and 4 h after the administration of 40 mg of propranolol. Twenty-three of these patients started chronic therapy with propanolol and were evaluated periodically (seven patients were excluded because they did not continue the therapy). The percentage of patients free from bleeding was 86.9% at the first year and 77.8% at the second year. Among a series of clinical, laboratory, and instrument-based parameters, the only one related to first bleeding, selected by the Cox regression model, was the percentage decrease in maximal portal flow velocity observed after initial administration of propranolol (P < 0.01). The best cutoff value for the percentage decrease in portal flow velocity (portal flow velocity test) was 12%. The prevalence of bleeding had been 25% (3 of 12) in patients with positive portal flow velocity test results (12% decrease or more), versus 64% (7 of 11) in patients with negative portal flow velocity test results. The actuarial probability of remaining free from bleeding (Kaplan-Meier analysis) was different in these two groups (log rank P < 0.01). The portal flow velocity test represents a safe and feasible method to predict the efficacy of beta-blockers in the prevention of a first bleeding episode in patients with cirrhosis. In patients with negative results on the portal flow velocity test, an alternative therapeutic approach should be considered.
1998
- Impact of nutrition on cognition and affectivity in the elderly: A review
[Articolo su rivista]
Salvioli, Gf; Ventura, Paolo
abstract
Preventive nutritional health care of old people is a pressing topic for physicians. In fact, malnutrition is related to impaired cognitive and affective performance in the elderly. Depression and dementia may sometimes initiate with weight lass, and selective and subclinical malnutrition (folic acid, vitamin B-12) can impair cognition and affectivity. The methods for revealing cobalamin and folic acid deficiencies need to be revised, since recommended dietary allowances and serum levels of these nutrients have not yet been established for the elderly. Homocysteine plasma concentration seems to be an appropriate and cost-effective marker of inadequate intake or bioavailability of these two vitamins, which are related to cognitive and affective performances in the elderly. in clinical practice, it is important to dispose of an instrument for adequately detecting malnutrition. One must also keep in mind that vitamin supplements may be useful in a large number of elders with psychogeriatric symptoms.
1998
- Increase of protein and lipid oxidation during hyperhomocysteinemia induced by methionine oral loading
[Abstract in Rivista]
Ventura, Paolo; Panini, Rossana; C., Verlato; G., Scarpetta; Salvioli, Gianfranco
abstract
Introduction: Hyperhomocysteinemia (HHcy) is a well-defined risk factor for vascular disease by a not still well clear molecular mechanism. It is known a pro-oxidant effect of Hcy “in vitro” in presence of metal ions (Fe e Cu). To assay a similar effect in vivo, we studied plasma markers of lipid and protein oxidation during hyperhomocysteinemia induced by methionine oral load.Materials and methods: 16 subjects (aged 79 14 years; 16f), 14 of which underwent a methionine (100 mg/Kg) oral load were studied; in all patients we assayed total plasma HCY, malonaldehyde (MDA) and conjugates dienes (DIE), oxidized protein (PTOX) (carbonilic groups) in basal conditions and after 4, 6, 8 and 24 hours from the oral load. In the two subjects who did not take the methionine load (controls), were made the same assays with the same timing of the probands. In all subjects we assayed basal and after 8 hours from the methionine load total plasma antioxidant (ANTOX) capacity.Results: table shows values (mean DS) of considered parameters in subjects who underwent the methionine loadParameterBasal4 h6 h8 h24 hHcy (nmol/ml)20.7 11.550.6 19.157.2 25.561.6 28.3 45.3 30.7PTOX (nmol/mg prot.)0.38 0.210.49 0.270.68 0.390.68 0.270.58 0.40DIE(nmol/ml)493 163562 181526 233590 202545 182MDA(nmol/ml)1.66 0.801.91 0.942.19 1.321.96 0.931.95 0.99ANTOX(nmol/ml)1.76 +/- 0.511.38 +/- 0.86 Conclusions: HHCY induces a correspondent increase of plasma oxidation makers. In absence of HHCY, no significant modifications were observed. This data, together with the reduction of ANTOX in correspondence of maximum plasma HCY increase, are suggestive of pro-oxidant effect of HHCY in vivo.
1998
- Is Hyperhomocysteinemia (HHcy) a nutritional marker of senile ementia ?
[Abstract in Rivista]
Ventura, Paolo; Panini, Rossana; M. C., Pasini; C., Verlato; Salvioli, Gianfranco
abstract
Introduction: Correlations between nutritional status and cognitive impairment still need to be defined. Mild hyperhomocysteinemia (Hcy>15 nmol/ml)) is a good marker of multiple (and often subclinical) vitamin (B12, B6 and folic acid) deficits, often associated with neurological disturbances and poor performance on neuropsychological tests. Several studies have shown cognitive impairment (spatial copying and memory tests) in elderly patients with normal values of blood folates and serum Vit. B12 levels but mild hyperhomocysteinemia. Aim of this study is to evaluate, in healthy elderly (HE) and in patients with senile dementia Alzheimer type (AD), the prevalence and the relevance of HHcy versus other common nutritional parameters Materials and methods: 108 patients affected by AD (DSM IV criteria) were compared with 64 age matched healthy elderly (HE). All subjects underwent a nutritional (biochemical and anthropometric parameters) and Hcy plasma level assessment. Statistical analysis were performed by standard methods. Results: The prevalence of HHcy is higher in the AD group (75%) with respect of HE group (45%). HHcy is an associated factor of AD, as suggested by an Odds Ratio value of 5.58 (2.71 11.48; 95% C.I.). A statistically significant (p<0.05, t test for independent samples) difference for all nutritional parameters and for Hcy plasma levels was found between AD and HE group. Entering these parameters into a multiple logistic regression analysis, taking the presence or absence of dementia as the dependent variable, we obtained a model predicting dementia with a likelihood of 78.5% based on the table parameters. ParameterBRSignificanceHHcy0.800.22p<0.01Albumin-1.20-0.14p<0.02Haemoglobin-0.65-0.19p<0.01Lymphocyte count-0.013-0.14p<0.02Folic acid-0.48-0.19p<0.01 Conclusions: Our data show a high prevalence of HHcy in elederly patients with AD, suggesting its importance as a nutritional risk factor for cognitive impairment.
1998
- Stosowanie niezbednych fosfolipidow (EPL) w marskosci watroby (Administration of essentiial phospholipids (EPL) in liver cirrhosis)
[Relazione in Atti di Convegno]
Salvioli, Gianfranco; Ventura, Paolo
abstract
The work deals with the modifications of cell membranes lipid content during the course of liver chronic diseases and the effect of essential phospholids administration in this kind of patients
1998
- Studi preformulativi sul complesso di inclusione tra acido ursodesossicolico e beta-ciclodestrine
[Abstract in Atti di Convegno]
Vandelli, Maria Angela; Ventura, Paolo; Ruozi, Barbara; Forni, Flavio; Bernabei, Maria Teresa
abstract
Studi preformulativi sul complesso di inclusione tra acido ursodesossicolico e beta-ciclodestrine
1998
- Ursodeoxycholic acid complexation with 2-hydroxypropyl-beta-cyclodextrin increases ursodeoxycholic acid biliary excretion after single oral administration in rats
[Abstract in Rivista]
Ventura, Paolo; Panini, Rossana; Montosi, Giuliana; Garuti, Cinzia; Vandelli, Maria Angela; G., Brunetti; Pietrangelo, Antonello; Salvioli, Gianfranco
abstract
Complexation of ursodeoxycholic acid (UDCA) with 2-hydroxypropyl-beta-cyclodextrin (HPbCD) (1:1 molar ratio) improves the water solubility and dissolution rate of UDCA and hence its bioavailability. We compared UDCA bile recovery (percentage of administered UDCA dose excreted in bile) after single oral (gavage) administration of UDCA in three different pharmaceutical forms in a bile fistula rat model. Male Sprague-Dawley rats were randomly assigned to 11 groups (6 rats per groups); the bile duct was cannulated after gavage to collect 4-h bile samples. Groups 1, 2 and 3 (fed 5, 10 and 50 mg/kg body weight UDCA/HPbCD complex, respectively) showed (mean values ± SD) 39.2 ± 5.9%, 25.7 ± 4.1% and 9.4 ± 3.1% UDCA bile recovery, respectively; in groups 4, 5 and 6 (fed UDCA suspension formulation containing 5, 10 and 50 mg/kg body weight, respectively) UDCA bile recovery was 33.2 ± 3.6%, 16.9 ± 4.7% and 6.3 ± 0.8%, respectively; groups 7, 8 and 9 (fed UDCA capsule formulation containing 5, 10 and 50 mg/kg body weight, respectively) showed 30.6 ± 9.0%, 21.7 ± 6.4% and 4.7 ± 1.8% UDCA recovery. Groups 10 and 11 (controls) were fed with HPbCD and saline, respectively. Results indicate a significantly (p<0.05) higher bile UDCA recovery in rats fed UDCA-HPbCD complex than in those fed UDCA suspension or UDCA capsule formulations at the same dose. In this model, oral UDCA/HPbCD complex increased UDCA biliary excretion making for greater UDCA enrichment of the bile acid pool than identical doses of common pharmaceutical formulations.
1997
- Correlation between plasma malonyldialdeide levels and paroxonase activity in healthy subjects and in patients with atherosclerotic disease
[Abstract in Rivista]
G., Scarpetta; Ventura, Paolo; Panini, Rossana; Salvioli, Gianfranco
abstract
Paraoxonase (PON) is a calcium-dependent HDL-associated ester hydrolase catalizying hydrolysis of organophosphates. Its biological role is still unknown: experimental studies suggest a hydroperoxidasic activity on lipoperoxides formed during LDL-oxidation, thus acting as a protective agent against atherogenesis. We evaluated PON activity in healthy subjects (HS) and in patients with cardiovascular (CHD) and cerebrovascular (CVD) disease ; PON activity was correlated with plasma malonyldialdeide (MDA) levels, as markers of lipid peroxidation Materials and Methods: 33 HS (age 7012 yr), 45 CHD (age 818 yr) and 38 CVD (age 8011 yr) patients were studied. Serum PON and plasma MDA levels were measured spectrophotometrically. Statististical analysis was performed by ANOVA univariate for groups comparation and by Pearson r test for values correlation Results: PON activity (mol min-1 ml-1) is higher in HS (0.0750.03) than in CHD (0.0450.03) and CVD (0.0560.03) patients (p<0.05 HS vs. CHD and CVD; ns CHD vs. CVD). MDA (mol/ml) levels are lower in HS (0.0280.023) than in CHD (0.0630.012) and in CVD (0.0560.036) patients (p<0.05 in HS vs. CHD and CVD, ns in CHD vs CVD). Table shows correlation between PON activity and MDA plasma levels in the three studied groups are shown below. rsignificanceHS-.43 p<0.05CHD-.39 p<0.01CVD-.33 p<0.05Conclusions: PON activity is significatively higher in HS than in CHD and CVD patients; whereas there are no significant difference between CHD e CVD patients. In all groups there is statistically significant negative correlation between PON activity and lipid peroxides content (MDA levels) in plasma. Our results suggest a protective role of PON activity against atherogenesis occurring with higher levels of lipoperoxides.
1997
- Distribution of homocysteine in plasma lipoproteins
[Abstract in Rivista]
Ventura, Paolo; Panini, Rossana; P., Paolello; G., Scarpetta; Salvioli, Gianfranco
abstract
Aim of study: Plasma Homocysteine (HCY) is free or bound to plasma proteins (PbHCY). A moderate increase of HCY is a risk factor for vascular disease, even though by mechanism not yet known: it may depend on oxidative HCY-induced modification of lipoproteins (LP). The present study aims to evaluate the LP-HCY binding in vivo. Materials and methods: 53 subjects (mean age 7120 yr) were studied. HCY was measured by HPLC method. Plasma lipoprotein fractions were separated by sequential ultracentrifugation. Single fraction purity was tested on agarose gel electrophoresis. HCY bound to single plasma protein fraction was calculated as difference between total and free HCY. Results: Pb-HCY (mean value: 19.4±2 nmol/ml) results on average about 80% of total plasma HCY (mean values 24.2±2.5 nmol/ml). Distribution (absolute and percentage mean values) of Pb-HCY (nmol/ml) among the different fractions and single fraction HCY/protein ratio (nmol of HCY/mg of protein) are shown in the table. FractionsPb-HCY % of Pb-HCYHCY/protein ratio VLDL1 ± 0.65.10.76 ± 0.4LDL1.5 ± 0.57.70.52 ± 0.3HDL1.9 ± 0.59.70.11 ± 0.1LFF*15.1 ± 277.5< 0.1*LFF= Lipoprotein free fraction (density > 1.21 g/ml) Conclusions: A fraction of plasma HCY circulates bound to LP (about 23% of Pb-HCY); if single Pb-HCY fraction values are considered in terms of ratio between Pb-HCY (nmol) and mg of protein, VLDL and LDL fractions show the highest “affinity” for HCY. These results might explain the damaging effect of HCY on the vessel wall.
1996
- Affinità dell'omocisteina per le lipoproteine
[Abstract in Atti di Convegno]
Ventura, Paolo; Panini, Rossana; M. C., Pasini; Salvioli, Gianfranco
abstract
Il lavoro affronta in modo approfondito il legame dell'omocisteina alle lipoprpoteine
1996
- Does the measurement of portal flow velocity have any value in the identification of patients with cirrhosis at risk of digestive bleeding ?
[Articolo su rivista]
G., Cioni; E., Tincani; A., Cristani; Ventura, Paolo; P., D'Alimonte; C., Sardini; F., Turrini; Gl, Abbati; R., Romagnoli; E., Ventura
abstract
Upper gastrointestinal bleeding is a leading cause of death in patients with liver cirrhosis. In most cases haemorrhage originates from oesophageal varices or from congestive gastropathy, and the evaluation of the bleeding risk is based on oesophagogastroduodenoscopic data. The aim of this prospective study was to determine whether the measurement of portal flow velocity by Duplex-Doppler, compared with endoscopic data, can help in detecting patients with cirrhosis at risk of bleeding. One hundred and seventy-three patients underwent endoscopy to ascertain the size of the varices and the severity of congestive gastropathy. For each patient maximal portal flow velocity measurements were obtained. No difference in portal flow velocity was observed between patients with or without oesophageal varices or congestive gastropathy. During a 2-year observation period, 27 patients (15.6%) had at least one episode of acute digestive bleeding. Stepwise multiple logistic regression analysis demonstrated a correlation between oesophageal varices and congestive gastropathy endoscopic grading and the incidence of bleeding; only the former was entered into the final regression equation (p < 0.001). No relationship between the max portal flow velocity value and incidence of bleeding was found. This study shows that portal flow velocity is unrelated to the degree of the endoscopic abnormalities in patients with liver cirrhosis and that it has no value in the identification of patients with cirrhosis at risk of upper gastrointestinal bleeding.
1996
- Omocisteina: modificazioni in rapporto alla dieta e all’invecchiamento
[Articolo su rivista]
Salvioli, Gianfranco; Ventura, Paolo; Mussi, Chiara
abstract
L'articolo affronta le cause di iperomocisteinemia nell'anziano con particolare riferimento alle forme conseguenti a malnutrizione
1996
- One- and two-dimensional NMR study of complexation of ursodeoxycholic acid with beta-cyclodextrin
[Articolo su rivista]
Mucci, Adele; Schenetti, Luisa; Vandelli, Maria Angela; Forni, Flavio; Ventura, Paolo; Salvioli, Gianfranco
abstract
The interaction of ursodeoxycholic acid (UDCA) with beta-cyclodextrin (beta-CD) is investigated through one and two-dimensional (ROESY) NMR spectroscopy. The relative orientation of host and guest is unequivocally established: the aliphatic side chain of UDCA enters the torus of B-CD on the side of the secondary hydroxy groups.
1996
- Problemi dell'iperomocisteinemia nell'anziano
[Relazione in Atti di Convegno]
M. C., Pasini; Ventura, Paolo; Panini, Rossana; Salvioli, Gianfranco
abstract
Il lavoro riguarda i problemi dell'iperomocisteinemia nell'anziano affrontando gli aspetti fisiopatologici e le possibili conseguenzze cliniche
1996
- THE INTERACTION OF BILIAR ACIDS WITH 2-HYDROXYPROPYL-CYCLODEXTRIN IN SOLUTION AND IN THE SOLID STATE
[Articolo su rivista]
Mucci, Adele; Schenetti, Luisa; Salvioli, Gianfranco; Ventura, Paolo; Vandelli, Maria Angela; Forni, Flavio
abstract
The interaction of two biliar acids (chenodeoxycholic acid and cholic acid) with 2-hydroxypropyl-beta-cyclodextrin (HP beta CD) in solution and in the solid state was studied using different techniques. The formation of an inclusion complex with a 1 : 1 stoichiometry was suggested by the phase solubility studies. Both differential scanning calorimetry and X-ray diffractometry exhibited the amorphous state of the complex. The inclusion of both biliar acids into the HP beta CD cavity was confirmed by the C-13-NMR studies. Cholic acid showed a weaker affinity with respect to chenodeoxycholic acid probably owing to the presence of a hydroxyl group on C(12) (12 alpha) close to the complexation site.
1994
- Duplex Doppler ultrasonographic comparison of the effects of propranolol and isosorbide-5-mononitrate on portal hemodynamics
[Articolo su rivista]
E., Tincani; G., Cioni; A., Cristani; P., D'Alimonte; A., Vignoli; G., Abbati; Ventura, Paolo; R., Romagnoli; E., Ventura
abstract
Eighteen cirrhotic patients with esophageal varices at risk for bleeding took part in a double-blind study. The variations in PFV induced by either 40 mg of propranolol or 60 mg of sustained-release isosorbide-5-mononitrate on two consecutive days were evaluated with a duplex Doppler device. Both drugs caused a significant decrease in maximum (propranolol, P = 0.002; isosorbide-5-mononitrate, P = 0.021). Four patients responded to propranolol, three to isosorbide-5-mononitrate, and eight to both drugs; three did not show any change. Duplex Doppler sonography may be of use in the selection of the right pharmacologic treatment for the individual patient for the prevention of a bleeding esophageal varix.
1994
- Roxatidine in the treatment of gastroduodenal mucosal lesions in hepatic cirrhosis
[Articolo su rivista]
C., Sardini; Ventura, Paolo; G. L., Abbati; G., Rigo; G., Cioni; A., Cristani; E., Tincani; E., Ventura
abstract
In about 50% of patients with liver cirrhosis, upper digestive bleeding is not due to oesaphageal varices rupture, but to a group of peculiar mucosal lesions usually referred as "congestive gastropathy" and "hepatogenic ulcer". The pathogenesis of such mucosal damage is still unclear: an important causative role is commonly thought to be played by portal hypertension, but the role of peptical pathway and of the mucosal barrier impairment must not be underscored as well. Aim of this study was to evaluate the effect of roxatidine in the long-term treatment of mucosal damage in 19 patients with liver cirrhosis. Patients showed a good tolerance and no side effects. The improvement of endoscopic pattern after a three months period of roxatidine therapy was statistically significant; moreover there was no occurrence of digestive bleeding. In conclusion, H2 antagonist may be considered as the drug of choice for the treatment of mucosal damage in patients with liver cirrhosis, for both its safety and effectiveness.
1993
- Relevance of reduced portal flow velocity, low platelet count and enlarged spleen diameter in the non-invasive diagnosis of compensated liver cirrhosis
[Articolo su rivista]
G., Cioni; E., Tincani; P., D'Alimonte; A., Cristani; Ventura, Paolo; G., Abbati; A., Vignoli; R., Romagnoli; E., Ventura
abstract
OBJECTIVES: The aim of this prospective study was to identify the combination of parameters best able to predict the diagnosis of compensated cirrhosis. METHODS: One hundred and fourteen patients with suspected chronic compensated liver disease were divided, on the basis of bioptical findings, into two groups: group A, without cirrhosis (n = 58) and group B, with cirrhosis (n = 56). A number of biochemical parameters, the extent of oesophageal varices, spleen size, portal vein diameter and maximum and mean portal flow velocity measured by duplex-Doppler ultrasonography were taken into account in a binary forward-stepwise multiple logistic regression analysis. RESULTS: Only three variables were present in the final regression equation, maximum portal flow velocity affording the highest correlation with the histological diagnosis of cirrhosis (p = 0.0007), with an overall predictive value of 87.7%. When associated with the bipolar diameter of the spleen (p = 0.0169) and the number of platelets (p = 0.0487), the predictive value rose to 94.7%. If all three parameters were normal, a non-cirrhotic liver disease was most likely (96% probability); if two or three of the parameters were abnormal, liver cirrhosis was almost certain (98% probability); if only one parameter was abnormal, the clinical diagnosis was uncertain. CONCLUSIONS: This study emphasizes the usefulness of duplex Doppler ultrasonography in the non-invasive diagnosis of compensated cirrhosis.
1993
- The activity of misoprostol on the gastric and duodenal mucosal damage in patients with liver cirrhosis
[Articolo su rivista]
G., Abbati; G., Cioni; A., Cristani; G., Rigo; A., Vignoli; Ventura, Paolo; E., Tincani; E., Ventura
abstract
Twenty-five liver cirrhosis patients with endoscopically demonstrated gastro-duodenal mucosal damage (microhemorrhages, erosions, ulcers) were treated with misoprostol (prostaglandin E1) 400 mg/die. Eleven patients (44%) had abdominal pain and diarrhea and stopped treatment. Three months later, a new endoscopy was performed in the 11 patients that completed the study (3 patients were lost at follow up). Mucosal damage was stable in 5 patients (45%) and improved in 6 patients (55%), with complete absence of mucosal lesions in 2 patients (P = 0.027, Wilcoxon Ranks test). No case of worsening was observed and no patient had digestive bleeding during treatment. Digestive bleeding is a common complication of liver cirrhosis, originating in about 50% of cases from gastro-duodenal mucosal damage. Misoprostol suggests itself as a possible alternative therapy to the drugs usually utilized in these lesions (beta-blockers, H2-inhibitors), but individual intolerance is frequent and must be preliminary excluded.
1993
- Valutazione della massa epatica funzionante in casi di cirrosi epatica complicata da encefalopatia
[Articolo su rivista]
I., Venturini; Ventura, Paolo; M. L., Zeneroli; G., Cioni; C., Vezzelli; S., Avanzato; G., Casalgrandi; Farina, Franco; E., Ventura
abstract
scopo dello studio è di valutare la masa epatica funzionante mediante l'uitlizzo del test della clearance dell'antipirina<, si coinclude che i pazienti cirrotici con encefalkopatia epatica costituiscono un gruppo relativamente omogeneo in cui la capacità metabolica del fegato sembra essere in eguale misura e che l'encefalopatia epatica spontanea interviene soltanto quando la riduzione della massa epatica funzionante diventa estremamente rilevante
1992
- Duplex-Doppler assessment of cirrhosis in patients with chronic compensated liver disease
[Articolo su rivista]
G., Cioni; P., D'Alimonte; A., Cristani; Ventura, Paolo; G., Abbati; E., Tincani; R., Romagnoli; E., Ventura
abstract
Portal venous flow velocity (PFV) was measured with duplex-Doppler equipment in 50 normal subjects and in 117 patients with suspected chronic liver disease who showed no evidence of decompensation such as ascites, hepatic encephalopathy, jaundice or oesophageal bleeding. All the patients underwent percutaneous liver biopsy which demonstrated non-cirrhotic liver disease in 58 cases (CH-patients: steatosis 8, persistent chronic hepatitis 8, active chronic hepatitis 42) and liver cirrhosis in the other 59 cases (LC-patients). The normal subjects and the CH-patients had similar values of max-PFV and mean-PFV (max-PFV 26.7 +/- 3.2 and 25.7 +/- 3.4 cm/s respectively; mean-PFV 22.9 +/- 2.8 and 22.4 +/- 3.8 cm/s respectively). The LC-patients' values (max-PFV 19.3 +/- 3.5; mean-PFV 16.9 +/- 2.9) were significantly lower than those of the normal subjects (P less than 0.001) and of the CH-patients (P less than 0.001). Considering the normal max-PFV to be in the range 20-33.1 cm/s (mean +/- 2 s.d. of the normal subjects, 95% confidence limits), max-PFV was reduced in 0/50 normal subjects, 1/58 CH-patients and 39/59 LC-patients (66.1% sensitivity; 98.2% specificity). In conclusion, the duplex-Doppler measurement of PFV is of great interest in the diagnostic study of patients with suspected chronic compensated liver disease and in the early diagnosis of cirrhosis. A low max-PFV is a reliable pointer to liver cirrhosis, whereas a normal max-PFV indicates a non-cirrhotic liver disease but is less probative. Each centre should standardize normal PFV values in order to establish their own threshold value for diagnosing liver cirrhosis.
1992
- Duplex-Doppler ultrasonography in the evaluation of cirrhotic patients with portal hypertension and in the analysis of their response to drugs
[Articolo su rivista]
G., Cioni; P., D'Alimonte; F., Zerbinati; Ventura, Paolo; A., Cristani; A., Vignoli; R., Romagnoli; E., Ventura
abstract
Sixteen patients (15 males, aged 48-70) affected by liver cirrhosis and oesophageal varices were subjected to duplex-Doppler ultrasonographic study (DDUS). Four patients (three with a portal thrombosis and one with a hepatofugal portal flow) were excluded from the subsequent pharmacological test. The twelve remaining patients took part in a double blind cross-over study that evaluated the variations of heart rate (HR), mean systemic arterial pressure (SAP), portal vein diameter (PVD), maximal and mean portal flow velocity (PFV) after the administration of either 40 mg of propranolol or placebo per os, on two consecutive days. Propranolol caused no significant variation in mean SAP and in PVD, whereas it reduced the HR from 67.7 +/- 8.0 to 58.4 +/- 7.0 beats/min (mean +/- s.d.; P less than 0.001); the maxPFV dropped from 18.2 +/- 5.4 to 14.0 +/- 3.7 cm/s (P less than 0.001) and the meanPFV dropped from 15.3 +/- 4.1 to 13.2 +/- 3.1 cm/s (P less than 0.005). No significant variation was observed with placebo. After propranolol administration eight patients exhibited a significant maxPFV decrease, whereas the other four patients exhibited only a drop in HR, suggesting either drug inefficacy, inappropriate dosage or inadequate duration of treatment. DDUS is the only non-invasive method for the examination of the portal vein system.(ABSTRACT TRUNCATED AT 250 WORDS)
1992
- Epatocarcinoma e cirrosi misconosciuta
[Articolo su rivista]
A., Cristani; G., Cioni; E., Tincani; Ventura, Paolo; A., Vignoli; F., Zerbinati; E., Ventura
abstract
L'articolo affronta i problemi connessi con la definizione dei programmi di screening per epatocarcinoma
1992
- Hepatocellular carcinoma and unknown cirrhosis
[Abstract in Rivista]
A., Cristani; G., Cioni; A., Vignoli; Ventura, Paolo; E., Tincani; G. L., Abbati; E., Ventura
abstract
n Italy the incidence of hepatocellular-carcinoma (HCC) in patients with liver cirrhosis is estimated approximately 5% per year. The new imaging technologies make it possible to perform screening programs for the early detection of HCC in these patients; early diagnosis of HCC is recommended as the best strategy in order to enable surgical approach, which seems to be the only effective therapy: screening programs must consider the cost-benefit ratio in the choice of patients and standards of investigation. In the Japanese authors' opinion all patients with liver cirrhosis must be screened every three months with an ultrasonographic liver examination (US) and a measurement of serum alpha-1-fetoprotein level (AFP) and every nine months with a computed tomography (CT) of the liver: at a 5% annual incidence of HCC the cost of a single diagnosis is estimated about 8000 +. In our opinion the cirrhotic patients in Child's C class (approximately 20%) can be excluded from the screening programs, since the survival expectation of these patients is always poor, whether HCC is present or not. Furthermore, considering the acknowledged reliability of the US in the detection of space occupying lesions of the liver, periodical CT examination seems to be unproductive. AFP has a low sensibility as a marker of HCC; nevertheless a progressive increase of its levels can be considered an index of possible blastomatous transformation of cirrhotic liver. In comparison with the Japanese screening programs, the proposed changes might obtain a 55% reduction of the cost of a single diagnosis of HCC, without significant diagnostic loss.(ABSTRACT TRUNCATED AT 250 WORDS)
1992
- Interindividual variability of the number connection test
[Articolo su rivista]
M. L., Zeneroli; G., Cioni; Ventura, Paolo; A. M., Russo; I., Venturini; G., Casalgrandi; E., V.
abstract
Significant interindividuakl variability of number connection test ( a test used to evaluate liver encephalopaty grade in patients with decompensated liver cirrhosis) is demostrated, this making questionnable itsreal feasibility
1992
- Relevance of reduced portal flow velocity, low platelet count and enlarged spleen diameter in the non-invasive diagnosis of compensated liver cirrhosis
[Abstract in Rivista]
E., Tincani; G., Cioni; P., D'Alimonte; Ventura, Paolo; G. L., Abbati; A., Vignoli; R., Romagnoli; E., Ventura
abstract
The work deals with the possdibility to make diagnosis of liver cirrhosis by non invasive techiques such as the combination of measurement of portal fdlow velocity, spleen diameter and platelet count
1991
- Early diagnosis of hepatocarcinoma: criteria for the performance of screening in patients with liver cirrhosis
[Articolo su rivista]
A., Cristani; G., Cioni; A., Vignoli; F., Zerbinati; Ventura, Paolo; E., Tincani; M., De Santis; E., Ventura
abstract
In Italy the incidence of hepatocellular-carcinoma (HCC) in patients with liver cirrhosis is estimated approximately 5% per year. The new imaging technologies make it possible to perform screening programs for the early detection of HCC in these patients; early diagnosis of HCC is recommended as the best strategy in order to enable surgical approach, which seems to be the only effective therapy: screening programs must consider the cost-benefit ratio in the choice of patients and standards of investigation. In the Japanese authors' opinion all patients with liver cirrhosis must be screened every three months with an ultrasonographic liver examination (US) and a measurement of serum alpha-1-fetoprotein level (AFP) and every nine months with a computed tomography (CT) of the liver: at a 5% annual incidence of HCC the cost of a single diagnosis is estimated about 8000 +. In our opinion the cirrhotic patients in Child's C class (approximately 20%) can be excluded from the screening programs, since the survival expectation of these patients is always poor, whether HCC is present or not. Furthermore, considering the acknowledged reliability of the US in the detection of space occupying lesions of the liver, periodical CT examination seems to be unproductive. AFP has a low sensibility as a marker of HCC; nevertheless a progressive increase of its levels can be considered an index of possible blastomatous transformation of cirrhotic liver. In comparison with the Japanese screening programs, the proposed changes might obtain a 55% reduction of the cost of a single diagnosis of HCC, without significant diagnostic loss.(ABSTRACT TRUNCATED AT 250 WORDS)
1991
- Time sequence of coagulation data in patients with decompensated liver cirrhosis and suspected disseminated intravascular coagulation
[Articolo su rivista]
G., Cioni; A., Cristani; E., Tincani; Ventura, Paolo; G., Zagni; E., Ventura
abstract
In patients with liver cirrhosis, especially in the advanced stage, the coexistence of low clotting factor levels, hypofibrinogenemia, thrombocytopenia and elevated fibrin(ogen) degradation product (FDP) and D-dimer levels may suggest the presence of disseminated intravascular coagulation (DIC). In this study we evaluated, in 21 patients with decompensated liver cirrhosis and elevated FDP and D-dimer levels, the time sequence of their coagulation data during a follow-up period of 15 days after the first observation; our aim was to clarify if these patients tend to develop during this time interval a severe consumption coagulopathy as an expression of overt DIC. We evaluated serum fibrinogen, platelet count, prothrombin activity, serum FDP and plasma D-dimer levels at days 1, 3, 6, 10 and 15. The coagulation data were fairly stable during the study period in all patients, even in the two patients who had upper digestive tract bleeding during the study time. Only two patients affected by infectious diseases showed a decrease of D-dimer and FDP levels after healing. Our data suggest that in decompensated liver cirrhosis the detection of elevated FDP and D-dimer levels is seldom related to the occurrence of an overt DIC, at least during a short time interval; in this condition heparin therapy seems therefore not advisable and even potentially dangerous.