HEPATOLOGY WATCH®
Timely
Information for Practicing Physicians
HIGHLIGHTS OF Digestive disease week® May 20-23, 2001,
atlanta
Chronic Hepatitis
C Virus (HCV) INFECTION
Pegylated interferon (PEG IFN). Kenneth
Rothstein et al performed a study comparing PEG IFN alfa-2a 180 μg weekly
vs. standard IFN alfa-2b plus ribavirin in patients with chronic hepatitis C
(n=412). At week 12, HCV RNA was undetectable in 46.8% of patients receiving
PEG IFN and 50.3% of patients given standard IFN plus ribavirin. PEG IFN was
associated with fewer adverse events (anemia, dyspnea, nausea, and pruritus)
and more favorable quality-of-life scores compared to therapy with standard IFN
plus ribavirin. These data suggest that standard IFN plus ribavirin and PEG IFN
have similar efficacy for chronic HCV infection and that PEG IFN is better tolerated.
In a second study, Ira Jacobson and coworkers reported the
preliminary results of a trial in which patients with chronic hepatitis C who
were nonresponders to prior IFN monotherapy or combination therapy or were
relapsers after combination therapy were randomized to one of two dose regimens
of PEG IFN alfa-2b weekly plus ribavirin (PEG IFN alfa-2b 1.0 μg/kg and
ribavirin 1000-1200 mg/d vs PEG IFN alfa-2b 1.5 μg/kg and ribavirin 800
mg/d). Thus far, 13 of 28 patients completing 24 weeks of therapy have achieved
a virological response (210 patients enrolled). These preliminary findings
suggest that PEG IFN and ribavirin may have efficacy in HCV patients who have
failed previous IFN-based treatments.
(Abstracts 416 and 1964)
NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) AND
Nonalcoholic Steatohepatitis (NASH)
Demographic characteristics.
NAFLD ranges from simple fatty liver to fat with inflammation and
fibrosis. Jeanne Clark and colleagues studied the prevalence of NAFLD in a
large population (n=13,500) from the Third National Health and Nutrition
Examination Survey (1988-1994). NAFLD was found to have a prevalence of 23.5%
and was the most common cause of abnormal liver enzyme levels. NAFLD was more
common among men than women and among African Americans compared to
Caucasians. However, Luisa Santos and
coworkers found NASH to be rare among African Americans (1.4%) compared to
Caucasians (7%) and Hispanics (8%) in a retrospective analysis of 51 NASH
patients derived from a large population of patients (n=861) evaluated in a
hepatology clinic. Nyingi Kemmer et al evaluated 60 patients enrolled from
endocrinology clinics and found that CT scan and ultrasound are valuable
screening tests for identifying fatty liver and that advanced NASH is common
among Mexican American women with type II diabetes. Sunil Ramrakhiani et al reviewed more than 3500 liver biopsies
and observed that patients with features of both steatohepatitis and another
chronic liver disease have risk factors commonly associated with NASH
(diabetes, obesity, and hyperlipidemia).
(Abstracts 344, 630, 631, and 632)
Cirrhosis
Esophageal varices. Gennaro
D'Amico and colleagues assessed the incidence of esophageal varices in 494
patients enrolled in a prospective study of the natural history of liver
cirrhosis between 1981 and 1984. At
baseline, 225 of these patients did not have esophageal varices. Patients underwent serial endoscopies at 1-
to 3-year intervals or at the time of bleeding. After a mean follow-up of 131 months, varices were detected in 93
patients (41%). Thirty patients bled; 30 patients with varices died; and 36
patients without varices died. In this
group of patients with newly diagnosed compensated cirrhosis at baseline, the
incidence of varices was 4.5% per year; mortality in patients without varices
was 3% per year; and mortality from bleeding was 0.5% per year. (Abstract 9)
Liver Transplantation
Prognostic factors for donor and recipient. Living
donor liver transplantation (LDLT) was first introduced in 1989 and its use is
rapidly expanding. The process of donor evaluation is variable. Sherfield
Dawson et al retrospectively analyzed liver biopsy, body mass index (BMI), and
ALT data from 56 donors from 1997 to 2000. They found that no patients with a
BMI <30 plus ALT <35 had steatosis >10% and that only 1 of 9 patients
with a BMI <30 with ALT >35 had steatosis >10%. These data suggest that assessment of donor
BMI and ALT may allow liver biopsy to be avoided in the evaluation of most
living donors. In addition, Kimberly Beavers and coworkers conducted a study in
which living donors (n=26) were asked to complete a questionnaire that included
an assessment of the donor process and a validated health assessment tool
(SF-12). Mean hospital stay was 8 days
(range, 3-14 days); mean recovery time was 12 weeks (range, 1-52 weeks);
hospitalization for donor-related adverse events occurred in 23% of patients;
and 32% experienced more pain than had been expected. However, 92% of donors
returned to their occupation. In regard
to transplant recipients, Preeti John et al reviewed the clinical records of 57
patients with pretransplant diabetes mellitus (PTDM) and 114 contemporary
nondiabetic controls that were age, sex, and race matched. Compared to the control group, the PTDM
patients had greater rates of several post-liver transplant complications and
their 5-year survival rate was less (19.3% vs 38.6%. P=0.02). These data show that PTDM is associated with
increased late post-transplant mortality.
(Abstracts 121, 125, and 491)
Mayo Clinic End-Stage Liver Disease
(MELD) Model
Prediction of survival.
The MELD model accurately predicts survival for patients treated
electively with TIPS and for non- transplant patients with cirrhosis. Patrick
Kamanth and associates at the Mayo Clinic evaluated the ability of the MELD
model to classify patients with a broad range of liver diseases according to
their risk of death in a defined time frame in 4 independent data sets. These
data sets included patients with cirrhosis hospitalized for decompensated liver
disease (n=385), ambulatory patients with noncholestatic cirrhosis (n=491), PBC
patients (n=418), and patients from the 1980s with cirrhosis (n=1622). Using
concordance statistical analysis, the MELD model was found to be a reliable
measure of short- to medium-term mortality for these patients. The authors
suggest that the MELD model may be used to prioritize organs for liver
transplantation. In contrast, Jesus
Carole et al studied 70 patients listed for liver transplantation at the
University of Nebraska Medical Center and found the MELD model to underestimate
mortality in high-risk patients and to overestimate mortality in low-risk
patients. These data indicated that the
MELD model did not accurately predict mortality in patients who were liver
transplant candidates. (Abstracts 338
and 411)
Primary
Sclerosing Cholangitis (PSC)
Association with other diseases. Some
patients with cystic fibrosis (CF) develop liver disease with cholangiographic
features resembling PSC. CF is due to mutations in CFTR; thus, Sunil Sheth and
colleagues investigated 18 patients with PSC and 35 controls (PBC [n=17] and
IBD without PSC [n=18]) for CFTR genotype and phenotype abnormalities. CFTR
mutations were present in 6 PSC patients compared to 2 controls (33% vs 6%, P=0.014).
Sweat chloride tests were normal in all patients; however, nasal potential
difference testing revealed a reduced chloride response in 8 of 16 PSC patients
compared to 3 of 32 controls (50% vs 9%, P=0.003). Thus, 12 PSC patients
(67%) compared to 6 controls (17%) had genotypic and/or phenotypic CFTR
abnormalities (P=0.0006), suggesting that the CF carrier state may
predispose to PSC. In a second study, Daniel Buckles et al investigated the
prevalence of gallbladder cancer in patients with PSC who underwent
cholecystectomy (n=102). Fourteen (13.7%) PSC patients had gallbladder masses
and 8 of the masses were found to be adenocarcinomas. This study suggests that
gallbladder tumors are common in PSC patients and are often malignant, thus
justifying cholecystectomy for gallbladder masses. (Abstracts 405 and 406)
SATELLITE SYMPOSIA
New approaches
for HCV infection using peginterferon (PEG IFN) alfa-2a. This symposium provided an update
on the current status of antiviral therapy for chronic hepatitis C, with
particular reference to the use of the pegylated IFN. The symposium was
co-chaired by Dr. Jenny Heathcote from the University of Toronto and Dr. Raj
Reddy from the University of Miami. Dr.
Tom Shaw-Stiffel from the University of Rochester reviewed the process of
pegylation - a pharmacological technique involving attachment of
PEG polymers to proteins to enhance pharmacokinetic properties. Currently two
types of PEG IFN are in clinical trials. PEG IFN alfa-2a (PEGASYS) has a 40 kDa
branched structure whereas PEG IFN alfa-2b (PEG-INTRON) has a 12 kDa linear
structure. Based on different structures and metabolism, some clinically
relevant differences in dosing have been ascertained. PEG IFN alfa-2a is used
in a uniform dose of 180 μg dispensed in a stable solution. Weight-based
dosing is necessary for PEG IFN alfa-2b with reconstitution of a lyophilized
powder before injection. No reduction in PEG IFN alfa-2a is necessary despite
renal impairment with creatinine clearances as low as 20 mL/min, while dose
reduction may be required for PEG IFN alfa-2b when creatinine clearance is less
than 50 mL/min. Dr. Raj Reddy reviewed the goals of therapy in HCV infection
and the initial clinical data using the PEG IFN initially as monotherapy and
more recently in combination with ribavirin.
Histological improvement may be seen even in the absence of a sustained
virological response (SVR). Dr. Graham
Cooksley from the University of Queensland provided additional information on
recently concluded studies using PEG IFN combined with ribavirin. The SVR was 54% for patients who received
PEG IFN alfa-2b in a dose of 1.5 μg/kg plus ribavirin for 48 weeks. For patients with genotype 1, the SVR was
42%. In a separate study of PEG IFN
alfa-2a 180 μg plus ribavirin, the overall SVR was 57% and 45% for
patients with genotype 1. Dr. Paul
Martin from Cedars-Sinai Medical Center in Los Angeles addressed therapy in
patient groups with poorer response rates. Of African American patients, 15%
had an SVR with PEG IFN alfa-2a compared to 0% treated with standard alpha IFN
monotherapy. Fourteen percent of African American patients had an SVR with PEG
IFN alfa-2b and 6% of Hispanics compared to 0% for both groups with standard
IFN alpha therapy. Genotype 4 patients
also had improved SVR rates with PEG IFN alfa-2a. Data were also presented from
various quality-of-life studies suggesting that PEG interferon therapy was at
least as well tolerated as therapy with the combination of standard interferon
and ribavirin. Data were also reviewed
from the study presented by Fried et al at DDW of PEG IFN alfa-2a plus
ribavirin about the predictive value of testing HCV RNA at week 12 of therapy.
Sixty-five percent of the group with a response by 12 weeks had an SVR, but
only 3% of patients without a virological response by this time achieved an
SVR.
Combination of peginterferon
alfa-2b and ribavirin. This event addressed new data on the combination of
PEG IFN alfa-2b and ribavirin. The meeting was chaired by Dr. Willis Maddrey;
speakers included Drs. Bruce Bacon, Luis Balart, Ira Jacobson and John
McHutchison. SVR rates with this new combination for initial treatment of
suitable chronic hepatitis C patients were superior to standard IFN alfa-2b
plus ribavirin (54% vs 47%), with a similar side effect profile. Weight-based
dosing of both drugs further increased these response rates to 61% when PEG IFN
alfa-2b (1.5 μg/kg/week) and ribavirin (13 ± 2 mg/kg/d) were dosed accordingly. Because adherence to
therapy enhances response rates further, strategies to manage side effects and
thus allow patients to receive most of their medications, treat depression, and
other issues were discussed in detail. Treatment of patients with normal ALT
values or mild disease showed that these patients have similar response rates
to those with elevated liver tests, and while still controversial, the approach
to these patients might be individualized. Preliminary data regarding
retreatment of IFN/ribavirin nonresponders with PEG IFN plus ribavirin were
also presented, suggesting that these results are promising and a significant
proportion of these patients do respond during retreatment, but sustained
response data are still awaited. The role of maintenance low-dose PEG IFN
monotherapy in nonresponders with significant fibrosis to delay progression and
prevent future disease and complications was also highlighted. To summarize,
PEG IFN alfa-2b (currently FDA approved) plus ribavirin will provide an
incremental advance for patients with chronic hepatitis C in terms of sustained
response, where 61% of patients can now achieve a sustained response and its
potential long-term benefits.
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