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HEPATOLOGY WATCH® |
Editorial Board: Emmet B. Keeffe, MD
(Chair); M. Eric Gershwin, MD; Ira S. Goldman, MD; John L. Gollan, MD, PhD; Kris V. Kowdley, MD; Paul
Martin, MD; Marion G. Peters, MD |
ABSTRACT HIGHLIGHTS OF DIGESTIVE DISEASE WEEK®
NONALCOHOLIC
STEATOHEPATITIS (NASH)
Studies
of pioglitazone therapy.
S. Harrison et al. report results of the initial 22 patients who have
completed the first double-blind, placebo-controlled study in which NASH
patients are randomized to receive pioglitazone (45 mg) (n = 12) or placebo (n
= 10) for 6 months. Pioglitazone
treatment resulted in improvements in the metabolic profile and liver histology
compared to placebo. Specific
improvements related to pioglitazone included decreases in ALT and AST levels
(p < 0.001) and increases in plasma adiponectin levels (p < 0.01)
associated with decreases in hepatic fat content by MRI (p < 0.05). In patients with type II diabetes mellitus,
pioglitazone therapy was associated with reductions in HbA1c (P <
0.04). Moreover, follow-up liver
biopsies in pioglitazone-treated patients showed significant improvement in
ballooning degeneration, steatosis, and fibrosis. Fifty patients are planned to be enrolled
into this study. In a second study, G.
Lutchman et al. found that significant increases in serum ALT levels and
worsening of insulin resistance and hepatic steatosis and inflammation
developed in 8 patients 48 weeks after discontinuation of pioglitazone
treatment for NASH. Fibrosis scores
remained unchanged. These results
suggest the need for pioglitazone maintenance therapy for NASH. (Abstracts 1 and 472)
Novel
genetic markers.
H. Huang and colleagues analyzed possible genetic markers associated
with NASH in 187 subjects (60 normals, 55 with steatosis, 50 with NASH, and 22
with NAFLD-related cirrhosis) with available DNA using a candidate gene
approach. An increased risk of NASH was
associated with a missense SNP in the gene coding DEAD box polypeptide 5 and a
SNP (N166S) in the gene coding microsomal triglyceride transfer protein. These findings are novel and interesting but
require confirmation in larger studies.
(Abstract 470)
FIBROSIS
Correlation
with FibroSpect II (FSII) results. FSII is a panel of serum markers consisting
of hyaluronic acid, tissue inhibitor of metalloproteinase I, and alpha2
macroglobulin. L. Jeffers and coworkers
prospectively compared FSII results with laparoscopic biopsy findings in 75
patients with chronic hepatitis C. The
prevalence of F2-F4 fibrosis was 85.3%, and FSII had a sensitivity of 67.2%,
specificity of 72.7%, positive predictive value of 93.5%, negative predictive
value of 27.6%, and an accuracy of 68%.
These results suggest a role for FSII in the evaluation of chronic
hepatitis C patients with a high prevalence of fibrosis. Further studies are warranted. (Abstract 82)
CIRRHOSIS
Model
for end-stage liver disease (MELD) predicts survival in cirrhotics after surgery. S.G. Teh and others performed a retrospective
analysis of the ability of MELD to predict survival in 1,076 cirrhotic patients
who underwent non-liver transplant surgery between 1980 and 2004. Survival rate was not related to when the
surgery was performed (1980-1991 vs. 1993-2004) or to the type of surgery. However, MELD scores were strongly associated
with both short-term and long-term survival.
Patients with a MELD score ≤ 10 may proceed with non-transplant
surgery without an evaluation for liver transplantation as a back-up for the
potential of decompensation. These
findings showed that MELD can accurately estimate post-operative mortality in
cirrhotic patients independent of the type of surgical procedure. (Abstract 4)
CHRONIC
HEPATITIS C VIRUS INFECTION (HCV)
Virologic
response at week 12 is predictive of sustained response. T. Poynard et al. conducted a study in which
575 HCV patients who failed to respond to or relapsed after treatment with
interferon alfa and/or ribavirin therapy received peginterferon alfa-2b (1.5
ug/kg subcutaneously once weekly) plus ribavirin (800-1400 mg/day based on
weight) for up to 48 weeks. Sustained
virological response (SVR) occurred in 21% of patients. Among patients who were HCV RNA-negative at
week 12, 61% achieved SVR. The SVR rate
was greater in previously relapsing patients compared to nonresponders (39% vs.
15%). However, previously relapsing
patients and nonresponders who were HCV RNA-negative at week 12 were equally
likely to achieve SVR (61% vs. 59%).
This study demonstrated that peginterferon alfa-2b is effective salvage
therapy for interferon alfa and ribavirin failures, and virologic response at
week 12 is predictive for SVR. (Abstract
5)
Effect
of race on response to therapy.
S.B. Missiha and others reviewed data from 472 previously untreated HCV
patients who participated in a multicenter study of peginterferon plus
ribavirin to investigate the affect of race on response rates. SVR was achieved in 45% of 417 Caucasian
patients and 67% of 55 Asian patients in this study (p = 0.0022). Multivariate logistic regression analysis
adjusted for genotype, adherence to drug therapy, and other factors identified
Asian race to be independently associated with a higher probability of
SVR. In a second study, J.B. Gross et
al. analyzed the response rate of 110 African American (AA) patients with HCV
infection who had not responded to initial interferon plus ribavirin therapy
and participated in a national study evaluating retreatment with ribavirin
(12-15 mg/kg/day) plus peginterferon alfa-2b for 48 weeks. Patients were randomized to receive either
1.5 or 3 mcg/kg/week of peginterferon alfa-2b.
SVR was achieved in 14% of AA patients treated with the higher
peginterferon dose compared to 2% treated with the lower dose (p = 0.032). SVR was not associated with body weight or
liver fibrosis. (Abstracts 86 and 87).
DRUG-INDUCED
LIVER DISEASE
Clinical
characteristics and prognosis.
E. Bjornsson and R. Olsson reviewed all hepatic drug adverse events with
a possible or probable causality assessment reported to the Swedish Adverse
Drug Reactions Advisory Committee from 1970 to 2004 to evaluate outcomes of a
large number of cases of drug-induced liver disease. A specific objective was to investigate if
the combination of a high aminotransferase level (ALT ≥ 3 x ULN) and
jaundice (bilirubin ≥ 2 x ULN) is associated with a high mortality rate
(Hy's rule). A total of 836 cases were
collected: 454 cases due to hepatocellular (HC) injury, 213 cases due to
cholestatic (CS) injury, and 169 cases due to mixed pattern injury. The mortality/transplantation rate was 11.8%
in the HC group. The death rates were
10.3% and 5.9% in the CS and mixed groups, respectively. A forward stepwise logistic regression
analysis identified AST and bilirubin levels to independently predict death or
transplantation in the HC group (p < 0.0001) while only the bilirubin level
was found to predict for death in the CS and mixed liver injury groups (p =
0.007). Mortality rates were seen to
vary according to the drug involved.
These data confirm that AST and bilirubin levels are the most important
predictors of death or transplantation.
(Abstract 181)
PRIMARY
BILIARY CIRRHOSIS (PBC)
Asymptomatic
PBC diagnosed at an advanced age does not affect survival. R. Terada and others reviewed the clinical
courses of 318 patients diagnosed with asymptomatic PBC at the
HEPATOCELLULAR
CARCINOMA (HCC)
Surgical
treatments. E. Johnson and
associates examined the hospital discharge database for the state of
CHRONIC
HEPATITIS B VIRUS INFECTION (HBV)
Viral
load is a predictor of cirrhosis. C.J. Chen et al determined that viral load is
a strong predictor for the development of cirrhosis in patients with chronic
HBV infection by prospectively following a cohort of 3,851 Taiwanese patients
with chronic HBV infection. The diagnosis of cirrhosis was based on
ultrasonography findings, and all cases of cirrhosis diagnosed within 6 months
of enrollment were excluded from the analysis.
It was observed that the risk of cirrhosis in both HBeAg-positive and
HBeAg-negative patients correlated with increasing serum HBV DNA levels in a
dose-dependent manner. (Abstract 319)
New
treatments. Two papers
reported results of studies of entecavir (ETV), a potent inhibitor of HBV DNA
polymerase. In the first study, R.G.
Gish and colleagues randomized 709 patients with HBeAg(+) HBV to receive 48
weeks of treatment with ETV or lamivudine (LVD). Patients who achieved a protocol-defined
complete response (CR) (serum HBV DNA < 0.7 MEq/mL by bDNA assay and HBeAg
loss) at 48 weeks discontinued therapy and were followed for 24 weeks. CR at week 48 was achieved by a greater
proportion of ETV-treated patients and than LVD-treated patients (p <
0.0001). At 24 weeks off treatment, 82%
of patients with CR at week 48 in the ETV group compared to 73% of patients
with CR at week 48 in the LVD group remained in CR. These data show that ETV-induced CRs are
frequently durable. ¨ In a second paper, R.G. Gish and others
reviewed 4 studies of ETV therapy to evaluate safety. They found that ETV has a similar safety
profile to LVD in nucleoside-naive and LVD-refractory patients. Discontinuations due to adverse events
occurred less frequently in ETV-treated patients than in LVD-treated patients. ¨ S. Hadziyannis
et al. reported the results of long-term adefovir dipivoxil (ADV) treatment in
patients with HBeAg(-) HBV. Seventy and
67 patients in this study continued ADV treatment for 144 and 192 weeks,
respectively. HBV DNA became
undetectable in 85% of patients. The
median decrease in serum HBV DNA levels was 3.71 log10 copies/mL. Serum ALT normalized in 44 (81%) of 54
evaluable patients and HBsAg seroconversion was observed in 4 patients. The cumulative incidences of ADV resistance
at weeks 48, 96, 144, and 192 were 0%, 3%, 11%, and 18%, respectively. ¨ Finally, in a
phase II study, C. Lai and colleagues report that 2 years of treatment with
telbivudine doubled the HBV DNA clearance rate and nearly doubled the ALT
normalization rate with a lower resistance-related treatment failure rate
compared to LVD therapy. (Abstracts 320,
321, 322, and 323)
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