HEPATOLOGY WATCH®
Timely
Information for Practicing Physicians
HIGHLIGHTS OF
DIGESTIVE DISEASE WEEK®
AND THE MEETING OF
THE AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES
May
21-24, 2000
GASTROENTEROLOGY,
VOLUME 118 (SUPPLEMENT 2), 2000
Cholestatic
Liver DiseaseS
Primary biliary cirrhosis (PBC). Several studies
were presented which investigated the histologic features and therapy of PBC
and related disorders. Albert Czaja and
colleagues prospectively reviewed the liver biopsies of 15 patients with
autoimmune cholangitis (AIC), which had been deduced to be an antimitochondrial
antibody (AMA)-negative PBC equivalent from previous retrospective
analyses. AIC is defined as: 1)
antinuclear antibodies, smooth muscle antibodies and/or hypergammaglobulinemia;
2) absence of AMA; 3) cholestatic and hepatitic clinical and laboratory
features; and 4) exclusion of other diagnoses.
They found that there is no single histologic feature associated with
AIC as 7 biopsies were suggestive of PBC, 6 resembled primary sclerosing
cholangitis, and 2 had nondiagnostic histological patterns. AIC may represent a heterogeneous group of
hepatic disorders or a single disease entity with a mixed histological pattern. The report that celiac disease occurred in
6% of European patients with PBC prompted Kozhikode Menon et al. to study the
prevalence of celiac disease in a North American population of 75 PBC
patients. All patients tested negative
for IgA anti-endomysial antibody, suggesting that the prevalence of celiac
disease is low in North American PBC patients.
Paul Angulo and coworkers analyzed liver biopsy specimens from 210
unselected, noncirrhotic patients with PBC and showed that 2 years of
ursodeoxycholic (UDCA) therapy delayed the rate of histologic stage progression
compared to placebo or d-penicillamine therapy (p=.005). In a second study by Paul Angulo et al.,
oral silymarin did not add benefit, as measured by liver biochemistries and the
Mayo risk score, to patients with PBC who were suboptimal responders to UDCA
therapy. Roberta Jorgensen and
associates presented data showing that weight gain is a side effect of UDCA
therapy. In their trial the average
weight gain of UDCA-treated patients with PBC was 3.56 +/- 5.27 kg compared to
0.74 +/- 4.86 kg for placebo patients (p=.001). (Abstracts 17, 22, 26, 30, and
31)
Primary sclerosing cholangitis
(PSC). UCDA at a dose of 13-15 mg/kg/day leads to
biochemical improvement in some patients with PSC but does not appear to
improve other outcomes. Denise Harnois
and colleagues evaluated high-dose UDCA (25-30 mg/kg/day) therapy in a pilot
study of patients with PSC. Twenty-two
of 30 patients completed one year of therapy and had marked improvements in
liver biochemistries and Mayo risk scores compared to baseline. These results suggest that high-dose UDCA is
a potentially effective therapy for PSC, but further studies are
warranted. In a second study Muhsin
Kaya et al. treated 71 patients with PSC and dominant strictures with balloon
dilation with or without stenting. They
found that stenting following balloon dilation did not improve cholestasis
compared to balloon dilation alone.
Furthermore, stenting was associated with more intervention-related
complications and a greater incidence of acute cholangitis. In another study, Paul Angulo and coworkers
conducted a retrospective analysis of the small-duct variant of PSC associated
with a normal cholangiogram, which is found in some patients with inflammatory
bowel disease. They reported that this
PSC variant is a small subgroup with clinical, biochemical, and histologic
features similar to those of classic PSC.
Over time, small-duct PSC may evolve to classic PSC with
cholangiographic abnormalities and progress to end-stage liver disease. (Abstracts 35, 35, and 33)
Bone histomorphometric changes in
cholestatic liver diseases. Severe osteopenia is seen in patients with
end-stage cholestatic liver disease. M.
Guichelaar and colleagues performed bone histomorphometric analyses on iliac
crest bone biopsies obtained from PBC (n=22) and PSC (n=30) patients at the
time of liver transplantation. All
patients had decreases in bone volume and osteoid deposition. In females (n=34), but not males (n=18),
markers of bone resorption were increased and markers of bone formation were
decreased. The osteopenia in females is
explained by these changes in bone resorption/formation parameters, but the
mechanism of osteopenia in males is unclear.
(Abstract 961)
Hepatitis
Autoimmune hepatitis (AIH). George Winters and
coworkers report the results of treating 6 AIH patients refractory to, or
intolerant of, standard therapy (prednisone and azathioprine) with FK506
(tacrolimus). Serum ALT levels were
reduced in all patients and normalized in 4 of the patients. Four patients were able to decrease their
doses or discontinue prednisone. Only
one patient reported a side effect (tardive dyskinesia-like symptoms that
resolved with vitamin C therapy). This
preliminary observation suggests that tacrolimus may be a potentially effective
therapy for refractory AIH, but larger studies with histologic assessment are
needed. (Abstract 14)
Minocycline hepatitis. Nasser Bayati et
al. compared clinical and histopathological features of 4 patients with
minocycline hepatitis with those of 10 AIH patients. Laboratory findings (ANA titers and liver biochemistries) were
similar between the two groups except for a trend toward higher IgG and ESR
levels in patients with AIH. No
histological differences were found to distinguish minocycline hepatitis from
AIH. A recent history of minocycline
ingestion must be excluded in order to establish the diagnosis of AIH. (Abstract 16)
Latent hepatitis B virus (HBV) in liver
transplantation. Hiroyuki Marusawa and associates studied the molecular forms of
latent HBV liver tissue infection in 32 liver organ donors positive for
anti-HBc but negative for HBsAg. HBV
DNA was not detected in the sera of any of the donors; however, covalently
closed circular (ccc) DNA forms of HBV were found in the liver tissue of 24 of
the donors. Detection of both anti-HBc
and anti-HBs or anti-HBe in serum was correlated with the presence of HBV
genome in the liver tissue. These
findings indicate that the majority of anti-HBc-positive/HBsAg-negative donors
are latently infected with HBV.
(Abstract 171)
Hepatitis C virus (HCV) infection
in African Americans (AAs). Thelma Wiley and coworkers reviewed the
records of 289 patients with HCV infection seen at the University of Illinois
from 1996 to 1999. There were 93 AA
patients and 196 non-AA patients. They
found that AAs were more likely to be infected with gentoype 1 HCV and tended
to progress more slowly. Early in the
course of HCV infection, AA patients had lower serum ALT levels, lower
histological activity index scores on liver biopsy, and a lower frequency of
cirrhosis compared to non-AA patients.
(Abstract 3585)
Esophageal
Varices
Meta-analysis of prophylactic
variceal ligation (PVL). Thomas Imperiale and colleagues performed a meta-analysis
of 8 randomized controlled trials investigating PVL. These trials had been identified through a MEDLINE search
(1993-1999). Five trials (n=601)
compared PVL to untreated controls and 3 trials (n=253) compared PVL to
beta-blocker therapy. Compared to
untreated controls, PVL reduced esophageal variceal bleed-related outcomes,
including all-cause mortality. Compared
to beta-blocker therapy, PVL reduced the risk for the first esophageal variceal
bleed but did not effect mortality.
Further studies are needed, but the authors suggest that PVL might be
considered for patients with large esophageal varices who cannot tolerate or
have contraindications to beta-blockers.
(Abstract 989)
Choledochal
Cysts
Treatment and complications. Clarence Wong et
al. retrospectively reviewed the clinical courses of 14 adult patients with
choledochal cysts. Abdominal pain was
the most common presentation (86%), followed by jaundice in 50%. The classic triad of abdominal pain,
abdominal mass and jaundice was found in only 2 patients (14%). Nine choledochol cysts were type I, two type
II, two type IVa and one type V.
Complications included acute cholangitis and cholangiocarcinoma. Early diagnosis with ERCP is recommended,
and surgical excision can result in symptomatic relief and prolonged
survival. (Abstract 10)
PEGYLATED INTERFERONS
At satellite symposia sponsored by Roche and Schering, the results of recently completed phase III studies comparing pegylated interferon (PEG IFN) with standard IFN for the treatment of chronic hepatitis C were reviewed. Polyethylene glycol (PEG) is a water-soluble polymer that can be covalently linked to proteins such as IFN, which markedly increases the half-life resulting in sustained serum levels and allowing once weekly dosing. Two PEG IFNs are being studied, the branched 40 kDa PEG IFN a-2a (Pegasys™, Roche) and the linear 12 kDa PEG IFN a-2b (PEG-Intron, Schering). At the Roche symposium, Dr. Shiffman reviewed the major clinical trials reported to date with Pegasys. Phase II studies revealed that the appropriate dose of Pegasys was 180 mg once weekly, resulting in a sustained virological response (SVR) rates of 36% with 48 weeks of therapy in noncirrhotic patients and 30% in cirrhotic patients. A large non-US based study of 531 naïve patients treated for 48 weeks showed a SVR rate of 39% with Pegasys compared to 19% with standard IFN a-2a [Zeuzem et al. J Hepatol 2000;32(Suppl 2):29]. At the Schering symposium, Dr. Lindsay presented data from the US/International study of weekly PEG-Intron versus INF a-2b tiw for 48 weeks in 1219 patients with untreated chronic hepatitis C [Trepo et al. J Hepatol 2000;32(Suppl 2):29]. The SVR rates were 25% with PEG-Intron 1.0 mg/kg and 23% with PEG-Intron 1.5 mg/kg versus 12% with IFN a-2b. Thus, PEG IFNs roughly double SVR rates compared to standard IFNs (39% vs. 19% with Pegasys, and 23% and 25% vs. 12% with PEG-Intron). In both studies, patients with genotype 1 and higher viral loads had reduced SVR rates. Both PEG IFNs were tolerated as well as the standard IFNs, with discontinuation rates ranging from 6% to 11% in all treatment groups. It is likely that the efficacy of the PEG IFNs will be enhanced by the addition of ribavirin to treatment regimens, as suggested by a small pilot study showing a SVR rate of 50%. The results of ongoing large studies of combination therapy with Pegasys or PEG-Intron and ribavirin are eagerly awaited.
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