HEPATOLOGY WATCH®
Timely
Information for Practicing Physicians
march 2002
Primary Biliary Cirrhosis (PBC)
Autoimmune
mechanism of disease. Antimitochondrial antibodies (AMAs) have
been shown to react with PDC-E2, a critical mitochondrial enzyme. Recent papers by Hirota Kita et al. and
Shuji Matsumura et al. describe potential autoimmune mechanisms underlying the
development of PBC. These studies
demonstrate that the region of PDC-E2 recognized by AMAs is virtually identical
for B cells, CD4+, as well as CD8+ T cells.
Furthermore, when biliary epithelial cells undergo apoptosis, they
release immunogenic fragments that are identical to those recognized by AMAs in
PBC. These data suggest that PBC starts
as an immunological insult to this same region of PDC-E2, either by chemical or
by molecular mimicry of an infectious agent.
(Kita H, et al. J Exp Med 2002;195:113-123 and Matsumura S, et
al. Hepatology 2002;35:14-22)
PBC with features of autoimmune hepatitis (AIH). A
clinical investigation performed by Supriya Joshi and colleagues studied the
effects of ursodeoxycholic (UDCA) therapy for PBC patients with additional
features of AIH as defined by 2 or more of the following criteria: 1) ALT >
5 x ULN; 2) IgG > 2 x ULN or positive smooth muscle antibody; and 3)
moderate to severe lobular inflammation on biopsy. After 2 years of treatment with UDCA, changes in serum
biochemistry and immunoglobulin levels were similar in PBC patients with or
without AIH features. Moreover, the
survival of ANA-positive patients was similar to that of ANA-negative
patients. Thus, the response to UDCA in
PBC patients with or without features of AIH is similar. (Joshi S, et al. Hepatology
2002;35:409-413)
CHRONIC Hepatitis C Virus (HCV)
INFECTION
Cognitive and
neuropsychological impairment. Daniel Forton and colleagues tested viremic
patients with mild chronic hepatitis C (n = 27) and patients who cleared HCV,
either spontaneously or after antiviral therapy, (n = 16) with a computer-based
cognitive assessment battery. The
results of these tests showed that HCV-infected patients were impaired on more
cognitive tasks than the patients who cleared HCV (p = 0.02). Further, cerebral proton magnetic resonance
spectroscopy (MRS) revealed the choline/creatine ratio to be elevated in the
basal ganglia and white matter of HCV-infected patients. This preliminary investigation demonstrated
cognitive impairment in HCV patients with mild liver disease; the abnormal
findings on MRS suggest a biological basis of this impairment. Robin Hilsabeck and coworkers administered
neuropsychological tests to patients with either chronic hepatitis C (n= 66) or
other chronic liver diseases (n = 14).
Cognitive impairment was observed in areas measuring sustained attention
and concentration. Test scores of
patients with chronic hepatitis C were similar to those of patients with other
chronic liver diseases. Greater hepatic
fibrosis was associated with poorer performance, however patients with and
without cirrhosis exhibited cognitive dysfunction. These findings indicate that progressive hepatic injury (whether
or not due to HCV infection) may result in cognitive impairment. Both of these studies are provocative but
must be considered preliminary; larger studies with further controls are needed
in this important area of research. (Forton DM, et al. Hepatology
2002;35:433-439 and Hilsabeck RC, et al. Hepatology 2002;35:440-446)
Nonalcoholic Steatohepatitis (NASH)
Association with
the insulin resistance syndrome. NASH is associated with disorders that are
characterized by hyperinsulinemia and insulin resistance (IR). Recent data indicate that NASH may be a
feature of the IR syndrome (central obesity, impaired glucose tolerance,
dyslipidemia, and hypertension).
Shivakumar Chitturi et al. utilized the homeostasis model assessment
(HOMA) to determine IR in 66 patients with NASH and 36 age- and sex-matched
controls with chronic hepatitis C. IR was confirmed in 65 NASH patients (98%),
and 55 (87%) of these patients fulfilled minimum criteria for the IR syndrome. The IR values and prevalence of IR syndrome
(75% vs 8.3%) were significantly higher in NASH patients than in comparable
cases of chronic hepatitis C. In a
second study, Gianfranco Pagano and colleagues analyzed 38 subjects (19
patients with NASH and 19 age- and sex-matched normal controls). NASH patients
were found to have lower insulin sensitivity (p = 0.0003) and higher total
insulin secretion (p = 0.001) than controls.
Furthermore, 9 NASH patients (47%) had at least 2 criteria required to
define the metabolic syndrome according to the European Group for the Study of
Insulin Resistance (EGIR). The data
from these 2 studies further support the concept that NASH is specifically
associated with the IR syndrome.
Finally, Kimberly Woodcroft and associates conducted studies of
molecular regulatory mechanisms showing that insulin mediates hepatic CYP2E1
expression by enhancing CYP2E1 mRNA degradation and by decreasing CYP2E1 gene
transcription. CYP2E1 has been
implicated in the generation of tissue-damaging hydroxyl radicals, a potential
“second hit” in patients with NASH. (Chitturi S, et al. Hepatology 2002;35:373-379;
Pagano G, et al. Hepatology 2002;35:367-372; Woodcroft KJ, et al. Hepatology
2002;35:263-273)
Hepatology Watch is produced through educational grants from
and 
Hepatology Watch is a registered trademark of Market Development Group