Primary biliary cirrhosis diagnosed during pregnancy. Does it have a different outcome?

Pregnancy in women with primary biliary cirrhosis (PBC) is uncommon, and once it occurs it usually does not worsen the liver disease. First manifestation of PBC during pregnancy in women with no known liver disease at the time of conception is very rare, and the natural history of this disease in such cases is yet unknown. Herein we describe a woman who had been diagnosed with PBC during the third trimester of pregnancy and, while she gave birth to a normal healthy child, her disease rapidly deteriorated and she has been listed for liver transplantation. It appears that PBC that is first noted during pregnancy might have a different course than that of PBC diagnosed before pregnancy.

Effects of therapy with interferon-alpha on peripheral blood lymphocyte subsets and NK activity in patients with chronic hepatitis C.

Longitudinal changes in lymphocyte subpopulations, including total and activated T cells, B cells, and NK cells as well as NK activity and 2',5'-oligoadenylate synthetase (2'5' AS) levels were determined in peripheral blood before, during, and after therapy with human recombinant interferon-alpha (HurIFN-alpha) in 39 patients with serologically and biopsy-confirmed chronic hepatitis C. Immunologic data obtained at baseline and during IFN-alpha administration were correlated with the clinical response to IFN-alpha therapy defined as a normalization of the serum alanine aminotransferase level. There were 23 responders (R) and 13 nonresponders (NR) to IFN-alpha and 3 patients were not evaluable. Prior to the use of IFN-alpha, the patients tended to have higher numbers of activated (DR+) T and NK cells but a lower number of CD3+CD25+ T cells than normal controls. During IFN-alpha therapy, highly significant induction of 2'5'AS was observed. The numbers of circulating WBC, total lymphocytes, and T and B cells were reduced during IFN-alpha therapy. In contrast, both the absolute number and percentage of activated CD3+CD25+ and CD4+DR+ T cells increased in response to the IFN-alpha therapy. The percentage of activated CD56+DR+ NK cells was also significantly elevated over the pretreatment baseline. IFN-alpha therapy had no effect on NK activity in peripheral blood mononuclear cells. No differences in the immunologic profile of R vs NR were noted, except that the number of IL2R+ T cells was increased transiently early during IFN-alpha therapy but only in the NR group. It was not possible to reliably discriminate between R vs NR to IFN-alpha therapy on the basis of longitudinal changes in the phenotype or function of immune effector cells.

Hepatocyte growth factor, blood clearance, organ uptake, and biliary excretion in normal and partially hepatectomized rats.

BACKGROUND: Hepatocyte growth factor (HGF) (also known as scatter factor (SF)) is a heterodimeric protein that is the most potent known complete mitogen for hepatocytes in culture. HGF is a mitogen for many epithelial cells including hepatocytes, kidney tubular epithelial cells, mammary epithelial cells, keratinocytes, etc. The protein encoded by the proto-oncogene c-met is the high affinity receptor for HGF. HGF concentration in the plasma dramatically increases after partial hepatectomy and in fulminant hepatic failure. This study describes the pharmacokinetics of HGF in the rat. EXPERIMENTAL DESIGN: Human recombinant HGF (a gift from Genentech) was radioiodinated and shown to retain biologic activity and structure. Approximately 74 ng of [125I]HGF was injected into the penile vein of male Fisher rats 5 minutes after a complete bile fistula and jugular venous catheterization were performed for blood and bile sampling. Half of the rats were subjected to 70% partial hepatectomy. RESULTS: The percentage of injected radioactivity present in the liver of control rats was 29.5% +/- 0.5% at 15 minutes and decreased to 8.6% +/- 1.0% at 120 minutes; the kidneys had 6.2% +/- 0.2% at 15 minutes, decreasing to 1.48% +/- 0.3% at 120 minutes. All the other organs examined had less than 1% of the injected radioactivity. The remaining radioactivity was present in low affinity sites in blood, bone, muscle, and skin. In control rats, radioactivity appeared in the bile within 3 minutes, reached a peak between 40 to 50 minutes, and tapered thereafter for a total 2-hour collection of 2.3% +/- 0.5%. In the partially hepatectomized rats, the HGF blood clearance was decreased (partial hepatectomy = 0.27 +/- 0.03 ml/minute; control = 0.53 +/- 0.06 ml/minute, p < 0.006), and the terminal half-life prolonged (partial hepatectomy = 124 +/- 11 minutes; control = 83 +/- 10 minutes, p < 0.03). The initial half-life for HGF, as extrapolated from the chart, was estimated at 3.8 minutes in control rats. CONCLUSIONS: Liver is the principle organ for initial uptake of [125I]HGF; disappearance from the blood suggests multicompartment kinetics with a rapid phase and a slower phase; only a portion of the hepatic uptake appears in the bile; and partial hepatectomy decreases the blood clearance of [125I]HGF. These results are correlated with previous findings bearing on the role of HGF elevation after partial hepatectomy as a stimulus for transfer of hepatocytes from G0 to G1 early in liver regeneration after partial hepatectomy.

Metabolism of HGF-SF and its role in liver regeneration.

HGF-SF is rapidly sequestered in the liver after intravenous injection. This demonstrates that liver is the major organ responsible for clearance of HGF-SF. A minor involvement of the kidney in that function was also shown. Plasma levels of HGF-SF mRNA increase by 15-17 fold rapidly after 2/3 partial hepatectomy. This increase precedes the increase of HGF-SF mRNA in liver following surgical resection. The findings strongly suggest that the observed rapid elevation in plasma HGF-SF after 2/3 partial hepatectomy is due to decrease of clearance by the liver. A mechanism is proposed whereby changes in HGF-SF levels due to removal of hepatic mass stimulate entry of hepatocytes from G0 to G1 and eventually lead to DNA synthesis.