Takeyuki Monna

Autoimmune hepatitis: The present status in Japan

SummaryA nationwide survey using questionnaires was carried out concerning lupoid hepatitis and related diseases (518 cases) during the 8-year period from January, 1975 to December, 1982. The following results were obtained.1.A total of 253 cases of autoimmune hepatitis, consisting of 97 lupoid hepatitis and 156 lupoid type CAH, were reported.2.Autoimmune hepatitis was overwhelmingly predominant in females, while male cases of B type CAH with a γ-globulin level of more than 2 g/dl significantly outnumbered female CAH cases of the same type.3.The liver function tests at the first examination demonstrated that transaminases, total bilirubin, ICG (R15) and γ-globulin were increased, and ChE was decreased in lupoid hepatitis. Lupoid type CAH showed a close similarity with lupoid hepatitis rather than to the nLnB type or B type with regard to liver function.4.Of the 289 patients who could be followed up, 280 cases (97%) received steroid hormones, and 247 (85%) received no another drug. Immunosuppressive treatment was also performed in 40% of the HBs antigen-positive cases of B type CAH.5.The efficacy was about 90% in the lupoid hepatitis group as well as in the lupoid type CAH group. It was no greater than approximately 70% in any other group.6.Analysis of survival revealed the following: 1) The cumulative survival rates of autoimmune hepatitis was lowest among the different types of CAH. 2) Patients who had a high serum level of total bilirubin tended to die sooner than those who had a low level. There was no correlation between the cumulative survival rate and serum γ-globulin concentration or antinuclear antibody titer. 3) The duration of steroid hormone therapy and the total dosage of immunosuppressants were thought to be important factors affecting the prognosis of autoimmune hepatitis.

Calcium-dependent prostaglandin biosynthesis by lipopolysaccharide-stimulated rat Kupffer cells

Isolated rat Kupffer cells produced and released prostaglandin (PG) E2, 6-keto-PGF1 alpha, and thromboxane B2 (TXB2) in response to lipopolysaccharide (LPS) stimulation. This elevation of PGE2, 6-keto-PGF1 alpha and TXB2 in the medium was not observed when cells were cultured in the absence of extracellular calcium or in the presence of an extracellular calcium chelator, EGTA. An intracellular calcium antagonist, TMB-8, also suppressed the production of PGE2, 6-keto-PGF1 alpha and TXB2 in a concentration-dependent manner. The intra-cellular calcium concentration of Kupffer cells elevated early after the addition of LPS determined by the use of fura-2 and a fluorescence microscopy. Moreover, calmodulin inhibitors, W-7 and W-13, apparently inhibited the production of PGF2, 6-keto-PGF1 alpha and TXB2. All these results suggest that LPS-induced PG production by stimulated rat Kupffer cells may be regulated by a calcium-calmodulin pathway.

A comparison of transcatheter arterial embolization with one shot therapy for the patients with hepatic cell carcinoma

SummaryIt has been confirmed gradually that transcatheter arterial embolization is the most effective, conservative therapy for the treatment of unresectable hepatic cell carcinoma (hepatoma). Embolization or one shot therapy was carried out in a clinical trial involving 41 patients with unresectable hepatoma visiting our department. Embolization group (emboli G): 19 cases. 1 to 6 embolizations in each case. One shot group (one shot G): 22 cases. Medications: Mitomycin C 10–40 mg and others.Disappearance rate of icterus after treatment was 50% (emboli G) and 25% (one shot G). Decrease in size of hepatomegaly or tumor was seen in 84% (emboli G) and 32% (one shot G) which was statistically significant (< 1 %). Serum AFP titer after embolization decreased in all cases but in only 5 of 12 cases (ca 41 %) after one shot (< 1 %). Effective cases measured by Karnofsky’s method were 18 out of 19 cases (95%) in emboli G, but in one shot G only 10 out of 22 cases (ca 45%)(< 0.1%). Survival rate after each therapy was 67% (emboli G) and 38% (one shot G) after 6 months, and 59% (emboli G) and 19% (one shot G) at 1 year respectively.One study showed that transcatheter arterial embolization therapy was much more effective than one shot therapy.

Longitudinal changes of bone mineral content with age in patients with cirrhosis of the liver

Abstract: Bone disorders are associated with cirrhosis. Knowledge of the natural course of bone changes in cirrhosis could help in decision-making about medical treatment. We carried out one measurement of bone mineral density (BMD) in 184 Japanese patients (98 men and 86 women) with cirrhosis by dual-energy X-ray absorptiometry. Differences in BMD values means ± SD between the 98 cirrhotic men and 283 healthy men of the same age reported in another study were not significant. In the 86 cirrhotic women, BMD tended to show a greater decrease with age than in healthy controls reported elsewhere. Differences in BMD values (means ± SD) between 622 healthy women reported elsewhere and our patients were not significant for women up to age 60 years, but at 60 years or more, the mean BMD in cirrhotic women (0.692 ± 0.100) was lower than that in healthy women (0.749 ± 0.101; P < 0.01). In 61 of the 184 patients (31 men and 30 women), the bone mineral content (BMC) of lumbar vertebrae was measured at least twice, at intervals of 10–72 months. In this longitudinal part of the study, the group mean of estimated annual change for cirrhotic men was −0.4%, close to that of healthy men (−0.2%). This mean in cirrhotic women was −2.8%, significantly different from that of healthy women (−1.1%; P < 0.05). As expected, cirrhotic women were the most likely to lose BMC, and many needed prompt treatment.

Detection of hypersensitivity to drugs by lymphocyte cultures in drug-induced allergic hepatitis

SummaryFifty-three out of 70 patients with drug-induced liver injury showed an immunological response to the drug using either the lymphocyte transformation test or the macrophage migration inhibitory test (MI test) or both. Both the separated lymphocyte culture and the microvolume whole blood culture technique are available as assay methods. The latter method is simpler and the results of both methods are comparable. The administration of a synthetic copolymer of polyadenylic and polyuridylic acid (poly A: U) to the culture medium enhances the lymphocyte response to antigen and is therefore very useful to detect weak responses.

Expression of cytochrome P450 isoforms in rat hepatic stellate cells.

The current study evaluated the expression and the inducibility of cytochrome P450 isoforms in rat hepatic stellate cells (HSCs). Immunoblotting study revealed that HSCs expressed several P450s and CYP2C11, 3A2, and 2D1 were major isoforms. The levels of CYP2B1, 2C11, 2D1, 2E1, and 3A2 in HSCs were 14 - 38% of those in hepatocytes. CYP1A2 content was similar in each cell type. These P450 levels in HSCs gradually decreased during culture as seen in hepatocytes; the level of CYP3A2 rapidly, whereas that of CYP2D1 slowly decreased. Phenobarbital, a typical inducer of CYP3A2 and 2B1 increased CYP3A2 level as well, but had less potency in the induction of CYP2B1 in HSCs. These results indicate that multiple P450 isoforms were present in HSCs, but their content and inducibility were different between HSCs and hepatocytes.

Induction of apoptosis in a human hepatocellular carcinoma cell line by a neutralizing antibody to transforming growth factor-α

A cell line derived from a Japanese man with hepatocellular carcinoma was established in culture and designated OCUH-16. The cell line has the morphological and chromosomal features of hepatocellular carcinoma cells and has a short doubling time (≈33 h). OCUH-16 cells were shown to express transforming growth factor-α, (TGF-α) in addition to albumin, DNA polymerase-α, c-JUN, and the retinoblastoma gene product. Electron microscopy revealed TGF-α immunoreactivity associated with the cell membrane, but TGF-α was not detected in medium conditioned by OCUH-16 cells by enzyme-linked immunosorbent assay. Reverse transcription and polymerase chain reaction analysis revealed the presence of TGF-α messenger RNA in these cells. Culture of OCUH-16 cells in the presence of a neutralizing antibody to TGF-α inhibited cell proliferation and induced many cells to undergo apoptosis (programmed cell death). These observations suggest that endogenous TGF-α is necessary for OCUH-16 cell growth.

Possible induction of fatty acid cyclo-oxygenase in lipopolysaccharide-stimulated rat Kupffer cells

In response to stimulation with lipopolysaccharide, isolated rat Kupffer cells released increased amounts of prostaglandin E2, prostaglandin D2, 6-keto-prostaglandin F1 alpha, and thromboxane B2. There was a lag of 2-6 hours before a significant release of these metabolites into the medium was detected. Nonstimulated Kupffer cells converted exogenous arachidonic acid to prostaglandins and thromboxane B2, and a major product was prostaglandin D2. Twenty-four hours after stimulation with lipopolysaccharide, Kupffer cells produced approximately 7 times more prostaglandin E2 and 2 times more prostaglandin D2, 6-keto-prostaglandin F1 alpha; and thromboxane B2 than nonstimulated cells. Western immunoblotting of microsomal proteins prepared from the stimulated rat Kupffer cells showed a 70-kilodalton component that was immunoreactive with a polyclonal anticyclo-oxygenase antibody. The intensity of the band increased with the time of the lipopolysaccharide stimulation. These results suggest that the accelerated arachidonate metabolism in lipopolysaccharide-stimulated rat Kupffer cells might be attributed to an induction of the cyclo-oxygenase enzyme.

Synthesis of eicosanoids by Propionibacterium acnes-elicited liver adherent cells and their effect on production of interleukin 1 and tumor necrosis factor.

When heat-killed Propionibacterium acnes (P. acnes) is intravenously injected into rats or mice, liver adherent cells including macrophages and Kupffer cells increase in number and they synthesize various kinds of biologically-active materials. We studied the production of eicosanoids and the cytokines, interleukin 1 (IL-1) and tumor necrosis factor (TNF), by P. acnes-elicited liver adherent cells and the regulatory mechanisms of eicosanoids in the synthesis of cytokines. As a result, P. acnes-elicited liver adherent cells synthesized not only prostaglandin (PG) E2, 6-keto-PGF1 alpha, thromboxane B2 and leukotriene B4, but also IL-1 and TNF. In addition, PGE2 and PGI2 suppressed the production of these cytokines. These results suggested that there are auto-regulatory mechanisms in production of cytokines in the liver.

Partial purification of the cholestatic factor derived from the lymphocytes of tuberculin-sensitized guinea pigs

SummaryWhen lymph node lymphocytes from the tuberculin-sensitized guinea pigs were stimulated in vitro with PPD (purified protein derivatives) and the culture fluid was injected into the mesenteric vein of rats, a marked reduction of bile flow was observed. These culture supernatants contained cholestatic activity were fractionated by gel filtration using a Sephadex G-75 column followed by DEAE-cellulose column chromatography. Both the cholestatic activity and the macrophage migration inhibitory factor (MIF) activity were detected predominantly in the fourth fraction by gel filtration. By further fractionation using a DEAEcellulose column chromatography, the cholestatic activity was separated into two fractions; one of them was shown to have both cholestatic activity andMIF activity, but the other did not have any detectableMIF activity.These results suggest that the cholestatic factor may be different at least partially from the MIF.