Eisuke Nagata

Association of exogenous insulin or sulphonylurea treatment with an increased incidence of hepatoma in patients with hepatitis C virus infection.

Background: Diabetes mellitus is frequently seen in hepatitis C patients and is often treated with antidiabetic agents that increase serum insulin levels. Because insulin is a growth‐promoting hormone, antidiabetic agents could pose a risk for hepatocellular carcinoma (HCC).

Serum glutamic oxalacetic transaminase/glutamic pyruvic transaminase ratios in hepatocellular carcinoma.

Serum enzyme activities were studied in 131 cases of hepatocellular carcinoma (HCC), 76 cases of metastatic liver carcinomas (MLC) and 234 cases of hepatic cirrhosis. SGOT was elevated above SGPT in most of the time in these patients, SGOT/SGPT was greater in HCC compared with other groups, and that this ratio increased during the preterminal period more markedly in patients with HCC because of the significant increase of SGOT in the face of relatively stable SGPT. Preterminal rises of alkaline phosphatase and LDH activities were more pronounced in MLC. Leucine aminopeptidase activity exhibited no characteristic feature of diagnostic value. Of the five enzymes, SGOT changes were more closely correlated with the growth of HCC; SGPT reflected more of the liver parenchymal damage while SGOT was probably accounted for in part by tumor‐derived GOT. Other clinical and pathological implications are discussed. Cancer 40:319–324, 1977.

Localized submassive liver cell necrosis as a terminal event of liver carcinoma.

Six cases of hepatocellular carcinoma (HCC) and one case of metastatic liver carcinoma in which SGOT, SGPT, and SLDH were suddenly and markedly elevated immediately before death are described. All had a large blood loss and systemic hypotension in the preterminal period; autopsy disclosed irregularly shaped, patchy necrotic areas or infarcts, often clearly demarcated by hemorrhagic rims, in the noncancerous liver parenchyma. Tumor growths in the intrahepatic portal branches were extensive in all six cases with HCC; in the metastatic case, invasion and narrowing of the portal branches were extensive. The incidence of this terminal catastrophe was 3.3% (6 of 184 cases) for HCC and 1.15% (1 of 87) for metastatic carcinoma. The terminal liver necrosis was probably a result of sudden reduction in portal perfusion which had been inadequate because of tumor thrombosis, combined with hypotension of hepatic arteries.

Hepatitis B Surface Antigenemia in Patients with Hepatocellular Carcinoma in Relation to Clinical Course and α-Fetoprotein

Hepatitis B surface antigen was determined in sera of 122 cases of hepatocellular carcinoma seen in Japan, using both the counterimmunoelectrophoresis and radioimmunoassay (RIA) techniques. It was positive in 49.2% of the patients with RIA, but the level of antigen in serum was relatively low since positivity rate by counterimmunoelectrophoresis was only 10.7%. The degree of antigenemia as assessed from the count relative to the cut-off value in RIA, was increased during the clinical course in 75% of the patients. The antigen tended to rise in concentration when the tumor grew at a rapid rate, when damage to liver parenchyma was extensive, or in patients receiving chemotherapy. There was also a tendency for less frequent positive antigen tests in patients with higher α-fetoprotein levels. Illustrative cases are presented with discussion on the possible explanation for the change in the degree of antigenemia.

Aging Modulates Susceptibility to Mouse Liver Mallory-Denk Body Formation

Mallory-Denk bodies (MDBs) are hepatocyte cytoplasmic inclusions found in several liver diseases and consist primarily of the cytoskeletal proteins, keratins 8 and 18 (K8/K18). Recent evidence indicates that the extent of stress-induced protein misfolding, a K8>K18 overexpression state, and transglutaminase-2 activation promote MDB formation. In addition, the genetic background and gender play an important role in mouse MDB formation, but the effect of aging on this process is unknown. Given that oxidative stress increases with aging, the authors hypothesized that aging predisposes to MDB formation. They used an established mouse MDB model—namely, feeding non-transgenic male FVB/N mice (1, 3, and 8 months old) with 3,5 diethoxycarbonyl-1,4-dihydrocollidine for 2 months. MDB formation was assessed using immunofluorescence staining and biochemically by demonstrating keratin and ubiquitin-containing crosslinks generated by transglutaminase-2. Immunofluorescence staining showed that old mice had a significant increase in MDB formation compared with young mice. MDB formation paralleled the generation of high molecular weight ubiquitinated keratin-containing complexes and induction of p62. Old mouse livers had increased oxidative stress. In addition, 20S proteasome activity and autophagy were decreased, and endoplasmic reticulum stress was increased in older livers. Therefore, aging predisposes to experimental MDB formation, possibly by decreased activity of protein degradation machinery.

301 AN ASSOCIATION BETWEEN USE OF SULFONYLUREAS OR EXOGENOUS INSULIN AND THE PRESENCE OF HEPATOCELLULAR CARCINOMA IN HEPATITIS C PATIENTS WITH DIABETES MELLITUS

Y. Morita1, E. Taniguchi2, T. Kawaguchi3,2, M. Shirachi4, H. Iwamoto2, T. Ide2, E. Nagata1, M. Sata2,3. 1Division of Gastroenterology, Nagata Hospital, Yanagawa, Japan; 2Department of Medicine, Kurume University School of Medicine, Kurume City, Japan; 3Department of Digestive Disease Information & Research, Kurume City, Japan; 4Division of Gastroenterology, Chikugo City Hospital, Fukuoka, Japan E-mail: taigadaiki@gmail.com

Pathogenesis and Significance of Restricted Diet and Exercise Therapy in Nonalcoholic Steatohepatitis (NASH)

The risk factors that are most strongly associated with nonalcoholic fatty liver disease (NAFLD) are: age greater than 40 to 50 years, and severe obesity, diabetes mellitus (DM), or hyperlipidemia (especially hypertriglyceridemia). The pathogenesis of nonalcoholic steatohepatitis (NASH) is multifactorial. Insulin resistance, fatty acids, and oxidant stress may be important pathogenic factors in NASH. Efforts are presently underway to define the role of these factors and to determine whether modifying them (for example, by improving insulin sensitivity) could be effective in the treatment of the condition. At present, lifestyle changes involving exercise and dietary restrictions appear to be an effective means of improving NASH. Physicians should actively check for the presence of NAFLD in those who are overweight and who have diabetes mellitus. The treatment is usually directed toward optimizing body weight. The role of pharmacological agents remains to be established, and much more work is necessary to define the pathogenesis of NASH and to develop effective treatments.

Serum type III procollagen N paptide(PIIIP) and laminin levels and hepatic immunohistochemical study in patients with various liver diseases.

各種肝疾患95例における血清タイプIIIプロコラーゲンNペプチド(PIIIP)やラミニン値の変動と肝生検組織における肝線維化,細胞浸潤および巣状壊死の程度,タイプIIIコラーゲンやラミニンの分布およびその産生細胞を観察し,さらに血清PIIIP,ラミニン値が肝線維化のマーカーになり得るか否かを検討した.血清PIIIPは活動性の肝病変を呈する疾患で高値を呈し,肝細胞障害に伴なうタイプIIIコラーゲンの形成を反映するものと思われた.また,血清ラミニンは肝線維化の高度な肝疾患例で高値を呈し,基底膜形成の増加をよく反映するものと思われ,血清PIIIPとラミニンを同時に測定することは,肝疾患の活動性,線維化の形成および程度の判定に有用と思われた.また,タイプIIIコラーゲンは伊東細胞,肝細胞,内皮細胞や線維芽細胞,ラミニンは内皮細胞,伊東細胞,肝細胞および胆管上皮細胞などにより産生されることが示唆された.