Shunichi Koga

Plasma Apolipoprotein A-IV Levels Decrease in Patients with Chronic Pancreatitis and Malabsorption Syndrome

An immunochemical method was developed for measurements of serum levels of apolipoprotein A-IV (apo A-IV). Using this technique, we found decreased levels of apo A-IV in patients with chronic pancreatitis and malabsorption syndrome and these low levels of apo A-IV in a patient with malabsorption syndrome were overcome after appropriate oral nutrition. Thus, measurements of apo A-IV may provide a good index for the assessment of fat intake and absorption.

Increased proportion of proapoliporotein A-I in HDL from patients with liver cirrhosis and hepatitis

SummaryWe examined the isoform pattern of apolipoprotein A-I (apo A-I) in high density lipoprotein from patients with liver disease. An increase in the proportion of proapo A-I was evident in patients with decompensated liver cirrhosis, acute hepatitis and hepatocellular carcinoma. The rate of conversion from proapo A-I to apo A-I was low in sera from those with liver disease, compared to normal controls. The proportion of proapo A-I showed a tendency toward increase with advance in liver damage. These results suggest that the liver is participating in the reaction converting proapo A-I to the mature apo A-I.

Effects of insulin, dexamethasone and glucagon on the production of apolipoprotein A-I in cultured rat hepatocytes

Cultured rat hepatocytes were used to study the effects of hormones on the production of apo A-I. In addition, we compared these effects with the production of albumin. Hepatocytes were isolated from normal adult rat livers and cultured in MEM, as nearly confluent monolayers. In the absence of hormones, apo A-I and albumin accumulated in the culture medium almost linearly for periods up to 24 h. The rates of accumulation of apo A-I and albumin in the medium were 22 ng/mg cell protein per h and 1.2 micrograms/mg cell protein per h, respectively. During the incubations the cellular contents of apo A-I remained constant. Insulin stimulated the production of albumin at concentrations over 10(-10) M, but inhibited the production of apo A-I at concentrations over 10(-8) M. Dexamethasone showed no significant effects on albumin production but stimulated apo A-I production at concentrations over 10(-6) M. Glucagon inhibited the production of albumin and apo A-I dose-dependently at concentrations over 10(-10) M. Thus, the production of albumin and apo A-I are presumably controlled by different regulatory mechanisms.

Phenotypes of Apolipoprotein E and Abnormalities in Lipid Metabolism in Patients With Non-Insulin-Dependent Diabetes Mellitus

Phenotypic expressions of apolipoprotein E (apo E) were studied in 94 Japanese patients with non-insulin-dependent diabetes mellitus (NIDDM) and in 91 normal controls. The apo E gene frequencies observed in patients with NIDDM (epsilon 4, 0.101; epsilon 3, 0.824; and epsilon 2, 0.075) were not significantly different from those in normal controls (epsilon 4, 0.093; epsilon 3, 0.863; and epsilon 2, 0.044). Subgrouping the diabetic patients with and without hyperlipidemia, the epsilon 2 allele was significantly more frequent in patients with hypertriglyceridemia. The levels of serum triglyceride, very low density lipoprotein-cholesterol (VLDL-C), and VLDL-triglyceride (VLDL-TG) were significantly higher in patients with the epsilon 2 heterozygote than in those without the epsilon 2 allele (P less than .01). The results suggest that variation in the apo E gene may be one factor related to the hypertriglyceridemia present in patients with NIDDM.

Effect of insulin, glucagon or dexamethasone on the production of apolipoprotein A-IV in cultured rat hepatocytes.

We studied the effects of insulin, glucagon or dexamethasone on the production of apolipoprotein A-IV (apo A-IV) by cultured rat hepatocytes, using specific radioimmunoassay for rat apo A-IV. We also compared the effect of these hormones on the production of apo A-IV with those of albumin and apo A-I, reported previously. In the absence of hormones, apo A-IV and albumin in culture medium increased almost linearly for periods up to 24 h. The rates of accumulation of apo A-IV and albumin in the medium were 15.4 ng/mg cell protein per h and 1.2 micrograms/mg cell protein per h, respectively. The concentration of intracellular apo A-IV remained constant during the incubation. Insulin stimulated the production of albumin, but inhibited the production of apo A-IV dose-dependently. Glucagon inhibited the production of both albumin, and apo A-IV dose-dependently. Dexamethasone showed no significant effects on albumin production, but stimulated apo A-IV production. Thus, apo A-IV production in hepatocytes is regulated by several hormones with different effects on albumin production. The regulatory effects of these hormones on apo A-IV production were almost identical with the effects observed in a course of apo A-I synthesis, suggesting that the production of the two apoproteins are regulated by similar mechanisms.

Alterations in plasma levels of apolipoprotein A-IV in various clinical entities.

SummaryThe serum levels of apolipoprotein A-IV (apo A-IV) were measured by rocket immunoelectrophoresis in disease-free humans, at fasting and after oral and intravenous fat administration. The studies were extended to patients with chronic pancreatitis, malabsorption syndrome, to postoperative patients on total parenteral nutrition and to patients with liver diseases, cholestasis, diabetes mellitus and chronic renal failure. Oral fat ingestion resulted in an increase of apo A-IV levels which remained elevated even when the postprandial hypertriglyceridemia had disappeared. A transient increase in apo A-IV levels was observed after intravenous fat infusion but the level declined simultaneously with decreases in triglyceride levels. Levels of serum apo A-IV were decreased under conditions where decreased fat intake or malabsorption of nutrients might have been present, such as in patients with chronic pancreatitis, malabsorption syndrome, acute hepatitis in the early stage, obstructive jaundice and in postoperative patients on total parenteral nutrition. On the other hand, the apo A-IV levels were high in patients with chronic renal failure and in those with diabetes mellitus and proteinuria.

Natural killing activities in chronic liver diseases and hepatocellular carcinoma

Previously we proposed a new analysis of natural killing activity, for comparison, employing an individual effector/ target cell ratio according to the peripheral number of effector cells. Using this analysis, we studied natural killing activities in chronic liver diseases and hepatocellular carcinoma (HCC). The activity in chronic persistent hepatitis remained nearly at the level of the nonactivated state, but that was significantly elevated in chronic active hepatitis. The activity in liver cirrhosis (LC) of Childs A or B grade was at the level of a nonactivated or reduced-activity state, while LC patients with impaired general conditions showed significantly elevated activities. In HCC, each of which was accompanied by LC in our cases, the activity appeared to be associated with the progression of HCC. Thus, natural killing activity showed a close relationship with the condition of chronic liver diseases.

Prediction of the prognosis of liver cirrhosis in Japanese using cox’s proportional hazard model

SummaryData on 155 patients with liver cirrhosis were analyzed, using Cox’s proportional hazard model. Twenty variables were screened, using a multiple linear regression analysis in a stepwise manner and 6 were considered to reflect the prognosis of cirrhotics. Three of the 6 variables were significantly prognostic, i.e. ascites, atrophy of the right lobe of the liver seen on liver scintigram and the concentration of serum albumin. The prognostic index (PI) for each patient was calculated by adding all the products of scores of these three variables with the corresponding coefficient: PI=0.895 X ascites (absent=0, present=l) + 0.983 X atrophy of right lobe of the liver on the liver scintigram (absent=0, present=l) + (-0.561) X serum albumin (g/dl). According to the PI, the subjects were separated into three groups; group 1: PI<-1.9, group 2: -1.9≦PK-0.6, group 3: PI≧0.6. The global 5 and 10-year survival rates of each group were 80% and 65% in group 1, 50% and 30% in group 2 and 12% and 0% in group 3, respectively. Four of the 14 deaths in group 1,8 of 47 in groups 2 and 10 of 24 in group 3 were caused by hepatocellular carcinoma. Our observations suggest that advanced stage cases of cirrhosis are at a high risk concerning development of hepatocellular carcinoma.

Decreased proapolipoprotein A-I processing in liver disease : evidence for hepatic participation in proapolipoprotein A-I conversion

We evaluated the proapolipoprotein A-I (proapo A-I)-converting activity to clarify the pathogenesis of the high proapo A-I/apo A-I ratio in the high-density lipoprotein (HDL) from patients with acute hepatitis and liver cirrhosis. The serum proapo A-I-converting activities were measured using 3H-labeled proapo A-I. 3H-labeled proapo A-I was purified from the media of cultured Hep G2 cells by immunoaffinity chromatography. The serum proapo A-I-converting activities were found to be significantly reduced in the patient with liver cirrhosis (140 +/- 53 dpm/ml per h) or acute hepatitis (140 +/- 48 dpm/ml per h) compared to normal subjects (315 +/- 32 dpm/ml per h). Serum proapo A-I-converting activity has a positive correlation with liver function tests such as serum albumin, choline esterase activity, ICG clearance and inverse correlation with proapo A-I/apo A-I ratio in HDL. These results suggest that the high proapo A-I/apo A-I ratio is due to the decreased proapo A-I-converting activity, and that the liver plays a significant role in the conversion of proapo A-I to apo A-I.

A case of combined primary biliary cirrhosis, ulcerative colitis and chronic myelocytic leukemia

SummaryA rare case of primary biliary cirrhosis, ulcerative colitis and chronic myelocytic leukemia is described in a 49-year-old Japanese diabetic woman. Primary biliary cirrhosis was diagnosed by characteristic liver histology and positive serum mitochondrial antibody test. Ulcerative colitis was diagnosed by typical findings of barium enema and colonoscopy, negative fecal test for pathogens and compatible rectal histology. Chronic myelocytic leukemia was determined by representative hematologic findings and positive result for Ph1 chromosome. This is the first case with combination of primary biliary cirrhosis, ulcerative colitis and chronic myelocytic leukemia.