Erythropoietic protoporphyria with severe liver dysfunction and acute pancreatitis.

A case of erythropoietic protoporphyria associated with severe hepatic dysfunction and acute pancreatitis is reported. The patient, a 33-year-old man, was admitted to our hospital complaining of upper abdominal pain, nausea, and vomiting of 3 days' duration. Laboratory tests on admission demonstrated liver dysfunction, anemia, and thrombocytopenia. On the third hospital day, the intensity of the upper abdominal pain increased, concomitantly with elevated levels of serum amylase. Ultrasonography and computed tomography scanning revealed a slightly enlarged pancreas. During this episode, he also complained of various neurological symptoms, including reduced mental alertness, weakness of extremities, constipation, profound sweating, and urinary retention. Porphyrin studies demonstrated markedly elevated erythrocyte and fecal protoporphyrin levels. Laparoscopic findings obtained after the attack subsided were compatible with porphyric liver cirrhosis. We therefore concluded that neurologic disorders and acute pancreatitis could develop in patients with erythropoietic protoporphyria with severe liver dysfunction.

Paradoxical progression of biliary strictures against recovery of biochemical parameters under ursodeoxycholic acid treatment in a case of primary sclerosing cholangitis with ulcerative colitis.

Ursodeoxycholic acid (UDCA) treatment for primary sclerosing cholangitis (PSC) has been considered a rational therapy, though its effectiveness in the clinical course is still open to discussion. In this report, we describe a 22-year-old man with PSC at an early stage, which was associated with ulcerative colitis (UC). He showed progressive strictures of bile ducts over a 1.5-year period in spite of an improvement in the biochemical parameters by UDCA treatment. Therefore, care should be taken in interpreting the effectiveness of UDCA, because the biochemical parameters may not change in parallel with the clinical course of PSC.

[Plasma fatty acids, lipids, lipoprotein and macroangiopathy].

Epidemiological studies have elucidated that diabetes mellitus (DM) is one of the risk factors of coronary heart disease and that DM often accompanies dyslipidemia. Dyslipidemia in DM can be classified as either quantitative or qualitative. Although dyslipdemia in DM is affected by the type of DM and glycemic conditions, the characteristics of dyslipidemia in DM, especially in NIDDM are the increase in triglycerides accompanied by the decrease in HDL-cholesterol level. Recently, new commercial kits for measurement of atherogenic lipoproteins which increase in DM are clinically available. The usefulness of these kits in DM was reviewed. Polyacrylamide electrophoresis can detect IDL and Lp(a) qualitatively. It has also become possible to estimate Lp(a) quantitatively by ELISA, TIA and LIA methods. Remnant lipoprotein can be measured in the fraction unbound to anti-apo A1 and anti-apo B100 antibodies by immunoaffinity gel analysis. Apoproteins, apoprotein E phenotype, post-heparin lipoprotein lipase, and Lp AI (HDL with apo AI and without apo AII) can be measured by the commercially available kits. Modified LDLs (glycated, oxidative) increase in DM, but their measurements remain complicated at the moment. Analysis of plasma fatty acids by gaschromatography is useful for dietary assessment. The measurement of these new markers seems to be useful to assess the extent of atherogenic risk in DM.

[Borderline values of laboratory data in patients with hyperlipidemia].

In Japanese, serum cholesterol levels have been increasing. This seems to be due to changes in life style, mainly the increase in dietary fat. Epidemiologic studies in the United States and Europe have shown that patients with hypercholesterolemia have a high risk of ischemic heart disease. Some guidelines for the management of hyperlipidemia have been developed in the United States, Europe, and Japan. The National Cholesterol Education Program (NECP) in the United States divides serum cholesterol level into three grades (desirable: below 200 mg/dl, borderline: between 200 mg/dl and 240 mg/dl, hypercholesterolemia: over 240 mg/dl). Borderline serum cholesterol is also a risk, especially in people complicated by other risk factor(s). As most borderline serum cholesterol seems to be due to polygenic hypercholesterolemia, an attempt to change the diet should be the first recommendation for treatment.

[An approach to adult diseases from the viewpoint of preventive medicine].

An increased prevalence of adult diseases such as cancers and arteriosclerotic diseases has recently been reported. Of these adult diseases, arteriosclerotic diseases seem to have the highest prevalence. We recently studied arteriosclerotic diseases from the viewpoint of preventive medicine. The study included analysis of background factors in these diseases (i.e., increase in risk factors such as obesity, hyperlipidemia and diabetes). In addition, we reviewed the recent topics on metabolic abnormalities and outlined the practical measures for avoidance of the risk factors for arteriosclerotic diseases.

Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation.

BACKGROUND AND METHODS: The plasma cholesteryl-ester transfer protein (CETP) catalyzes the transfer of cholesteryl esters from high-density lipoprotein (HDL) to other lipoproteins. We recently described a Japanese family with increased HDL levels and CETP deficiency due to a splicing defect of the CETP gene. To assess the frequency and phenotype of this condition, we screened 11 additional families with high HDL levels by means of a radioimmunoassay for CETP and DNA analysis. RESULTS: We found the same CETP gene mutation in four families from three different regions of Japan. Analysis of restriction-fragment-length polymorphisms of the mutant CETP allele showed that all probands were homozygous for the identical haplotype. Family members homozygous for CETP deficiency (n = 10) had moderate hypercholesterolemia (mean total cholesterol level [+/- SD], 7.01 +/- 0.83 mmol per liter), markedly increased levels of HDL cholesterol (4.24 +/- 1.01 mmol per liter) and apolipoprotein A-I, and decreased levels of low-density lipoprotein cholesterol (1.99 +/- 0.80 mmol per liter) and apolipoprotein B. Members heterozygous for the deficiency (n = 20), whose CETP levels were in the lower part of the normal range, had moderately increased levels of HDL cholesterol and apolipoprotein A-I and an increased ratio of HDL subclass 2 to HDL subclass 3, as compared with unaffected family members (1.5 +/- 0.8 vs. 0.7 +/- 0.4). CETP deficiency was not found in six unrelated subjects with elevated HDL cholesterol levels who were from different parts of the United States. CONCLUSIONS: CETP deficiency appears to be a frequent cause of increased HDL levels in the population of Japan, possibly because of a founder effect. The results that we observed in heterozygotes suggest that CETP normally plays a part in the regulation of levels of HDL subclass 2. There was no evidence of premature atherosclerosis in the families with CETP deficiency. In fact, the lipoprotein profile of persons with CETP deficiency is potentially antiatherogenic and may be associated with an increased life span.

Rapid changes in urinary serine and branched-chain amino acid excretion among diabetic patients during insulin treatment.

In a preliminary experiment, we found a good correlation between 24-h urinary amino acid excretion and the 24-h average plasma levels of the same amino acids. Examining diabetics who were just beginning insulin therapy, we found that insulin normalized the abnormally high levels of excretion of branched-chain amino acids and serine. Interestingly, when expressed in terms of mol/g of creatinine, the normalization of serine excretion brought about by insulin was roughly equal to the normalization of glycine excretion brought about by insulin (-0.39 mM/g of creatinine vs. + 0.33 mM/g of creatinine over 24 h). Since plasma serine is primarily produced in the kidneys from glycine, this suggests that insulin affects the regulation of the serine-glycine metabolic pathway. In turn, measurement of urinary serine and glycine may provide a useful gauge of insulin activity in the tissues, including the kidneys.

Further evidence for insulin hypersecretion not as an initial event but as a consequence of body growth and maturation in juvenile-onset obesity.

According to our previous study, hyperinsulinism develops not before 10 years of age despite the presence of obesity but during the maturation years of 10-20. We aimed here at examining the growth-related islet B-cell change together with pituitary activity in non-familial juvenile obesity. Measurement of 24 h urine hormones was shown to be useful for evaluation of the diurnal hormones in plasma. In 56 non-obese and obese juveniles, a significantly positive correlation was found between age (6-18 years) and 24 h urine insulin and c-peptide, thus indicating that the age-related absolute value of body weight significantly affects insulin and c-peptide excretions both in non-obese and obese subjects. Consequently, urinary insulin and c-peptide excretions per kg of body weight were highly similar between obese and non-obese juveniles. However, when the lower specific gravity of fat mass compared with lean body mass and the relative shortage of circulating plasma in fat tissues are taken into consideration, it is obvious that obesity by itself specifically augments this physiologic B-cell maturation between 10 and 20 years of age. The possible interactions of growth hormone and pituitary gonadotropin in hyperinsulinism are discussed.

Evidence for direct effect of growth hormone on capillary basement membrane thickness.

In order to investigate the direct effect of growth hormone on the capillary basement membrane thickness (CBMT), we performed, in normal and diabetic rats, ultrastructural morphometric studies on the capillaries of the skin loci where the intracutaneous injections of physiologic saline and human growth hormone (HGH) in various concentrations had been repeated daily for 28 days. In the normal group, the injection (0.1 ml daily) of HGH solutions in concentrations of 0.5 micrograms/ml and 2 micrograms/ml did not significantly alter the CBMT, and only at the concentration of 10 micrograms/ml, HGH significantly (p less than 0.001) increased the CBMT. In the diabetic group, however, the injection of any of the HGH solutions significantly (p less than 0.001 approximately 0.05) increased the CBMT. In another diabetic rat series, HGH, human albumin, human menopausal gonadotropin and human globulin (each in a concentration of 10 micrograms/ml) were repeatedly injected into four separate skin portions for 28 days, and it was found that the net increase in CBMT was most striking in the HGH-treated portion. These data demonstrated the direct and specific effect of HGH on CBMT.

Diabetes mellitus in familial hyperlipoproteinemia.

The relationship between a certain form of type 2 diabetes mellitus and familial endogenous hyperlipoproteinemia still remains confused. Therefore, we examined glucose tolerance and insulin secretion in 133 members (6-80 years old) of 15 families with a history of endogenous hyperlipoproteinemia. A segregation study was carried out to compare the prevalence of diabetes in hyperlipoproteinemic and normolipoproteinemic relatives, and the results seemed to support the recent concept that diabetes and hyperlipoproteinemia are inherited independently. However, the age-group analysis revealed that insulin secretion was progressively impaired with aging and about a third of the elderly group was significantly insulinopenic. Diabetes thus occurred in 0-2.6% of subjects under 40 years of age, 9.8% of those of 41-60 years of age and in 26.3% of those over the age of 61 years, occasionally complicated by diabetic retinopathy. Interestingly, insulinopenic diabetes was not accompanied by hyperlipoproteinemia, but hyperinsulinemic cases remained hyperlipoproteinemic. Therefore, the possibility arises that the independent occurrence of diabetes mellitus and hyperlipoproteinemia suggested by this crosssectional segregation study may result from bidirectional deviations in individuals who started out with uniform familial disorders such as insulin resistance.

Low density lipoprotein-sialic acids in patients with non-insulin dependent diabetes mellitus.

The important function of sialic acids in glycoproteins is to prolong the half life of the glycoproteins in the circulation. In this study, the sialic acid content of plasma low density lipoprotein (LDL)-apoproteins (predominantly B-100 apoprotein, a sialoglycoprotein) was analyzed together with relative electrophoretic mobility of LDL in 46 hypercholesterolemic and normo-cholesterolemic diabetics and non-diabetics. There was a significant positive correlation between the LDL-sialic acid content and LDL mobility either in the non-diabetics (r = 0.534, p less than 0.01) or in the diabetics (r = 0.482, p less than 0.02). Thus, the effect of the LDL-sialic acids upon the LDL electric charge was apparent. However, the LDL-sialic acids in the hypercholesterolemic diabetics were significantly (p less than 0.01) decreased to 9.64 +/- 0.63 micrograms/mg LDL protein (mean +/- S.E.) as compared with that in the normocholesterolemic diabetics (12.85 +/- 0.62 micrograms/mg LDL protein). Since the relatively sialic acid-poor LDL particles are rather accumulated in plasma of diabetic patients, the grade of sialylation of glycoprotein seems to have no role in the interaction with peripheral cells and therefore, the glycoprotein turnover, as far as the LDL apoproteins are concerned.

Apoprotein b-poor very low density lipoprotein in diabetic patients without hyperlipoproteinemia.

In order to see if there is a latent metabolic disorder of plasma very low density lipoprotein (VLDL) in uncontrolled diabetic patients without hyperlipoproteinemia, 28 diabetic patients and 13 matched normal subjects were analyzed for the compositions of fasting plasma VLDL. Although the lipid profiles and total apoproteins were similar among the normals, normolipoproteinemic well-controlled diabetics and normolipoproteinemic poorly-controlled diabetics, VLDL apoprotein B content tended to be decreased in poorly-controlled diabetics. Consequently, triglyceride/apoprotein B ratio was found to be increased significantly (p less than 0.02) to 12.5 +/- 1.3 (mean +/- S.E.) in the normolipoproteinemic poorly-controlled diabetics as compared with that in the normals (8.1 +/- 0.7). Since plasma VLDL is known to become relatively enriched with apoprotein B as the VLDL delipidation proceeds, the apoprotein B-poor VLDL in the normolipoproteinemic poorly-controlled diabetics seems to reflect a latent delayed turnover of circulating VLDL and this might be the disorder characteristic to diabetes mellitus.

Effect of insulin on the lysosomal function of rat aortic smooth muscle cells and subcutaneous fibroblasts in tissue culture.

Extracellular and intracellular activities of N-acetyl-beta-glucosaminidase (NAG), a representative lysosomal enzyme, in rat aortic smooth muscle cells and subcutaneous fibroblasts cultured for 6 days with an insulin-enriched (200 microU/ml of insulin) or an insulin-deprived medium were measured. The culture medium was changed every 2 days. The net release of NAG into the medium between the 4th and the 6th day was significantly inhibited in the insulin-enriched culture of both smooth muscle cells and fibroblasts. The inhibition was more marked in the fibroblasts series than in the smooth muscle cell series. On the other hand, the intracellular NAG activity of both cell series was almost similar in the insulin-enriched culture and in the insulin-deprived culture. The results indicate that insulin has an inhibitory effect on the net extracellular release of NAG and, therefore, regulates the lysosomal function in these mesenchymal cells.

A familial form of obesity without hyperinsulinism at the outset.

A total of 32 pairs of obese fathers or mothers and their obese offsprings, aged 20 yr or younger, from 25 families with established hyperinsulinemic obesity aged 11-20 yr equally showed an insulin hyperresponse to glucose, the offspring 10 yr or younger revealed a rather normal insulin response, despite the presence of obesity, and this contrasted with their fathers or mothers. No difference was found in the estimated age of onset between the two groups of offspring. The offsprings in both age groups ate a similar high carbohydrate, high calorie diet. The results suggest that the insulin hypersecretion is not the primary trait in this form of familial obesity and that the insulin response to glucose becomes augmented during the maturation years of 11-20, thus resulting in the accumulation of hyperinsulinemic and hyperlipidemic adults in the family.

Effects of a glucoside-hydrolase inhibitor (Bay g 5421) on serum lipids, lipoproteins and bile acids, fecal fat and bacterial flora, and intestinal gas production in hyperlipidemic patients.

Significant decrease in serum very low density lipoproteins and low density lipoproteins was observed after Bay g 5421 trial (300 mg/day for 6 weeks) in 14 hyperlipidemic patients. Although no significant changes were demonstrated in serum fractions of bile acids, the alteration in the patterns of fecal bacterial flora including the increase in obligate anaerobes was observed after the trial and this was accompanied by the increase in fecal fat excretion. Thus, the possible change in the intestinal bile acid metabolism with the altered flora may lead to an increased catabolism of cholesterol and to the reduction of serum low density lipoproteins. The meteorism developed in several patients but its etiology was shown to be independent of the patterns of the pre-trial bacterial flora and diet composition.