Bunichiro Kishino

Effects of probucol on xanthomata regression in familial hypercholesterolemia

Fifty-one patients with familial hypercholesterolemia were treated for 2 to 4 years with probucol, cholestyramine, clofibrate and compactin in various combinations. Mean baseline serum cholesterol was 359 +/- 10 mg/dl in the heterozygote, and 582 +/- 52 mg/dl in the homozygote patients. We found that a combination of probucol, cholestyramine and compactin decreased serum cholesterol to normal or near normal in most of the heterozygote patients. In 3 severely affected heterozygote and all 8 homozygote patients, adequate cholesterol reduction was only possible with plasmapheresis plus a hypolipidemic agent. Measurement of the Achilles tendon after 12 to 16 months of treatment showed that reductions in thickness occurred in all patients taking probucol, even in a single-drug regimen, in those undergoing plasmapheresis, especially if probucol was used and in those receiving a combination of cholestyramine and compactin. Probucol was most effective in patients who experienced the greatest decreases in high density lipoprotein (HDL) levels, whereas the cholestyramine-compactin combination worked without decreasing HDL concentrations. Combined clofibrate-cholestyramine therapy, by contrast, led to increased tendon thickness in all but 1 patient. It is believed that probucol exerts its positive effect on xanthomata regression by reducing the size of HDL particles, as was shown in this study. It has already been reported that smaller HDL particles are more active in reverse cholesterol transport. The direct peripheral action of probucol may have aided regression as well.

Effects of probucol on homozygous cases of familial hypercholesterolemia

A marked reduction of serum cholesterol was obtained by treatment with probucol in heterozygous as well as in homozygous cases of familial hypercholesterolemia. A strict dietary regimen (low-fat, low-calories) intensified the hypocholesterolemic effect of the drug. The drug was also useful in diminishing the rebound of serum cholesterol after plasma exchange. Probucol reduced serum triglycerides in heterozygous cases of familial hypercholesterolemia, but there was a slight increase in triglycerides in homozygous cases. Treatment with probucol resulted in the regression of cutaneous and tendon xanthomas. Although it caused a decrease in HDL, it seems to be very effective in the treatment of familial hypercholesterolemia.

Thiazolidinedione derivative improves fat distribution and multiple risk factors in subjects with visceral fat accumulation—double-blind placebo-controlled trial

BACKGROUND It has been clarified that visceral fat accumulation leads to atherosclerosis through multiple risk factors such as insulin resistance, glucose intolerance, hyperlipidemia and hypertension. So far, it has been reported that a thaizolidinedione derivative, troglitazone, improves the insulin resistance in subjects with diabetes, glucose intolerance and obesity. However, it has not been reported yet that troglitazone affects fat distribution in subjects concomitant with visceral fat accumulation and multiple risk factors. METHODS Twenty-nine subjects with visceral fat accumulation who had at least two risk factors including glucose intolerance, hyperlipidemia and hypertension were investigated. They were randomly assigned to receive either 200 or 400 mg per day of troglitazone or placebo for 12 weeks. A 75 g oral glucose tolerance test (OGTT) was performed before and after the treatment for 12 weeks. Fasting plasma glucose, insulin, HbA(1c), total serum cholesterol (T-chol), triglyceride (TG), HDL-cholesterol (HDL-C), and blood pressure, as well as the number of risk factors were measured periodically during the treatment. The change of the abdominal fat distribution was evaluated using computed tomographic scanning (CT scan) at the umbilicus level. RESULTS After the treatment for 12 weeks, the area under the curve (AUC) of plasma glucose from a 75 g OGTT decreased dose-dependently. HbA(1c) and TG decreased significantly in the high-dose troglitazone group (400 mg per day) compared with the placebo group (P<0.05). Systolic blood pressure was significantly lower in subjects with hypertension in the pooled troglitazone group than in the placebo group (P<0.05). Therefore, the number of risk factors decreased with the troglitazone treatment. The ratio of visceral fat area (VFA) to subcutaneous fat area (SFA) (V/S ratio) decreased in the troglitazone groups due to decreased VFA and increased SFA. CONCLUSION These results suggest that thiazolidinedione derivative may be a useful drug to improve multiple risk factors by changing the fat distribution in subjects with visceral fat accumulation.

Common Mutations in the Low-Density-Lipoprotein–Receptor Gene Causing Familial Hypercholesterolemia in the Japanese Population

Familial hypercholesterolemia (FH) is a common genetic disorder caused by mutations of the LDL-receptor gene. In the present study, we investigated four Japanese FH homozygotes and identified five point mutations: a splice site mutation in intron 12 (the 1845 + 2 T-->C mutation), a missense mutation in exon 7 (the C317S mutation), a nonsense mutation in exon 17 (the K790X mutation), a missense mutation in exon 14 (the P664L mutation), and a missense mutation in exon 4 (the E119K mutation). We developed simple methods for detecting these mutations. When we examined the presence of these mutations in 24 unrelated FH homozygotes, the 1845 + 2 T-->C mutation was found in 7 of them, and the other four mutations were unique for each proband. We also screened 120 unrelated FH heterozygotes for these mutations and found that the frequencies of the 1845 + 2 T-->C, C317S, K790X, P664L, and E119K mutations were 13.3% (16/120), 6.7% (8/120), 6.7% (8/120), 3.3% (4/120), and 1.7% (2/120), respectively. These mutations were found in more than 30% of unrelated Japanese FH patients. By using the detection methods developed in this study, the diagnosis of more than 30% of the genetic bases of Japanese FH heterozygotes is expected.

Abnormalities in plasma catecholamine response and tissue catecholamine accumulation in streptozotocin diabetic rats: A possible role for diabetic autonomic neuropathy

Plasma catecholamine levels, determined by high performance liquid chromatography, were elevated in response to blood withdrawal in normal rats. Such a response was also observed in streptozotocin diabetic rats 2 and 6 weeks after disease onset, but was no longer seen at 13 weeks. Tissue (adrenal, heart, skin, kidney) catecholamine levels in diabetic rats were increased at 6 weeks as well as at 13 weeks. These abnormalities were corrected by insulin treatment in at least a part of diabetic rats. The present data suggest that there might be a catecholamine accumulation, which is later accompanied with an impairment of catecholamine secretion, in diabetic rats, and they gave a basis for an inference that similar changes might play some role in the pathogenesis of diabetic autonomic neuropathy in man.

Mutations of the low density lipoprotein receptor in Japanese kindreds with familial hypercholesterolemia

SummaryMutations of the low density lipoprotein (LDL) receptor in 16 Japanese kindreds with homozygous familial hypercholesterolemia (FH) were studied using an anti-LDL receptor antibody. The LDL receptor mutations in Japanese FH were heterogeneous and included defects in synthesis, posttranslational processing, ligand-binding activity, and internalization of the LDL receptor. Of the 16 kindreds, 10 were receptor-negative and 5, receptor-defective types and 1 was an internalization-defective type with respect to LDL binding. The receptor-negative group was further subdivided into four groups: those with cells producing (i) no immunodetectable receptor (five kindreds); (ii) 160-kd mature receptors, which were quite scarce (two kindreds); (iii) receptors that could not be processed to the mature receptor properly (two kindreds); and (iv) receptors with an apparent molecular weight smaller than normal (one kindred). The last kindred synthesized an about 155-kd mature receptor that was rapidly degraded. This finding is compatible with the low concentration of the cell surface LDL receptors and decreased binding activity for LDL in the cells of this kindred. The receptor-defective group, which could produce a residual amount of functional receptors, exhibited a lower tendency to coronary artery disease than the receptor-negative group.

THE DIFFERENTIAL DIAGNOSIS OF CYSTIC NECK MASSES BY THE DETERMINATION OF THYROGLOBULIN CONCENTRATIONS IN THE ASPIRATES

Thyroglobulin (Tg) concentrations in the aspirates of various types of cystic neck masses were measured by RIA to assess the usefulness of this determination in differential diagnosis. The subjects consisted of 16 patients, whose final diagnoses were all established on the basis of operative results; three patients had follicular thyroid adenomas (F‐Ad), 11 had papillary thyroid carcinomas (P‐Ca), one had a thyroglossal duct cyst (TDC) and one had a lateral cervical cyst (LCC). Tg concentrations in the cyst fluids of F‐Ad and P‐Ca were very high (0·042–2·83 mg/ml) compared with serum Tg concentrations. There was no difference in Tg concentrations in the fluids of P‐Ca between primary lesions (n= 5) and metastatic lesions (n= 6). On the other hand, Tg concentrations of TDC and LCC were very low (< 100 ng/ml). Difficulty was experienced in diagnosing three patients, even though they had been examined by all nonsurgical diagnostic techniques. However, an occult thyroid carcinoma with lymph node metastasis was diagnosed by demonstrating a high Tg concentration in the aspirate of the cystic lymph node. T3 concentrations in cyst fluids of F‐Ad were higher than those of P‐Ca. T3 concentrations in the fluids of P‐Ca, TDC and LCC did not differ, and were similar to serum T3 levels. Cytology of cyst fluids was positive in four of 10 patients examined with P‐Ca. In conclusion, we can clearly confirm the thyroid origin of a cystic neck mass by demonstrating a high Tg concentration in the aspirate. This is especially useful for diagnosis in patients with thyroid carcinoma, including occult thyroid carcinomas with cystic lymph node metastasis.

Impaired catecholamine secretion as a cause of diabetic autonomic neuropathy

Human and animal studies were performed to investigate the causes of diabetic autonomic neuropathy. Human diabetics, with and without autonomic neuropathy, were measured for plasma catecholamine response to insulin hypoglycemia and for urinary catecholamine excretion. In streptozotocin-diabetic rats, plasma catecholamine response and tissue catecholamine concentrations were measured at various stages of the disease. As the duration of the diabetic state lengthens in rats, there is a time-proportional stepwise decrease in plasma catecholamine response. This is similar to the clinical course observed in human diabetics, which also includes a reduction of catecholamine excretion after the appearance of autonomic neuropathy. After 6 weeks of diabetes, rat tissue is found to have an increased concentration of catecholamines; this may represent a compensatory reaction to the difficulties of secretion. At 13 weeks of diabetes, tissue catecholamine concentrations return to almost normal, when plasma responses have disappeared. These results suggest that the impaired secretion of catecholamines in diabetics may be a cause of diabetic autonomic neuropathy.

PLASMA CELL DYSCRASIA WITH POLYNEUROPATHY, ORGANOMEGALY, ENDOCRINOPATHY, M PROTEIN, and SKIN CHANGES: THE POEMS SYNDROME, ASSOCIATED WITH PRECEDING POLYCYTHEMIA VERA. A Case Report and Review of the Literature

A case of plasma cell dyscrasia with polyneuropathy and endocrine disorder is reported. Clinically, polycythemia vera, gynecomastia, pigmentation of the skin, hepatosplenomegaly, renal enlargement and severe polyneuropathy in the lower extremities were recognized. The peculiarity of this case was polycythemia vera that had been present for several years before manifestation of the clinical symptoms. Microscopically, retroperitoneal lymph nodes showed angio‐follicular lymphoid hyperplasia and plasma cell infiltration in the inter‐follicular region. By means of the avidin‐biotin‐peroxidase complex method, plasma cells were positive for A light chain, IgA and IgG. Severe segmental demyelination and slight axonal atrophy were found in a sural nerve biopsy.

ELEVATED SERUM THYROGLOBULIN AS A MANIFESTATION OF ACUTE HAEMORRHAGE INTO THE THYROID GLAND

Clinical observations and serial determinations of serum thyroglobulin (Tg) were made in five patients with acute haemorrhage into the thyroid gland. Fever, local pain and acceleration of erythrocyte sedimentation rate were minimal or were not observed, and serum T4 and T3 were normal. Although all patients showed an increase in serum Tg, this was most obvious in three subjects and it gradually decreased as the nodule became smaller. There was no correlation between the serum Tg concentration and the nodular size. Acute haemorrhage into the thyroid gland should be added as one of the causes to increase serum Tg concentrations.