Search

A 62-year-old woman complained of repeated hypoglycemic events. A 75g oral glucose tolerance test (75 gOGTT) showed a marked increase in the plasma insulin level and impaired glucose tolerance. The patient exhibited a high titer of plasma anti-insulin autoantibodies. Her diagnosis was insulin autoimmune syndrome (IAS). Following the cessation of loxoprofen-sodium (LOXs), she experienced no further hypoglycemic episodes. However, the hypoglycemic attacks recurred following the accidental readministration of LOXs in an adhesive skin patch. Considering the changes in the titer of anti-insulin autoantibodies, the repeated 75 gOGTT and the repeated Scatchard analysis, we determined LOXs to be the cause of the IAS and evaluated the characteristics of the autoantibodies. © 2013 by The Japanese Society of Internal Medicine.

Background Statins decrease cholesteryl ester transfer protein (CETP) levels, which have been positively associated with hepatic lipid content as well as serum low density lipoproteins-cholesterol (LDL-C) levels. However, the relationship between the CETP status and statin-induced reductions in LDL-C levels has not yet been elucidated in detail. We herein examined the influence of the CETP status on the lipid-reducing effects of pitavastatin in hypercholesterolemic patients with type 2 diabetes mellitus as well as the molecular mechanism underlying pitavastatin-induced modifications in CETP levels. Methods Fifty-three patients were treated with 2 mg of pitavastatin for 3 months. Serum levels of LDL-C, small dense (sd) LDL-C, and CETP were measured before and after the pitavastatin treatment. The effects of pitavastatin, T0901317, a specific agonist for liver X receptor (LXR) that reflects hepatic cholesterol contents, and LXR silencing on CETP mRNA expression in HepG2 cells were also examined by a real-time PCR assay. Results The pitavastatin treatment decreased LDL-C, sdLDL-C, and CETP levels by 39, 42, and 23 %, respectively. Despite the absence of a significant association between CETP and LDL-C levels at baseline, baseline CETP levels and its percentage change were an independent positive determinant for the changes observed in LDL-C and sdLDL-C levels. The LXR activation with T0901317 (0.5 μM), an in vitro condition analogous to hepatic cholesterol accumulation, increased CETP mRNA levels in HepG2 cells by approximately 220 %, while LXR silencing markedly diminished the increased expression of CETP. Pitavastatin (5 μM) decreased basal CETP mRNA levels by 21 %, and this was completely reversed by T0901317. Conclusion Baseline CETP levels may predict the lipid-reducing effects of pitavastatin. Pitavastatin-induced CETP reductions may be partially attributed to decreased LXR activity, predictable by the ensuing decline in hepatic cholesterol synthesis. Trial registration UMIN Clinical Trials Registry ID UMIN000019020

Our purpose in this study was to evaluate the new JAS guidelines as a risk assessment tool in Japanese patients with hypercholesterolemia, using the cohort of the Holicos-PAT study. The Holicos-PAT study was designed as a prospective observational study. 2039 patients were followed with or without pravastatin for 5 years. We assessed coronary heart disease (CHD) and cerebrovascular disease (CVD) risks by the patient categories described in the JAS guidelines. In the Holicos-PAT study, the primary endpoints were CHD, and the secondary endpoints were CVD and total mortality. CHD event includes onset and worsening of angina pectoris, performing CABG or PTCA, non-fatal and fatal myocardial infarction, and death from CHD including heart death and sudden death. CVD events are onset or recurrence of cerebral infarction, onset of cerebral hemorrhage, and death from cerebral infarction or hemorrhage. The event rates were calculated by the person-years method, and the differences in event rates between category groups were analyzed by chi-square test. The event rates of CHD in Category A, B1, B2, B3, B4 and C, were 1.1, 4.0, 2.8, 5.7, 18.2 and 38.8 per 1,000 person-years. The rates of CHD events in the higher risk category groups, Category B4 group (p = 0.004 in whole patients) and C group (p < 0.001 in whole patients), were significantly higher than that in the combined category groups A + B1 + B2. The event rates of CVD in Category A, B1, B2, B3, B4 and C, were 2.1, 1.8, 1.8, 0.6, 10.8 and 6.4 per 1,000 person-years. The event rates of CHD in men were significantly higher than those in women, in categories B4 (p < 0.001) and C (p < 0.001). From these results, each category classified by accumulation of risk factors, showed increasing event rates of CHD and CVD. The categories in the JAS guidelines are useful to assess CHD and CVD risk in Japanese patients with hypercholesterolemia. However, the risk evaluation by the JAS guideline categories may underestimate the risk in men and overestimate it in women.

Objectives. This study was undertaken to 1) compare the regional myocardial tracer distributions between rest technetium (Tc)-99m tetrofosmin and rest–redistribution thallium (Tl)-201 images in patients with coronary artery disease and left ventricular dysfunction; and 2) assess the comparative values of these agents for predicting functional recovery after revascularization. Background. Tc-99m tetrofosmin is a new myocardial perfusion imaging agent, but its role for detecting viable myocardium is still unclear. Methods. Thirty-six patients with coronary artery disease and left ventricular dysfunction underwent rest Tc-99m tetrofosmin, rest–redistribution Tl-201 and gated blood pool scintigraphy. In 21 patients with successful revascularization confirmed by follow-up angiography, gated blood pool scintigraphy was repeated after revascularization. Optimal threshold cutoffs to separate reversible from irreversible dysfunction were determined by receiver operating characteristic analysis. Results. Regional Tc-99m tetrofosmin activity highly correlated with redistribution Tl-201 activity (r = 0.93). The diagnostic performance for predicting functional recovery, as measured by the area under the receiver operating characteristic curves, measured 0.66 ± 0.07 (mean ± SD) for Tc-99m tetrofosmin and 0.67 ± 0.07 for Tl-201 (p = 0.60, 96.7% power to detect difference in area of 0.10). The optimal threshold cutoffs for viability were considered to be 50% of peak activity for Tc-99m tetrofosmin and 55% of peak activity for Tl-201. The positive and negative predictive values for reversible dysfunction were, respectively, 69% and 82% for Tc-99m tetrofosmin and 69% (p = 0.99 vs. Tc-99m tetrofosmin) and 71% (p = 0.66 vs. Tc-99m tetrofosmin) by Tl-201. Conclusions. The diagnostic performance of quantitative rest Tc-99m tetrofosmin imaging in predicting functional recovery after revascularization is comparable to that of rest–redistribution Tl-201. (J Am Coll Cardiol 1997;29:1226–33)

Iodine 123-labeled 15-iodophenyl-3-methyl-pentadecanoic acid (BMIPP) has been proposed as a potential myocardial fatty acid probe. We studied BMIPP uptake in ischemic myocardium identified by thallium reinjection. Fifty-five patients with coronary artery disease who had persistent defects on standard exercise-redistribution thallium imaging were investigated. Patients underwent exercise-redistribution-reinjection thallium and resting BMIPP imaging. BMIPP uptake less than that seen with thallium on reinjection imaging was observed in 105 (82%) of 128 myocardial segments with new fill-in after thallium reinjection and 87 (37%) of 238 segments with reversible thallium defects. In contrast, only 32 (19%) of 166 segments with no fill-in showed discordantly decreased BMIPP uptake. Quantitative analysis showed reduction in BMIPP activity compared with differential uptake of thallium, an index of resting myocardial perfusion, especially in the area of fill-in (53.5% +/- 15.0% vs 76% +/- 12.1% of peak; p0.01). These observations are consistent with impaired fatty acid uptake in ischemic myocardium, particularly in the area of fill-in after thallium reinjection.

Thesis of Ohtani, Rumiko / 大谷 留珠子 博士学位論文(金沢大学 / 大学院医薬保健学総合研究科), Background: The half of hyperalphalipoproteinemia (HALP) in Japan is caused by CETP gene mutations. Other than two prevalent mutations (D442G and Intron 14 splicing donor site +. 1G>A), some rare CETP mutations are found in Japanese HALP subjects. Methods: CETP gene analysis of genomic DNA from subjects was performed by restriction fragment length polymorphism (RFLP) and sequencing analysis. Mutations which were suspected to cause a splicing defect or a protein secretion defect were investigated in COS-1 cells transfected with a CETP minigene construct or a cDNA expression vector. Results: Each of three subjects was identified as a carrier of CETP gene mutation of a compound heterozygote of c.653_654delGGinsAAAC and Intron 14 splicing donor site +. 1G>A, a heterozygote of c.658G>A or a homozygote of L261R. The c.658G>A mutation was located at the last nucleotide of exon 7, and it was confirmed to cause splicing abnormality revealed by the CETP minigene analysis. The L261R CETP was not secreted to conditioned media of the cells. Conclusions: Three novel CETP gene mutations are responsible for HALP by CETP deficiency. It is predicted that there are more rare CETP gene mutations in Japanese, and these multiple rare mutations alone or a combination with each of prevalent mutations is responsible for mild-to-moderate or marked HALP, respectively. © 2011 Elsevier B.V.

Adult growth hormone deficiency (AGHD) is a recently recognized endocrine disorder characterized by low peak GH levels during provocative tests. The AGHD has a negative impact on bone mineral density, skeletal muscle strength, physical capacity and psychosocial well-being. Furthermore, the girls with GHD have delayed pubertal development, and in adulthood present a condition of subfertility. Treatment for AGHD with GH replacement therapy has been officially approved since 2006 in Japan. The patient was diagnosed as pituitary dwarfism at age 9. She was treated with GH replacement therapy since diagnosis until her height reached 155cm at age 15. When she was 24 years old, she suffered from clinical symptoms relating to GH deficiency, and she visited our hospital for reintroduction of the therapy to alleviate these clinical symptoms. She has been treated with the replacement therapy since then. The patient’s dysmenorrhea improved. And she was found to be 8 weeks pregnant at age 28 years 7 months. We immediately ceased replacement therapy and carefully observed the patient, because it is not indicated for female patient with pregnancy. She delivered a healthy girl at 40 weeks of pregnancy, no recognizable side-effects were observed in either mother or baby. To our knowledge, there are no other reports of a Japanese patient becoming pregnant during GH replacement therapy, and few cases have been reported in other countries. It remains uncertain whether the therapy is safe and essential for fetal development, fertility, and continuation of pregnancy in AGHD subjects.

The proband, a 42-year-old woman without any symptoms or hypertension, was admitted for examination of accidentally discovered bilateral adrenal masses. Physical examination disclosed bilateral nodular goiter and mild sinus tachycardia. Pheochromocytomas and medullary thyroid carcinomas were revealed by biochemical and histopathological examinations. Hypercholesterolemia and abnormal glucose metabolism returned to normal after bilateral total adrenalectomy and thyroidectomy. Screening examination showed four affected family members. Three of them were also asymptomatic and normotensive. In pheochromocytoma patients, normotension, hypercholesterolemia, and impaired glucose metabolism might be signs of excess secretion of epinephrine rather than norepinephrine.

Troglitazone is a thiazolidinedione antidiabetic agent with insulin-sensitizing activities that was withdrawn from the market in 2000 due to its association with idiosyncratic hepatotoxicity. To address the suspected autoantibody production associated with troglitazone, we investigated autoantibodies in sera from patients with type II diabetes mellitus with troglitazone-induced liver dysfunction. Two female patients (47- and 70-year-old) ceased taking troglitazone (400 mg/day) after 23.5 and 16 weeks, respectively, due to increased serum ALT. Using two-dimensional electrophoresis and amino acid sequence analyses, aldolase B was identified as an autoantigen that reacted with antibodies in sera from both patients. The titer of anti-aldolase B remained high for several weeks after stopping troglitazone administration. The mean reactivity of autoantibodies to aldolase B determined by ELISA with sera of patients with chronic hepatitis (n = 40) and liver cirrhosis (n = 40) was significantly higher (p < 0.05 and p < 0.001, respectively) than with sera of healthy subjects (n = 80). These findings suggest that liver injury may cause the appearance of autoantibodies to aldolase B which may then aggravate the hepatitis. In addition, the anti-aldolase B titer might indicate the severity of liver dysfunction.

Defect size on exercise-rest technetium (Tc)-99m tetrofosmin myocardial perfusion imaging was compared with that on exercise-reinjection thallium-201 imaging with 20 patients with 1-vessel coronary artery disease. In each patient, exercise-reinjection thallium-201 single-photon emission computed tomography (SPECT) and exercise-rest Tc-99m tetrofosmin SPECT imaging were performed. For visual analysis of the obtained SPECT images, the left ventricular myocardium was divided into 20 segments based on 3 short-axis slices from the apical, middle, and basal ventricular levels. For quantitative analysis, a square region of interest was placed on the center of each segment which was used for visual analysis, and relative regional activity to the normal reference region was calculated for each segment. By visual interpretation of the images, exercise Tc-99m tetrofosmin imaging showed a smaller defect size than exercise thallium-201 imaging (6.9 +/- 3.9 vs 8.8 +/- 3.0 segments, p

A deficiency of plasma cholesteryl ester transfer protein (CETP) is one of the genetic causes of increased serum high density lipoprotein (HDL)-cholesterol levels (hyperalphalipoproteinemia). A splicing defect (G--A mutation) at the +1 position of intron 14 of the human CETP gene is a common mutation in the Japanese CETP deficiency. A rapid screening method for the splicing defect by means of primer-specified restriction map modification was described. The frequency of the mutation in hyperalphalipoproteinemia was determined, and its frequency in the general population was estimated. During polymerase chain reaction (PCR) with a modified primer, a novel NdeI restriction endonuclease site was created from the mutated allele in the PCR products, which could be visualized after electrophoresis of the digested products. As a result, 21 of 121 unrelated hyperalphalipoproteinemic subjects with HDL-cholesterolor = 60 mg/dl (1.55 mmol/l), were found to have the G--A mutation. Of the 21 individuals, 8 were found to be homozygous for the mutation. Allele frequency of the mutation was 1.5% (1/68), 2.8% (2/72), 7.1% (4/56), and 47.8% (22/46) in the groups with HDL-cholesterol levels of 60-79 mg/dl, 80-99 mg/dl, 100-119 mg/dl, andor = 120 mg/dl, respectively. Based on the percentage of the area under the computed normal distribution curve of serum HDL-cholesterol, the frequency of the mutated allele in the general population was estimated to be 0.81% from the present results. This rapid detection method facilitates large-scale screening of CETP deficiency caused by the splicing defect. The mutation was frequent in Japanese subjects with hyperalphalipoproteinemia, especially in the group with HDL-cholesterolor = 120 mg/dl.

Lipoprotein (Lp)(a) concentrations were measured in eight patients with nephrotic syndrome in the age range of 8 to 69 yrs. Mean (+/- SE) levels of serum Lp(a) were elevated in the nephrotic patients compared to controls (76.5 +/- 19.7 vs 18.6 +/- 0.9 mg/dl, p less than 0.001). After treatment with prednisolone, Lp(a) concentrations were decreased from 85.2 +/- 21.6 to 42.2 +/- 14.0 mg/dl. During the treatment, serum total cholesterol showed a negative correlation with serum albumin concentration. However, no correlation was noted between Lp(a) and serum albumin concentration. There were no significant correlations between Lp(a) and other lipoprotein lipid and apolipoprotein levels. It was concluded that hyperLp(a)aemia may be an independent risk factor in the development of premature atherosclerosis in patients with nephrotic syndrome.

49才女性.労作時の前胸部圧迫感を主訴にて来院し,亜硝酸薬にて症状は軽快したが,精査のため入院.血圧110/60mmHg,脈拍68拍/分,整.胸部写真では心胸郭比53%と軽度の心拡大を,マスターのダブル負荷心電図ではV3～6のST下降を認めた.心カテーテル検査にて左冠動脈は左Valsalva洞より派生し,通常の走行をしていたが,右冠動脈も同様に左Valsalva洞より派生していた.そしてdynamic CTにて,右冠動脈近位部は大動脈と肺動脈の間を通過していた.なお左右冠動脈に狭窄病変はなく,心内圧も正常であった.以上,まれな右冠動脈左Valsalva洞起始症の1例と診断し,冠動脈の走行の確認にdynamic CT法を応用した.

Serum lipid and lipoprotein levels were studied in 17 normal subjects, and in 40 heterozygous and 4 homozygous patients with familial hypercholesterolemia (FH) in Japan. The serum cholesterol (Chol) levels (mean ± SD) in normal subjects, heterozygotes and homozygotes were 173 ± 22, 358 ± 70 and 532 ± 44 mg/dl, respectively. LDL-Chol levels in heterozygotes (254 ± 59 mg/dl) were significantly higher than in normal subjects (94 ± 21 mg/dl) and lower than in homozygotes (432 ± 66 mg/dl). IDL-Chol levels in heterozygotes and homozygotes were significantly higher than normal; serum triglyceride (TG) levels in heterozygotes were significantly higher than normal; LDL-TG levels in patients with FH were significantly higher than normal, as were serum phospholipid (PL) levels. LDL-PL levels in heterozygotes were significantly higher than in normal subjects ( P P Serum Chol levels correlated highly with the LDL-Chol levels. The regression equation was Y(LDL-Chol in mg/dl)= 0.873X(serum Chol in mg/dl)−58.132 ( r : 0.977, P r : 0.913, v P

Serum lipids and lipoprotein lipids were studied in 53 patients (21 males and 32 females) with xanthelasma palpebrarum and 40 age-matched normal controls (20 males and 20 females). Patients were subdivided into patients with normolipidemia, hyperlipidemia or familial hypercholesterolemia (FH). In both male and female patients with hyperlipidemia or FH, the serum cholesterol (Chol) levels were significantly higher than in normal controls. In both male and female patients with normolipidemia or hyperlipidemia, the VLDL-Chol levels were significantly higher than in normal controls. Male patients with FH showed significantly higher levels of VLDL-Chol than normal controls. Both male and female patients with normolipidemia, hyperlipidemia or FH showed significantly higher levels of LDL-Chol, lower HDL-Chol levels and lower HDL-Chol/LDL-Chol ratios than normal controls. In both male and female patients with hyperlipidemia and in male patients with FH, the serum triglyceride (TG) levels were significantly higher than in normal controls. Both male and female hyperlipidemic patients showed significantly higher levels of VLDL-TG than normal controls. In male patients with FH, the VLDL-TG levels were significantly above the control levels. In male patients with normolipidermia, the LDL-TG levels were significantly higher than in normal controls. In both male and female patients with hyperlipidemia or FH, the LDL-TG levels were significantly higher than in normal controls. The HDL-TG levels in patients with normolipidemia (males) or FH (females) were significantly lower than in normal controls. The prevalence of coronary heart disease in patients with normolipidemia, hyperlipidemia or FH was 29.4%, 24.0% and 45.4%, respectively.

We studied the effects of the bile acid sequestrant cholestyramine, alone and in combination with the experimental agent compactin (ML-236B), a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on serum levels of lipoproteins in 10 heterozygous patients with familial hypercholesterolemia. After cholestyramine treatment alone for 2 to 16 months, serum total and low-density lipoprotein cholesterol decreased by 20 and 28 per cent, respectively. With the addition of compactin for 12 weeks there was a 39 per cent total decrease in serum cholesterol from the control value--from 356 +/- 14 to 217 +/- 10 mg per deciliter (9.27 +/- 0.36 to 5.64 +/- 0.26 mmol per liter [mean +/- S.E.M.]; P less than 0.001)--and a 53 per cent decrease in low-density lipoprotein cholesterol--from 263 +/- 13 to 125 +/- 10 mg per deciliter (6.84 +/- 0.34 to 3.25 +/- 0.26 mmol per liter; P less than 0.001). High-density lipoprotein cholesterol, which had increased during cholestyramine treatment, remained at its higher level. No adverse effects were observed. If long-term safety can be demonstrated, the compactin-cholestyramine regimen may prove useful in heterozygous familial hypercholesterolemia. prove useful in heterozygous familial hypercholesterolemia.

金沢大学大学院医学系研究科, We studied biochemical genetics of low density lipoprotein (LDL) receptor mutations in fibroblasts from six homozygous and five heterozygous patients with familial hypercholesterolemia (FH). Three of six homozygotes are receptor-negative type and the other three homozygotes are receptor-defective type. In the cells from three receptor-negative homozygotes, the receptor binding, internalization, and degradation of 125I-LDL were 0.5 ± 0.3 ng/mg protein (mean ± SEM), 14 ± 8 and 8 ± 6 ng/mg protein per 6 h (four normal cells; 44 ± 3, 386 ± 32, and 1,335 ± 214 ng/mg protein per 6 h), respectively. In the cells from three receptor-defective homozygotes, the receptor binding, internalization, and degradation of 12:5I-LDL were 6 ± 2, 29 ± 8, and 90 ± 32 ng/mg protein per 6 h, respectively. In these six homozygotes, two pairs of siblings are included. Two siblings in the same family were classified as receptor-negative and two siblings in another family were classified as receptor-defective. The receptor-negative phenotypes and the receptor-defective phenotypes bred true in individual families. The cells from five heterozygotes showed ~46% of the normal activities of receptor. ML-236B, competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), completely inhibited the incorporation of [14C]acetate into digitonin-precipitable sterols in fibroblasts from normal subjects and heterozygous and homozygous patients with FH with the concentration of 0.5 μg/ml. However, at 0.05 μg/ml of ML-236 B sterol synthesis in fibroblasts from homozygotes was not completely suppressed in contrast to normal and heterozygous cells. Moreover, after preincubation with 0.05 μg/ml of ML-236B for 24 h in medium containing lipoproteins, sterol synthesis in the cells from receptor-negative homozygote showed 75% of the initial activity compared with that of 25% without preincubation. In the cells from a normal subject and heterozygote, sterol synthesis was inhibited even after preincubation. These results suggest that (a) the inhibitory effect of ML-236B is overcome in homozygote cells by their high intracellular levels of HMG-CoA reductase and (b) that a higher dose of ML-236B may be required to lower serum cholesterol levels in FH homozygotes than in heterozygotes.

A 13-year-old female patient had noticed tuberoeruptive xanthomas since 3 years of age. Her serum, VLDL, and IDL cholesterol levels were high (348, 158, and 60 mg/dL, respectively), while LDL and HDL cholesterol levels were 56 and 62 mg/dL, respectively. VLDL-cholesterol/serum triglyceride ratio was extremely high (0.86), suggesting type III hyperlipoproteinemia (HLP). Her apo E was undetectable by the single radial immunodiffusion studies and SDS-polyacrylamide gel electrophoresis. Her parents showed hypertriglyceridemia and her two siblings were normolipidemic, and their apo E levels were normal. Genomic DNA digested with BamHI or EcoRI did not show gross differences in the restriction fragment length between the apo-E-deficient patient and normal controls. Thus, apo E deficiency may be characterized by early appearance of clinical manifestations of type III HLP and higher VLDL-cholesterol/serum triglyceride ratio.

Dietary fatty acids are incorporated into chylomicrons and the chylomicron triglycerides are degraded by the action of lipoprotein lipase. The resultant particles, remnants, are selectively metabolized by the liver [ 11. Sherrill and Dietschy demonstrated that unmetabolized chylomicrons were taken up at very low rates, whereas chylomicron remnants were taken up by the perfused liver at much higher velocities [2]. Recently, Carrella and Cooper demonstrated that there was a high affinity receptor for the chylomicron remnant on the surface of the hepatocytes [3]. This study was undertaken to examine the effects of chylomicrons and their remnants on the fatty acid synthesis in isolated rat hepatocytes. Chylomicrons in the medium containing postheparin rat plasma significantly inhibited fatty acid synthesis in hepatocytes. On the other hand, chylomicrons in the medium containing pre-heparin rat plasma caused inhibition to a much smaller extent. Remnants prepared from the chylomicrons injected into functionally hepatectomized rats inhibited fatty acid synthesis to a greater extent than unmetabolized chylomicrons. Thus the chylomicron remnants produced by the action of lipoprotein lipase may play an important role in the regulation of hepatic fatty acid synthesis.

角膜にコレステロール結晶の沈着するまれな遺伝性疾患であるSchnyder's corneal dystrophyを伴った家族性高コレステロール血症(FH)の1例を経験した.症例は41才男性で父に高コレステロール血症と角膜混濁を認める.患者は小学校時代より両角膜の混濁に気付くも放置. 10年来虚血性心疾患にて加療中,昭和60年FHと診断されたが61年心精査のため入院となった.手背・アキレス腱に黄色腫を認めた.両角膜では表層部に針状結晶が集簇し,また混濁は中央部に強く, Schnyder角膜変性症と診断された.本例ではHDL/LCAT系は正常だったが,角膜のコレステロール沈着と全身性脂質代謝異常(FH)との関連において,そのメカニズムは不明であった.

A new variant of the low density lipoprotein receptor (LDLR) gene was ascertained through Southern blotting analysis of LDLR genes of 35 unrelated Japanese patients with heterozygous familial hypercholesterolemia (FH). This mutant gene had a 6 kilobase deletion which had eliminated only exon 15, an exon that encodes the O-linked sugar domain. The mutation was recognized in two patients with heterozygous FH. We refer to these patients as 'FH-Tonami', since they were both born in the Japanese district of Tonami. Although there is no evidence of a relation between families, the possibility of a common ancestor with FH does exist. Neonatal diagnosis of FH in two fetuses from one family was possible through analyses of their LDLR genes in cord blood samples at delivery.

Five out of 15 homozygotes and 41 out of 527 heterozygotes of familial hypercholesterolemia (FH) died during the past 10 years. Sudden death or heart failure was the cause of death in each of the 5 deceased homozygotes. Twenty heterozygotes died of myocardial infarction, 9 of sudden death, and 1 died after AC bypass surgery. Thus, 30 heterozygotes (73.2%) died of coronary heart disease (CHD). The mean age of death was significantly younger in male heterozygotes (54 years) than in the females (68 years). Rate of death from CHD in heterozygotes was 11 times higher than in the general population in Japan. Rate of death from pancreas cancer in FH was significantly higher than in the general population. These results suggest that FH is highly associated with pancreas cancer as well as CHD.

Familial hypercholesterolemia is an autosomal dominant disorder characterized by elevated levels of low-density lipoprotein (LDL) cholesterol, tendon xanthomas, and premature coronary artery disease (CAD) (1). The disorder results from a complete or partial defect of the LDL receptor (1) that normally controls the degradation of LDL. Reduction of LDL-cholesterol levels has proved to be effective in decreasing the incidence of CAD (2, 3). Compactin (4) and mevinolin (5), competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, are effective in lowering cholesterol levels of patients with familial hypercholesterolemia. These drugs lower plasma LDL by decreasing the rate of LDL production and stimulating the production of LDL receptor in the liver (6) (Fig. 1). LDL receptor has a specific binding activity Open image in new window for apolipoproteins B and E (7). The apolipoprotein B is present in very low-density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and LDL (8), which are highly associated with CAD (9, 10). Apolipoproteins A-I and A-II are primary apolipo-proteins in high-density lipoprotein (HDL) (8), and apolipoprotein A-I in patients with CAD has been demonstrated to be decreased (11).