A Pedigree Analysis of a Family With Familial Hypercholesterolemia

Objective The current study was designed to investigate the features of a family with familial hypercholesterolemia(FH). Methods Twenty members of three generations in a family with FH were enrolled in the study. The data collected were from clinical observation and subjected to pedigree analysis. Results The proband was a 41 years old male who suffered from angina pectoris with multi-vessel stenosis of coronary artery at the age of 40. Among 20 members, 8 individuals were demonstrated with hypercholes-terolemia in this family with the total incidence of 40% [54.5% (6/11) in male and 22. 2% (2/9) in female The serum total cholesterol level was elevated in childhood from 7. 1 to 10. 8 mmol/L and tended to be raised with increasing age. In addition, the level of total cholesterol was found to be elevated both in a monozy-gote twin brothers and their offspring in the family. Conclusion FH appears to be a hereditary disease of autosomal dominance inheritance and the outcome of FH patients with coronary hea     

家族性高胆固醇血症一家系分析

目的高胆固血脂一家系调查。调查一家族性高胆固醇血症（FH）三代共20名成员，其中包括一对孪生兄弟的患病情况。结果提示HF患者共8例。总患病率为40％，男性患病率为54．5％（6／11），女性患病率为22．2％（2／9），符合常染色体显性遗传。结论本例FH的家系特点为：①血清总胆固醇（TC）从儿重期始有增高，且随年龄的增长有增高趋势；②家系中一对单卵双生的孪生同胞均为患病者，其后代亦有TC增高；③先证者41岁起即以典型的卧位型心绞痛起病，冠状动脉造影提示三支冠状动脉多处严重狭窄，似提示FH家系中的冠心病患者发病早且病变严重。     

The Trp-Stop and Trp-Gly mutations in the LDL receptor gene: common causes of familial hypercholesterolemia in Denmark

Mutations in the gene for the low density lipoprotein (LDL) receptor cause the autosomal dominant disease familial hypercholesterolemia (FH), the prevalence of which is about 0.2% in most populations. By PCR-SSCP analysis and direct sequencing, we identified the receptor-negative Trp²³-Stop LDL receptor mutation (FH Cincinnati-5) in 10 of 63 FH probands and the receptor-defective Trp⁶⁶-Gly LDL receptor mutation (FH French Canadian-4) in another 10 of the 63 FH probands. These two mutations thus account for 30% of diagnosed FH families in Denmark. Comparison of the mean lipid concentrations (unadjusted and adjusted for age), including serum total cholesterol and LDL-cholesterol, showed no significant differences between the two groups of FH heterozygote probands (cholesterol: 10.7 mmol/l vs. 10.7 mmol/l) and between the probands and 16 and 22 non-proband family members with the Trp²³-stop (cholesterol: 10.1 mmol/l) and Trp⁶⁶-Gly (cholesterol: 10.7 mmol/l) mutations, respectively.     

一例纯合子型家族性高胆固醇血症及其系谱分析

报道１例纯合子型家族性高胆固醇血症及其系谱分析结果。方法根据患者及其家系的临床症状和血脂检查资料。结果先证者男性初诊时为６岁，血清胆固醇浓度为２１．３ｍｍｏｌ／Ｌ，出笔时即有黄色瘤，之后多处出现黄色瘤，并有角膜环和主动脉瓣狭窄，多次发生我痛。８     

Long-term outcome after living donor liver transplantation for two cases of homozygous familial hypercholesterolemia from a heterozygous donor

AIM: We experienced two pediatric siblings with homozygous familial hypercholesterolemia (FH) who received living donor liver transplantation (LDLT) from their parents who were heterozygous for FH. METHODS: The elder brother presented orange cutaneous xanthomas and was diagnosed as homozygous FH at the age of one. The plasma lipid profile showed that his total cholesterol level was 898 mg/dL (23.2 mmol/L), LDL cholesterol level was 756 mg/dL (19.6 mmol/L) and triglyceride level was 60 mg/dL (0.7 mmol/L). There were no living donors with a normal LDL receptor in their family, and it was difficult to find a deceased donor in Japan; thus he underwent LDLT with his father as the donor. His sister was born 2 years after his LDLT. She underwent ABO-incompatible LDLT at the age of 2 with her mother as the donor. RESULTS: The boy's liver function tests normalized immediately after transplantation, and his cholesterol has remained controlled at around 280 mg/dL (7.2 mmol/L), with HMG-CoA reductase inhibitor for 6 years after LDLT. The girl's cholesterol remained stable at around 280 mg/dL (7.2 mmol/L) under treatment with HMG-CoA reductase inhibitor two years after LDLT. At present, the four patients, including the two donors, are leading normal daily lives. CONCLUSION: Living-donor liver transplantation from a donor with heterozygous FH is a feasible indication for the treatment of homozygous FH.     

Perspectives in familial hypercholesterolemia: with particular reference to associated ischemic heart disease

Seventy heterozygous patients with familial hypercholesterolemia (FH), aged 3 to 91 years (37 men and 33 women), from 38 different families were studied to ascertain their clinical profiles including the pattern of distribution of total cholesterol (TC), Achilles tendon thickness (ATT), and a sex difference in age at the onset of ischemic heart disease (IHD). Eighteen family members who died of IHD were included in this study. The TC level was 332.2 +/- 95.0 mg/dl (mean +/- SD), and the ATT was 12.0 +/- 2.7 mm. IHD was observed in 20 men and 8 women, with an incidence in men 2.5 times higher than that in women. The mean age at the onset of IHD in men was in the sixth decade, one decade younger than in women. IHD was even observed in patients with TC levels of nearly 230 mg/dl. One of the 18 family members was considered a homozygote of the disease by autopsy findings. Twelve of the remaining members died suddenly, and another five had fatal myocardial infarction. We conclude that, (1) IHD is frequently associated with FH, even though TC levels are 230-300 mg/dl, (2) complications of IHD peak earlier in men (sixth decade) than in women (seventh decade) and (3) relatively large numbers of family members died suddenly, especially men.     

Familial defective apolipoprotein B versus familial hypercholesterolemia: an assessment of risk

Patients with familial hypercholesterolemia (FH) or familial defective apolipoprotein B (FDB) have severely increased low-density lipoprotein (LDL)-cholesterol levels and increased risk for premature coronary artery disease (CAD). Previous data on FDB patients were collected in patients referred to lipid clinics and were therefore subject to referral bias. We assessed the clinical phenotype of FDB in a population free from selection on CAD to compare the atherosclerotic burden with that of heterozygous FH. The study population was actively recruited in a large-scale screening program for inherited hypercholesterolemia in which FH and FDB heterozygotes were diagnosed by standard molecular techniques. Patients with FH and FDB had significantly higher plasma total cholesterol and LDL-cholesterol levels compared with their unaffected relatives. As with previous findings in FH, in FDB 19% of the carriers and 17% of the noncarriers of apoB mutations would have been misdiagnosed by cholesterol measurement alone, taking the age- and sex-specific 95th percentile as the diagnostic criterion. In FH patients the CAD risk was 8.5 relative to unaffected family members, whereas FDB patients had a 2.7-fold higher risk of CAD than unaffected relatives. FDB patients, free from clinical selection bias, do show lower total and LDL-cholesterol levels and lower CAD risk compared with FH heterozygotes. However, FDB patients are still exposed to a substantially higher CAD risk compared with unaffected relatives.     

Vascular dilatory functions of ovo-lactovegetarians compared with omnivores

Familial hypercholesterolemia (FH) and familial defective apolipoprotein B-100 (FDB) cause early onset of coronary heart diseases (CHD). According to the recommendations of the international MEDPED program, we tried to find FH cases. We analyzed 73 FH probands and their 304 first-degree relatives. A total of 39 probands were found from the 21000 subjects screened (1:538) from family doctors' registers recording all citizens, while the remaining 34 were derived from screened patients from lipid clinics. In our FH probands, four cases of FDB (R3500Q mutation) were diagnosed with allele-specific PCR, and the mutation was also detectable in five cases out of seven living family members. In the remaining 69 FH families, 156 people were diagnosed clinically with FH, and 31.8% of the males (against 13% of the not clinically diagnosed FH males, P<0.01), and 32.4% of the females (against 13.5% of the not clinically diagnosed FH females, P<0.01) suffered from early onset CHD. The plasma total cholesterol level of the FDB patients, especially in the younger patients, was very close to normal values. Therefore, the FDB patients seem to be under-represented in this type of survey. Because FDB is one of the independent causes of early onset CHD, the R3500Q mutation should be considered in families with a high frequency of cardiovascular diseases.     

Percepção Inadequada do Risco Cardiovascular e Baixo Conhecimento sobre Hipercolesterolemia Familiar em Indivíduos com Hipercolesterolemia Grave

BackgroundIndividuals with severe hypercholesterolemia are at a high risk of developing atherosclerotic cardiovascular disease (ASCVD). Many of them have familial hypercholesterolemia (FH).ObjectivesTo assess from a patient perspective the degree of awareness about severe hypercholesterolemia, especially FH, ASCVD risk perception, cascade screening performance, and treatment of individuals participating in a routine health evaluation program.MethodsFrom a database of 70,000 Brazilian individuals evaluated between 2006 and 2016, 1,987 (2.8%) met the inclusion criteria (age ≥ 18 years and LDL-C ≥ 190 mg/dL or ≥ 160 mg/dL, respectively, if not in use of statins or on statin therapy). Two-hundred individuals were randomly invited to complete an extensive questionnaire. FH was diagnosed if suspected by the attending physician.ResultsAlthough 97% of the sample (age 48±9 years; 16% women; 95% college/university education; 88% primary prevention; LDL-C 209±47 mg/dL) had severe hypercholesterolemia, only 18% and 29.5% believed to be at high ASCVD risk and reported knowledge of their recommended LDL-C goal, respectively. Fifty-eight percent reported being informed that high cholesterol could be a family disease, 24.5% (n = 49) had ever heard about FH, and merely 14% (n = 29) had been previously identified as suspected of having FH (age at FH diagnosis 35±12 years; 79% and 31% diagnosed, respectively, > 30 and > 40 years old). Only 2.5% underwent genetic tests, 17% underwent cascade screening, and 17% were not in use of pharmacological treatment.ConclusionsAn important gap in risk perception, cholesterol management, and aspects related to FH was encountered in individuals with severe hypercholesterolemia. (Arq Bras Cardiol. 2021; [online].ahead print, PP.0-0)     

Past,Present, and Future of Familial Hypercholesterolemia Management

Familial hypercholesterolemia (FH) is a monogenic form of severe hypercholesterolemia that, if left untreated, is associated with early onset of atherosclerosis. FH derives from genetic variants that lead to inefficient hepatic clearance of low-density lipoprotein (LDL) particles from the circulation. The FH phenotype is encountered in approximately 1 of every 300 people. The risk of atherosclerotic cardiovascular disease (ASCVD) is higher in those with FH than in normolipidemic individuals and in those with polygenic hypercholesterolemia. FH is usually diagnosed by clinical scores that consider hypercholesterolemia, family history of early ASCVD and hypercholesterolemia, and cutaneous stigmata. Genetic diagnosis is important and should be offered to individuals suspected of FH. Family cascade screening is important to identify asymptomatic hypercholesterolemic individuals. Despite the high risk of ASCVD, this risk is heterogenous in heterozygous FH and depends not only on high LDL cholesterol (LDL-C) but also on other risk biomarkers. Risk can be evaluated by considering biomarkers such as male sex, late-onset therapy (> age 40), LDL-C > 310 mg/dL, low high-density lipoprotein cholesterol, elevated lipoprotein(a), obesity, diabetes, and hypertension by using specific risk equations and by detecting subclinical coronary atherosclerosis. Statins are the main therapy for FH and change the natural history of ASCVD; however, most individuals persist with elevated LDL-C. PCSK9 inhibitors provide robust and safe LDL-C lowering in FH, although elevated costs preclude their widespread use. Newer therapies such as ANGPTL3 inhibitors add intensive LDL-C lowering for refractory forms of FH. Finally, while it is possible to normalize LDL-C in people with FH, the disease unfortunately is still severely underdiagnosed and undertreated.     

Differences in [14C]glycerol utilization in normal and familial hypercholesterolemic fibroblasts

It is known that cultured fibroblasts from familial hypercholesterolemia (FH) patients lack the normal cell receptor for low density lipoprotein (LDL) and that the absence of receptor-mediated transport of LDL cholesterol into these cells results in increased cellular synthesis of cholesterol. After 20 h perincubation in lipid-free medium, cultured FH fibroblasts incorporated significantly greater amounts of [14C]glycerol into cellular lipids than did normal fibroblasts. Relative to the control medium which contained only bovine serum albumin (BSA), preincubation with 5% fetal bovine serum or 50 micrograms LDL/ml decreased [14C]glycerol incorporation by both cell types. FH cells utilized more [14C]glycerol for phospholipid synthesis and less for triglyceride synthesis than normal cells. This study indicates that LDL may be important in the transport of glycerides, as well as cholesterol, to cells.     

Detection of silent coronary artery disease in adolescents and young adults with familial hypercholesterolemia by single-photon emission computed tomography thallium-201 scanning.

Familial hypercholesterolemia (FH), a genetic disease characterized by increased levels of total and low-density lipoprotein cholesterol in the blood, results in a markedly increased incidence of atherosclerosis and coronary artery disease in homozygotes and to a lesser extent in heterozygotes. The purpose of this study was to detect the presence of myocardial ischemia, particularly in heterozygotes, with stress single-photon emission computed tomography thallium-201 scanning and to determine if there were any differentiating variables between heterozygotes with normal and abnormal thallium-201 scans. Fifty-four patients (mean age 16 years; range 8 to 24) with FH were analyzed (4 homozygotes and 50 heterozygotes). Eleven heterozygotes and 3 homozygotes had abnormal thallium-201 scans. Family history, lipid profile, age and sex of heterozygotes with FH did not predict the presence of myocardial ischemia. The mean total cholesterol level in heterozygotes with normal thallium-201 scans was 7.68 +/- 2.29 mmol/liter (297 mg/dl), which was not significantly different from that in heterozygotes with abnormal scans (7.63 +/- 1.07 mmol/liter [295 mg/dl]; p = 0.91). The coronary angiography of 1 homozygote who had an abnormal thallium-201 scan demonstrated a 50% stenosis of the left anterior descending artery. Aggressive, repetitive plasma exchange was then instituted. The 11 heterozygotes with abnormal thallium-201 scans underwent more rigorous dietary and drug therapy. It is concluded that myocardial ischemia with stress in heterozygotes with FH can occur at a young age and that thallium-201 scanning should be performed early as a screening test and to guide patient management.     

Coronary angiographic characteristics in Japanese patients with heterozygous familial hypercholesterolemia

Coronary angiographic findings were analyzed in 51 consecutive patients (36 males and 15 females) with heterozygous familial hypercholesterolemia (FH) and 279 consecutive patients (216 males and 63 females) without FH (non-FH). The coronary stenosis index and over 75% stenosis vessel subset were almost three times as high in the FH group. The incidence of myocardial infarction was almost twice as high in the FH group. Levels of total cholesterol and its lipoprotein fractions, except HDL-cholesterol, were almost twice as high in the FH group. In the FH group aged under 50 years, the two parameters of coronary angiogram and the incidence of myocardial infarction were significantly higher in males than in females. However, in the group aged over 50 years, all three parameters were not significantly different between those in males and females. The level of HDL-cholesterol was significantly lower in males than in females. A significantly higher incidence (18%) of coronary ectasia was observed in the FH group compared with the incidence (2%) in non-FH. All patients with coronary ectasia were males, except one female with FH. On comparison of the males among the FH patients with those among the non-FH patients matched for total cholesterol, age and other risk factors, the FH patients were associated with a significantly higher degree of coronary atherosclerosis and lower level of HDL-cholesterol. Seven FH patients with a normal coronary angiogram were observed. However, any factors as regards age, total cholesterol, HDL-cholesterol and Achilles tendon thickness failed to distinguish between the FH patients with a normal coronary angiogram and those without.(ABSTRACT TRUNCATED AT 250 WORDS)     

A suggestion for familial hypercholesterolemia (FH) heterozygosity clinical diagnosis based on epidemiological observations in a large Italian population

We selected 247 subjects from 29 large familial hypercholesterolemia (FH) kindreds from 550 probable FH subjects in Emilia Romagna (Italy) on the basis of LDL-cholesterol plasmatic levels and family trees, in order to define the best diagnostic criteria for heterozygous patients. Familial hypercholesterolemia is a monogenic disease of cholesterol metabolism inherited as an autosomal dominant trait and characterised by early cardiovascular disease. A low xanthomas and xanthelasmas prevalence was found (8.6%); coronary heart disease (CHD) death occurs very frequently in heterozygous males (72% of all deaths; mean age at death 52 years), while in females the primary cause of death was thrombotic stroke (55%; mean age 69 years). Total cholesterol (TC) mean values were 389.8 (m) and 373.3 mg/dl (f) for FH trait carriers, and 223.3 (m) and 228.8 (f) for healthy relatives. No age-related change in TC was found in heterozygotes, while unaffected relatives of FH families showed mean TC and LDL-C values, and a TC frequency distribution and a TC age-related increasing trend similar to the expected values for the Italian population. The TC frequency distribution curve appeared bimodal, with a mid-point between heterozygous and homozygous FH modal values of 280 mg/dl. To identify the FH patients, the final FH heterozygosity risk was evaluated in an unselected free-living population (from 0.07 to 0.8%, respectively, for TC between 265-274 and 295-304 mg/dl) and in hypercholesterolemic families (31 to 83%, and the same TC classes). Our conclusion is that the clinical picture is rarely pathognomonic, while the FH heterozygosity final risk evaluation and the 280 mg/dl cut-off point can be used to guide the practical clinical diagnosis and to select the patients destined for B-E receptor activity evaluation.     

Assessment by transesophageal echography of atherosclerosis of the descending thoracic aorta in patients with hypercholesterolemia

This study assesses atheromatous lesions and aortic stiffness of the descending thoracic aorta (DTA) in patients with hyperlipidemia by transesophageal echography (TEE) and investigates the relations between atherosclerotic lesions and aging or serum cholesterol levels in these patients. Subjects included 16 patients with familial hypercholesterolemia (FH), 15 non-FH hyperlipidemic patients (non-FH), and 17 age-matched normal subjects. With use of TEE, the DTA was divided into 4 longitudinal portions of equal length, and the atheromatous lesions of each portion of DTA were scored according to their character and extension by biplane 2-dimensional TEE. The scores of atheromatous lesions from all 4 portions were added together to give the total atheromatous score. Then, after measuring the instantaneous dimensional changes of DTA in a cardiac cycle by M-mode TEE and blood pressure (BP) by a cuff method, we calculated the aortic stiffness parameter beta = ln(systolic BP/diastolic BP)/([Dmaximum - Dminimum]/Dminimum). The beta was significantly higher in FH and non-FH subjects than in normal subjects. In both FH and non-FH subjects, the total atheromatous score correlated with total serum cholesterol levels (r = 0.64 [p <0.01]; r = 0.58 [p <0.05], respectively). There were significant correlations between age and beta in all 3 groups (FH, r = 0.67 [p <0.005]; non-FH, r = 0.53 [p <0.05]; normal subjects, r = 0.49 [p <0.05]), and the slopes of the regression lines of FH and non-FH subjects were much steeper than those of normal subjects. The incidence of atherosis in the DTA was significantly higher in hyperlipidemic patients than in normal subjects, even among the younger members of the hyperlipidemic population with progressive aortic stiffness.     

Identification and treatment of heterozygous familial hypercholesterolemia in children and adolescents

Heterozygous familial hypercholesterolemia (FH) is completely expressed at birth and early in childhood by significant elevations in plasma total and tow density lipoprotein (LDL) cholesterol levels. High density lipoprotein cholesterol can be low in such FH children; the triglyceride levels are usually within the normal range. Screening of children for heterozygous FH using a LDL cholesterol level is reasonably efficient in families with known FH, but for general population screening, the LDL cholesterol level is often too nonspecific. Screening of offspring with a positive family history of premature coronary artery disease will provide a panoply of different lipoprotein phenotypes, reflecting the presence of other genetic conditions, including familial combined hyperlipidemia. Guidelines have been developed by the National Cholesterol Education Program (NCEP) Expert Panel on Blood Cholesterol levels in Children and Adolescents to assist in the evaluation and treatment of children with high LDL cholesterol levels. Although heterozygous FH probably counts for ≤5% of premature coronary artery disease, its identification and treatment are important, because FH often causes marked premature coronary artery disease early in adulthood, and can be successfully treated with a combined dietary and drug approach.     

Familial hypercholesterolemia in Utah kindred with novel R103W mutations in exon 4 of the LDL receptor gene

Heterozygous familial hypercholesterolemia (FH) is a serious disorder causing twice normal low-density lipoprotein cholesterol levels early in childhood and very early coronary disease in both men and women. Previously published blood cholesterol criteria greatly under-diagnosed new cases of FH among members of known families with FH and over-diagnosed FH among participants of general population screening. Thus, there is a need for accurate and genetically validated criteria for the early diagnosis of heterozygous FH. In the course of investigations of coronary artery disease in Utah, we identified a family whose proband showed elevated plasma levels of LDL cholesterol. To carry out molecular genetic diagnosis of the disease, we screened DNA samples for mutations in all 18 exons and the exon- intron boundaries of the low-density lipoprotein (LDL) receptor gene. Novel point mutations were identified in the proband: a C-to-T transversion at nucleotide position 369, causing substitution of Tryptophan for Arginine at codon 103 in exon 4 of the LDL receptor gene. The SSCP method was used to examine seven members of the family recruited for the diagnosis. This method helped to unequivocally diagnose only the proband as heterozygous for this particular LDL receptor mutation while excluding the remaining six individuals from carrier status with FH.     

Long-term efficacy of low-density lipoprotein apheresis on coronary heart disease in familial hypercholesterolemia

Familial hypercholesterolemia (FH) is characterized by severe hypercholesterolemia and premature coronary heart disease (CHD). The lower the plasma cholesterol level, the more likely it is that CHD can be prevented or retarded; aggressive cholesterol-lowering therapies may be indicated for FH patients with CHD. This study describes the long-term (6 years) safety and efficacy of intensive cholesterol-lowering therapies with low-density lipoprotein (LDL) apheresis in heterozygous FH patients with CHD. One hundred thirty heterozygous FH patients with CHD documented by coronary angiography had been treated by cholesterol-lowering drug therapy alone (n = 87) or LDL apheresis combined with cholesterol-lowering drugs (n = 43). Serum lipid levels and outcomes in each treatment group were compared after approximately 6 years. Both treatment groups had significant reductions in serum cholesterol, LDL cholesterol, and high density lipoprotein cholesterol levels. LDL apheresis significantly reduced LDL cholesterol levels from 7.42 ± 1.73 to 3.13 ± 0.80 mmol/L (58%) compared with group taking drug therapy, from 6.03 ± 1.32 to 4.32 ± 1.53 mmol/L (28%). With Kaplan-Meier analyses of the coronary events including nonfatal myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, and death from CHD, the rate of total coronary events was 72% lower in the LDL-apheresis group (10%) than in drug therapy group (36%) (p = 0.0088). It is concluded that LDL-apheresis is effective as treatment of CHD in FH heterozygotes, and may become the therapy of choice in severe types of FH.     

SERUM LIPID AND APOLIPOPROTEIN A AND B LEVELS IN FAMILIAL HYPERCHOLESTEROLEMIA

Serum lipid and apolipoprotein A (apo A) and B (apo B) levels were studied in a family with familial hypercholesterolemia (FH), which comprised two heterozygous parents, five heterozygous children, one homozygote and one normal child. Lipid levels were compared with those of age- and sex-matched normal controls. All subjects with FH had total serum cholesterol and low density lipoprotein-cholesterol (LDL-C) levels greater than the 90th percentile value for the reference range. High density lipoprotein-cholesterol (HDL-C) levels were less than the corresponding 13th percentile in heterozygous subjects. The homozygous child had grossly elevated levels of LDL-C and apo B, and very low levels of HDL-C and apo A. The most powerful discriminating variable between normal, heterozygous and homozygous family members was the LDL-C/HDL-C ratio.     

Ultrasonography in the detection of Achilles tendon xanthomata in heterozygous familial hypercholesterolemia.

We have examined the usefulness of ultrasound (US) in the detection of Achilles tendon (AT) xanthomata in heterozygous familial hypercholesterolemia. Our study is based on 30 adult subjects with heterozygous familial hypercholesterolemia (FH) (16 men, 14 women), 27 subjects with other non-familial forms of severe hypercholesterolemia (non-FH) with serum total cholesterol levels > or = 8 mmol/l (13 men and 14 women) and 31 subjects without marked hypercholesterolemia of the same age (control group; serum total cholesterol < 8 mmol/l) (15 men, 16 women). The three groups were comparable with respect to age, sex and body mass index. In the control group the mean sagittal thickness of AT was 4.5 mm (95% CI 3.2, 5.9 mm) and the mean coronal breadth of AT 11.0 (95% CI 9.0, 13.0 mm). Mean thickness of AT was 4.9 (range 4-7) mm in the non-FH group and 11.1 (5-16) mm in the FH group. The mean breadth of AT was in these groups 12.0 (10-17) mm and 19.2 (12-27) mm, respectively. Using the upper 95% confidence interval cut-off point in the control group as a criterion for normal AT thickness and breadth, 6 (22%) of non-FH and 29 (97%) of FH patients had increased AT thickness and 5 (19%) vs. 26 (87%) patients had increased AT breadth, respectively. The sensitivity of AT thickness for identifying FH was 0.97, specificity 0.78 and positive predictive value 0.83. The sensitivity of AT breadth in identifying FH was 0.87, specificity 0.81 and positive predictive value 0.84. None of the control subjects and none of the non-FH patients showed structural abnormalities of AT in the US, whereas 89% of FH-patients showed hypoechogenicity of AT. FH-score obtained by summing up the number of abnormal US findings gave a sensitivity of 0.93, a specificity of 0.96 and a positive predictive value of 0.96 for AT US in discriminating FH from non-FH. In conclusion, US examination of AT is a useful method in the detection of AT xanthomata and thus of help in the diagnosis of heterozygous FH.