Familial hypercholesterolaemia

Familial hypercholesterolaemia (FH) is a common (1 in 500) autosomal dominant group of syndromes associated with early onset coronary artery disease or sudden death in heterozygotes. Clinical signs are not universal but the family history is often a good indicator for initial screening. Prognosis without treatment is dependent on family history and the presence of other cardiovascular risk factors. Family screening is necessary but treatment of affected children is usually postponed until puberty. Treatment of adults is primarily with statins but removal of lipoproteins by apheresis is used in severe refractory cases or in patients with homozygous FH. FH is an easily diagnosed disorder with a reasonable prognosis after treatment and therefore cases should be identified and treated.     

Familial hypercholesterolaemia in Portugal

Familial hypercholesterolaemia (FH) is characterised clinically by an increased level of circulating LDL cholesterol that leads to lipid accumulation in tendons and arteries, premature atherosclerosis and increased risk of coronary heart disease (CHD). Although Portugal should have about 20,000 cases, this disease is severely under-diagnosed in our country, this being the first presentation of Portuguese data on FH. A total of 602 blood samples were collected from 184 index patients and 418 relatives from several centres throughout Portugal. Fifty-three different mutations were found in 83 index patients, 79 heterozygous and 4 with two defective LDLR alleles. Additionally, 4 putative alterations were found in 8 patients but were not considered mutations causing disease, mainly because they did not co-segregate with hypercholesterolaemia in the families. Three unrelated patients were found to be heterozygous for the APOB(3500) mutation and two unrelated patients were found to be heterozygous for a novel mutation in PCSK9, predicted to cause a single amino acid substitution, D374H. Cascade screening increased the number of FH patients identified genetically to 204. The newly identified FH patients are now receiving counselling and treatment based on the genetic diagnosis. The early identification of FH patients can increase their life expectancy and quality of life by preventing the development of premature CHD if patients receive appropriate pharmacological treatment.     

Familial hypercholesterolaemia in a Belgian community

Familial hypercholesterolaemia (FH) is a genetic disease in which low-density lipoproteins are defectively removed from plasma as a result of mutations that impair the function either of the LDL receptor or of the apolipoprotein B. The consequences are an elevated concentration of LDL-cholesterol and the early occurrence of cardiovascular diseases. Although FH is well understood, it remains a diagnostic challenge for the clinician. Differentiating FH from other causes of hypercholesterolaemia has, however, important clinical and therapeutic implications: FH being associated with early and severe cardiovascular risk, the plasma LDL-cholesterol must be lowered as drastically and as early as possible; because FH is a dominantly inherited disorder, family members need to be screened and counseled. Prevalence, morbidity and genetic characterization of FH have never been explored in our country. Through our experience of large-scale screening of LDL-receptor and Apo B amongst suspected individuals, we are beginning to understand the molecular spectrum of FH in Belgium. Furthermore, using the large collection of clinical data accumulated amongst patients with genetically ascertained FH, we have attempted to establish specific and sensible diagnostic criteria useful and feasible in routine medical practice.     

Familial hypercholesterolaemia and LDL receptor mutations.

Inherited defects in the gene for the low density lipoprotein (LDL)-receptor give rise to familial hypercholesterolaemia (FH), a disorder in which defective catabolism of LDL causes a marked increase in its concentration in plasma. As a result, there is excessive deposition of cholesterol in the arterial wall leading to accelerated atherosclerosis and premature coronary heart disease in most patients, although there are differences in its severity. Many different mutations have been found in the LDL receptor genes of FH patients, and although this heterogeneity has provided information about the relationship between structure and function in different domains of the protein, it makes simple DNA-based diagnosis of the disease impossible. When sufficient groups of patients with defined mutations are available it will be possible to determine the relative importance of any particular mutation compared with other genetic or environmental factors in relation to the severity of their symptoms or their response to treatment.     

Possible Neoangiogenesis in Achilles Tendon Xanthoma with Familial Hypercholesterolemia: A Novel Approach to Achilles Tendon Xanthoma

Achilles tendon xanthoma (ATX) is one of the typical features of familial hypercholesterolemia (FH). The morphological evaluation of ATX by X-ray radiography is widely recognized; however, the utility of other imaging modalities remains unclear. We herein report two cases of FH in which Doppler ultrasound imaging demonstrated a microvascular flow in ATX that only rarely could be observed in normal Achilles tendons. Neoangiogenesis accompanies chronic inflammation and it may play an important role in the deposition of cholesterol crystals leading to ATX. In addition to the morphological evaluation of ATX, the assessment of neoangiogenesis may therefore be essential for the evaluation of ATX.     

Tuberculous fasciitis with tenosynovitis

A case of tuberculous fasciitis with tenosynovitis is described. No other organs were affected and tissue histology was not diagnostic. The diagnosis was confirmed by tissue culture and our patient was treated by surgical debridement and antituberculous drug therapy. A high index of suspicion for tuberculosis will alert clinicians to the correct diagnosis in unusual clinical presentations.     

Factors Associated with Carotid Atherosclerosis and Achilles Tendon Thickness in Japanese Patients with Familial Hypercholesterolemia: A Subanalysis of the Familial Hypercholesterolemia Expert Forum (FAME) Study

Aims: Familial hypercholesterolemia (FH) is characterized by high low-density lipoprotein (LDL) cholesterol levels, xanthomas including Achilles tendon thickening, and premature coronary artery disease (CAD). Carotid intima-media thickness (IMT) is a well-established surrogate marker for CAD in FH and Achilles tendon thickening is a specific physical finding in patients with FH. The objective of the present study was to identify factors associated with carotid IMT and Achilles tendon thickness in FH heterozygotes on lipid-lowering therapy. This study also aimed to examine the follow-up changes in carotid IMT and Achilles tendon thickness among them in the current real-world FH practice. Methods: The current study is a subanalysis of the Familial Hypercholesterolemia Expert Forum (FAME) Study. The severity of carotid atherosclerosis was assessed with the maximal and mean IMT using ultrasonography, and Achilles tendon thickness was measured using X-rays. The present study used 571 patients under medical treatment for heterozygous FH who had baseline measurements for maximal IMT (n=511), mean IMT (n=459), or Achilles tendon thickness (n=486). The IMT was measured annually, and Achilles tendon thickness was evaluated every two years. Results: Higher LDL cholesterol (LDL-C) level and lower HDL cholesterol (HDL-C) level were associated with greater maximal and mean IMT as well as greater Achilles tendon thickness. Achilles tendon thickness tended to be greater in patients who had a smoking history than in never-smokers. Maximal IMT and Achilles tendon thickness were significantly greater in patients with CAD than in those without. Additionally, lower HDL-C level and hypertension were associated with higher values of maximal and mean IMT, suggesting the importance of comprehensive risk management including reduced HDL-C and blood pressure control in FH care. In longitudinal observations, percentage changes in maximal IMT and mean IMT gradually increased during the observation period. In contrast, percentage changes in Achilles tendon thickness became progressively thinner throughout the observation period. Conclusions: We found a positive association between LDL-C levels and severity of carotid atherosclerosis in heterozygous FH patients on treatment. This observation suggests the insufficiency of lipid-lowering therapy and the presence of therapeutic inertia among clinicians in the real-world FH practice.     

Achilles Tendon Thickness Assessed by X-ray Predicting a Pathogenic Mutation in Familial Hypercholesterolemia Gene

Aim: The 2017 Japan Atherosclerosis Society (JAS) familial hypercholesterolemia (FH) criteria adopt a cut-off value of ≥ 9 mm of Achilles tendon thickness (ATT) detected by X-ray as one of the three key items. This threshold was determined based on an old data evaluating the ATT of 36 non-FH individuals that was published in 1977. Although the specificity of these clinical criteria is extremely high due to a strict threshold, there are a significant number of patients with FH whose ATT ＜9 mm. We aimed to determine a cut-off value of ATT detected by X-ray to differentiate FH and non-FH based on genetic diagnosis. Methods: The individuals (male/female=486/501) with full assessments of genetic analyses for FH-genes (LDLR andPCSK9), serum lipids, and ATT detected by X-ray at the Kanazawa University Hospital and National Cerebral and Cardiovascular Center Research Institute were included in this study. Receiver operating characteristic (ROC) analyses were conducted to determine a better cut-off value of ATT that predicts the pathogenic mutation of FH. Results: The ROC analyses revealed that the best cut-off values of ATT are 7.6 mm for male and 7.0 mm for female, with the sensitivities/specificities of 0.83/0.83 for male and 0.86/0.85 for female, respectively. If the thresholds of ATT of 8.0/7.5 mm and 7.5/7.0 mm were applied to the diagnosis of male/female FH, the sensitivities/specificities predicting the pathogenic mutation of FH by the 2017 JAS FH clinical criteria would be 0.82/0.90 and 0.85/0.88, respectively. Conclusions: These results suggest that the cut-off value of ATT detected by X-ray is obviously lower than 9.0 mm, which was adopted by the 2017 JAS FH clinical criteria.     

A boy with autosomal recessive hypercholesterolaemia

We describe a 9-year-old Iranian boy with tuberous xanthomas, elevated LDL-cholesterol levels of 15.5 mmol/l, and vague complaints of chest pain while playing soccer. The consanguineous parents of the boy had normal cholesterol concentrations, which indicated an autosomal recessive disorder rather than autosomal dominant familial hypercholesterolaemia. The diagnosis of autosomal recessive hypercholesterolaemia (ARH) was confirmed by the presence of a mutation in the phosphotyrosine binding domain of a putative adaptor protein, which prevents normal internalisation of the LDL receptor (LDLR) in the liver. The clinical phenotype of ARH is similar to that of classical homozygous familial hypercholesterolaemia caused by defects in the LDLR gene, but it is more variable, generally less severe, and more responsive to lipid-lowering therapy. The patient's complaints of chest pain were not caused by ischaemia as was tested by an exercise and 24-hour electrocardiogram and by a myocardial perfusion scan. His LDL-C dropped by about 6o% after being treated with a combination of 40 mg atorvastatin and 10 mg ezetimibe.     

Metabolic studies with probucol in hypercholesterolaemia

Probucol (1 g/day) was administered for 6 months to 16 hypercholesterolaemic patients previously stabilized on diet alone. Total plasma cholesterol fell by 16%, LDL cholesterol by 14% and HDL cholesterol by 41%. The ratio of total cholesterol to HDL cholesterol increased by 40%. Total plasma triglycerides showed a slight upward trend. The extent of the fall in HDL cholesterol was directly proportional to the pre-treatment HDL cholesterol concentration. In 2 patients studied, treatment with Probucol produced a sustained increase in the excretion of endogenous faecal steroids, due to increased faecal bile acids. In 3 patients studied, Probucol increased the degree of cholesterol saturation in gall bladder bile. The Lithogenic Index approximated to pathological levels in 1 patient whose bile was previously relatively saturated with cholesterol. Probucol also appeared to cause a modest reduction in the degree of platelet activation in vivo, with reduced platelet prostaglandin synthesis and reduced release of platelet peptides.     

Treatment of rheumatoid tenosynovitis with cytokine inhibitors

Hand function depends on tendon integrity, but in rheumatoid arthritis tenosynovitis can result in tendon adhesions and rupture. Cytokine inhibitors have proved effective in rheumatoid joint disease; however, their effect on the tenosynovium is not well understood. We investigated the ability of inhibitors of tumour necrosis factor alpha and interleukin 1 to reduce production of collagenolytic matrix metalloproteinases 1 and 13 in tenosynovial tissue obtained from patients with rheumatoid arthritis. Our data show that cytokine blockade can reduce collagenase concentrations in tenosynovial tissue, suggesting cytokine inhibitors could be effective in reduction of tendon damage.