The German CaRe high registry for familial hypercholesterolemia - Sex differences, treatment strategies, and target value attainment.

Background and aims: Familial hypercholesterolemia (FH) is among the most common genetic disorders in primary care. However, only 15% or less of patients are diagnosed, and few achieve the goals for low-density lipoprotein cholesterol (LDL-C). In this analysis of the German Cascade Screening and Registry for High Cholesterol (CaRe High), we examined the status of lipid management, treatment strategies, and LDL-C goal attainment according to the ESC/EAS dyslipidemia guidelines. Methods: We evaluated consolidated datasets from 1501 FH patients diagnosed clinically and seen either by lipid specialists or general practitioners and internists. We conducted a questionnaire survey of both the recruiting physicians and patients. Results: Among the 1501 patients, 86% regularly received lipid-lowering drugs. LDL-C goals were achieved by 26% and 10% of patients with atherosclerotic cardiovascular disease (ASCVD) according to the 2016 and 2019 ESC/EAS dyslipidemia guidelines, respectively. High intensity lipid-lowering was administered more often in men than in women, in patients with ASCVD, at higher LDL-C and in patients with a genetic diagnosis of FH. Conclusions: FH is under-treated in Germany compared to guideline recommendations. Male gender, genetic proof of FH, treatment by a specialist, and presence of ASCVD appear to be associated with increased treatment intensity. Achieving the LDL-C goals of the 2019 ESC/EAS dyslipidemia guidelines remains challenging if pre-treatment LDL-C is very high.

Cutaneous manifestations in familial hypercholesterolaemia.

BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) is associated with high cardiovascular risk and underdiagnosed. Cutaneous manifestations are traditionally used as a major criterion of FH. They are included in the Dutch Lipid Clinic Network or Simon Broome registry criteria. The objective of this study was to evaluate cutaneous manifestations in contemporary FH patients. METHODS: We prospectively analysed the clinical presentation of FH patients referred to a University lipid clinic and validated these data in the German FH registry CaRe High. RESULTS: Physical examination revealed that only 14.4% of the FH patients in the lipid clinic cohort (n = 223) showed cutaneous manifestations. An arcus cornealis was present in 0.9%, xanthomata in 1.8%, and xanthelasmata in 12.1%. Xanthelasmata are not part of the clinical scores, but represented 84.4% of all cutaneous manifestations. In 42.6% (n = 95) of the patients, genetic analysis was available. A causal FH mutation was detected in 50.5%. Among carriers, 66.7% had no cutaneous manifestation, 8.3% exhibited an arcus cornealis or xanthomata, and 25.0% had xanthelasmata. In the CaRe High FH registry, data on cutaneous manifestations were available in n = 1274 patients. 3.5% had xanthomata, 5.7% an arcus cornealis, and 7.7% at least one of both; xanthelasmata were present in 10.3%. CONCLUSIONS: Cutaneous manifestations are only present in a minority of contemporary patients with FH including the subgroup with monogenic FH mutations. Although rare, the cutaneous signs have value in terms of specificity. However, the clinical characteristics shared by the majority of FH patients may be better suited for screening purposes.

The Role of Regulatory CD4 T Cells in Maintaining Tolerance in a Mouse Model of Autoimmune Hepatitis.

BACKGROUND: The role of regulatory CD4 T cells (Treg) in immune-mediated liver disease is still under debate. It remains disputed whether Treg suppress T cell-mediated hepatitis in vivo and whether hepatic regulatory T cells are functional in patients with autoimmune hepatitis. METHODS: We used TF-OVA mice, which express ovalbumin in hepatocytes, to investigate the impact of Treg in a model of autoimmune hepatitis. Treg isolated from inflamed livers of TF-OVA mice were tested for their functionality in vitro. By employing double transgenic TF-OVAxDEREG (DEpletion of REGulatory T cells) mice we analyzed whether Treg-depletion aggravates autoimmune inflammation in the liver in vivo. RESULTS: CD25+Foxp3+ CD4 T cells accumulated in the liver in the course of CD8 T cell-mediated hepatitis. Treg isolated from inflamed livers were functional to suppress CD8 T-cell proliferation in vitro. Depletion of Treg in TF-OVAxDEREG mice dramatically amplified T cell-mediated hepatitis. Repeated administration of antigen-specific CD8 T cells led to a second wave of inflammation only after depletion of Treg. CONCLUSION: Our data add to the evidence for an important role of Treg in autoimmune hepatitis and show that Treg reduce the severity of T-cell mediated hepatitis in vivo. They constitute a key immune cell population that actively maintains a tolerogenic milieu in the liver and protects the liver against repeated inflammatory challenges.