Familial Combined Hyperlipidemia: Current Knowledge, Perspectives, and Controversies

Abstract

Familial combined hyperlipidemia (FCHL) is the most prevalent primary dyslipidemia; however, it frequently remains undiagnosed and its precise definition is a subject of controversy. FCHL is characterized by fluctuations in serum lipid concentrations and may present as mixed hyperlipidemia, isolated hypercholesterolemia, hypertriglyceridemia, or as a normal serum lipid profile in combination with abnormally elevated levels of apolipoprotein B. FCHL is an oligogenic primary lipid disorder, which can occur due to the interaction of several contributing variants and mutations along with environmental triggers. Controversies surrounding the relevance of identifying FCHL as a cause of isolated hypertriglyceridemia and a differential diagnosis of familial hyper-triglyceridemia are offset by the description of associations with USF1 and other genetic traits that are unique for FCHL and that are shared with other conditions with similar pathophysiological mechanisms. Patients with FCHL are at an increased risk of cardiovascular disease and mortality and have a high frequency of comorbidity with other metabolic conditions such as type 2 diabetes, non-alcoholic fatty liver disease, steatohepatitis, and the metabolic syndrome. Management usually requires lipid-lowering therapy directed toward reducing cholesterol and triglyceride concentrations along with cardiovascular risk protection. In recent years, the number of research studies on FCHL has been decreasing, mainly due to a lack of recognition of its impact on disease burden and comorbidity and the complexity in identifying probands for studies. This creates areas of opportunity to develop research for FCHL in epidemiology, genetics, pathophysiology, therapeutics, and cardiovascular risk management, which are discussed in depth in this review.

Molecular and Metabolic Pathogenesis of Familial Combined Hyperlipidemia and Association with Metabolic Syndrome

“…While Framingham's hyperlipidemia classification of type-2b with mixed hyperlipidemia is the initial clicker to include FCHL in your diagnosis, still we do learnt from above discussion that the FCHL phenotypes differ in terms of lipid levels, lipid types, associated metabolic component, clinical presentations, underlying genetics and inconsistent data on the subject. [5,6] These considerations make the diagnosis of FCHL very much heterogeneous and a real life diagnostic dilemma for diagnosticians. Alongside we must appreciate the atherosclerotic cardiovascular disease associations of FCHL in terms of very high prevalence in patients having myocardial ischemia.…”

“…Molecular and genetic studies and phenotypic disease presentations have identified it as heterogeneous disease which not only vary in terms of temporo-spatial presentation clinical traits, being very pleiotropic due to probable multiple molecular triggers and the clinical appreciation variability resulting from the subtype of cholesterol surge or decline and very high prevalence in myocardial survivors. [5,3,6] All these differential presentation surrounding the singular label "FCHL" and inputs from small scale studies focusing upon few aspects of this broad-spectrum pathology makes it difficult to define the disease. [7] Nonetheless literature search converges to a few common traits which may help elucidate a criteria for nominating a person with FCHL.…”

A novel mutation in USF1 gene is associated with familial combined hyperlipidemia

“…Familial combined Hyperlipidemia (FCHL) is the most common genetic and metabolic form of hyperlipidemia with prevalence of 0.5% to 2% worldwide and about 10% of these patients suffer from cardiovascular disease (CAD). This number has increased by approximately 11.3% in young survivors of myocardial infarction (MI) and by 40% among all the people who survived an MI . Based on previous studies about 3.5 million people in Europe and 7.2 million people in the United States are affected by this disorder .…”

“…This number has increased by approximately 11.3% in young survivors of myocardial infarction (MI) and by 40% among all the people who survived an MI. [1][2][3][4] Based on previous studies about 3.5 million people in Europe and 7.2 million people in the United States are affected by this disorder. 5,6 Biochemically, FCHL is associated with increased levels of triglyceride, total cholesterol, or both, and increased levels of VLDL, LDL, decreased HDL, and increased apo B level.…”

“…1,7 Based on a combination of past and recent definitions, FCHL is now been recognized as a common metabolic disorder and is characterized in a family by an increased serum triglyceride and LDL in two members of a family accompanied by increased risk of premature coronary artery disease. 4,8 FCHL is genetically complex; in addition to the role of environmental factors, the FCHL is genetically heterogeneous. 9,10 Three important genetic loci for FCHL have been identified: 1q21-23, apolipoprotein A-I/C-III/A-IV cluster on chromosome 11 and lipoprotein lipase (LPL) gene on 8p that in several different studies had significant LOD scores with FCHL.…”