Low cholesterol states: clinical implications and management

Hypocholesterolemia results from genetic - both monogenic and polygenic - and non-genetic causes and can sometimes be a source of clinical concern. We review etiologies and sequelae of hypocholesterolemia and therapeutics inspired from genetic hypocholesterolemia.

Monogenic hypocholesterolemia disorders caused by the complete absence of apolipoprotein (apo) B-containing lipoproteins (abetalipoproteinemia and homozygous hypobetalipoproteinemia) or an isolated absence of apo B-48 lipoproteinemia (chylomicron retention disease) lead to clinical sequelae. These include gastrointestinal disturbances and severe vitamin deficiencies that affect multiple body systems, i.e. neurological, musculoskeletal, ophthalmological, and hematological. Monogenic hypocholesterolemia disorders with reduced but not absent levels of apo B lipoproteins have a milder clinical presentation and patients are protected against atherosclerotic cardiovascular disease. Patients with heterozygous hypobetalipoproteinemia have somewhat increased risk of hepatic disease, while patients with PCSK9 deficiency, ANGPTL3 deficiency, and polygenic hypocholesterolemia typically have anunremarkable clinical presentation.

In patients with severe monogenic hypocholesterolemia, early initiation of high-dose vitamin therapy and a low-fat diet are essential for optimal prognosis. The molecular basis of monogenic hypocholesterolemia has inspired novel therapeutics to help patients with the opposite phenotype - i.e. elevated apo B-containing lipoproteins. In particular, inhibitors of PCSK9 and ANGPTL3 show important clinical impact.