Peripheral artery occlusive disease (obstruction of the arteries of the legs) occurs mainly in people with FH who smoke; this can cause pain in the calf muscles during walking that resolves with rest (intermittent claudication) and problems due to a decreased blood supply to the feet (such as gangrene). Atherosclerosis risk is increased further with age and in those who smoke, have diabetes, high blood pressure and a family history of cardiovascular disease. Diagnosis
Approximately 85% of individuals with this disorder have not been diagnosed and consequently are not receiving lipid-lowering treatments. Physical examination findings can help a physician make the diagnosis of FH. Tendon xanthomas are seen in 20-40% of individuals with FH and are pathognomonic for the condition. A xanthelasma or corneal arcus may also be seen. These common signs are supportive of the diagnosis, but are non-specific findings. Lipid measurements
Cholesterol levels may be determined as part of health screening for health insurance or occupational health, when the external physical signs such as xanthelasma, xanthoma, arcus are noticed, symptoms of cardiovascular disease develop, or a family member has been found to have FH. A pattern compatible with hyperlipoproteinemia type IIa on the Fredrickson classification is typically found: raised level of total cholesterol, markedly raised level of low-density lipoprotein (LDL), normal level of high-density lipoprotein (HDL), and normal level of triglycerides. Total cholesterol levels of 350–550 mg/dL are typical of heterozygous FH while total cholesterol levels of 650–1000 mg/dL are typical of homozygous FH.
Like LDLR, the number of abnormal copies determines the severity of the hypercholesterolemia. PCSK9
Mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene were linked to autosomal dominant (i.e. requiring only one abnormal copy) FH in a 2003 report. The gene is located on the first chromosome (1p34.1-p32) and encodes a 666 amino acid protein that is expressed in the liver. It has been suggested that PCSK9 causes FH mainly by reducing the number of LDL receptors on liver cells. LDLRAP1
Abnormalities in the ARH gene, also known as LDLRAP1, were first reported in a family in 1973. In contrast to the other causes, two abnormal copies of the gene are required for FH to develop (autosomal recessive). The mutations in the protein tend to cause the production of a shortened protein. Its real function is unclear, but it seems to play a role in the relation between the LDL receptor and clathrin-coated pits. People with autosomal recessive hypercholesterolemia tend to have more severe disease than LDLR-heterozygotes but less severe than LDLR-homozygotes. Pathophysiology
LDL cholesterol normally circulates in the body for 2.5 days, and subsequently the apolipoprotein B portion of LDL cholesterol binds to the LDL receptor on the liver cells, triggering its uptake and digestion. This process results in the removal of LDL from the circulatory system. Synthesis of cholesterol by the liver is suppressed in the HMG-CoA reductase pathway.