How long had FH been around?
Familial Hypercholesterolemia (FH) was first discovered by the Norwegian pathologist Dr. Francis Harbitz (1867-1950), who reported on several cases of sudden death and xanthomatosis associated with the disorder. Dr. Harbitz's observations laid the foundation for understanding the genetic nature of FH, a condition that causes dangerously high cholesterol levels in the blood.
An interesting historical note is that Leonardo da Vinci’s famous painting Mona Lisa is believed to depict visual signs suggestive of Familial Hypercholesterolemia (FH) in the portrayal of Madonna Lisa Maria de Gherardini, the woman thought to be the subject of the painting. Some art historians and medical researchers have suggested that the distinctive appearance of her eyes and skin in the artwork may be indicative of FH, particularly the presence of xanthomas, which are yellowish deposits of cholesterol often found in individuals with the condition. This theory offers a unique intersection of art and medicine, suggesting that da Vinci may have inadvertently captured the clinical features of this genetic disorder centuries before it was formally recognized.
So what is FH?
Familial Hypercholesterolemia is a common inherited autosomal-dominant, monogenetic disorder with high penetrance of >90%, which means if a person’s first degree relative has FH, then they have a “high likelihood” of inheriting the FH disorder. FH is present from birth and is characterized by extremely high levels of low-density lipoprotein (LDL) cholesterol, often referred to as “bad cholesterol”. The accumulation of LDL cholesterol in the bloodstream significantly increases the risk of developing premature atherosclerosis, particularly in the proximal segments of the coronary arteries and the aorta. This can lead to early-onset cardiovascular diseases, such as coronary artery disease. In severe cases, the condition can also lead to supravalvular aortic stenosis.
FH is one of the most prevalent disorders of lipid metabolism, affecting approximately 30 million individuals worldwide which roughly equates to 1 in every 500 individuals. Early detection and treatment are crucial in managing the disorder and preventing life-threatening cardiovascular complications. Treatment typically involves lifestyle modifications, dietary changes, and pharmacological interventions such as statins, which lower LDL cholesterol levels and reduce the risk of atherosclerosis. Genetic counseling and testing are also recommended for family members of affected individuals to assess their risk.
How does genetic mutation occur?
Familial Hypercholesterolemia (FH) is a genetic disorder caused by mutations in key genes, including LDLR, APOB, or PCSK9. The most common genetic defect associated with FH is in the LDLR gene, which is responsible for approximately 90% of cases. Mutations in the APOB and PCSK9 genes are rarer. Individuals who inherit an abnormal gene from one parent develop Heterozygous FH (HeFH), a less severe form of the disorder. In males with HeFH, premature cardiovascular disease may develop as early as 30 to 40 years of age due to persistently elevated LDL cholesterol. In females, premature cardiovascular disease typically manifests around 40 to 50 years of age. If left untreated, they are at a higher risk of dying due to sudden cardiovascular events.
However, when a child inherits abnormal genes from both parents, they have a higher chance of developing Homozygous FH (HoFH), a more severe form of the FH. Nevertheless, the prevenance is estimated to be about 1 in every 1 million individuals. HoFH is characterized by extremely high cholesterol levels from birth and requires early intervention, such as ???statin therapy, lipid-lowering medications, or even cholesterol apheresis, to prevent life-threatening cardiovascular disease.
While genetic mutations play a central role in the development of FH, environmental and lifestyle factors can influence the severity and prevalence of the disorder. However, the hallmark physical traits of FH, such as the presence of xanthomas (cholesterol deposits), are directly inherited and remain crucial for diagnosis. Early detection and management of FH are essential to reducing the risk of cardiovascular complications and improving long-term health outcomes.
Prevalence in Australia
The prevalence of Familial Hypercholesterolemia (FH) in Australia is estimated to affect 1 in 300 individuals. This equates to approximately 90 408 Australians, according to the Australian Bureau of Statistics in 2024. However, as of October 2018, only 4% of those with FH have been formally diagnosed. This means that 83,400 individuals in Australia remain undiagnosed and are gradually developing preventable cardiovascular disease (CVD) due to untreated high cholesterol levels.