High cholesterol levels are exceedingly common, with an estimated 94 million Americans exhibiting concentrations greater than 200 mg/dL. According to the CDC, 47 million are taking statins and other agents to help decrease these levels.

CDC. High cholesterol facts. Centers for Disease Control and Prevention.

 

 

Some lipid disorders, however, are less common. If encountered, they should be managed by specialists.

 

Sitosterolemia

This rare genetic disease, which is autosomal recessive and caused by mutations to the ABCG5 or ABCG8 genes, results in the body producing plant sterols.

Usually, people excrete plant sterols via the gut, but individuals with sitosterolemia are unable to rid themselves of these compounds. Instead, they accumulate in the blood and arteries.

Sitosterolemia. NORD (National Organization for Rare Disorders).

 

Typical lipid panels don’t test for plant sterols, so this diagnosis can be missed unless special tests are ordered. Clinical presentations are varied, which can further contribute to missed or delayed diagnosis. Untreated disease can result in atherosclerosis and early death.

Recent data cited by the National Organization of Rare Disorders (NORD) indicate the prevalence of sitosterolemia is at least one in 2.6 million for the ABCG5 gene mutation and one in 360,000 for the ABCG8 gene mutation.

Results from a recent study published in Clinica Chimica Acta indicated that in a small cohort of 36 patients, 100% demonstrated cutaneous/tendon xanthomas; 25%, premature atherosclerosis; 16%, arthritis; and 22%, blood abnormalities.

Tada H, Kojima N., Yamagami K, et al. Clinical and genetic features of sitosterolemia in Japan. Clinica Chimica Acta. 2022;530:39-44.

 

Ezetimibe is the treatment of choice for this condition, with other treatments including statins, colestimide, evolocumab, probucol, and LDL apheresis. Ezetimibe works by decreasing plant sterol levels in those with the condition, although these concentrations still remain high, necessitating combination approaches. Current research is examining the efficacy of the bile sequestrant colesevelam.

 

Fish-eye disease

This rare condition affects the eyes and causes corneal clouding. This can eventually result in vision loss and can begin in adolescence. Atherosclerosis also may result. This condition is autosomal-recessive and secondary to mutations in the LCAT gene, which, when functioning normally, helps remove cholesterol from blood and tissues; the LCAT gene helps cholesterol attach to HDL.

Fish-eye disease. Genetic and Rare Diseases Information Center (GARD).

 

Based on clinical suspicion, genetic testing can be done to identify mutations in the LCAT gene. The enzyme encoded by the gene can also be tested for functionality, as well as the use of urine/blood tests.

Patients should establish routine care with an ophthalmologist, with corneal transplantation needed in severe cases. According to the research cited by the NIH’s Genetic and Rare Diseases Information Center, statins may also help lower the risks of atherosclerosis.

 

Familial LCAT deficiency

Familial LCAT deficiency is the other form of LCAT deficiency. Mutations with familial LCAT deficiency are more pervasive and impair the ability of the LCAT enzyme to bind to HDL, low-density lipoprotein, and very low-density lipoprotein, resulting in not only corneal opacities and atherosclerosis but also hemolytic anemia, hepatomegaly, splenomegaly, and lymphadenopathy.

Familial LCAT Deficiency. Genetic and Rare Diseases Information Center (GARD).

 

Strategies include restriction of fat intake, exercise, statins, ARBs, corneal transplant, and dialysis/kidney transplant. Prognosis varies, but kidney failure predicts particularly poor survival according to GARD.

 

Homozygous familial hypercholesterolemia

In its heterozygous form, familial hypercholesterolemia is well-known to physicians, and affects one of 200–500 people. The homozygous form, however, is much less prevalent and affects one of 160,000–1,000,000 people. Inheritance is usually autosomal co-dominant, with homozygous carriers exhibiting twice the LDL levels of heterozygous individuals.

Sing S, Bittner V. Familial hypercholesterolemia--epidemiology, diagnosis, and screening. Curr Atheroscler Rep. 2015;17(2):482.

Autosomal recessive inheritance is rare.

 

Overall, mutations in four genes occur in those with familial hypercholesterolemia: LDL receptor (most common), apolipoprotein B (Apo B), proprotein convertase subtilin/kexin 9 (PCSK9), and low-density lipoprotein receptor adaptor protein (LDLRAP). In most cases, inheritance is autosomal co-dominant, with homozygotes harboring double the LDL cholesterol levels of heterozygotes. Autosomal recessive inheritance is rare.

PCSK9 inhibitors are emerging as effective treatment for heterozygous familial hypercholesterolemia, and may be useful in some patients with homozygous form, according to the authors of a study published in Frontiers in Physiology.

Katzmann JL, Gouni-Berthold I, Laufs U. PCSK9 Inhibition: Insights From Clinical Trials and Future Prospects. Front Physiol. 2020;11:595819.

Notably, statins don’t work well in those with this disease.

 

“In patients with the more common heterozygous FH (HeFH) who have at least one normal LDLR allele and therefore, residual functionality of the LDL receptor pathway,” the authors wrote, “PCSK9 antibodies still cause marked reductions in LDL-C, comparable to the reductions observed in patients without proven HeFH. In contrast, in the rare homozygous FH (HoFH), the efficacy of PCSK9 antibodies depends on the mutations these patients have and their ability of upregulating the LDL receptor.”