INTRODUCTION — From time to time, a lipid profile obtained in the process of screening for an elevated low density lipoprotein cholesterol (LDL-C) may reveal a very low value. This cause may be genetic or acquired. (See "Screening for lipid disorders in adults".)

The most frequent genetic cause of low LDL-C is familial hypobetalipoproteinemia, with an incidence of around 1 in 10,000. In some populations of African descent, loss-of-function mutations of PCSK9 are also prevalent. Other less common genetic causes of low LDL-C have also been identified.

APPROACH TO THE PATIENT — Cholesterol measurement undertaken to screen for cardiovascular disease risk occasionally reveals unexpected hypocholesterolemia (LDL-C <50 mg/dL in the United States) [1,2]. (See "Screening for lipid disorders in adults".)

This can be due to an inherited cause or may be due to an acquired disease. A careful history and physical examination is necessary with appropriate investigations, because many of the acquired causes (table 1) require treatment and early detection may thus be beneficial.

When no acquired cause is found, it is often helpful to measure cholesterol in relatives of the patient, because the most common genetic cause of hypocholesterolemia, familial hypobetalipoproteinemia, is dominantly inherited. The finding of low LDL-C in a relative greatly increases the likelihood of this diagnosis.

ABETALIPOPROTEINEMIA — Abetalipoproteinemia is a rare recessive disorder caused by a mutation in the gene encoding microsomal transfer protein (MTP). MTP is responsible for the intracellular assembly of apolipoprotein B (apo B) and lipids in the liver and intestine [3]. Consequently, no apo B-containing lipoproteins are found in the plasma (and thus LDL-C levels are near zero), and this results in impaired transport of fat-soluble vitamins (A, D, E, K). This condition is manifest in infancy, and it is characterized by intellectual disability and growth abnormalities. Some patients with abetalipoproteinemia can have peripheral neuropathies. (See "Neuroacanthocytosis", section on 'Abetalipoproteinemia'.)

HYPOBETALIPOPROTEINEMIA — Familial hypobetalipoproteinemia in its heterozygous form is the most likely genetic cause of low LDL-C, occurring with a frequency of about 1 in 10,000.

Familial hypobetalipoproteinemia is usually due to the insertion of a premature stop codon in the apoB100 gene. In different families, this can occur at various stages in translation, giving rise to shorter, lower molecular mass apoB, which interferes with hepatic secretion. The shorter apoB variants tend to be associated with a greater likelihood of fatty liver [3-5]. It is usually asymptomatic but, clinical manifestations may include intestinal fat malabsorption, intraperitoneal fat, hepatic steatosis, and fat soluble vitamin deficiencies [6]. Monitoring for symptoms of fat-soluble vitamin deficiency is recommended. Measurement of fat-soluble vitamin levels is recommended with supplementation of the deficient vitamins as dictated by the magnitude of the vitamin deficiency. Patients have very low levels of plasma apo B and LDL-C (<5^th percentile of age- and sex-specific values; LDL-C levels between 25 and 40 mg/dL [0.65 and 1.03 mmol/L), as well as low levels of very low density lipoprotein cholesterol. (See "Approach to the adult patient with suspected malabsorption".)

A 2010 report of one family with hypobetalipoproteinemia not linked to apo B has not only shed light on the genetics lipid disorders, but has also raised the possibility of a new mechanism for LDL-C lowering [4]. In this family, premature coronary heart disease was absent. Four family members had very low levels of high density lipoprotein cholesterol, LDL-C, and triglycerides. A relationship between ANGPTL3 and lipid levels was found.

FAMILIAL COMBINED HYPOLIPIDEMIA — Angiopoietin-like proteins (ANGPTLs) are regulators of lipoprotein metabolism. ANGPTL3 is a hormone produced by the liver and inhibits lipoprotein lipase, an enzyme that breaks down plasma triglycerides (see "Lipoprotein classification, metabolism, and role in atherosclerosis", section on 'Endogenous pathway of lipid metabolism'). The use of monoclonal antibodies to decrease ANGLPT3 is discussed separately. (See "Familial hypercholesterolemia in adults: Treatment", section on 'Homozygous individuals'.)

Loss-of-function genetic variants in the gene encoding for ANGPTL3 (and ANGPTL4) have been identified. These variants are associated with increased lipoprotein lipase activity, as well as low levels of plasma LDL-C, high density lipoprotein cholesterol (HDL-C), and triglycerides.

Loss-of-function mutations in ANGPTL3 causes familial combined hypolipidemia (FHBL2) [7]. In a study that included 14 homozygotes, 8 compound heterozygotes, 93 heterozygotes, and 402 controls, carriers of two mutant alleles had no detectable ANGPTL3 protein while heterozygotes had protein concentrations that ranged from 34 to 88 percent, depending on the genotype. As compared with controls, homozygotes and heterozygotes have reduced levels of all plasma lipoproteins except lipoprotein(a). FHBL2 individuals had no differences in the risk of fatty liver disease, whereas homozygotes had no diabetes or cardiovascular disease.

Subsequent genetic and therapeutic studies, of which the following two are representative, have confirmed the association between low levels of ANGPTL3 and decreased levels of LDL-C and triglycerides:

●In a study of 58,335 participants in five cohorts whose DNA was available for analysis, individuals with heterozygous loss-of-function variants in ANGPTL3 had significantly lower levels of triglyceride, HDL-C, and LDL-C than participants without those variants [8]. In addition, loss-of-function variants were found in 0.33 percent of case patients with coronary artery disease and in 0.45 percent of controls (adjusted odds ratio 0.59, 95% CI 0.41-0.85). A small phase 1 study evaluated the use of evinacumab (a human monoclonal antibody against ANGPTL3) in 83 individuals with varying degrees of dyslipidemia. The antibody led to a dose-dependent reduction in fasting triglyceride levels of up to 76 percent and LDL-C levels of up to 23 percent.

●In a study of 44 human participants, oligonucleotides targeting ANGPTL3 mRNA led to reductions in levels of ANGPTL3 protein between 47 and 85 percent, as well as significant reductions in levels of triglycerides and LDL-C [9].

VARIANT ASGR1 — Two loss-of-function variants of ASGR1, which encodes a subunit of the asialoglycoprotein receptor, have been identified (see "Biology and normal function of von Willebrand factor", section on 'Clearance of VWF from the circulation'). In individuals heterozygous for one or the other of these, non-high density lipoprotein cholesterol (which is predominantly LDL-C in most people) is significantly lower (approximately 15 mg per deciliter [0.40 mmol/L]) than in individuals without the haploinsufficiency [10]. The clinical implication of these loss-of-function variants has not been well studied.

PCSK9 — Loss-of-function variants in PCSK9 are associated with reduced LDL-C levels. The LDL-C level depends on the type of mutation. Nonsense mutations in one of two locations encoding Y142X and C679X are present in 2 percent of African Americans [11]. These nonsense mutations are associated with a 40 percent reduction LDL-C. (See "PCSK9 inhibitors: Pharmacology, adverse effects, and use", section on 'Mechanisms of action'.)

Affected White individuals more commonly have a missense mutation (137G arrow to T) encoding R46L. This variant is present in 3.2 compared with 0.6 percent of Black individuals, and it is associated with a 21 percent reduction in LDL-C. Compound heterozygosity for PCSK9 loss-of-function variants is characterized by LDL-C levels of 14 mg/dL. No clinical abnormalities are observed in these individuals [12].

CHYLOMICRON RETENTION DISEASE (ANDERSON'S DISEASE) — Chylomicron retention disease (Anderson’s disease) is another cause of low LDL-C [13]. It is an autosomal recessive condition that presents in infancy with failure to thrive and steatorrhea, abdominal distension, and vomiting. There is a profound deficiency of vitamin E and other fat-soluble vitamins, which may have neurological consequences. Both LDL-C and high density lipoprotein cholesterol are low. Although chylomicron production is impaired, triglyceride levels are normal. Small bowel biopsy invariably shows fat-laden enterocytes, and hepatic steatosis is also frequent. Creatine kinase is raised. There is a mutation of Sar1b involved in protein transport from the endoplasmic reticulum to the Golgi in enterocytes. Treatment requires removal of long chain fatty acids from the diet, nutritional support, and supplements of fat-soluble vitamins.

ACQUIRED LOW LDL-C — Multiple diseases have been associated with low LDL-C (table 1). Low cholesterol may be present in carcinoma of the colon [14] or prostate [15] before they are otherwise clinically evident. The low LDL-C is often accompanied by low high density lipoprotein cholesterol, but in contrast to familial hypobetalipoproteinemia, triglyceride levels may be moderately elevated (for example: in malabsorption) [16].

Chronic anemia can be associated with hypocholesterolemia [17].

Paraproteinemia due to multiple myeloma, monoclonal gammopathy of unknown significance (MGUS), or benign paraproteinemia can occasionally be associated with either hyperlipidemia or hypolipidemia, depending on whether the paraprotein binding to lipoproteins decreases or accelerates their clearance [18,19]. In the more advanced stages of myeloma, cachexia, as in other neoplastic disease, is also a cause of low LDL-C. There is a rare syndrome termed "necrobiotic xanthogranulomatosis" in which florid planar xanthomata occur in association with paraproteinemia. Typically, for many years, the paraproteinemia behaves as MGUS or benign paraproteinemia, and the skin lesions can be distressing. Treatment is unsatisfactory, particularly as with the exception of the xanthomata, the paraproteinemia does not progress to frank myeloma or myelodysplastic disease. Thalidomide and its derivatives may be anecdotally effective, but melphalan, fibrates, and statins are ineffective.

In hospitalized patients, hypocholesterolemia is associated with severe illness [20,21]. Some causes of hypocholesterolemia are given in a table (table 1). Case descriptions are often anecdotal or difficult to obtain [22].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lipid disorders in adults".)

SUMMARY

●Cholesterol measurement undertaken to screen for cardiovascular disease risk occasionally reveals an unexpectedly low value of low density lipoprotein cholesterol (LDL-C). (See 'Approach to the patient' above.)

●Two principal genetic disorders causing extremely low levels of LDL-C have been identified: abetalipoproteinemia and hypobetalipoproteinemia. Both of these are relatively uncommon. (See 'Abetalipoproteinemia' above and 'Hypobetalipoproteinemia' above.)

●In patients discovered to have a low value of LDL-C, a search for a correctable cause should be made. When no acquired cause is found, it is often helpful to measure LDL-C in relatives of the patient, because the most common genetic cause of hypocholesterolemia, familial hypobetalipoproteinemia, is dominantly inherited. The finding of low LDL-C in a relative greatly increases the likelihood of this diagnosis. (See 'Approach to the patient' above.)

●Disease associations with low LDL-C include malignancy and malabsorption. (See 'Acquired low LDL-C' above.)