INTRODUCTION — A screening lipid profile sometimes reveals an unexpectedly low value for low-density lipoprotein cholesterol (LDL-C). The cause of the low value may either be genetic or acquired. Low LDL is defined as LDL-C <5th percentile or LDL-C <50 mg/dL (or 1.29 mmol/L). Some would call this hypocholesterolemia.
The most frequent genetic cause of low LDL-C in the United States is heterozygous familial hypobetalipoproteinemia, with an incidence of around 1 in 10,000 [1-3]. Other genetic causes of low LDL-C have even lower prevalence rates.
The etiologies and approaches to diagnosis of low LDL-C are outlined in this topic. Other issues related to lipids and lipoproteins, such as their role in atherosclerosis, are discussed separately. (See "Lipoprotein classification, metabolism, and role in atherosclerosis" and "Measurement of blood lipids and lipoproteins" and "Screening for lipid disorders in adults".)
ETIOLOGY — Causes of low LDL-C can be classified as either genetic or acquired. Genetic causes can manifest in infancy or be detected later in life, usually with more subtle presentations.
Genetic causes — Genetic conditions can present in infancy or early childhood with failure to thrive or later in childhood or adulthood with milder or absent symptoms:
The three genetic causes that typically present in early childhood are:
●Abetalipoproteinemia – This 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 (apoB) and lipids in the liver and intestine . No apo-B-containing lipoproteins are found in the plasma (and thus very low-density lipoprotein [VLDL] and LDL levels are near zero). High-density lipoprotein (HDL) is the only means of cholesterol transport, and its apoE component is increased to permit cellular entry via the LDL receptor (as is normal in the fetus and cerebrospinal fluid). (See "Neuroacanthocytosis", section on 'Abetalipoproteinemia'.)
●Chylomicron retention disease (Anderson disease) – This is an autosomal recessive cause of low LDL-C  that also causes low HDL-C. There is a mutation of Sar1b involved in protein transport from the endoplasmic reticulum to the Golgi in enterocytes. (See 'Chylomicron retention disease' below.)
●Familial hypobetalipoproteinemia – The most frequent genetic cause of low LDL-C in the United States is familial hypobetalipoproteinemia, with an incidence of around 1 in 10,000 [1-3].
This is caused by the genetic mutation in APOB and results from the insertion of a premature stop codon that produces a truncated apoB molecule. The apoB gene makes two proteins: apoB-100 and apoB-48. ApoB-100 is a structural protein for VLDL, intermediate-density lipoprotein (IDL), LDL, and lipoprotein(a). ApoB-48 is a truncated form of B-100 that contains 48 percent of B-100 and is required for assembly and secretion of chylomicrons.
Variants of familial hypobetalipoproteinemia are more severe when the truncation results in a shorter apoB. Adopting similar terminology to that used for apoB-100 (normally produced in the liver) and apoB-48 (normally produced by the gut), a wide range of apoB variants have been described that are associated with low-circulating LDL-C, ranging from apoB 2 to apoB 89.1. Truncated apoB 27.6 or less is undetectable in the circulation.
The presentation of homozygous condition is more severe than in heterozygotes  (see 'Homozygous familial hypobetalipoproteinemia' below). Given the low prevalence of heterozygosity, this condition is likely to have arisen by consanguinity rather than from compound heterozygosity (ie, a variant that occurs when each parent donates one alternate allele, and these are located at different loci within the same gene).
Heterozygous familial hypobetalipoproteinemia usually presents later in life and with less severe manifestations. (See 'Heterozygous familial hypobetalipoproteinemia' below.)
●Other genetic causes – Familial combined hypolipidemia 2 is due to loss-of-function mutations in ANGPTL3 [6-8]. Angiopoietin-like proteins 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').
Evinacumab is a human monoclonal antibody against ANGPTL3, approved by the U S Food and Drug Administration for the treatment of homozygous familial hypercholesterolemia. This is discussed separately. (See "Familial hypercholesterolemia in adults: Treatment", section on 'Our approach'.)
Loss-of-function PCSK9 and variant ASGR1 genetic defects cause low LDL, and are associated with protection from cardiovascular disease, greater longevity, and not associated liver dysfunction. Heterozygous loss-of-function mutations of PCSK9 are associated with a less marked decrease in LDL-C levels than homozygous pathogenic variants and occur in 2 to 3 percent of people.
Acquired causes — Acquired causes of low LDL can either be due to secondary medication or an underlying illness (table 1). In the latter, the low LDL-C is often accompanied by low HDL-C, but in contrast to familial hypobetalipoproteinemia, triglyceride levels may be moderately elevated (for example, in malabsorption) .
●Medication-related low LDL – PCSK9 inhibitors, prescribed to lower LDL-C among people who are either intolerant or refractory to LDL-C-lowering pharmacotherapy, can lower LDL by 70 percent. This can result in low LDL-C. Other medications prescribed in familial hypercholesterolemia patients that can result in a low LDL-C include evinacumab and lomitapide.
●Hematologic disorders and malignancies – Chronic anemia can be associated with hypocholesterolemia . Paraproteinemia due to multiple myeloma, monoclonal gammopathy of unknown significance, 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 [13,14]. In the more advanced stages of myeloma, cachexia, as in other neoplastic disease, is also a cause of low LDL-C. Some studies suggest that low LDL-C may be associated with a worse prognosis in people with malignancy . Low LDL-C is associated with myelodysplasia, paraproteinemia, and leukemia .
●Hospitalized patients – Hypocholesterolemia is associated with severe illness [15,16]. In an acute myocardial infarction or severe trauma, lipids have been noted to drop within a few hours . Case descriptions are often anecdotal or difficult to obtain .
●Infection – Several infectious diseases can cause low LDL-C (eg, tuberculosis, hepatitis C, and HIV and others) .
●Hepatic parenchymal disease – Cirrhosis and other forms of liver disease can cause low LDL .
●Neuropsychiatric – Low LDL-C in severe depression with suicidal ideation has been described .
●Thyrotoxicosis – Low LDL-C has been described in several case reports and resolves with treatment .
In some patients, the underlying illness is readily apparent, whereas in others, low LDL-C is the first clue that an occult illness is present. (See 'Patients in whom the cause remains obscure' below.)
APPROACH TO THE PATIENT — Most commonly, hypocholesterolemia is an unexpected finding that is discovered during routine lipid panel screening, usually obtained to evaluate cardiovascular disease risk. (See "Screening for lipid disorders in adults".)
There is a wide spectrum of genetic and acquired conditions that can lead to a low LDL-C level. Some conditions present in infancy or childhood with failure to thrive and/or malabsorption and require immediate treatment. Conversely, other etiologies for low LDL-C have no obvious adverse clinical manifestations, do not require treatment, and may actually be associated with longevity.
Information to gather — The following information can be useful prior to narrowing the differential diagnosis for low LDL-C:
●General clinical information – A history and physical examination may identify features that increase the likelihood of specific diagnoses.
•PCSK9 inhibitors can cause substantial LDL-C lowering.
•A careful family history, including history of low LDL-C in a first-degree relative.
•Concurrent or recent history of underlying severe illness, including (but not limited to) malignancy, hematologic dyscrasia, gastrointestinal illness, infectious disease, autoimmune disease, or cirrhosis.
•Symptoms of malabsorption from a genetic-related low LDL-C condition or a gastrointestinal infection causing acquired low LDL-C (eg, giardiasis).
•Symptoms of occult cancer or other chronic disease including weight loss, night sweats, fatigue, and targeted review of symptoms.
•Features suggestive of non-alcoholic fatty liver disease (NAFLD). Some patients with NAFLD have hepatomegaly, right upper quadrant tenderness on examination, and/or abnormal liver function tests. (See "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults".)
•Lipid panel including LDL-C, HDL-C, triglycerides, and total cholesterol. In addition, a non-HDL-C (calculated), apolipoprotein B (apoB), LDL-C particle number, and Lp(a) can sometimes be helpful.
•Liver function tests.
•Complete blood count, C-reactive protein, and plasma protein electrophoresis (immunoglobulins).
Approach based on clinical presentations
Patients with an identified secondary cause — If the patient has an obvious severe underlying illness, then low LDL-C can be assumed to be secondary to the illness. In such cases, treatment of the underlying illness will generally lead to normalization of the LDL-C.
Patients with low LDL-C while taking PCSK9 inhibitors can be reassured by low LDL-C levels in this setting. PCSK9 inhibitors can reduce cardiovascular risk and have a good safety profile even among patients treated to very low LDL-C levels. (See "PCSK9 inhibitors: Pharmacology, adverse effects, and use".)
Malabsorption in infancy — If the patient presents in infancy or early childhood with malabsorption symptoms of failure to thrive and diarrhea, the differential diagnosis includes abetalipoproteinemia, homozygous familial hypobetalipoproteinemia, and chylomicron retention disease. An undetectable LDL-C suggests either abetalipoproteinemia or homozygous hypobetalipoproteinemia. On the other hand, a very low LDL-C level (of approximately 15 mg/dL or 0.39 mmol/L) suggests presence of chylomicron retention disease.
Abetalipoproteinemia — The diagnosis of abetalipoproteinemia is suspected in a patient with steatorrhea and failure to thrive present at birth. In addition, malabsorption, low LDL-C, acanthocytosis, malabsorption of fat-soluble vitamins, and retinitis pigmentosa are seen. The diagnosis is confirmed by genetic testing.
Treatment involves dietary fat restriction and supplementation of fat-soluble vitamins, without which spinocerebellar degeneration begins in childhood.
Abetalipoproteinemia is discussed in detail separately. (See "Neuroacanthocytosis", section on 'Abetalipoproteinemia'.)
Chylomicron retention disease — This condition 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 (eg, retinopathy, hypo- or areflexia, myopathy) .
Small bowel biopsy invariably shows fat-laden enterocytes, and hepatic steatosis is also frequent. On laboratory testing, chylomicron production is impaired, and triglyceride levels are normal. Creatine kinase is elevated. Genetic testing can confirm the diagnosis.
Treatment requires removal of long-chain fatty acids from the diet, nutritional support, and supplements of fat-soluble vitamins .
Homozygous familial hypobetalipoproteinemia — The clinical presentation is identical to abetalipoproteinemia, particularly with shorter truncations of the apoB. In compound heterozygotes, when both apoB variants are shorter than apoB-48, chylomicron secretion will be impaired and steatorrhea results, sometimes presenting soon after birth. With shorter apoB truncation, the decrease in LDL-C can be profound, often with absent LDL-C. Some case reports have described LDL-C levels up to 20 mg/dL (or 0.52 mmol/dL) at diagnosis . At the milder end of the disease spectrum, acanthocytosis may be the only manifestation apart from low LDL-C. The treatment is the same as for abetalipoproteinemia. (See "Neuroacanthocytosis", section on 'Abetalipoproteinemia'.)
Patients presenting with possible non-alcoholic fatty liver disease — Two genetic causes of low LDL-C without obvious symptoms that can lead to NAFLD in a small subset of patients include heterozygous familial hypobetalipoproteinemia and familial combined hypolipidemia 2.
Heterozygous familial hypobetalipoproteinemia — This condition is dominantly inherited, and thus one parent will be similarly affected. Therefore, testing of relatives can be helpful to identify this condition. Measuring an apoB level in patients in whom this diagnosis is suspected can be helpful, as it will usually be low in concordance with a low LDL-C level.
Most commonly, patients are entirely asymptomatic. However, some patients can present with NAFLD symptoms or increased liver function tests as the initial presenting symptoms. NAFLD is more likely with shorter truncations of apoB, which interfere more severely with hepatic secretion of both VLDL-containing mutant apoB and apoB-100. The frequency with which hepatic steatosis progresses to clinically significant cirrhosis is unknown.
In people who do not have liver disease, annual examinations with liver function testing are reasonable to assess for liver dysfunction. Monitoring liver function is particularly important in people with shorter apoB mutations in order to detect fatty liver, and in some people, cirrhosis and hepatoma patients with liver disease should be managed by a hepatologist. (See "Approach to the patient with abnormal liver biochemical and function tests".)
Increased longevity (from a decrease in a major risk factor for atherosclerosis) has been reported .
Familial combined hypolipidemia 2
●Laboratory features – Both heterozygotes and homozygotes with familial combined hypolipidemia 2 have low levels of plasma LDL-C, HDL-C, and triglycerides [6,25,26]; in contrast, lipoprotein(a) levels are not reduced .
●Clinical features – Homozygotes (but not heterozygotes) have the possibility of liver dysfunction from NAFLD . Annual examinations with liver function testing are reasonable for monitoring development of liver dysfunction. Patients with liver disease should be managed by a hepatologist. (See "Liver biochemical tests that detect injury to hepatocytes".)
Homozygotes have a very low incidence of cardiovascular disease; heterozygotes also have substantial protection from cardiovascular disease [24,26].
●Treatment – No specific treatment for this condition is needed; however, monitoring for development of fatty liver disease in people with homozygous variants is reasonable.
Patients in whom the cause remains obscure — When the cause of low LDL-C on routine screening remains obscure after initial testing, a genetic cause may be suspected.
For patients in whom no cause is identified, a careful history and initial targeted testing should be performed to uncover potential occult malignancy, infection, or other disease.
Other genetic conditions — In otherwise healthy patients with no identifiable cause of low LDL-C, we often suspect a genetic etiology. Referral to a lipid specialist and/or a genetics counsellor can be a helpful next step in securing the diagnosis. Heterozygous familial hypobetalipoproteinemia and familial combined hypolipidemia 2 (discussed previously) remain possible diagnoses, as well as loss-of-function mutations of PCSK9 and variant ASGR1. (See 'Heterozygous familial hypobetalipoproteinemia' above and 'Familial combined hypolipidemia 2' above.)
There is no clinical imperative to make diagnoses in this category. There are no known adverse clinical findings for two other loss-of-function mutations that can result in low LDL-C, PCSK9 and ASGR1. Most patients with heterozygous hypobetalipoproteinemia and ANGPTL3 loss-of-function variants do not have liver dysfunction. (See 'Heterozygous familial hypobetalipoproteinemia' above and 'Familial combined hypolipidemia 2' above.)
●Loss-of-function mutations of PCSK9 – Loss-of-function variants of PCSK9 are associated with decreased LDL-C. Among heterozygotes, LDL-C is decreased by 15 to 28 percent (ie, may not meet the definition of low), but more profound reductions generally occur when both PCSK9 alleles carry loss-of-function variants. A wide spectrum of mutations occur in PCSK9, and because of the relatively high frequency of heterozygotes for these, most affected biallelic individuals will be compound heterozygotes. Compound heterozygotes have LDL-C levels <5th percentile.
Both heterozygous and compound heterozygous loss-of-function PCSK9 variants are associated with diminished risk of atherosclerotic cardiovascular disease .
In compound heterozygotes, the likelihood of hepatic steatosis is not increased, which is encouraging for the therapeutic application of PCSK9 inhibitors in hypercholesterolemia.
●Variant ASGR1 – Two loss-of-function variants of ASGR1, which encodes a subunit of the asialoglycoprotein receptor, have been identified.
In individuals heterozygous for one or the other of these, non-HDL-C (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 . The clinical implication of these loss-of-function variants has not been well studied, but protection against atherosclerotic cardiovascular disease is likely present.
●Gain-of-function mutation in LIPC – A gain-of-function genetic variant in LIPC-E97G-encoding hepatic lipase was shown to cause combined hypocholesterolemia (ie, low LDL-C, low HDL-C, low-normal triglyceride, and apoB concentrations) . The pathogenic variant was discovered in a male who developed atherosclerotic cardiovascular disease at age 61 despite a low level of LDL-C (40 mg/dL or 1 mmol/L). This pathogenic variant was also detected in six members of his family; all of them had low LDL-C values (between 20 and 53 mg/dL). Two other members of his family did not carry the pathogenic LIPC variant and had normal LDL-C levels. Further human and translational studies are needed to better understand associations between LIPC pathogenic variants and cardiovascular, hepatic, and other diseases.
Evaluation for secondary conditions — In order to uncover potential underlying illness, we solicit relevant symptoms:
●Gastrointestinal symptoms or malabsorption indicative of gastrointestinal infection or malignancy.
●Weight loss, cachexia, or other symptoms of occult malignancy. (see link to approach to patient with unexplained weight loss). (See "Approach to the patient with unintentional weight loss".)
●Reproductive system symptoms and/or abnormalities indicative of occult malignancy (eg, prostate in males and breast, uterine, or ovary in women).
●Joint pain, fatigue, or other symptoms of rheumatologic disease.
A complete blood count, C-reactive protein, and serum protein electrophoresis/urine protein electrophoresis can sometimes be helpful tests in identifying an underlying illness causing acquired low LDL-C. Patients should be up to date on recommended cancer screening, particularly if they present with symptoms of occult malignancy. (See "Overview of preventive care in adults", section on 'Cancer screening'.)
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 AND RECOMMENDATIONS
●Definition and etiology – Low low-density lipoprotein cholesterol (LDL-C) is usually detected on routine lipid screening and defined as LDL-C <5th percentile or <50 mg/dL (or 1.29 mmol/dL).
●Approach to evaluation and diagnosis – The cause of low LDL-C can often be inferred from the clinical setting (algorithm 1).
•Patients with acquired conditions are usually identified on the basis of clinical history. Patients with medication-related low LDL-C can generally be reassured. The approach to treating low LDL-C secondary to an illness is to treat the underlying condition. Usually, the low LDL-C will rise upon treatment of the illness.
•Patients who present in infancy or childhood with low LDL-C and malabsorption may have either abetalipoproteinemia, chylomicron retention disease, or homozygous familial hypobetalipoproteinemia.
•Other genetic causes of low LDL-C, heterozygous familial hypobetalipoproteinemia, and familial combined hypobetalipoproteinemia 2 may have associated non-alcoholic fatty liver disease (NAFLD).
For other patients, we investigate for other secondary conditions. When no cause is found, we often suspect an underlying genetic cause; however, these do not usually require specific treatment, and patients can be followed.
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