Hypocholesterolemia is defined as total cholesterol (TC) and/or low-density lipoprotein cholesterol (LDL-C) levels below the 5th percentile for age, sex, and race, corresponding to TC values typically less than 3.0 mmol/L (116 mg/dL) in children and less than 3.0–3.5 mmol/L (116–135 mg/dL) in adults, with LDL-C thresholds below 1.0–1.3 mmol/L (38–51 mg/dL) in the most severe cases.
According to the American Heart Association only total cholesterol levels below 160 mg/dL or 4.1 mmol/L are to be classified as hypocholesterolemia.
In the general population, hypocholesterolemia is rare.
Hypocholesterolemia is an uncommon but clinically significant laboratory finding, most often serving as a marker of underlying disease, malnutrition, or systemic inflammation rather than a benign or protective state.
Cholesterol is an essential component of mammalian cell membranes and is required to establish proper membrane permeability and fluidity.
It is not clear if a lower than average cholesterol level is directly harmful; however, it is often encountered in particular illnesses.
A national pediatric screening program in Slovenia found a prevalence of 2.7% among 5-year-old children, with most cases being asymptomatic and only a minority attributable to identifiable genetic variants.
In adults, hospital-based studies report a prevalence of less than 0.5% for TC ≤3.0 mmol/L, with hypocholesterolemia more frequently observed in high-risk groups such as the elderly, hospitalized/critically ill patients.
Among elderly individuals aged 75 and older, the prevalence increases, and low cholesterol is associated with deteriorating health and increased mortality.
In critically ill and hospitalized populations, hypocholesterolemia is much more common, reflecting the burden of acute and chronic illness, malnutrition, and systemic inflammation.
Primary hypocholesterolemia is most often due to rare monogenic disorders affecting lipoprotein metabolism: familial hypobetalipoproteinemia (FHBL), abetalipoproteinemia, familial combined hypolipidemia, and chylomicron retention disease.
Secondary or acquired hypocholesterolemia is far more common than primary forms and encompasses a wide range of systemic diseases, nutritional states, and pharmacologic exposures.
The most frequent secondary causes include malnutrition, cachexia, advanced malignancy, chronic liver disease (cirrhosis, hepatitis), intestinal fat malabsorption (celiac disease, Crohn’s disease, chronic pancreatitis), hyperthyroidism, poorly controlled diabetes mellitus, acute and chronic inflammatory states (sepsis, burns, major surgery), renal disease (advanced CKD, uremia), excessive alcohol intake, chronic infections (tuberculosis, HIV), autoimmune diseases, and drug effects (statins, androgens, progestins, β-blockers, antipsychotics), abetalipoproteinemia – a rare genetic disease that causes cholesterol readings below 50 mg/dL. It is found mostly in Jewish populations., hypobetalipoproteinemia – a genetic disease that causes cholesterol readings below 50 mg/dL, manganese deficiency Smith–Lemli–Opitz syndrome,Marfan syndrome,leukemias and other hematological diseases[
In hospitalized patients hypocholesterolemia is most commonly observed in patients with sepsis, post-operative states, malignancy, and those in intensive care units, where it correlates with severity of illness and increased mortality.
Primary hypocholesterolemia, particularly hypobetalipoproteinemia due to APOB mutations, is associated with a markedly increased risk of hepatic complications, including hepatic steatosis, cirrhosis, and primary liver cancer.
Primary genetic forms are rare and usually asymptomatic, but carry a specific risk for hepatic complications, including steatosis, cirrhosis, and liver cancer.
In contrast, hypocholesterolemia due to increased LDL clearance (e.g., PCSK9 loss-of-function variants) is not associated with hepatic steatosis or increased hepatic risk.
Acquired hypocholesterolemia is frequently a marker of severe underlying disease, malnutrition, or systemic inflammation, and is associated with increased risk of non-cardiovascular morbidity and mortality, including cancer, chronic pulmonary disease, and gastrointestinal disorders.
Acquired hypocholesterolemia is associated with increased morbidity and mortality, reflecting the severity of the underlying condition, and is a robust prognostic marker in hospitalized and critically ill patients.
Hypocholesterolemia can impair immune function and increase susceptibility to infections, particularly in the context of malnutrition or critical illness.
In the NHANES I follow-up, serum cholesterol below 4.1 mmol/L (158 mg/dL) was associated with a 40–70% increased risk of death, particularly in older, less active individuals:these associations are often confounded by underlying illness, frailty, or malnutrition, and are less pronounced after excluding early deaths.
Cholesterol is essential for immune cell membrane integrity, lipid raft formation, and the synthesis of immunomodulatory oxysterols, such as 25-hydroxycholesterol, which regulate both innate and adaptive immunity.
Epidemiological studies demonstrate that low total and LDL cholesterol are associated with increased risk of serious infections, including sepsis.
Clinical observations suggest that hypocholesterolemia may compromise immune competence, especially in the context of malnutrition or critical illness.
The prognostic value of hypocholesterolemia is most pronounced in hospitalized and critically ill patients.
The relationship between cholesterol and mortality is context-dependent:chronic heart failure, an inverse association is observed, with lower cholesterol linked to higher mortality.
In patients with coronary artery disease, hypocholesterolemia on admission is independently associated with increased 30-day and 3-year mortality after percutaneous coronary intervention, regardless of statin therapy.
However, statin use itself is protective, and there is no evidence of harm from achieving low cholesterol levels through pharmacologic means.
The reversibility of hypocholesterolemia depends on its etiology.
With secondary (acquired) hypocholesterolemia, normalization of cholesterol levels is frequently observed following successful treatment of the underlying disease: hyperthyroidism, hepatitis C, nutritional recovery
Primary (genetic) hypocholesterolemia is not reversible, as these conditions are due to inherited defects in lipoprotein synthesis or secretion.
Heterozygous carriers are usually asymptomatic and have normal quality of life, except for an increased risk of hepatic steatosis and, in some cases, progression to cirrhosis or liver cancer.
Homozygous or compound heterozygous individuals may develop fat-soluble vitamin deficiencies, neurological dysfunction, and growth impairment if not treated with appropriate vitamin supplementation.
There is no evidence that attempts to raise cholesterol in these patients improve outcomes; management focuses on monitoring for complications and supportive care.
In acquired hypocholesterolemia, improvement in cholesterol levels parallels recovery from the underlying condition and is associated with better outcomes.
There is no evidence that interventions aimed solely at raising cholesterol, independent of treating the underlying disease, improve clinical outcomes.
There are currently no guidelines that provide dedicated, disease-specific recommendations for the evaluation and monitoring of patients with hypocholesterolemia as a primary disorder.
The cause of hypocholesterol should be identified through a systematic evaluation for secondary etiologies, including malnutrition, chronic liver disease, malabsorption, malignancy, endocrine disorders, and drug effects.
In adults, the presence of hypocholesterolemia should prompt a comprehensive assessment for underlying disease or poor nutritional status.
There are no disease-specific clinical guidelines for hypocholesterolemia, but expert consensus supports a systematic evaluation for secondary causes and targeted monitoring in genetic forms with hepatic risk.
Primary genetic forms are rare and usually asymptomatic, but carry a specific risk for hepatic complications, including steatosis, cirrhosis, and liver cancer.
Acquired hypocholesterolemia is associated with increased morbidity and mortality, reflecting the severity of the underlying condition, and is a robust prognostic marker in hospitalized and critically ill patients.
Hypocholesterolemia can impair immune function and increase susceptibility to infections, particularly in the context of malnutrition or critical illness.
The reversibility of hypocholesterolemia depends on its etiology, with normalization of cholesterol levels serving as a marker of recovery in secondary forms.
There are no disease-specific clinical guidelines, but expert consensus recommends systematic evaluation for secondary causes and targeted monitoring in genetic forms with hepatic risk. The identification of hypocholesterolemia should prompt a comprehensive assessment for underlying disease or poor nutritional status, with management focused on treating the primary condition and monitoring for complications as indicated.
Demographic studies suggest that cholesterol levels form a U-shape curve when plotted against mortality; this suggests that low cholesterol is associated with increased mortality, mainly due to depression, cancer, hemorrhagic stroke, aortic dissection and respiratory diseases.
It is possible that whatever causes the low cholesterol level also causes mortality, and that the low cholesterol is simply a marker of poor health.
Links with depression have been supported by studies.
No evidence was found for a link with hemorrhagic stroke.
In the elderly, low cholesterol may confer a health risk that may not be offset by the beneficial effects of cholesterol lowering.
Similarly, for elderly patients admitted to hospital, low cholesterol may predict short-term mortality.
In the setting of critical illness, low cholesterol levels are predictive of clinical deterioration, and are correlated with altered cytokine levels.