Low cholesterol states: clinical implications and management

Figures & data

Table 1. Non-genetic secondary causes of low LDL cholesterol.

Secondary factor	Cause	Reference
Lifestyle	Alcohol intake Low-fat diet Malnutrition Vegan or vegetarian diet	[2] [3]
Non-communicable diseases	Acute renal failure Anemia Beta-thalassemia intermedia Cancer cachexia Cystic fibrosis Chronic pancreatitis Gaucher disease Hyperthyroidism Inflammatory response syndrome Malabsorption states [4,5] Sickle cell disease Smith-Lemli-Opitz syndrome	[6] [7] [4] [8] [23] [5] [9] [10] [11] [12] [5] [13,14]
Infectious diseases	Amebic liver abscess Hepatitis C Human immunodeficiency virus Visceral leishmaniasis	[15] [16] [17] [18]
Medications	Interleukin-2 Lipid-lowering medications (i.e. statins, PCSK9 inhibitors)	[19] [20,21]

Figure 1. Simplified lipid pathway demonstrating the role of the key proteins from each monogenic hypocholesterolemia disorder. The proteins involved in apo B lipoprotein production (apoB48, apoB100, MTP), secretion (SAR1B) and catabolism (LDLR) are shown in green. The proteins involved in modulating apoB lipoproteins (PCSK9 and ANGPTL3) are shown in red. Lipoproteins are labeled in blue, with smaller, denser lipoproteins corresponding with darker shades of blue. Abbreviations: ANGPTL3, angiopoietin-like 3; APOB, apolipoprotein B; HL, hepatic lipase; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; LPL, lipoprotein lipase; LDLR, LDL receptor; LRP, low density lipoprotein receptor-related protein 1; MTP, microsomal triglyceride transfer protein; PCSK9, proprotein convertase subtilisin/kexin type 9; SAR1B, secretion associated Ras related GTPase 1B; TG, triglyceride; VLDL, very-low density lipoprotein.

Table 2. Summary of the epidemiology, genetic, and clinical features of the primary causes of low LDL cholesterol.

	ABL	Homozygous FHBL	CRD	Heterozygous FHBL	Polygenic hypocholesterolemia	PCSK9 deficiency	ANGPTL3 deficiency	LDLR gain of function
Epidemiology	<1 in 10^6	<1 in 10^6	<1 in 10^6	1 in 1000–3000	10% of the population	Het: 1–3 in 100 Homo: <1 in 10^5	Het: 1 in 300 Homo: <1 in 10^6	7 members of 1 Icelandic family
Genetic Basis	Autosomal recessive; biallelic variants in MTTP	Autosomal co-dominant; biallelic variants in APOB	Autosomal recessive; biallelic variants in SAR1B	Autosomal co-dominant; heterozygous variants in APOB	Polygenic; common variants associated with modulating LDL cholesterol levels	Autosomal semi-dominant; heterozygous or biallelic variants in PCSK9	Autosomal semi-dominant; heterozygous or biallelic variants in ANGPTL3	Autosomal dominant; GOF 2.5kb deletion spanning the LDLR 3’ UTR
Pathology	Impaired packaging and secretion of apoB lipoproteins		Impaired secretion of apo B lipoproteins	Reduced secretion of apo B lipoproteins	Dependent on carrier status of SNPs measured.	Reduced uptake and degradation of LDLR	Reduced lipoprotein and endothelial lipase inhibition	Enhanced lipolysis of apoB100 lipoproteins
Clinical Features	− Acanthocytosis		− Absent acanthocytosis	− Absent acanthocytosis − Increased risk of hepatic disease	None
	− Gastrointestinal signs − Hepatic disease (i.e. hepatic steatosis, fibrosis, cirrhosis, elevated serum transaminases) − Fat soluble vitamin deficiency causing multisystemic sequelae: - Ophthalmic (i.e. retinitis pigmentosa)^† - Musculoskeletal (i.e. myopathy, osteopenia) - Neurological (i.e. neuropathy)^† - Hematological (i.e. coagulopathy, bruising)
Biochemical Features	↓↓ LDL cholesterol ↓↓ total cholesterol ↓↓ apo B ↓↓ TG		↓↓LDL cholesterol ↓↓HDL cholesterol ↓↓total cholesterol ↓↓ apo B Normal TG	↓LDL cholesterol ↓total cholesterol ↓ apo B ↓ TG	↓ LDL cholesterol ↓ apo B	↓LDL cholesterol ↓total cholesterol ↓ apo B ↓ TG	↓LDL cholesterol ↓HDL cholesterol ↓total cholesterol ↓ apo B ↓ TG	↓LDL cholesterol ↓total cholesterol ↓ apo B Normal TG
Treatment	High dose oral vitamin therapy, dietary recommendations, and monitoring (Refer to Table 3)			Monitor for hepatic disease	No specific treatment

Symbols: ↓↓ very low; ↓ low; † milder ophthalmic and neurological complications for CRD patients; Abbreviations: ABL, abetalipoproteinemia; apo B, apolipoprotein B; CRD, chylomicron retention disease; FHBL, familial hypobetalipoproteinemia; GOF, gain-of-function; HDL, high-density lipoprotein; Het, heterozygous; Homo, homozygous; LDL, low-density lipoprotein; LDLR, LDL receptor; RBC, red blood cell; SNP, single nucleotide polymorphism; TG, triglyceride.

Table 3. Treatment and clinical follow-up of patients with monogenic hypocholesterolemia: abetalipoproteinemia, homozygous familial hypobetalipoproteinemia, and chylomicron retention disease.

	Evaluation				Frequency
Growth	Height and weight on track with growth curve for age				6–12 months
Diet	− Low fat diet (<10–30% of total caloric intake) − Ensure total caloric intake is adequate − Reduced long-chain fatty acid intake − Supplementation of essential fatty acids (i.e. 1–2 teaspoons or 5–10 ml of polyunsaturated fatty acid rich oils) − Supplementation of medium chain TG not required				Daily
Vitamin therapy	Vitamin A 100–400 IU/kg/day (15 000 IU/day for CRD)	Vitamin D 800–1200 IU/day	Vitamin E 100–300 IU/kg/day (50 IU/kg/d for CRD)	Vitamin K 5–35 mg/week	Daily – weekly
Laboratory investigation	Lipid levels − total cholesterol − TG − LDL cholesterol − HDL cholesterol − apo B − apo A1	Hepatic function − AST − ALT − GGT − total and direct bilirubin − ALP − Albumin	Vitamin levels − Beta-carotene − 25-OH vitamin D − Plasma or RBC vitamin E − INR	Other − CBC − Vitamin B12 − Folate − Calcium − Phosphate − Uric acid − TSH	Annual (Exception: lipid levels will not usually change on an annual basis)
Clinical features for monitoring (lifelong)	Gastrointestinal − Abdominal distention − Appetite − Diarrhea − Esophagitis − Jaundice − Nausea/Vomiting	Neurological − Monitor development and function − Ataxia − Dysarthria − Hyporeflexia − Muscle pain or weakness − Proprioception loss − Reduced or lost deep tendon reflex	Hepatic − Hepatomegaly Ophthalmological − Nyctalopia (night blindness) − Retinopathy − Retinitis pigmentosa − Xerophthalmia		6–12 months
Commence after age 10	Musculoskeletal − DXA for bone mineral density − Echocardiography to monitor heart activity and muscle	Neuromuscular − Electromyography to monitor skeletal muscle and peripheral nervous system activity	Hepatic− Ultrasonography or FibroScan) to screen for hepatic steatosis, fibrosis & cirrhosis− Fibrosis-4 (FIB 4) index to estimate fibrosis		3 years

Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; apo, apolipoprotein; AST, aspartate aminotransferase; CBC, complete blood count; DXA, dual-energy x-ray absorptiometry; GGT, gamma glutamyl transferase; FIB-4, Fibrosis-4; HDL, high-density lipoprotein; INR, international normalized ratio; LDL, low-density lipoprotein; RBC, red blood cells; TG; triglyceride; TSH, thyroid stimulating hormone. Adapted from Lee & Hegele, 2014 (35**) & Bredefeld et al. 2020 (42).

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