Hypobetalipoproteinemia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aravind Kuchkuntla, M.B.B.S[2]

Synonyms and keywords: Familial hypobetalipoproteinemia, FHBL, normotriglyceridemic hypobetalipoproteinemia

Overview

These are a set of diseases caused my mutations in genes involved in triglyceride(TG), cholesterol transport and metabolism. These diseases primarily cause low plasma LDL C and triglyceride levels less than in the 5th percentile of normal population. Clinical manifestations can vary from being completely asymptomatic to multiple features of vitamin deficiencies, and fat malabsorption. Clinical symptoms of vitamin E are seen early in the course of the disease as the amount of vitamin E is parallel to the total lipid level in the body. Failure to diagnose and to initiate timely vitamin supplementation results in the development of neurological symptoms. The mutations causing low LDL levels are widely studied as newer lipid lowering therapies are based on similar mechanisms of these diseases.

Historical Perspective

• In 1960, Salt reported absence of betalipoprotein in the plasma of a patient associated with very low cholesterol levels in the parents. Low cholesterol levels in the parents differentiates familial homozygous hypobetalipoproteinemia from abetalipoproteinemia.
• In 1961, Anderson suggested failure of formation of chylomicron and lipid malabsorption as a cause of severe steatorrhea in children. Patients did not have acanthocytes on the peripheral smear and neuro-ocular symptoms like familial hypobetalipoproteinemia.
• Roy in 1987 and Kane in 1989 described chylomicron retention disease.
• In 2003, the mutation in SAR1B gene was identified by jones.
• Conklin identified the ANGPTL3 gene in 1999 and its function of inhibiting lipoprotein lipase was established in 2013 by Arca.

Pathophysiology

Pathogenesis

Hypobetalipoproteinemias are caused by mutations in the genes involved in triglyceride transport and metabolism.

• Cholesterol and triglycerides are insoluble in the plasma and they require a transport protein in the form of apolipoprotein B. These lipoproteins transport cholesterol and trigylcerides in spherical particles with cholesterol esters and triglyceride forming the central core.
• Apolipoprotein B is the major carrier for triglycerides and cholesterol from the intestine and liver to the periphery.
• Apolipoprotein B exits in two forms: apolipoprotein B48 and apolipoprotein B100.

APOB gene is responsible for the production of Apo B48 in intestine which is critical for the formation and secretion of chylomicrons , and Apo B100 in the liver which is released into circulation as VLDL.

Mutation in the APOB gene affects the translation of mRNA of apolipoprotein B causing familial hypobetalipoproteinemia. The severity of clinical phenotype in familial hypobetalipoproteinemia depends on length of trucated Apo B and zygosity.

MTP transfers triglycerides from cytsol onto nacent apolipoprotein B in endoplasmic reticulum which is required for assembly and secretion of VLDL and chylomicrons. Mutation in MTP causes abetalipoproteinemia.

In Apo B48 associated chylomicrons, transport of proteins from endoplasmic reticulum to golgi complex is dependent on coat protien complex 2(COP II), secretion-associated, Ras-related GTPase 1B (Sar1b) encoded by the gene SAR1B is a major part of the protein essential for this intra cellular transport. Mutation in Sar1b causes chylomicron retention disease.

In the periphery by the action of lipoprotein lipase in the endothelium of the capillaries and glycosylphosphatidylinositol-anchored high-density lipoprotein- binding protein 1 (GPIHBP1), a transporter for lipoprotien lipase, triglycerides are hydrolysed to form free fatty acids and glycerol.

This results in the formation of VLDL remnant(Intermediate density lipoprotein) and chylomicron remnants. The lipases are inhibited by Angiopoietin-like protein 3 (ANGPTL3) thereby decreasing the triglyceride and LDL C.

Loss of function mutations or complete absence of ANGPTL3 gene cause familial combined hypolipidemia.

IDL on further removal of triglycerides forms a cholesterol ester rich LDL C. The chylomicron and VLDL remnants removal is apolipoprotein E dependent via the LDL receptors and LDL receptor related protiens.

LDL C is removed from the circulation by binding to LDL receptors in the liver. The receptor degradation is enhanced by Proprotein convertase subtilisin kexin 9 (PCSK9).

Mutation causing loss of function of the enzyme causes low LDL C levels, and gain of function mutations are associated with familial hypercholesterolemia.

Genetics

The genetic defect, transmission and the result of the mutation in various diseases is described below:

	Homozygous familial hypobetalipoproteinemia(FHBL)	Heterozygous familial hypobetalipoprotienemia	Chylomicron Retention Disease	Familial Combined Hypolipidemia
Inheritance	Autosomal codominant	Autosomal codominant	Autosomal recessive	Autosomal codominant
Defective Gene	APOB gene on chromosome locus 2p23-24	APOB gene	SAR1B gene on chromosome 5q31	ANGPTL3 gene on chromosome 1
Pathophysiology	Absence of apolipoprotein B results in absent plasma VLDL, triglyceride and LDL C	Truncated apolipoprotein B protein is formed which affects the lipidation and secretion of the apolipoprotein B particles. These poorly lipidated particles are are rapidly catabolized.	Intracellular transport of chylomicrons is affected ,resulting in the accumulation of lipids in the cells of the intestine and liver.	Loss of function mutation results in the failure of inhibition of Lipoprotien lipase, leading to low LDL, VLDL and HDL levels.

• Less common causes of familial hypobetalipoproteinemia are mutations in PCSK9 and ANGPTL3 S17X.
• Mutations in loss of function of PCSK9 do not cause any clinical symptoms but are shown to be associated with decreasing cardiovascular disease risk.
• Mutation in ANGPTL3 S17X causes low LDL C and triglyceride levels along with reduction in plasma glucose level by increasing insulin sensitivity which is secondary to the increased lipoprotien lipase activity.

Causes

The following are the list of causes of primary hypobetalipoproteinemia:

• Abetalipoproteinemia
• Familial hypobetalipoproteinemia
• Chylomicron retention disease
• PCSK9 deficiency
• Familial combined hypolipidemia

Epidemiology and Demographics

The prevalence of these diseases is as follows:

	Prevalence
Abetalipoproteinemia	<1:1,000,000
Familial Hypobetalipoproteinemia	1:1000 – 1:3000
Chylomicron Retention Disease	Very rare
Familial Combined Hypolipidemia	Very rare
PCSK9 Deficiency	Very rare

Natural History, complications and Prognosis

	Homozygous Familial Hypobetalipoproteinemia	Heterozygous Familial Hypobetalipoproteinemia	Chylomicron Retention Disease	Familial Combined Hypolipidemia
Disease Course	Steatorrhea early in infancy and progression to neurological symptoms which begin in the 1st or 2nd decade.	Usually benign, few patients may present with steatorrhea.	Early onset of symptoms with diarrhea and failure to thrive.	Benign
Complications	Neurologic degeneration, Anemia, Blindness	Liver cirrhosis, Hepatocellular carcinoma.	Neurological symptoms with areflexia in the 1st decade, more severe symptoms like ataxia, myopathy and sensory neuropathy are seen with advancing age. Retinopathy and poor bone mineralization due to vitamin A and vitamin D deficiency.	None
Prognosis	Poor prognosis when the diease manifests in early childhood. Excellent prognosis in moderate form without cytolysis and hepatic steatosis.	A familial syndrome of longevity has been observed in the benign forms of HBL and many patients live over the age of 85.	Poorly documented evidence on prognosis.	Good

Diagnosis

History, Symptoms and Physical Examination

Hypobetalipoproteinemias present with varying severity of similar symptoms based on the type of mutation as follows:

	Homozygous Familial Hypobetalipoproteinemia	Heterozygous Familial Hypobetalipoproteinemia	Chylomicron Retention Disease	Familial Combined Hypolipidemia
Age of Presentation	Infancy	Asymptomatic	2 months to 1 year	Asymptomatic
History and Symptoms	Similar to abetalipoproteinemia Steatorrhea, failure to thrive Without vitamin E replacement symptoms progress and include reduced visual acuity, ataxia, dysarthria, loss of vibration and proprioception and areflexia as the posterior columns are affected	Patients are asymptomatic, malabsorption can occur in patients with short trucated apolipoprotein B forming mutations Common feature is hepatic steatosis	Diarrhea, steatorrhea, abdominal distention, and failure to thrive, neurological symptoms manifest if vitamin E supplementation is not initiated. Essential fatty acid deficiency.	Normal health
Physical Examination	Growth Retardation Malnutrition Retinal degeneration changes Hepatomegaly Truncal Ataxia Muscle weakness and atrophy Diminished deep tendon reflexes Loss of vibration sense and proprioception	Hepatomegaly	Growth Retardation Malnutrition Retinal degeneration changes Hepatomegaly Truncal Ataxia Muscle weakness and atrophy Diminished deep tendon reflexes Loss of vibration sense and proprioception	Normal Physical Exam

Laboratory Results

Definitive gold standard for diagnosis is gene sequencing for APOB, MTTP, SAR1B, ANGPTL3 to see the exact mutation. Laboratory findings consistent with the diagnosis of hypobetalipoproteinemias include as follows:

	Homozygous Familial Hypobetalipoproteinemia	Heterozygous Familial Hypobetalipoproteinemia	Chylomicron Retention Disease	Familial Combined Hypolipidemia
Lipid analysis	ApoB <5th percentile LDL-C between 20- 50 mg/dL	LDL C is one third of normal value and not 50% of expected for age and sex. Due to decreased production and increased catabolism of VLDL apo B-100. This causes decreased secretion of triglycerides and low LDL C levels.	LDL and HDL 50% of normal Normal triglyceride levels is the characteristic laboratory finding.	Homozygotes and compound heterozygotes show panhypolipidemia with LDL low triglyceride and reduced HDL C. Heterozygotes: Normal HDL, with LDL <25th percentile.
Other findings	Low fat soluble vitamin level. Mild elevation of LFTs Acanthocytosis	Mild elevation of LFTs	Failure of chylomicron secretion after a lipid rich meal. Low fat soluble vitamin level. Endoscopy shows a typical white stippling. The enterocytes on biopsy show accumulations of large lipid droplets free in the cytoplasm as well as membrane-bound lipoprotein-sized structures. Mild elevation of liver transaminases. Elevated creatine kinase	None

	Abetalipoprotienemia	Familial Homozygous Hypobetalipoproteinemia	Familial Heterozygous Hypobetalipoproteinemia	PCSK9 deficiency	Chylomicron Retention Disease	Familial Combined Hypolipidemia
LDL C	↓↓↓ (0)	↓↓↓	↓	↓	↓↓	↓↓
Apo B	↓↓↓( 0)	↓↓↓	↓	N	↓↓	N
TG	↓↓↓	↓↓↓	↓	↓	N	↓
TC	↓↓↓	↓↓↓	↓	↓	↓↓	↓
HDL	↓↓	↓↓	N	N	↓↓	↓↓
VLDL	↓↓	↓↓	↓	N	↓↓	↓
Apo A1	↓↓	↓↓	↓	N	↓↓	N

Approach to patient with Low LDL C

Low LDL C <5th percentile

Rule out secondary causes of low LDL Anemia Criticial illness Chronic inflammation Chronic liver disease Hyperthyroidism Infection Malabsorption Malignancy

Once secondary causes are ruled out consider primary diseases based on analysis of Lipid profile

Normal Triglycerides

Low Triglycerides

Chlyomicron retention disease (Confirm with gene sequencing)

Screen the lipid profile of the patient's parents

Normal Parental Lipid Profile

If Parental Lipid Profile <50% of Normal on: *LDL *Total Cholesterol *Triglycerides

Abetalipoproteinemia (Confirm with gene sequencing)

Familial Homozygous hypobetalipoproteinemia (Confirm with gene sequencing)

Treatment

Medical Therapy

• The mainstay of management of familial hypobetalipoproteinemia include early diagnosis and early initiation of low fat diet and fat soluble vitamin supplementation in all symptomatic patients, with yearly follow up to assess the growth and nutritional status, diet compliance, neurological function, lipid panel.
• FHBL heterozygous patients with elevated liver enzyme, regular ultrasound imaging is recommended to monitor for progression of fatty liver to cirrhosis or hepatocellular carcinoma.

Chylomicron Retention Disease Management

• If the patient is diagnosed early in the course of the disease diet modification and oral supplementation of vitamins improved outcomes.
  • Low-fat diet
  • Vegetable oil enriched in essential fatty acids ± Enriched in medium-chain triglycerides
  • Vitamin E (hydrosoluble form): 50 IU/kg/d
  • Vitamin A: 15,000 IU/d (adjust according to plasma levels)
  • Vitamin D: 800-1200 IU/kg/d or 100,000 IU/2 month if < 5 y old, and 600,000 IU/2 month if > 5 y old
  • Vitamin K: 15 mg/week (adjust according to INR and plasma levels)
• If patient is diagnosed late and with neurological disease, combined oral and parental supplementation is recommended:
  • Fatty acids-intralipid 20% 2g/kg/month
  • Vitamin E 4 to 6 mg/kg/month
  • Vitamin A 500 IU/kg/month once a month is recommended

Follow up

• Annual follow up to 10 years to assess the growth and nutritional status, diet compliance, neurological function, lipid profile.
• Every 3 year follow up to check bone mineral density, liver function with ultrasound, ophthalmologic exam for fundus, color vision, visual evoked potentials and electroretinography after the age of 10years.
• Echocardiography in adulthood.

Surgical Therapy

• No surgical options are available.

Prevention

Primary Prevention

• As the set of the diseases are rare there are no primary preventive measures.

Secondary Prevention

• Regular follow up to look for complications and strict adherence to therapy has shown to prevent progression of the disease.