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

Pathophysiology

Pathogenesis

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


 
 
 
APOB gene is responsible for the production of Apo B48 in intestine which is critical for the formation and secretion of chylomicrons[7] , 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.[8]
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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.[9]
 
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.[10] Mutation in Sar1b causes chylomicron retention disease.[4]
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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)[11], 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.[12][13]
 
Loss of function mutations or complete absence of ANGPTL3 gene cause familial combined hypolipidemia.[14][15]
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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.[16]
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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).[17]
 
Mutation causing loss of function of the enzyme causes low LDL C levels, and gain of function mutations are associated with familial hypercholesterolemia.[18]
 
 

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[19]
Pathophysiology Absence of apolipoprotein B results in absent plasma VLDL, triglyceride and LDL C Intracellular transport of chylomicrons is affected ,resulting in the accumulation of lipids in the cells of the intestine and liver.[20] Loss of function mutation results in the failure of inhibition of Lipoprotien lipase, leading to low LDL, VLDL and HDL levels.

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:[23]

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 None
Prognosis A familial syndrome of longevity has been observed in the benign forms of HBL and many patients live over the age of 85.[27] Poorly documented evidence on prognosis.[28] 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
Physical Examination Hepatomegaly 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
  • 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.[34] This causes decreased secretion of triglycerides and low LDL C levels.[35]
Other findings
  • Mild elevation of LFTs
  • 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.[40]

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.[32]
    • 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:
Follow up

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.

References

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