Hypobetalipoproteinemia
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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.

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

# Natural History, complications and Prognosis

# Diagnosis

## History, Symptoms and Physical Examination
Hypobetalipoproteinemias present with varying severity of similar symptoms based on the type of mutation as follows:

## 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:

## Approach to patient with Low LDL C

# 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
Vitamin K: 15 mg/week (adjust according to INR and plasma levels)
- 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
- 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
- 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
- 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.