Familial hyperchylomicronemia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Vishal Devarkonda, M.B.B.S[2]Aysha Aslam, M.B.B.S[3]

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Synonyms and keywords: Type I hyperlipoproteinemia, Burger-Grutz syndrome, Primary hyperlipoproteinemia, lipoprotein lipase deficiency, LPL deficiency, Idiopathic hyperlipemia, Essential hyperlipemia, Familial hyperlipemia, Lipase D deficiency, Hyperlipoproteinemia type IA, Familial chylomicronemia, Familial lipoprotein lipase deficiency, and Familial hyperchylomicronemia.

Overview

This very rare hyperlipidemia is due to a deficiency of lipoprotein lipase (LPL) or altered apolipoprotein C2, resulting in elevated chylomicron which are the particles that transfer fatty acids from the digestive tract to the liver. Lipoprotein lipase is also responsible for the initial breakdown of endogenously made triacylglycerides in the form of very low density lipoprotein (VLDL). As such, one would expect a defect in LPL to also result in elevated VLDL. Its prevalence is one in 1,000,000 population.

Historical Perspective

• In 1932, Familial LPL deficency was first described by Burger and Grutz
• In 1967, Fredrickson using paper electrophosresis, classified lipoprotein disorder

Classification

There is no established classification system for Type I hyperlipoproteinemia. However, based on the pathogenesis involved type 1 hyperlipoproteinemia can be classified into:

Type 1a: Lipoprotein lipase deficiency

Type 1b: Apolipoprotein c-IIdeficiency

Type 1c: Presence of lipoprotein lipase inhibitor

Pathophysiology

• Type I hyperlipoproteinemia is a rare autosomal recessive disorder of lipoprotein metabolism.

Pathogenesis

• Lipoprotein lipase(LPL) hydrolyzes triglyceride-rich lipoproteins (TG) such as chylomicrons and very low-density lipoproteins. It catalyzes, the removal of TG from the bloodstream generating free fatty acids for tissues.
• For full enzymatic activity, LPL requires following cofactors:
  • Apolipoprotein C-II and apolipoprotein A-V that are LPL activators
  • Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein
  • Lipase maturation factor 1
• Familial lipoprotein lipase inhibitor inherited in an autosomal dominant fashion. Inhibit the action of lipoprotein lipase, resulting in decreased postheparin plasma LPL activity, elevated adipose tissue LPL activity, and normal plasma levels of functional apoC-I1.

• Functionally inactive or absent lipoprotein lipase enzyme, results in massive accumulation of chylomicrons, with extremely high level of plasma triglycerides.

Genetics

• More than 220 mutations in the LPL gene have been found to cause familial lipoprotein lipase deficiency. The most common mutation in people of European ancestry replaces the protein building block (amino acid) glycine with the amino acid glutamic acid at position 188 in the enzyme (written as Gly188Glu or G188E).

Causes

The cause of type 1 hyperlipidemia remains genetic.

Gene 1	Variants Detected 2	Variant Detection Frequency by Test Method 3	LPL	Sequence variants 4 (including p.Gly188Glu 5)	~97% 6
Partial- and whole-gene deletions and duplications	~3% 8

Epidemiology and Demographics

Epidemiological and demographics of familial hyperchylomicronemia are discussed below:

Prevalence

• The prevalence of familial LPL deficiency is approximately one in 1,000,000 in the general US population

Demographics

Age

• 25% of affected children develop symptoms before one year of age.
• The majority of patients develop symptoms before ten years of age.
• Few individuals develop symptoms, at the time of pregnancy.

Gender

• Males and females are equally affected by familial chylomicronemia..

Race

• The disease has been described in all races.
• The prevalence is much higher in some areas of Quebec, Canada, as a result of a founder effect.

Screening

• There are no screening guidelines for Familial hyperchylomicronemia.
• It may be appropriate to measure plasma triglyceride concentration in at-risk siblings during infancy; early diagnosis and implementation of dietary fat intake restriction can prevent symptoms and related medical complications.

Natural History, Complications, and Prognosis

Natural history, complications and prognosis of type 1 hyperlipoproteinemia include:

Natural History

• If left untreated, pancreatitis can develop into a chronic condition that can damage the pancreas and, in rare cases it could be life-threatening.

Complications

• Pancreatitis and recurrent episodes of abdominal pain may develop.
• Intestinal ischemia
• Depression,
• Memory loss
• Intellectual decline

Prognosis

• People with this condition who follow a very low-fat diet have a good prognosis.

Diagnosis

History and symptoms

Presumptive diagnosis can be made, when an infant presents with a history of failure to thrive or recurrent abdominal pain with a documented high fasting plasma triglyceride concentration.

Symptoms of Type I hyperlipoproteinemia include:

• Abdominal pain (may appear as colic in infancy)
• Loss of appetite, fatigue and irritability
• Nausea
• Pain in the muscles and bones (musculoskeletal pain)
• Vomiting
• Small yellow papules localized over the trunk, buttocks, knees, and extensor surfaces of the arms
• Blood in stools(Intestinal ischemia)
• In rare cases, neurological features of depression, memory loss, and mild intellectual decline (dementia) develop

Physical examination

Signs of Type 1 hyperlipoproteinemia include:

• Enlarged liver and spleen
• Failure to thrive in infancy
• Fatty deposits in the skin (xanthomas)
• Pale retinas and white-colored blood vessels in the retinas
• Pancreatitis that keeps returning
• Yellowing of the eyes and skin (jaundice)

• 

Laboratory findings

• Diagnosis of Type I hyperlipoproteinemia is confirmed by detection of low or absent LPL enzyme activity in an assay system, that contains either normal plasma or apoprotein C-II excluding hepatic lipase.

• Laboratory findings consistent with the Type I hyperlipoproteinemia include the following:

Laboratory finding
Phenotype	Lipoprotein(s) Elevated	Serum total cholesterol	HDL	VLDL	Serum triglycerides	Plasma appearance	Postheparin lipolytic activity	Glucose tolerance	Carbohydrate inducibility	Fat tolerance
Hyperlipoproteinemia type 1	Chylomicrons ↑↑↑↑	Normal to elevated	↓↓↓	↓	↑↑↑↑	Creamy	Decreased	Normal	May be abnormal	Markedly abnormal

Molecular Genetic Testing

• Diagnosis can be confirmed by molecular genetic testing that can detect mutations in the LPL gene.
• The test is often not necessary to confirm a diagnosis of type I hyperlipidemia.

Treatment

Treatment for hyperlipoproteinemia type 1 is intended to control blood triglyceride levels. There is currently no pharmacotherapy approved for the treatment of familial hyperchylomicronemia in the United States The mainstay of treatment includes dietary modification and control.

Medical Therapy

There is currently no pharmacotherapy approved for the treatment of familial hyperchylomicronemia in the United States

Dietary Management

Dietary management of hyperlipoproteinemia type 1 include the following:

• Controlling blood triglyceride levels with a very low-fat diet
• It is recommended that individuals with this condition eat no more than 20 grams of fat per day.
• Medium-chain fatty acids (such as coconut oil) can be incorporated into the diet, as they are absorbed by the body in a different manner.
• Dietary counseling may be helpful to maintain adequate calorie and nutrient intake.

Pregnancy Management

• Pregnant women may experience significant changes in lipid level in second and third trimester, and may require strategies to lower fat intake. Pregnancy management of type 1hyperlipoproteinemia involves the following:
• Periodic assessment of plasma triglycerides is highly recommended
• Comprehensive analysis of risks versus benefits is required before the use of fibrates, nicotinic acid and omega-3 fatty acid

Investigative Therapies

• Orlistat, in conjunction with a low fat diet has been used to treat some patients with familial hyperchilomicronemia caused by compound heterozygous LPL deficiency.

Gene Therapy

• Alipogene tipavovec(Glybera) gene therapy was approved by European commission(2012), in treating adult patients with recurrent episodes of pancreatitis.

Prevention

Primary Prevention

• There are no primary preventive measures to protect against type I hyperlipoproteinemia. There is currently no known intervention to prevent someone from inheriting this condition.
• Genetic counseling is recommended for patients and family members.

Secondary prevention

Secondary prevention involves the following:

• Prevention of acute recurrent pancreatitis decreases the risk of development of diabetes mellitus and fat malabsorption.
• Maintaining the plasma triglyceride concentration at less than 2000 mg/dl, keeps the individual with familial LPL deficiency free of symptoms. This can be accomplished by restriction of dietary fat to no more than 20 g/day or 15% of total energy intake.
• Periodic assessment of plasma triglycerides levels is highly recommended.
• Patients should avoid agents that increased endogenous triglyceride levels like alcohol, diuretics, oral estrogens, isoretinoin, glucocorticords, and beta-blockers.