Familial hyperchylomicronemia: Difference between revisions
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Revision as of 13:41, 7 November 2016
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Vishal Devarkonda, M.B.B.S[2]
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 form 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 0.1% of the population.
Classification
Type 1A
It occurs due to deficiency of lipoprotein lipase enzyme.
Type 1B
Altered apolipoprotein C2 causes type 1B hyperlipoproteinemia
Type 1C
Presence of LPL inhibitor is the cause of type 1C hyperlipoproteinemia
Historical Perspective
Pathophysiology
- Type I hyperlipoproteinemia is a rare autosomal recessive disorder of lipoprotein metabolism. [1][2][3]
Pathogenesis
- Lipoprotein lipase(LPL) hydrolysis Triglyceride-rich lipoproteins (TG) such as chylomicrons and very low-density lipoproteins. It catalyzes, the removal of TG from 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
- Development of Type I hyperlipoproteinemia is the result of functional mutations in one of all these genes result in type I hyperlipoproteinemia.
Familial lipoprotein lipase inhibitor
- Familial lipoprotein lipase inhibitor seems to be inherited as an autosomal dominant trait.
- Postheparin plasma LPL activity is decreased, adipose tissue LPL activity is elevated, and plasma levels of functional apoC-I1 are normal.
- Functionally inactive or absent lipoprotein lipase emzyme, results in massive accumulation of chylomicrons, with extremely high level of plasma triglycerides.
Causes
The cause of type 1 hyperlipidemia remains genetic.
Differential diagnosis
| Diseases | Laboratory Findings | Physical Examination | History and symptoms | other findings |
|---|---|---|---|---|
| Familial combined hyperlipidemia | ||||
| Monogenic familial hypertriglyceridemia | ||||
| Secondary causes of hypertriglyceridemia | ||||
| Diabetes mellitus | ||||
| Paraproteinemic disorders | ||||
| Alcohol usage | ||||
| Estrogen thearapy | ||||
| Glucocorticoids | ||||
| Isotretinoin | ||||
| Antihypertensive agents |
Brunzell & Deeb 2001
Epidemiology and Demographics
Epidemiology
- 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.
- 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.
- Majority develop symptoms before ten years of age.
- Few individuals develop symptoms, at the time of pregnancy.
Gender
- Males and females are equally affected.
Screening
- There are no screening guidelines for Familial hyperchylomicronemia .
- Evaluation of Relatives at Risk.It is appropriate to measure plasma triglyceride concentration in at-risk sibs 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
If left untreated, pancreatitis can develop into a chronic condition that can damage the pancreas and, in rare cases, be life-threatening.
Complications
- Pancreatitis and recurrent episodes of abdominal pain may develop.
- Xanthomas are not usually painful unless they are rubbed a lot.
Prognosis
- People with this condition who follow a very low-fat diet can live into adulthood.
Diagnosis
- Presumptive diagnosis can be made, when an infant presents with a history of failure to thrive or recurrent abdominal pain, with an documented high fasting plasma triglyceride concentration.
- Diagnosis is confirmed by low or absent LPL enzyme activity in an assay system that contains either normal or
- Diagnosis of familial lipoprotein lipase deficiency 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.
History and symptoms
Symptoms may include any of the following
- Abdominal pain (may appear as colic in infancy)
- Loss of appetite
- 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
Physical examination
Signs of this condition include:
Enlarged liver and spleen Failure to thrive in infancy Fatty deposits in the skin (xanthomas) High triglyceride levels in the blood Pale retinas and white-colored blood vessels in the retinas Pancreatitis that keeps returning Yellowing of the eyes and skin (jaundice
Laboratory finding
| Laboratory finding | ||||||||
|---|---|---|---|---|---|---|---|---|
| Phenotype | Lipoprotein(s)
Elevated |
Serum total
cholesterol |
Serum
triglycerides |
Plasma
appearance |
Postheparin
lipolytic activity |
Glucose
tolerance |
Carbohydrate
inducibility |
Fat tolerance |
| Hyperlipoproteinemia type 1 | Chylomicrons | Normal to
elevated |
Elevated | Creamy | Decreased | Normal | May be abnormal | Markedly abnormal |
Prevention
Genetic counseling.
Familial lipoprotein lipase deficiency is inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family are known.
Prevention of Primary Manifestations
Medical nutrition therapy. 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.
Prevention of Secondary Complications
Prevention of acute recurrent pancreatitis decreases the risk of development of diabetes mellitus. Fat malabsorption is very rare.
- ↑ Pingitore P, Lepore SM, Pirazzi C, Mancina RM, Motta BM, Valenti L; et al. (2016). "Identification and characterization of two novel mutations in the LPL gene causing type I hyperlipoproteinemia". J Clin Lipidol. 10 (4): 816–23. doi:10.1016/j.jacl.2016.02.015. PMID 27578112.
- ↑ Young SG, Zechner R (2013). "Biochemistry and pathophysiology of intravascular and intracellular lipolysis". Genes Dev. 27 (5): 459–84. doi:10.1101/gad.209296.112. PMC 3605461. PMID 23475957.
- ↑ Pasalić D, Jurcić Z, Stipancić G, Ferencak G, Leren TP, Djurovic S; et al. (2004). "Missense mutation W86R in exon 3 of the lipoprotein lipase gene in a boy with chylomicronemia". Clin Chim Acta. 343 (1–2): 179–84. doi:10.1016/j.cccn.2004.01.029. PMID 15115692.