Familial hyperchylomicronemia
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
Differential diagnosis
Epidemiology and Demographics
Familial hyperchylomicronemia, is a rare autosomal recessive disorder of lipoprotein metabolism estimated to affect approximately one per million individuals. In some ethnic groups, the frequency of this disorder is several fold higher (i.e., French Canadians, Afrikaner).
Risk Factors
Risk to Family Members
Parents of a proband
The parents of an affected individual are obligate heterozygotes and therefore carry a single copy of a pathogenic variant in LPL. Heterozygotes (carriers) are asymptomatic but may have moderate hypertriglyceridemia and may be at mild risk for premature atherosclerosis. Sibs of a proband
At conception, 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. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Heterozygotes (carriers) are asymptomatic but may have moderate hypertriglyceridemia and may be at mild risk for premature atherosclerosis. Offspring of a proband. The offspring of an individual with familial lipoprotein lipase deficiency are obligate heterozygotes (carriers) for a pathogenic variant in LPL.
Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier.
Carrier Detection
Carrier testing is possible if the pathogenic variants in the family are known.
Related Genetic Counseling Issues
See Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.
Family planning
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Prenatal Testing and Preimplantation Genetic Diagnosis
Once the LPL pathogenic variants have been identified in an affected family member, prenatal testing and preimplantation genetic diagnosis for a pregnancy at increased risk for familial lipoprotein lipase deficiency are possible options.
Requests for prenatal testing for conditions which (like familial lipoprotein lipase deficiency) do not affect intellect and have effective treatment available are not common. Differences in perspective may exist among medical professionals and in families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate. In practice, prenatal testing is rarely requested because of the availability of effective treatment.
Screening
- There are no screening guidelines for seborrheic dermatitis.
Natural History, Complications, and Prognosis
Natural History
Complication
Prognosis
Risk Factors
Diagnosis
History/symptoms
The signs and symptoms of hyperlipoproteinemia type 1 usually begin during childhood. Approximately 25 percent of affected individuals develop symptoms before age 1. The characteristic features of hyperlipoproteinemia type 1 include: Abdominal pain (may manifest as colic in infancy) Nausea, vomiting, loss of appetite Failure to thrive in infancy Musculoskeletal pain (pain in the muscles and bones) Xanthomas (small, yellow, fat deposits in the skin) Pancreatitis Enlarged liver and spleen
Physical examination
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 |
Treatment
The main therapeutical approach of Type I hyperlipoproteinemia is based on diet treatment to reduce triglyceride (TG) levels.20 TG-lowering drugs, such as niacin and fibrates, are not effective in patients with type I hyperlipoproteinemia.21 Orlistat, a gastric lipase inhibitor that reduces fat availability, has been used successfully in the treatment of moderate and severe LPL deficiency.22 and 23 Recently, gene replacement using alipogene tiparvovec has been the very first therapy approved by European Medicines Agency for the treatment of type I hyperlipoproteinemia.24 Alipogene tiparvovec introduces a human LPL gene into the body, resulting in the production of functional LPL. 25 However, this gene therapy is indicated only in adults with genetic diagnosis of LPL deficiency who have had recurrent pancreatitis and with a residual lipoprotein mass in the circulation. 24 and 26 Thus, careful genetic screening and functional testing of LPL are required to identify patients eligible for this new therapeutic approach.
Prevention
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.