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
The cause of type 1 hyperlipidemia remains genetic.
Differential diagnosis
However, the majority of individuals with chylomicronemia and plasma triglyceride concentration greater than 2000 mg/dL do not have familial LPL deficiency; rather, they have one of the more common genetic disorders of triglyceride metabolism (i.e., familial combined hyperlipidemia and monogenic familial hypertriglyceridemia) occurring simultaneously with, and independently of, a common acquired secondary form of hypertriglyceridemia [Brunzell & Deeb 2001].
Secondary causes of hypertriglyceridemia are diabetes mellitus, paraproteinemic disorders, use of alcohol, and therapy with estrogen, glucocorticoids, Zoloft®, isotretinoin, and certain antihypertensive agents. In one series of 123 individuals evaluated for marked hypertriglyceridemia, 110 had an acquired cause of hypertriglyceridemia combined with a common genetic form of hypertriglyceridemia, five had familial LPL deficiency, five had other rare genetic forms of hypertriglyceridemia, and three had an unknown cause.
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). Prevalence
The prevalence of familial LPL deficiency is approximately one in 1,000,000 in the general US population.
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.
Consanguinity is often observed in families with homozygous familial LPL deficiency.
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 .
- 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.
Complication
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
To confirm/establish the diagnosis in a proband. Persistent severe hypertriglyceridemia (1000-2000 mg/dL) in an infant or child that is responsive to dietary fat intake is indicative of LPL deficiency.
When LPL deficiency is first suspected, a history of failure to thrive as an infant or recurrent abdominal pain as a child should be sought. A fasting plasma triglyceride concentration should be obtained at least once for documentation. Note: Neither measurement of post-heparin plasma LPL enzyme activity nor LPL molecular genetic testing is required to make a presumptive clinical diagnosis.
Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.
Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variants in the family.
History/symptoms
Abdominal pain (may appear as colic in infancy) Loss of appetite Nausea Pain in the muscles and bones (musculoskeletal pain) Vomiting 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
Familial lipoprotein lipase (LPL) deficiency usually presents in childhood with episodes of abdominal pain, recurrent acute pancreatitis, eruptive cutaneous xanthomata, and hepatosplenomegaly. Males and females are affected equally.
Approximately 25% of affected children develop symptoms before age one year and the majority develop symptoms before age ten years; however, some individuals present for the first time during pregnancy. The severity of symptoms correlates with the degree of chylomicronemia, which varies by dietary fat intake.
The abdominal pain, which can vary from mildly bothersome to incapacitating, is usually mid-epigastric with radiation to the back. It may be diffuse and mimic an acute abdomen, often leading to unnecessary abdominal exploratory surgery. The pain probably results from chylomicronemia leading to pancreatitis.
Kawashiri et al [2005] reported that individuals with LPL deficiency can lead a fairly normal life on a diet very low in total fat content. The secondary complications of pancreatitis — diabetes mellitus, steatorrhea, and pancreatic calcification — are unusual in individuals with familial LPL deficiency and rarely occur before middle age. Pancreatitis in LPL deficiency may rarely be associated with total pancreatic necrosis and death.
About 50% of individuals with familial LPL deficiency have eruptive xanthomas, small yellow papules localized over the trunk, buttocks, knees, and extensor surfaces of the arms. Xanthomas are deposits of lipid in the skin that result from the extravascular phagocytosis of chylomicrons by macrophages. They can appear rapidly when plasma triglyceride concentration exceeds 2000 mg/dL.
Xanthomas may become generalized. As a single lesion, they may be several millimeters in diameter; rarely, they may coalesce into plaques. They are usually not tender unless they occur at a site susceptible to repeated abrasion.
Hepatomegaly and splenomegaly often occur when plasma triglyceride concentrations are markedly increased. The organomegaly results from triglyceride uptake by macrophages, which become foam cells.
When triglyceride concentrations exceed 4000 mg/dL, the retinal arterioles and venules, and often the fundus itself, develop a pale pink color ("lipemia retinalis"), caused by light scattering by large chylomicrons. This coloration is reversible and vision is not affected.
Reversible neuropsychiatric findings, including mild dementia, depression, and memory loss, have also been reported with chylomicronemia
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 |
Testing
Chylomicronemia / plasma triglyceride concentration
Affected individuals Chylomicrons are large lipoprotein particles that appear in the circulation shortly after the ingestion of dietary fat; normally, they are cleared from plasma after an overnight fast. In familial LPL deficiency, clearance of chylomicrons from the plasma is impaired, causing triglycerides to accumulate in plasma and the plasma to have a milky ("lactescent" or "lipemic") appearance. Plasma triglyceride concentrations In the presence of chylomicrons plasma triglyceride concentrations can be estimated fairly accurately by visual inspection. Plasma triglyceride concentrations are usually greater than 2000 mg/dL in the untreated state. It is important to measure the plasma triglyceride concentration once as a baseline. Routine measurement of non-fasting plasma triglyceride concentration can be used when fasting samples are difficult to obtain (e.g., in infants). Plasma triglyceride concentration is an excellent measure of compliance with dietary fat restrictions. Carriers. Heterozygotes have normal to moderately elevated plasma triglyceride concentrations. Measurement of lipoprotein lipase enzyme activity
Affected individuals. The 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 (a cofactor of LPL) and excludes hepatic lipase (HL). LPL enzyme activity can be assayed in plasma ten minutes following intravenous administration of heparin (60 U/kg body wt). The absence of lipoprotein lipase enzyme activity in postheparin plasma is diagnostic of familial LPL deficiency. LPL enzyme activity may be assayed directly in biopsies of adipose tissue. LPL enzyme activity can be measured in selected children and young adults. For more information, contact the author at ude.notgnihsaw.u@lleznurb. Carriers. Heterozygotes exhibit a 50% decrease of LPL enzyme activity in plasma following intravenous administration of heparin. Molecular Genetic Testing
Gene. LPL is the only gene in which pathogenic variants are known to cause familial lipoprotein lipase deficiency.
Clinical testing
Table 1.
Summary of Molecular Genetic Testing Used in Familial Lipoprotein Lipase Deficiency
Gene 1 Test Method Variants Detected 2 Variant Detection Frequency by Test Method 3 LPL Sequence analysis Sequence variants 4 (including p.Gly188Glu 5) ~97% 6 Deletion/duplication analysis 7 Partial- and whole-gene deletions and duplications ~3% 8 1. See Table A. Genes and Databases for chromosome locus and protein.
2. See Molecular Genetics for information on allelic variants.
3. The ability of the test method used to detect a pathogenic variant that is present in the indicated gene
4. Examples of pathogenic variants detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
5. The pathogenic variant p.Gly188Glu, common in Europe, is present in fewer than 40% of individuals with LPL deficiency.
6. Brunzell & Deeb [2001], Gilbert et al [2001]
7. Testing that identifies exon or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
8. Brunzell & Deeb [2001]
Testing Strategy
To confirm/establish the diagnosis in a proband. Persistent severe hypertriglyceridemia (1000-2000 mg/dL) in an infant or child that is responsive to dietary fat intake is indicative of LPL deficiency.
When LPL deficiency is first suspected, a history of failure to thrive as an infant or recurrent abdominal pain as a child should be sought. A fasting plasma triglyceride concentration should be obtained at least once for documentation. Note: Neither measurement of post-heparin plasma LPL enzyme activity nor LPL molecular genetic testing is required to make a presumptive clinical diagnosis.
Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.
Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variants in the family
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.
Pregnancy Management
During pregnancy in a woman with LPL deficiency, extreme dietary fat restriction to less than two grams per day during the second and third trimester with close monitoring of plasma triglyceride concentration can result in delivery of a normal infant with normal plasma concentrations of essential fatty acids [Al-Shali et al 2002].
One woman with LPL deficiency delivered a normal child following a one-gram fat diet and treatment with gemfibrozil (600 mg 1x/day) [Tsai et al 2004]. Despite concerns about the possibility of essential fatty acid deficiency in the newborn, normal essential fatty acids were found in cord blood, as were normal levels of fibrate metabolites.
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.