Familial hyperchylomicronemia: Difference between revisions
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Presence of [[LPL]] inhibitor is the cause of type 1C hyperlipoproteinemia | Presence of [[LPL]] inhibitor is the cause of type 1C hyperlipoproteinemia | ||
==Historical Perspective== | ==Historical Perspective== | ||
==Pathophysiology== | ==Pathophysiology== | ||
*Type I hyperlipoproteinemia is a rare autosomal recessive disorder of lipoprotein metabolism. <ref name="pmid27578112">{{cite journal| author=Pingitore P, Lepore SM, Pirazzi C, Mancina RM, Motta BM, Valenti L et al.| title=Identification and characterization of two novel mutations in the LPL gene causing type I hyperlipoproteinemia. | journal=J Clin Lipidol | year= 2016 | volume= 10 | issue= 4 | pages= 816-23 | pmid=27578112 | doi=10.1016/j.jacl.2016.02.015 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27578112 }} </ref><ref name="pmid23475957">{{cite journal| author=Young SG, Zechner R| title=Biochemistry and pathophysiology of intravascular and intracellular lipolysis. | journal=Genes Dev | year= 2013 | volume= 27 | issue= 5 | pages= 459-84 | pmid=23475957 | doi=10.1101/gad.209296.112 | pmc=3605461 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23475957 }} </ref><ref name="pmid15115692">{{cite journal| author=Pasalić D, Jurcić Z, Stipancić G, Ferencak G, Leren TP, Djurovic S et al.| title=Missense mutation W86R in exon 3 of the lipoprotein lipase gene in a boy with chylomicronemia. | journal=Clin Chim Acta | year= 2004 | volume= 343 | issue= 1-2 | pages= 179-84 | pmid=15115692 | doi=10.1016/j.cccn.2004.01.029 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15115692 }} </ref> | *Type I hyperlipoproteinemia is a rare autosomal recessive disorder of lipoprotein metabolism. <ref name="pmid27578112">{{cite journal| author=Pingitore P, Lepore SM, Pirazzi C, Mancina RM, Motta BM, Valenti L et al.| title=Identification and characterization of two novel mutations in the LPL gene causing type I hyperlipoproteinemia. | journal=J Clin Lipidol | year= 2016 | volume= 10 | issue= 4 | pages= 816-23 | pmid=27578112 | doi=10.1016/j.jacl.2016.02.015 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27578112 }} </ref><ref name="pmid23475957">{{cite journal| author=Young SG, Zechner R| title=Biochemistry and pathophysiology of intravascular and intracellular lipolysis. | journal=Genes Dev | year= 2013 | volume= 27 | issue= 5 | pages= 459-84 | pmid=23475957 | doi=10.1101/gad.209296.112 | pmc=3605461 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23475957 }} </ref><ref name="pmid15115692">{{cite journal| author=Pasalić D, Jurcić Z, Stipancić G, Ferencak G, Leren TP, Djurovic S et al.| title=Missense mutation W86R in exon 3 of the lipoprotein lipase gene in a boy with chylomicronemia. | journal=Clin Chim Acta | year= 2004 | volume= 343 | issue= 1-2 | pages= 179-84 | pmid=15115692 | doi=10.1016/j.cccn.2004.01.029 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15115692 }} </ref> | ||
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**Postheparin plasma LPL activity is decreased, adipose tissue LPL activity is elevated, and plasma levels of functional apoC-I1 are normal. | **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. | *Functionally inactive or absent lipoprotein lipase emzyme, results in massive accumulation of chylomicrons, with extremely high level of plasma triglycerides. | ||
==Causes== | ==Causes== | ||
The cause of type 1 hyperlipidemia remains genetic. | The cause of type 1 hyperlipidemia remains genetic. | ||
==Differential diagnosis== | ==Differential diagnosis== | ||
{| class="wikitable" | {| class="wikitable" | ||
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==Screening== | ==Screening== | ||
*There are no screening guidelines for . | *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. | *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. | ||
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==Diagnosis== | ==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. | *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 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. | *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. | ||
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|} | |} | ||
==Treatment== | ==Treatment== | ||
Revision as of 20:39, 4 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 |
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.