Hyperlipoproteinemia type 5
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ;Associate Editor(s)-in-Chief: Shivani Chaparala M.B.B.S [2] Venkata Sivakrishna Kumar Pulivarthi M.B.B.S [3]
Synonyms and keywords: : Hyperchylomicronemia, Late-Onset Hyperchylomicronemia With Hyperprebetalipoproteinemia, Familial mixed hyperlipidemia, Type V hyperlipemia, Hyperlipidemia type V, Type 5 hyperlipoproteinemia, Type 5 hyperlipemia, Type 5 HLP, Type V HLP, Combined fat and carbohydrate Induced hyperlipidemia, Mixed hypertriglyceridemia, Endogenous hypertriglyceridemia.
Overview
Type 5 Hyperlipoproteinemia (HLP) is a severe type of hyperlipidemia, characterized by an increase in both very-low-density lipoproteins (VLDLs) and chylomicrons in the plasma of fasting subjects on a regular diet. The metabolic defects responsible for type 5 HLP have been a matter of dispute.Although some patients seem to have "primary" type 5 HLP, this phenotype is often associated with secondary factors, eg, diabetes, obesity, alcoholism, nephrotic syndrome, or hypo- thyroidism. Primary type 5 HLP usually appears first in adulthood, a characteristic that distinguishes it from familial deficiency of lipoprotein lipase (type 1 HLP), which is present from birth. Type 5 HLP has been postulated to be the result of a defective clearance of triglycéride (TG)-rich lipoproteins,although lipoprotein lipase is not absent. Another suggested mechanism is of VLDL TG's overproduction.This abnormality could cause an increase in both VLDL and chylomicrons because these two lipoproteins compete with each other for clearance from plasma; in other words, excess production of VLDL alone theoretically could saturate the lipolytic system for plasma TGs and thereby interfere with removal of chylomicrons. It is a more complicated form of type I and more closely related with acquired environmental factors but no association with reduced Lipoprotein lipase or apolipoprotein C-II activity as in type I.
Historical Perspective
Classification
Pathophysiology
The two main sources of plasma triglycerides (also known as triacylglycerol) are exogenous (i.e., from dietary fat) and carried in chylomicrons, and endogenous (from the liver) and carried in very-low-density lipoprotein (VLDL) particles. In capillaries within fat and muscle tissue, these lipoproteins and chylomicrons are hydrolyzed by lipoprotein lipase into free fatty acids. After a meal, over 90% of the circulating triglycerides originate in the intestine and are secreted in chylomicrons, whereas during periods of fasting, endogenous triglycerides secreted by the liver as VLDL predominate. The increase in plasma of triglyceride-rich lipoproteins results from increased production from the liver and intestine (by means of upregulated synthetic and secretory pathways) or through decreased peripheral catabolism (mainly from reduced lipoprotein lipase activity).
Pathogenesis
The pathogenesis of type V is not fully understood. However; VLDL appears to be the most affected lipoprotein fraction in type V and there is three-fold increase in synthesis rate as well as decreased fractional catabolism of VLDL.The molecular basis for Type V HLP is not clearly understood.Apolipoprotein E mutatio type V hyperlipoproteinaemia is associated predominantly with TG-rich lipoproteins (chylomicrons and VLDL) and has also been detected on HDL particles.Mutations in the APOA5 gene, leading to truncated apolipoprotein A-V devoid of lipid-binding domains located in the carboxy-terminal end of the protein, if present in the homozygous state, are expected to cause severe type V hyperlipidemia in patients with no mutations in LPL or APOC2 genes. If present in the heterozygous state, these mutations predispose to hypertriglyceridemia in combination with other genetic factors or pathological conditions.The absence of manifestations until middle age, suggest that the cause of type V hyperlipoproteinemia(HLP) is multifactorial including a combination of environmental, hormonal and genetic factors. In patients with type V HLP, the presence of underlying diseases or contributing factors such as Diabetes and alcohol abuse is confirm in ~67% of patients and the remaining patients usually show type IV HLP and have hypertriglyceridemia in the family.Transiently impaired LPL activity with no defect in LPL enzyme induced severe hypertriglyceridemia in infants. The transient occurrence of inhibitor(s) for LPL was proposed.
Genetics
Precise genetic patterns have not been determined for type V HLP and it has been suggested that type V may be due to number of genetic defects. Among them, the apo E and its isoforms may have an important clinical significance in type V HLP and may affect the catabolism of triglyceride rich lipoproteins. The presence of apo E4 allele may be the genetic factor that predisposes to the development of type V due to delayed lipoprotein clearance.
Associated Conditions
- diabetes mellitus
- alcohol abuse
- glycogen storage disease type I
- Hyperuricemia
- Pancreatitis
- xanthomatosis.
Causes
Type V hyperlipoproteinemia is more complicated and more closely related to acquired environmental factors. It rarely shows familial occurrence, but its inheritance is variable. Therefore, type V HLP is usually considered to be triggered by acquired environmental factors in individuals with some congenital susceptibility to altered triglyceride metabolism (genetic factors). While the involved environmental factors vary, involvement of heavy drinking, type 2 Diabetes, hormonal therapy and medications are frequently observed.[1]
Causes by Pathophysiology
| Congenital (Genetic) Factors | Acquired (Environmental) Factors |
|---|---|
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Differentiating HLP type 5 from other Hyperlipoproteinemias
HLP type 5 must be differentiated from other diseases that cause abnormal increase in lipids in the blood.
- Familial hyperchylomicronemia
- Familial hypercholesterolemia/ Familial combined hyperlipidemia
- Dysbetalipoprotenemia
- Primary hypertriglyceridemia/ Primary hypertriglyceridemia
Epidemiology and Demographics
Prevalence/Incidence
It is difficult to accurately estimate the prevalence of HLP V in the general population, but a survey of about 40,000 people by the Lipid Research Clinic reported the frequency of individuals with a plasma TG level of 2,000 mg/dl or higher to be about 0.018%
Age
Average triglyceride levels in type V hyperlipoproteinemia are lower for women than for men before age 50
Gender
Race
n Western population, LPL gene abnormalities were observed in 10% of patients with type V HLP.
Risk Factors
- Family history of dyslipoproteinemia
- Diabetes
- Alcohol abuse
- Obesity
Screening
Natural History, Complications and Prognosis
Natural History
Mixed hyperlipidemia—a common disorder that becomes more prevalent with increasing age.A history of acute pancreatitis was observed in about 17% of the patients, demonstrating that hyperlipidemia is frequently complicated by pancreatitis also in Japanese, in whom the fat intake is lower than in Western people, and stressing the importance of its prevention and management.
Complications
Prognosis
The prognosis is uncertain due to the risk of Pancreatitis.Increased fat intake may cause recurrent bouts of illness possibly leading to pseudocyst formation,hemorrhage and death.
Diagnosis
Diagnostic Criteria
- I. Demonstration of an increase in VLDL in addition to hyperchylomicronemia.
- II. The absence of LPL deficiency, Apolipoprotein C-II deficiency, Apo E deficiency.
Definitely diagnosed if both I and II are fulfilled.
- Fasting chylomicronemia can be diagnosed by confirming the presence of chylomicrons and excess VLDL on agarose gel electrophoresis or ultracentrifugal analysis. A simple technique is to refrigerate plasma overnight and examine the specimen for a creamy supernatant from chylomicrons and a turbid VLDL-rich infranatant.This latter finding of a turbid infranatant is not seen in patients with type I hyperlipoproteinemia, in which only chylomicrons accumulate and the infranatant is clear.
History and Symptoms
- Recurrent abdominal pain
- Eruptive xanthomas
- Family history of Diabetes
Physical Examination
Laboratory Findings
Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
- Lipid lowering drugs
NOTE:Caution against possible exacerbation of glucose tolerance is necessary in the treatment of Diabetic patients with Nicotinic acid.
Surgery
Primary Prevention
Secondary Prevention
- Strict restriction of fat intake
- Elimination of acquired environmental factors
- Weight reduction
References
[2] [3] [4] [5] [6] [7] [8] [7] [9] [10] [[[11]]] [12]
- ↑ Diagnosis and Management of Type I and Type V Hyperlipoproteinemia Takanari Gotoda1), Koji Shirai2), Takao Ohta3), Junji Kobayashi4), Shinji Yokoyama5) 17), Shinichi Oikawa6), Hideaki Bujo7), Shun Ishibashi8), Hidenori Arai9), Shizuya Yamashita10), Mariko Harada-Shiba11), Masaaki Eto12), Toshio Hayashi13), Hirohito Sone14), Hiroaki Suzuki15), Nobuhiro Yamada
- ↑ Park JR, Jung TS, Jung JH, Lee GW, Kim MA, Park KJ et al. (2005) A case of hypothyroidism and type 2 diabetes associated with type V hyperlipoproteinemia and eruptive xanthomas. J Korean Med Sci 20 (3):502-5. DOI:10.3346/jkms.2005.20.3.502 PMID: 15953878
- ↑ Nagasaka H, Kikuta H, Chiba H, Murano T, Harashima H, Ohtake A et al. (2003) Two cases with transient lipoprotein lipase (LPL) activity impairment: evidence for the possible involvement of an LPL inhibitor. Eur J Pediatr 162 (3):132-8. DOI:10.1007/s00431-002-1133-3 PMID: 12655414
- ↑ Calandra S, Priore Oliva C, Tarugi P, Bertolini S (2006) APOA5 and triglyceride metabolism, lesson from human APOA5 deficiency. Curr Opin Lipidol 17 (2):122-7. DOI:10.1097/01.mol.0000217892.00618.54 PMID: 16531747
- ↑ Gotoda T, Shirai K, Ohta T, Kobayashi J, Yokoyama S, Oikawa S et al. (2012) Diagnosis and management of type I and type V hyperlipoproteinemia. J Atheroscler Thromb 19 (1):1-12. PMID: 22129523
- ↑ Marçais C, Verges B, Charrière S, Pruneta V, Merlin M, Billon S et al. (2005) Apoa5 Q139X truncation predisposes to late-onset hyperchylomicronemia due to lipoprotein lipase impairment. J Clin Invest 115 (10):2862-9. DOI:10.1172/JCI24471 PMID: 16200213
- ↑ 7.0 7.1 Ghiselli G, Schaefer EJ, Zech LA, Gregg RE, Brewer HB (1982) Increased prevalence of apolipoprotein E4 in type V hyperlipoproteinemia. J Clin Invest 70 (2):474-7. PMID: 7096573
- ↑ Dallongeville J (2000) Apolipoprotein E mutations, type V hyperlipoproteinaemia and diet. Br J Nutr 83 (6):573-4. PMID: 10911764
- ↑ Piolot A, Nadler F, Cavallero E, Coquard JL, Jacotot B (1996) Prevention of recurrent acute pancreatitis in patients with severe hypertriglyceridemia: value of regular plasmapheresis. Pancreas 13 (1):96-9. PMID: 8783340
- ↑ Titanji R, Paz-Guevara A (1992) Hypertriglyceridemia: severe type V hyperlipidemia in a young woman. Md Med J 41 (3):231-3. PMID: 1602929
- ↑ Stuyt PM, Stalenhoef AF, Demacker PN, van't Laar A (1982) Hyperlipoproteinemia type V and apolipoprotein E4. Lancet 2 (8304):934. PMID: 6126778
- ↑ Fallat RW, Glueck CJ (1976) Familial and acquired type V hyperlipoproteinemia. Atherosclerosis 23 (1):41-62. PMID: 1078394