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Hyperlipoproteinemia Type 1

Hyperlipoproteinemia Frederickson Type I

Hyperlipoproteinemia type 1 is a rare genetic disorder characterized by dysfunction of lipoprotein lipase or determined apolipoproteins. Patients suffering from this disease present with recurrent abdominal pain due to pancreatitis, hepatosplenomegaly as well as eruptive cutaneous xanthomas. Blood sample analysis in these patients reveal severe hypertriglyceridemia.

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Presentation

HLP1 is a genetic disorder and symptom onset occurs early in life. About 25% of affected individuals manifest first symptoms within their first year of life and the vast majority of patients seek medical attention before reaching the age of ten [5]. Recurrent episodes of abdominal pain are the most frequent cause of consultation; its severity may vary from mild to incapacitating. Since abdominal pain originates from an inflamed pancreas, it is generally localized to the mid-epigastric area. However, radiation of pain to adjacent regions may also be reported. Physical examination may further reveal hepatosplenomegaly. Patients may show multiple eruptive xanthomata that indicate disturbances of lipid metabolism and severe hyperlipidemia. These cutaneous lesions may be restricted to determined parts of the body, wherein arms, trunk, and buttocks are most commonly affected. These cutaneous lesions may also develop in a more generalized manner. If an ophthalmological examination is carried out, lipemia retinalis may be detected. Retinal vessels appear to be cream-colored in case of extreme hyperlipidemia [10]. Neuropsychiatric disorders have been related to HLP1 and may possibly be explained by functional impairment of brain LPL [11]. In this context, dementia may be expected in HLP1 patients.

Coronary Artery Disease
  • Clinical manifestations may vary but often include markedly premature coronary artery disease, supravalvular aortic stenosis due to aortic root atheroma, and cutaneous manifestations such as tendon xanthomata. Although ...[centerwatch.com]
  • Scandinavian Simvastatin Survival Study Group: Randomized trial of cholesterol lowering therapy in 4444 patients with coronary artery disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994, 344: 1383-1389.[lipidambulanz.charite.de]
  • Pre beta 1-high-density lipoprotein increases in coronary artery disease. Clin Chem 1996; 42:1992. PubMed Google Scholar 40. Miida T, Kawano M, Fielding CJ, Fielding PE.[link.springer.com]
  • The clinical importance in the present homozygous patient was to foresee a very early development of severe coronary artery disease, and myocardial infarction which can occur in the first and second decades of life. References 1.[ijdvl.com]
  • Urgent action Patients with documented, stable coronary artery disease and/or diabetes mellitus should have their lipid levels measured and be started on appropriate lipid management, including lifestyle modifications.[marionwellness.com]
Abdominal Pain
  • Type 1 hyperlipoproteinemia is an autosomal recessive disorder characterized by severely elevated plasma triglyceride levels, which may lead to abdominal pain and pancreatitis, eruptive xanthomas and failure to thrive.[ncbi.nlm.nih.gov]
  • Recurrent episodes of abdominal pain are the most frequent cause of consultation; its severity may vary from mild to incapacitating. Since abdominal pain originates from an inflamed pancreas, it is generally localized to the mid-epigastric area.[symptoma.com]
  • Last updated July 9, 2017 The signs and symptoms associated with Familial Lipoprotein Lipase Deficiency include recurrent attacks of pancreatitis resulting in abdominal pain, nausea, vomiting, and loss of appetite.[dovemed.com]
  • […] adults Pathology deficiency in lipoprotein lipase , or deficiency in apolipoprotein C2 increased plasma chylomicrons Genetics recessve form associated with defect in lipoprotein lipase associated with defects in USF1 Clinical-manifestations recurrent abdominal[anvita.info]
  • This condition is characterized by inflammation of the pancreas (pancreatitis), abdominal pain, enlargement of the liver and spleen (hepatosplenomegaly), and small yellow skin lesions called eruptive xanthomas.[diseaseinfosearch.org]
Vomiting
  • Last updated July 9, 2017 The signs and symptoms associated with Familial Lipoprotein Lipase Deficiency include recurrent attacks of pancreatitis resulting in abdominal pain, nausea, vomiting, and loss of appetite.[dovemed.com]
  • Because of sustained high TG levels, patients with FCS are also at risk of a painful condition called pancreatitis , which is inflammation of the pancreas Patients may also experience vomiting and diarrhea.[fcsfocus.com]
  • She had experienced similar episodes of abdominal pain and vomiting 6 wk before presentation, all of which resolved without any intervention. Otherwise, she was healthy before that. Physical examination revealed a thin (weight, 20 kg; 2 .[academic.oup.com]
  • Recurrent episodes of ill-defined abdominal pain that may be accompanied by nausea and vomiting are the most common presenting symptom, but chest pain and dyspnea may sometimes occur.[emedicine.medscape.com]
Recurrent Abdominal Pain
  • abdominal pain hepatosplenomegaly eruptive xanthomas lipemia retinalis acute pancreatitis peritonitis manifests in childhood Laboratory examination of the specimen for a creamy layer (evidence of chylomicrons ) fasting lipid panel - increased triglycerides[anvita.info]
  • Patients suffering from this disease present with recurrent abdominal pain due to pancreatitis, hepatosplenomegaly as well as eruptive cutaneous xanthomas. Blood sample analysis in these patients reveal severe hypertriglyceridemia.[symptoma.com]
  • In kindred A, an 11-year-old boy had triglyceride levels as high as 1,100 mg/100 ml and recurrent abdominal pain. His father had type V hyperlipoproteinemia; his mother was normal.[pediatrics.aappublications.org]
  • abdominal pain and/or pancreatitis and a family history of high plasma triglyceride levels ( Brunzell 1993 ).[pancreasfoundation.org]
Nausea
  • Last updated July 9, 2017 The signs and symptoms associated with Familial Lipoprotein Lipase Deficiency include recurrent attacks of pancreatitis resulting in abdominal pain, nausea, vomiting, and loss of appetite.[dovemed.com]
  • Symptoms While severe abdominal pain is the most common symptom of FCS, the symptoms of FCS can be clinical, emotional and cognitive and may include (Brahm and Hegele, 2015; Davidson et al. 2017): abdominal pain (daily low-level to debilitating) nausea[pancreasfoundation.org]
  • Recurrent episodes of ill-defined abdominal pain that may be accompanied by nausea and vomiting are the most common presenting symptom, but chest pain and dyspnea may sometimes occur.[emedicine.medscape.com]
Severe Abdominal Pain
  • Symptoms While severe abdominal pain is the most common symptom of FCS, the symptoms of FCS can be clinical, emotional and cognitive and may include (Brahm and Hegele, 2015; Davidson et al. 2017): abdominal pain (daily low-level to debilitating) nausea[pancreasfoundation.org]
Hepatosplenomegaly
  • Hypertriglyceridemia is the hallmark of HLP1; it is also the cause of acute pancreatitis and hepatosplenomegaly.[symptoma.com]
  • […] deficiency in lipoprotein lipase , or deficiency in apolipoprotein C2 increased plasma chylomicrons Genetics recessve form associated with defect in lipoprotein lipase associated with defects in USF1 Clinical-manifestations recurrent abdominal pain hepatosplenomegaly[anvita.info]
  • This condition is characterized by inflammation of the pancreas (pancreatitis), abdominal pain, enlargement of the liver and spleen (hepatosplenomegaly), and small yellow skin lesions called eruptive xanthomas.[diseaseinfosearch.org]
  • The disease is characterized by atherosclerosis , hepatosplenomegaly, polyneuropathy and orange tonsils. *phew* That's all![medicowesome.com]
  • […] fatigue impaired memory difficulty concentrating and problem solving “brain fog” anxiety/fear/worry about health eruptive xanthomas (pink bumps that appear on your body, arms and legs) lipaemia retinalis (milky appearance of blood vessels in the eye) hepatosplenomegaly[pancreasfoundation.org]
Jaundice
  • We report a unique 10-year-old male of Indian origin who presented in neonatal period with transient obstructive jaundice and xanthomas in the pancreas and kidneys.[ncbi.nlm.nih.gov]
Xanthoma
  • We report a unique 10-year-old male of Indian origin who presented in neonatal period with transient obstructive jaundice and xanthomas in the pancreas and kidneys.[ncbi.nlm.nih.gov]
  • "Eruptive xanthomas associated with olanzapine use". Arch Dermatol. vol. 139. 2003. pp. 1045-1048. (Three cases of eruptive xanthomas associated with the use of an atypical antipsychotic drug.[dermatologyadvisor.com]
  • Many type III subjects have cutaneous xanthomas, particularly tuberoeruptive or tuberous xanthomas and xanthomas of the palmar creases (xanthoma striata palmaris); the latter have not been identified in any other disorder.[ommbid.mhmedical.com]
  • Type 1 hyperlipoproteinemia is an autosomal recessive disorder characterized by severely elevated plasma triglyceride levels, which may lead to abdominal pain and pancreatitis, eruptive xanthomas and failure to thrive.[ncbi.nlm.nih.gov]
  • Eruptive xanthomas and hepatomegaly are common phenotypical manifestations. Milk intolerance in childhood is often reported.[medical-genetics.de]
Koebner Phenomenon
  • Eruptive xanthoma can demonstrate the Koebner phenomenon arising in areas of trauma to the skin. (Courtesy of the Betty E.[dermatologyadvisor.com]
Lipemia Retinalis
  • Type I hyperlipoproteinemia (T1HLP) usually presents with extreme hypertriglyceridemia, recurrent episodes of acute pancreatitis, lipemia retinalis, and cutaneous eruptive xanthomas.[ncbi.nlm.nih.gov]
  • If an ophthalmological examination is carried out, lipemia retinalis may be detected. Retinal vessels appear to be cream-colored in case of extreme hyperlipidemia.[symptoma.com]
  • retinalis acute pancreatitis peritonitis manifests in childhood Laboratory examination of the specimen for a creamy layer (evidence of chylomicrons ) fasting lipid panel - increased triglycerides ( chylomicrons ) serum amylase may be falsely normal due[anvita.info]
  • C: Lipemia retinalis. A milky appearance of the retinal vessels and pink retina can be seen when plasma triglyceride concentration exceeds 35 mmol/L.[cmaj.ca]
  • These patients develop eruptive xanthomas, lipemia retinalis, and pancreatitis. Their serum triglycerides are greatly elevated.[dermatologyadvisor.com]
Back Pain
  • Patients often have severe, sometimes daily, stomach pain and often experience back pain.[fcsfocus.com]
  • Case Reports A 9-yr-old African-American female presented with abdominal and back pain and emesis for 1 d before admission.[academic.oup.com]

Workup

Blood samples taken from HLP1 patients are frequently cloudy, exhibiting a milky haze. Suspicion of hyperlipidemia is confirmed by biochemical analysis, with triglyceride levels being a sensitive but non-specific indicator of HLP1. Due to physiological postprandial increases of triglyceride concentrations, blood samples should be obtained on an empty stomach. The reference range for triglycerides is up to 200 mg/dl. In HLP1 patients, physiological values may be exceeded by more than tenfold. As a rule of thumb, both eruptive xanthoma and lipemia retinalis are indicative of serum triglyceride levels above 1500 mg/dl [5] [10]. If such symptoms are presented by a pediatric patient, primary dyslipidemias should seriously be taken into account. To this end, it is important to acquire a detailed family history and to carry out a target-oriented approach to HLP1 diagnosis:

  • Lipoprotein electrophoresis to confirm chylomicrons to account for hypertriglyceridemia.
  • Measurement of LPL activity in plasma.
  • Assessment of purified LPL activation in the patient's plasma in order to distinguish LPL alterations from ApoC-II deficiencies and other less prevalent forms of HLP1.

Detection of gene defects associated with HLP1 are diagnostic of the disease, but such analyses are not generally feasible. Also, minor shares of HLP1 cases cannot be ascribed to a known gene defect despite extensive genetic screens. Nevertheless, the identification of the precise mutation is a requirement for family analysis, genetic counselling, and prenatal testing.

Hypertriglyceridemia
  • Hypertriglyceridemia is the hallmark of HLP1; it is also the cause of acute pancreatitis and hepatosplenomegaly.[symptoma.com]
  • Type I hyperlipoproteinemia (T1HLP) usually presents with extreme hypertriglyceridemia, recurrent episodes of acute pancreatitis, lipemia retinalis, and cutaneous eruptive xanthomas.[ncbi.nlm.nih.gov]
  • Loss of function GCKR variants, by enhancing glucose uptake in hepatocytes, may induce de novo lipogenesis and TG biosynthesis, resulting in extreme hypertriglyceridemia.[ncbi.nlm.nih.gov]
  • Patients with Type I Hyperlipoproteinemia (T1HLP) have a rare form of hypertriglyceridemia marked by significant chylomicronemia and recurrent episodes of acute pancreatitis.[clinicaltrials.gov]
  • Prior to a therapy of hypertriglyceridemia with fibrates which acts via transcriptional activation of LPL gene expression, it is advisable to check if a functional LPL allele is present.[medical-genetics.de]
Chylomicrons Increased
  • Type I hyperlipoproteinemia Chylomicrons increased in childhood. VLDL increased later in life. Lab findings: Increase in serum triglycerides. Why? CPL (Capillary lipprotein lipase) hydrolyzes triglycerides in lipoproteins.[medicowesome.com]

Treatment

Serum triglyceride levels should be lowered as far as possible. In general, concentrations below 1000 mg/dl should be aimed at, and significant reductions of morbidity and mortality can be expected below 2000 mg/dl [5]. Reduction of dietary fat is the mainstay of treatment. HLP1 patients should be advised not to consume more than 20 g of lipids per day, and ideally, dietary fat mainly consists of medium-chain triglycerides [12]. If dietary adjustments are insufficient to reduce serum triglyceride concentrations, alternative treatment options have to be considered.

In 2012, alipogene tiparvovec has been approved for HLP1 therapy, although evidence of its long-term efficacy is still lacking. Still, delivery of the LPL gene variant LPLS447X in a vector derived from adeno-associated virus serotype 1 has been shown to augment LPL activity and this can decrease serum triglyceride concentrations and the frequency of pancreatitis episodes [13].

Parenteral nutrition is only a short-term solution in reducing hypertryglyceridemia in acute settings, but it does prevent chylomicron formation. Of note, pancreatitis should be treated according to standard procedures. Hepatosplenomegaly generally resolves spontaneously as soon as serum triglyceride levels are reduced.

Prognosis

HLP1 may cause recurrent acute pancreatitis and eventually chronic pancreatitis. About 5% of patients diagnosed with hypertriglyceridemic acute pancreatitis die from this complication [2]. Development of steatorrhea or diabetes mellitus secondary to pancreatitis is rare.

Furthermore, HPL1 patients are at extremely high risk of developing life-threatening cardiovascular diseases associated with chronic hypertriglyceridemia, e.g., atherosclerosis, coronary heart disease, peripheral vascular disease, and stroke. It has been estimated that hypertriglyceridemia increases the individual risk of coronary heart disease by 30% in men and 75% in women [9]. Since being overweight,obesity and diabetes mellitus type 2 are risk factors for cardiovascular disorders, controlling these risk factors comprise both an adequate therapy for HPL1 and a preventive strategy for disease-related complications. Compliance with diet recommendations and regular exercise may largely contribute to an improved outcome.

Etiology

The hallmark of HLP1 is hypertriglyceridemia, and triglycerides accumulate in affected individuals due to an ineffective breakdown of chylomicrons. The single most important enzyme for this process is LPL, and it is encoded by a gene located on the short arm of chromosome 8. It is mainly expressed by endothelial cells of capillaries. Mutations of this gene may alter the enzyme's functionality, resulting in severely reduced or absent LPL activity. LPL mutations are the most common cause of HLP1.

LPL depends on ApoC-II as a cofactor. Thus, mutations of the gene encoding for ApoC-II similarly interfere with lipid metabolism and lead to hypertriglyceridemia. It is located on the long arm of chromosome 19.

Besides LPL and ApoC-II mutations, other gene defects have recently been related to HLP1, e.g., mutations of genes encoding for apolipoprotein A-V (ApoA-V), lipase maturation factor 1 (LMF1), glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GP1HBP1) and glucokinase regulator (GCKR) [4]. ApoA-V facilitates LPL-mediated hydrolysis of triglycerides, LMF1 is required for folding and assembly of LPL, GP1HBP1 is expressed by endothelial cells and binds LPL, and GCKR induces hepatic lipogenesis.

Still, some cases of HLP1 cannot be ascribed to either of those gene defects and presumably result from as-of-yet unknown mutations.

Of note, all known forms of HLP1 are inherited with an autosomal recessive trait. Although heterozygous carriers do not develop HLP1, they may manifest with mild dyslipidemia.

Epidemiology

Although hyperlipoproteinemia is a common condition, few cases correspond to HLP1. In most parts of the world, prevalence of HLP1 is about 1 in 1,000,000 persons [5]. Interestingly, the disease has been reported to affect 1 in 6,000 inhabitants in a geographically isolated region of Quebec, Canada, with about 2% of the population being carriers of LPL mutations [6]. Most likely, this is due to a founder effect. Similarly increased prevalence rates are to be expected in ethnic groups of higher consanguinity.

Despite known racial and gender differences in lipid metabolism [7] [8]., predilection of the corresponding groups of patients has not been described for HLP1.

Sex distribution
Age distribution

Pathophysiology

After digestion of dietary fat, fatty acids, monoglycerides, and diglycerides are absorbed by the mucous membrane of the small intestine. Here, they serve as substrates for triglyceride biosynthesis, and these lipids are eventually combined with cholesterol and apolipoproteins B-48, A-I, A-II and A-IV to form chylomicrons. Chylomicrons are then released into lymphatic vessels, are transported within those vessels up to the thoracic duct and finally reach the cardiovascular system. In a maturation process, the composition of chylomicrons changes. They release determined apolipoproteins and bind others. ApoC-II is among those new constituents of chylomicrons, and it is required for triglyceride breakdown upon delivery of lipids to end organs like the heart, muscles and adipose tissue. Endothelial cells lining the capillaries of those organs express LPL and are thus able to digest the arriving nutrients and to use them for energy supply.

In HLP1 patients, the previously mentioned chain of events is interrupted at the point of delivery to end organs. Due to functional deficits in ApoC-II or LPL, chylomicrons cannot be metabolized. On the one hand, this condition causes an abnormal accumulation of chylomicron constituents in the patient's circulation; on the other hand, cardiac, muscular and adipose tissues are deprived of their main energy supply. In the long term, the former poses a much higher risk since it predisposes for life-threatening cardiovascular disease.

Prevention

HLP1 is a genetic disorder and corresponding gene defects are inherited in an autosomal recessive manner. If the precise mutation underlying an individual case of HLP1 is known, family members at risk may be tested to identify carriers. Moreover, genetic counselling and prenatal screens may be offered to affected families if patients wish to procreate.

Summary

Hyperlipoproteinemia type 1 (HLP1) is a rare metabolic disease triggered by diverse gene defects. The disease may also be referred to as familial lipoprotein lipase (LPL) deficiency or hyperchylomicronemia syndrome, and those terms comprise both the cause and the main symptom of the disease. HLP1 patients show reduced LPL activity, either due to mutations of the gene encoding for that enzyme or because of functional deficiencies of cofactors and associated molecules [1]., and because LPL is responsible for the breakdown of chylomicrons, these substances accumulate in the patient's circulation. Chylomicrons are mainly composed of triglycerides and lipoproteins, which explains the designation HLP1.

Hypertriglyceridemia is the hallmark of HLP1; it is also the cause of acute pancreatitis and hepatosplenomegaly. Pancreatitis accounts for acute mortality rates of approximately 5% [2]., but considerable morbidity and mortality is also associated with long-term sequelae of this lipid disorder. HLP1 patients are at high risk of disabling and life-threatening cardiovascular diseases. In order to prevent conditions like coronary heart disease and stroke, a multidisciplinary approach is required. Accordingly, treatment consists in lowering serum levels of triglycerides by means of dietary adjustments, and in educating about additional risk factors that complicate hyperlipidemia [3].

Patient Information

Hyperlipoproteinemia type 1 (HLP1) is a rare metabolic disease associated with severely increased levels of serum lipids. Large parts of serum lipids originate from dietary fats. Consumed fat is digested in the gastrointestinal tract, metabolites are absorbed by the small intestine and are converted to lipid-rich molecules called chylomicrons. Chylomicrons are subsequently released into the circulation. Chylomicrons constitute assemblies of lipoproteins and lipids that are "ready to dispatch". Their recipients are endothelial cells lining the capillaries of heart, muscle and adipose tissue. These cells dispose of an enzyme, namely lipoprotein lipase (LPL), that allows for the degradation of chylomicrons and the utilization of lipids as a source of energy. However, lipoprotein lipase activity is significantly reduced or even undetectable in HLP1 patients. Thus, chylomicrons cannot be degraded and instead it accumulates in the patient's blood.

Symptom onset often occurs during the first year of life, and in the vast majority of HLP1 patients, takes place before they reach ten years old. Because the main component of chylomicrons are triglycerides, HLP1 patients are initially diagnosed with hypertriglyceridemia. This condition may trigger episodes of abdominal pain and pancreatitis as well as cutaneous lesions referred to as eruptive xanthomas. Moreover, in the long-term, HLP1 and hypertriglyceridemia may have detrimental consequences for the cardiovascular system. HLP1 patients are at high risks of atherosclerosis, coronary heart disease, peripheral vascular disease, and stroke. In order to relieve both acute and chronic symptoms caused by high serum concentrations of lipids, dietary adjustments are recommended. Patients are advised to restrict their daily fat intake and to preferentially use fat consisting of medium-chain fatty acids. In most cases, such measures combined with an overall healthy lifestyle may contribute to decrease trigylceride levels in the blood.

References

Article

  1. Hooper AJ, Crawford GM, Brisbane JM, et al. Familial lipoprotein lipase deficiency caused by known (G188E) and novel (W394X) LPL gene mutations. Ann Clin Biochem. 2008; 45(Pt 1):102-105.
  2. Gubensek J, Buturovic-Ponikvar J, Romozi K, et al. Factors affecting outcome in acute hypertriglyceridemic pancreatitis treated with plasma exchange: an observational cohort study. PLoS One. 2014; 9(7):e102748.
  3. Leaf DA. Chylomicronemia and the chylomicronemia syndrome: a practical approach to management. Am J Med. 2008; 121(1):10-12.
  4. Shetty S, Xing C, Garg A. Type 1 Hyperlipoproteinemia due to Compound Heterozygous Rare Variants in GCKR. J Clin Endocrinol Metab. 2016;jc20162179.
  5. Brunzell JD. Familial Lipoprotein Lipase Deficiency. GeneReviews(R). Seattle,WA: University of Washington, Seattle;2014.
  6. Dionne C, Gagne C, Julien P, et al. Genetic epidemiology of lipoprotein lipase deficiency in Saguenay-Lac-St-Jean (Quebec, Canada). Ann Genet. 1992; 35(2):89-92.
  7. Sumner AE, Cowie CC. Ethnic differences in the ability of triglyceride levels to identify insulin resistance. Atherosclerosis. 2008; 196(2):696-703.
  8. Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011; 123(20):2292-2333.
  9. Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk. 1996; 3(2):213-219.
  10. Rymarz E, Matysik-Wozniak A, Baltaziak L,et al. Lipemia retinalis - an unusual cause of visual acuity deterioration. Med Sci Monit. 2012; 18(8):Cs72-75.
  11. Paradis E, Clement S, Julien P, et al. Lipoprotein lipase affects the survival and differentiation of neural cells exposed to very low density lipoprotein. J Biol Chem. 2003; 278(11):9698-9705.
  12. Rouis M, Dugi KA, Previato L, et al. Therapeutic response to medium-chain triglycerides and omega-3 fatty acids in a patient with the familial chylomicronemia syndrome. Arterioscler Thromb Vasc Biol. 1997; 17(7):1400-1406.
  13. Haddley K. Alipogene tiparvovec for the treatment of lipoprotein lipase deficiency. Drugs Today (Barc). 2013; 49(3):161-170.

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Last updated: 2018-06-21 20:17