Familial combined hyperlipidemia in a North Indian kindred
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《美国医学杂志》
1 Department of Pediatrics,All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
2 Department of Cardiology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
Abstract
Familial combined hyperlipidemia is the most common genetic hyperlipidemia and is responsible for premature coronary artery disease. It is genetically heterogenous and no single diagnostic marker exists. The authors report an affected North Indian kindred spanning three successive generations with a possible autosomal dominant pattern of inheritance and all of them had combined dyslipidemia [elevated total cholesterol, predominantly the low density lipoprotein (LDL) fraction and elevated triglycerides]. The proband, a 4-month-old male baby, was incidentally discovered to have a lipaemic serum and so further evaluated. Both the index case and his maternal grandmother, a non-obese diabetic (type 2) with hypertension, had an atherogenic lipoprotein phenotype. Lipaemia retinalis was documented in this baby but xanthomas and coronary artery disease were not noted in the kindred. The present case report highlights the failure of dietary therapy in the proband and explores new options
Keywords: Familial combined hyperlipidemia; Hypercholesterolemia; Hypertriglyceridemia
Familial combined hyperlipidemia (FCHL) has a prevalence of 1-2% in the general population and is a definite risk factor for premature cardiovascular morbidity.[1],[2],[3] No specific diagnostic marker exists.[4] In the report is presented a North Indian kindred with FCHL. The affected members were from three successive generations. The index case was a 4-month-old male baby with very high triglyceride values and lipaemia retinalis but did not manifest any serious complications of the disease.
Case Report
A-four-month old male baby was admitted to the tertiary care hospital with complaints of fever, fast breathing and chest retractions for two days. The antenatal and birth history was unremarkable and his early development was normal. No parental consanguinity was present. He was exclusively breast-fed till then and weighed 4.4 kg (approximately 66 percent of the NCHS reference median weight for his age group). His head circumference was 41 cm (approximately 50th percentile of the appropriate NCHS reference standards). The physical examination revealed no abnormalities other than those pertaining to the respiratory system. The patient was treated for pneumonia and improved well. Incidentally, the serum sample obtained for blood counts was discovered to be lipaemic and the case was subsequently investigated for dyslipidemia.
On evaluation, the serum cholesterol was reported by the laboratory to be over 400 mg/dl. A fasting lipid profile was then performed and the results were: total cholesterol (TC) was 677 mg/dl (95th percentile value for the reference age group being 203 mg/dl) and a triglyceride (TG) value of 10, 400 mg/dl (95th percentile cut off being 99 mg/dl). The lipid electrophoresis done at the same time was consistent with the above- LDL cholesterol value of 447.3 mg/dl (95th percentile reported as 126 mg/dl), high density lipoprotein (HDL) cholesterol was 30 mg/dl (5th percentile valve being 39 mg/dl) and very low density lipoprotein (VLDL) cholesterol was 199.6 mg/dl (which was also elevated). The apolipoprotein B (Apo-B) level was increased (450 mg/dl, normal reference range was between 63 and 114 mg/dl) while the apolipoprotein A-1 (Apo-A-1) value was normal (131.0 mg/dl, normal reference range was 110 to 176 mg/dl). Thus the patient had a combined hyperlipidemia with elevated TC and TG levels. No secondary cause for dyslipidemia was found, the blood sugar profile, liver, renal and thyroid function tests being normal. Edema, hypoalbuminemia or albuminuria were not present. The proband and the immediate family members were screened for xanthomas but none could be documented. A fundus examination of the index case revealed lipaemia retinalis but that of his parents and siblings was normal. Hyperamylasemia was not found in the patient and no history suggestive of pancreatitis was given by any of the other family members. The CT scan of the patient's abdomen was within normal limits.
The detailed work-up done further was suggestive of familial combined hyperlipidemia (FCHL) with a possible autosomal dominant pattern of inheritance. The lipid profile of his elder sister, mother and maternal uncle showed a pattern of combined hyperlipidemia with elevated TC, TG and LDL cholesterol values (albeit not to the same extent as the proband) alongside a HDL cholesterol value near the lower limit of normal table1. No cause for secondary hyperlipidemia was noted in them and they were not found to be obese on examination. The father's evaluation revealed no abnormalities in the lipid profile. Another interesting fact was that the maternal grandmother (who weighed 55 kg at 48 years of age) was under treatment for non-insulin dependent diabetes mellitus (NIDDM) for the last 10 years and suffered from the complication of peripheral neuropathy. She was also hypertensive. A family history of premature coronary heart disease was not forthcoming either from the grandmother or her children. Her lipid profile was similar to the rest of the affected kindred i.e., hypercholesterolemia with moderately elevated LDL cholesterol levels and hypertriglyceridemia (a value of 3039 mg/dl) with a low HDL cholesterol (of 28.5 mg./dl, 5th percentile of age matched normal reference value being 35 mg/dl) in the absence any xanthomas. She was already on dietary fat restriction and hypocholesterolemic drugs (Simvastatin) by that time.
The patient's mother and sister were advised dietary therapy while the baby was weaned on a diet providing normal calorie requirements for his age but with a lowered fat content (not more than 30% of total calories from fat, as any further reduction would compromise growth). Regular follow-up done subsequently revealed a growth and weight pattern consistent with his age (between 25 and 50th percentile as per NCHS standards) but the dietary therapy had no significant effect on his lipid profile. He was otherwise asymptomatic. At eighteen months of age the child weighed 10.9 kg and had a TC valve of 458 mg/dl, TG of 6162 mg/dl while HDL cholesterol was still low (13.3 mg/dl). Additional therapeutic possibilities at this stage and a review of the clinical condition is considered further.
Discussion
Familial combined hyperlipidemia (FCHL) is the most common genetic hyperlipidemia (prevalence of 1 to 2% in the general population) and is responsible for 10-20% of premature coronary artery disease (CAD).[1],[2],[3] The characteristic dyslipidemic combination of small, dense LDL particles, decreased plasma HDL cholesterol (especially HDL 2) and apo A-I with increased plasma TG and apo B levels represents the atherogenic lipoprotein phenotype (ALP) which is associated with an increased risk for CAD.[2],[5] The proband indeed had such a phenotype (elevated TG and apo B with low HDL cholesterol, though the apo A-I levels were normal). The constellation of features that delineate the metabolic syndrome X, such as central obesity, insulin resistance, hypertension, coagulopathy and atherogenic lipoprotein phenotype are also present in patients with type 2 diabetes mellitius and FCHL.[5] With reference to the clinical context, it is noteworthy that the maternal grandmother who was dyslipidemic also had hypertension and NIDDM with a suggestive lipid phenotype but she was not obese.
The genetic defect and detailed pathophysiology have still not been fully elucidated. Most probably, FCHL cohorts have been classified by using the 95th percentile as cut point and it has followed suit.[4] The affected kindred spanned three successive generations, all of whom had combined hyperlipidemia consistent with an autosomal dominant pattern of inheritance described in literature.[1] A few patients may have xanthomas though none was documented in the kindred.[6] The lipaemia retinalis documented in the present case has been described in the literature in a neonate with hypertriglycerdemia and hyperchylomicronaemia.[7]
After secondary causes of hyperlipidemia are ruled out, the first line of medical management in any child with a TC > 4.39 mmol/l (>170 mg/dl) or an LDL cholesterol > 2.84 mmol/l (>110 mg/dl) is dietary modification and weight control.[1] The guidelines are based on National Cholesterol Education Programme (NCEP) recommendations which state that all healthy children above 2 years of age adopt eating patterns that meet nutritional needs.[8] The borderline risk category (with TC of 4.4-5.1 mmol/dl or 170-197 mg/dl and LDL cholesterol of 2.8-3.3 mmol/l or 108-128 mg/dl) is treated with a step one diet - that is no more than 30% of calories from fat, with < 10% from saturated fat, and cholesterol intake < 300 mg/dl or 100 mg/1000 calories, whichever is lower. High risk children (with TC > 5.2 mmol/l or 201 mg/dl and LDL-cholesterol > 3.4 mmol/l or 132 mg/dl) are treated with either a step one or, if necessary a step two diet - that is calories from saturated fat < 7% and cholesterol intake < 200 mg/day.[1], [5] Keeping in mind the very young age of the patient (4 months) his caloric intake from fats to less than 30% without significant emphasis on saturated fat intake was restricted. A very strict dietary adherence was impossible in this situation and would have compromised his growth. After an adequate trial of atleast 6 to 12 months of dietary modification, if the LDL cholesterol remains 3 4.9 mmol/1 or 3 4.15 mmol/L (plus a family history of premature CAD or the presence of two or more additional risk factors) pharmacotherapy with anion exchange resins like cholestyramine should be considered in patients over 10 yrs of age.[8], [9] Dietary therapy was clearly unsuccessful in this case but treatment options were limited. An alternative approach proposed by Ose and Tonstad uses risk stratification and permits the use of either an anion exchange resin or a statin in children who do not adequately respond to dietary modifications.[10]
Children with familial hyperlipidemias often have very high lipid levels (as in the present case), and in the great majority dietary therapy alone is insufficient (again highlighted by this experience) while bile acid binding resins are associated with poor long term compliance.[8],[10] The latter when used alone often results in significant increases in plasma TG levels and this clearly summarizes the dilemma in using them here.[6] Though the use of HMG CO-A reductase inhibitors (statins) is controversial in children, short term safety and effectiveness have been documented. Low dose combination of a bile acid-binding resin and a statin may result in better lipid lowering though compliance is still a problem.[8]
FCHL is the most common genetic hyperlipidemia and contributes significantly to premature CAD.[1],[2],[3] It should be ruled out in any child with primary hyperlipidemia by performing family screening. No single diagnostic marker exists and the definition is based on fractile cut points for serum lipids (i.e. TC and TG).[4] The first line of medical management is dietary fat restriction, but this is often insufficient as highlighted by the author's experience. Anion exchange resins are to be considered in patients over 10 yrs who are unresponsive to dietary modification. The long term use of statins in children is a matter of intense debate but short term efficacy and safety have been demonstrated by some.[1],[9],[10],[11]
References
1. Cortner JA, Coates PM, Liacouras CA, Jarvik GP. Familial combined hyperlipidemia in children: Clinical expression, metabolic defects and management. J Pediatr 1993; 123: 177-184.
2. Allayee H, Dominguez KM, Aouizerat BE, Krauss RM, Rotter JL, Lu J, Cantor RM, de Bruin TWA, Lusis AJ. Contribution of the hepatic lipase gene to the atherogenic lipoprotein phenotype in familial combined hyperlipidemia. J Lipid Res 2000; 41: 245-252.
3. Xydakis AM, Ballantyne CM. Combination therapy for combined dyslipidemia. Am J Cardiol 2002; 90 (Suppl): 21K - 29K.
4. Porkka KVK, Nuotio I, Pajukanta P, Ehnholm C, Suurinkeroinen L, Syvanne M, Lehtimaki T, Lahdenkan A-T, Lahdenpera S, Ylitalo K, Antikainen M, Perola M, Raitakari OT, Kovanen P, Viikari JSA, Peltonen L, Taskinen MR. Phenotype expression in familial combined hyperlipidemia. Atherosclerosis 1997; 133: 245-253.
5. Ayyobi AF, Brunzell JD. Lipoprotein distribution in the metabolic syndrome, type 2 diabetes mellitus, and familial combined hyperlipidemia. Am J Cardiol 2003; 92(Suppl): 27J-33J.
6. John P Kane, Richard J Havel. Disorders of the biogenesis and secretion of lipoproteins containing the B apolipoproteins. In Charles R Scriver, Arthur L Beaudet et al, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th edn. New York; McGraw-Hill, 2001; 2717-2752.
7. Hayasaka S, Fukuyo T, Kitaoka M, Suzuki H, Omura K, Kondo Y, Nakagawa M. Lipaemia retinalis in a 29-day-old infant with type 1 hyperlipoproteinaemia. Br J Ophthalmol 1985; 69: 280-282.
8. McCrindle BW, Helden E, Cullen-Dean G, Conner WT. A randomized cross over trial of combination pharmacologic therapy in children with familial hyperlipidemia. Pediatr Res 2002; 51: 715-721.
9. Thompson GR. Lipid lowering in the young. Heart 1996; 76: 1-2.
10. Liacouras CA, Coates PM, Gallagher PR, Cortner JA. Use of cholestyramine in the treatment of children with familial combined hyperlipidemia. J Pediatr 1993; 122: 477-482.
11. Richard J Havel, John P Kane. Introduction: structure and metabolism of plasma lipoproteins. In Charles R Scriver, Arthur L Beaudet et al eds. The Metabolic and Molecular Bases of Inherited Disease. 8th edn. New York; McGraw-Hill, 2001; 2705-2716.(Sriram CS, Gulati Sheffal)
2 Department of Cardiology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
Abstract
Familial combined hyperlipidemia is the most common genetic hyperlipidemia and is responsible for premature coronary artery disease. It is genetically heterogenous and no single diagnostic marker exists. The authors report an affected North Indian kindred spanning three successive generations with a possible autosomal dominant pattern of inheritance and all of them had combined dyslipidemia [elevated total cholesterol, predominantly the low density lipoprotein (LDL) fraction and elevated triglycerides]. The proband, a 4-month-old male baby, was incidentally discovered to have a lipaemic serum and so further evaluated. Both the index case and his maternal grandmother, a non-obese diabetic (type 2) with hypertension, had an atherogenic lipoprotein phenotype. Lipaemia retinalis was documented in this baby but xanthomas and coronary artery disease were not noted in the kindred. The present case report highlights the failure of dietary therapy in the proband and explores new options
Keywords: Familial combined hyperlipidemia; Hypercholesterolemia; Hypertriglyceridemia
Familial combined hyperlipidemia (FCHL) has a prevalence of 1-2% in the general population and is a definite risk factor for premature cardiovascular morbidity.[1],[2],[3] No specific diagnostic marker exists.[4] In the report is presented a North Indian kindred with FCHL. The affected members were from three successive generations. The index case was a 4-month-old male baby with very high triglyceride values and lipaemia retinalis but did not manifest any serious complications of the disease.
Case Report
A-four-month old male baby was admitted to the tertiary care hospital with complaints of fever, fast breathing and chest retractions for two days. The antenatal and birth history was unremarkable and his early development was normal. No parental consanguinity was present. He was exclusively breast-fed till then and weighed 4.4 kg (approximately 66 percent of the NCHS reference median weight for his age group). His head circumference was 41 cm (approximately 50th percentile of the appropriate NCHS reference standards). The physical examination revealed no abnormalities other than those pertaining to the respiratory system. The patient was treated for pneumonia and improved well. Incidentally, the serum sample obtained for blood counts was discovered to be lipaemic and the case was subsequently investigated for dyslipidemia.
On evaluation, the serum cholesterol was reported by the laboratory to be over 400 mg/dl. A fasting lipid profile was then performed and the results were: total cholesterol (TC) was 677 mg/dl (95th percentile value for the reference age group being 203 mg/dl) and a triglyceride (TG) value of 10, 400 mg/dl (95th percentile cut off being 99 mg/dl). The lipid electrophoresis done at the same time was consistent with the above- LDL cholesterol value of 447.3 mg/dl (95th percentile reported as 126 mg/dl), high density lipoprotein (HDL) cholesterol was 30 mg/dl (5th percentile valve being 39 mg/dl) and very low density lipoprotein (VLDL) cholesterol was 199.6 mg/dl (which was also elevated). The apolipoprotein B (Apo-B) level was increased (450 mg/dl, normal reference range was between 63 and 114 mg/dl) while the apolipoprotein A-1 (Apo-A-1) value was normal (131.0 mg/dl, normal reference range was 110 to 176 mg/dl). Thus the patient had a combined hyperlipidemia with elevated TC and TG levels. No secondary cause for dyslipidemia was found, the blood sugar profile, liver, renal and thyroid function tests being normal. Edema, hypoalbuminemia or albuminuria were not present. The proband and the immediate family members were screened for xanthomas but none could be documented. A fundus examination of the index case revealed lipaemia retinalis but that of his parents and siblings was normal. Hyperamylasemia was not found in the patient and no history suggestive of pancreatitis was given by any of the other family members. The CT scan of the patient's abdomen was within normal limits.
The detailed work-up done further was suggestive of familial combined hyperlipidemia (FCHL) with a possible autosomal dominant pattern of inheritance. The lipid profile of his elder sister, mother and maternal uncle showed a pattern of combined hyperlipidemia with elevated TC, TG and LDL cholesterol values (albeit not to the same extent as the proband) alongside a HDL cholesterol value near the lower limit of normal table1. No cause for secondary hyperlipidemia was noted in them and they were not found to be obese on examination. The father's evaluation revealed no abnormalities in the lipid profile. Another interesting fact was that the maternal grandmother (who weighed 55 kg at 48 years of age) was under treatment for non-insulin dependent diabetes mellitus (NIDDM) for the last 10 years and suffered from the complication of peripheral neuropathy. She was also hypertensive. A family history of premature coronary heart disease was not forthcoming either from the grandmother or her children. Her lipid profile was similar to the rest of the affected kindred i.e., hypercholesterolemia with moderately elevated LDL cholesterol levels and hypertriglyceridemia (a value of 3039 mg/dl) with a low HDL cholesterol (of 28.5 mg./dl, 5th percentile of age matched normal reference value being 35 mg/dl) in the absence any xanthomas. She was already on dietary fat restriction and hypocholesterolemic drugs (Simvastatin) by that time.
The patient's mother and sister were advised dietary therapy while the baby was weaned on a diet providing normal calorie requirements for his age but with a lowered fat content (not more than 30% of total calories from fat, as any further reduction would compromise growth). Regular follow-up done subsequently revealed a growth and weight pattern consistent with his age (between 25 and 50th percentile as per NCHS standards) but the dietary therapy had no significant effect on his lipid profile. He was otherwise asymptomatic. At eighteen months of age the child weighed 10.9 kg and had a TC valve of 458 mg/dl, TG of 6162 mg/dl while HDL cholesterol was still low (13.3 mg/dl). Additional therapeutic possibilities at this stage and a review of the clinical condition is considered further.
Discussion
Familial combined hyperlipidemia (FCHL) is the most common genetic hyperlipidemia (prevalence of 1 to 2% in the general population) and is responsible for 10-20% of premature coronary artery disease (CAD).[1],[2],[3] The characteristic dyslipidemic combination of small, dense LDL particles, decreased plasma HDL cholesterol (especially HDL 2) and apo A-I with increased plasma TG and apo B levels represents the atherogenic lipoprotein phenotype (ALP) which is associated with an increased risk for CAD.[2],[5] The proband indeed had such a phenotype (elevated TG and apo B with low HDL cholesterol, though the apo A-I levels were normal). The constellation of features that delineate the metabolic syndrome X, such as central obesity, insulin resistance, hypertension, coagulopathy and atherogenic lipoprotein phenotype are also present in patients with type 2 diabetes mellitius and FCHL.[5] With reference to the clinical context, it is noteworthy that the maternal grandmother who was dyslipidemic also had hypertension and NIDDM with a suggestive lipid phenotype but she was not obese.
The genetic defect and detailed pathophysiology have still not been fully elucidated. Most probably, FCHL cohorts have been classified by using the 95th percentile as cut point and it has followed suit.[4] The affected kindred spanned three successive generations, all of whom had combined hyperlipidemia consistent with an autosomal dominant pattern of inheritance described in literature.[1] A few patients may have xanthomas though none was documented in the kindred.[6] The lipaemia retinalis documented in the present case has been described in the literature in a neonate with hypertriglycerdemia and hyperchylomicronaemia.[7]
After secondary causes of hyperlipidemia are ruled out, the first line of medical management in any child with a TC > 4.39 mmol/l (>170 mg/dl) or an LDL cholesterol > 2.84 mmol/l (>110 mg/dl) is dietary modification and weight control.[1] The guidelines are based on National Cholesterol Education Programme (NCEP) recommendations which state that all healthy children above 2 years of age adopt eating patterns that meet nutritional needs.[8] The borderline risk category (with TC of 4.4-5.1 mmol/dl or 170-197 mg/dl and LDL cholesterol of 2.8-3.3 mmol/l or 108-128 mg/dl) is treated with a step one diet - that is no more than 30% of calories from fat, with < 10% from saturated fat, and cholesterol intake < 300 mg/dl or 100 mg/1000 calories, whichever is lower. High risk children (with TC > 5.2 mmol/l or 201 mg/dl and LDL-cholesterol > 3.4 mmol/l or 132 mg/dl) are treated with either a step one or, if necessary a step two diet - that is calories from saturated fat < 7% and cholesterol intake < 200 mg/day.[1], [5] Keeping in mind the very young age of the patient (4 months) his caloric intake from fats to less than 30% without significant emphasis on saturated fat intake was restricted. A very strict dietary adherence was impossible in this situation and would have compromised his growth. After an adequate trial of atleast 6 to 12 months of dietary modification, if the LDL cholesterol remains 3 4.9 mmol/1 or 3 4.15 mmol/L (plus a family history of premature CAD or the presence of two or more additional risk factors) pharmacotherapy with anion exchange resins like cholestyramine should be considered in patients over 10 yrs of age.[8], [9] Dietary therapy was clearly unsuccessful in this case but treatment options were limited. An alternative approach proposed by Ose and Tonstad uses risk stratification and permits the use of either an anion exchange resin or a statin in children who do not adequately respond to dietary modifications.[10]
Children with familial hyperlipidemias often have very high lipid levels (as in the present case), and in the great majority dietary therapy alone is insufficient (again highlighted by this experience) while bile acid binding resins are associated with poor long term compliance.[8],[10] The latter when used alone often results in significant increases in plasma TG levels and this clearly summarizes the dilemma in using them here.[6] Though the use of HMG CO-A reductase inhibitors (statins) is controversial in children, short term safety and effectiveness have been documented. Low dose combination of a bile acid-binding resin and a statin may result in better lipid lowering though compliance is still a problem.[8]
FCHL is the most common genetic hyperlipidemia and contributes significantly to premature CAD.[1],[2],[3] It should be ruled out in any child with primary hyperlipidemia by performing family screening. No single diagnostic marker exists and the definition is based on fractile cut points for serum lipids (i.e. TC and TG).[4] The first line of medical management is dietary fat restriction, but this is often insufficient as highlighted by the author's experience. Anion exchange resins are to be considered in patients over 10 yrs who are unresponsive to dietary modification. The long term use of statins in children is a matter of intense debate but short term efficacy and safety have been demonstrated by some.[1],[9],[10],[11]
References
1. Cortner JA, Coates PM, Liacouras CA, Jarvik GP. Familial combined hyperlipidemia in children: Clinical expression, metabolic defects and management. J Pediatr 1993; 123: 177-184.
2. Allayee H, Dominguez KM, Aouizerat BE, Krauss RM, Rotter JL, Lu J, Cantor RM, de Bruin TWA, Lusis AJ. Contribution of the hepatic lipase gene to the atherogenic lipoprotein phenotype in familial combined hyperlipidemia. J Lipid Res 2000; 41: 245-252.
3. Xydakis AM, Ballantyne CM. Combination therapy for combined dyslipidemia. Am J Cardiol 2002; 90 (Suppl): 21K - 29K.
4. Porkka KVK, Nuotio I, Pajukanta P, Ehnholm C, Suurinkeroinen L, Syvanne M, Lehtimaki T, Lahdenkan A-T, Lahdenpera S, Ylitalo K, Antikainen M, Perola M, Raitakari OT, Kovanen P, Viikari JSA, Peltonen L, Taskinen MR. Phenotype expression in familial combined hyperlipidemia. Atherosclerosis 1997; 133: 245-253.
5. Ayyobi AF, Brunzell JD. Lipoprotein distribution in the metabolic syndrome, type 2 diabetes mellitus, and familial combined hyperlipidemia. Am J Cardiol 2003; 92(Suppl): 27J-33J.
6. John P Kane, Richard J Havel. Disorders of the biogenesis and secretion of lipoproteins containing the B apolipoproteins. In Charles R Scriver, Arthur L Beaudet et al, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th edn. New York; McGraw-Hill, 2001; 2717-2752.
7. Hayasaka S, Fukuyo T, Kitaoka M, Suzuki H, Omura K, Kondo Y, Nakagawa M. Lipaemia retinalis in a 29-day-old infant with type 1 hyperlipoproteinaemia. Br J Ophthalmol 1985; 69: 280-282.
8. McCrindle BW, Helden E, Cullen-Dean G, Conner WT. A randomized cross over trial of combination pharmacologic therapy in children with familial hyperlipidemia. Pediatr Res 2002; 51: 715-721.
9. Thompson GR. Lipid lowering in the young. Heart 1996; 76: 1-2.
10. Liacouras CA, Coates PM, Gallagher PR, Cortner JA. Use of cholestyramine in the treatment of children with familial combined hyperlipidemia. J Pediatr 1993; 122: 477-482.
11. Richard J Havel, John P Kane. Introduction: structure and metabolism of plasma lipoproteins. In Charles R Scriver, Arthur L Beaudet et al eds. The Metabolic and Molecular Bases of Inherited Disease. 8th edn. New York; McGraw-Hill, 2001; 2705-2716.(Sriram CS, Gulati Sheffal)