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Metabolic Studies in an Unusual Case of Asymptomatic Familial Hypobetalipoproteinemia with Hypoalphalipoproteinemia and Fasting Chylomicronemia

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Metabolic Studies in an Unusual Case of Asymptomatic Familial Hypobetalipoproteinemia with Hypoalphalipoproteinemia and Fasting Chylomicronemia Metabolic Studies in an Unusual Case of Asymptomatic Familial Hypobetalipoproteinemia with Hypoalphalipoproteinemia and Fasting Chylomicronemia Daniel Steinberg, … , W. Virgil Brown, John J. Albers J Clin Invest. 1979;64(1):292-301. https://doi.org/10.1172/JCI109451. Research Article A new kindred with asymptomatic hypobetalipoproteinemia is reported. The proband, age 67, differs from previously described cases in several respects: (a) unusually low levels of low density lipoprotein (LDL) cholesterol (4-8 mg/dl); (b) normal triglyceride levels; (c) low levels of high density lipoprotein; (d) mild fat malabsorption; and (e) a defect in chylomicron clearance. On a high-carbohydrate diet his plasma triglyceride levels, instead of rising, actually fell. Turnover of triglycerides in very low density lipoproteins (VLDL) was low (2.8 mg/kg per h). Fractional catabolic rate of LDL protein was just above the normal range (0.655/d) but net turnover was <10% of normal (0.65 mg/kg per d). The half-life of his chylomicrons was 29 min, five times the normal value. Postheparin lipoprotein lipase activity was normal and apolipoprotein C-II, the activator protein for lipoprotein lipase, was present and functional. Apolipoprotein C-III1, however, was not detected in the VLDL fraction, a finding previously reported in patients with abetalipoproteinemia. Fecal excretion of cholesterol was almost twice normal; total sterol balance was increased by ≅40%. The unusual features in the proband that distinguish him from previously described cases and from his affected first-degree relatives suggested that, in addition to the basic gene defect affecting LDL metabolism, he might have a second abnormality affecting clearance of chylomicrons and VLDL. The ratio of apolipoprotein E3 to […] Find the latest version: https://jci.me/109451/pdf Metabolic Studies in an Unusual Case of Asymptomatic Familial Hypobetalipoproteinemia with Hypoalphalipoproteinemia and Fasting Chylomicronemia DANIEL STEINBERG, SCOTT M. GRUNDY, HENRY Y. I. MOK, JOHN D. TURNER, DAVID B. WEINSTEIN, W. VIRGIL BROWN, and JOHN J. ALBERS, Division of Metabolic Disease, Department of Medicine, University of California San Diego, La Jolla, California 92093; Veteran's Administration Hospital, San Diego, California 92191; Northwest Lipid Research Clinic, University of Washington, Seattle, Washington 98104 A B S T R A C T A new kindred with asymptomatic normal, suggesting heterozygosity for E3 deficiency. hypobetalipoproteinemia is reported. The proband, age Whether or not this contributes to his hypertriglyc- 67, differs from previously described cases in several eridemia remains to be established. respects: (a) unusually low levels of low density lipo- protein (LDL) cholesterol (4-8 mg/dl); (b) normal tri- INTRODUCTION glyceride levels; (c) low levels of high density lipopro- tein; (d) mild fat malabsorption; and (e) a defect in Extremely low levels of plasma ,8-lipoproteins are en- chylomicron clearance. On a high-carbohydrate diet his countered in at least two distinct inherited disease plasma triglyceride levels, instead of rising, actually states (1). In "abetalipoproteinemia" no apoprotein B fell. Turnover of triglycerides in very low density lipo- is detected in the plasma even by the most sensitive proteins (VLDL) was low (2.8 mg/kg per h). Fractional immunochemical assays. Ordinary methods fail to catabolic rate of LDL protein was just above the normal reveal low density lipoprotein (LDL),1 very low density range (0.655/d) but net turnover was < 10% of nornal (0.65 lipoprotein (VLDL), or chylomicrons. By concentrating mg/kg per d). The half-life of his chylomicrons was 29 the fraction with d < 1.063 it is possible to demonstrate min, five times the normal value. Postheparin lipopro- lipoproteins but these are abnormal in composition and tein lipase activity was normal and apolipoprotein C-II, structure, i.e., they do not represent normal LDL or the activator protein for lipoprotein lipase, was present VLDL (1-4). This apparently total deficiency of lipo- and functional. Apolipoprotein C-l1, however, was proteins containing apoprotein B is associated with a not detected in the VLDL fraction, a finding previously severe clinical syndrome, usually apparent in infancy reported in patients with abetalipoproteinemia. Fecal (5). The syndrome is characterized by fat malabsorp- excretion of cholesterol was almost twice normal; total tion, retinitis pigmentosa, neurologic involvement (in- sterol balance was increased by -40%. The unusual cluding cerebellar ataxia and mental retardation), and features in the proband that distinguish him from pre- acanthocytosis. The inheritance pattern is autosomal viously described cases and from his affected first-degree recessive, with parents having normal lipoprotein levels relatives suggested that, in addition to the basic gene and none of the clinical manifestations. defect affecting LDL metabolism, he might have a In "hypobetalipoproteinemia" plasma LDL can be second abnormality affecting clearance of chylomicrons demonstrated but the levels are sharply reduced. This and VLDL. The ratio of apolipoprotein E3 to E2 in his partial deficiency of LDL is not associated with the VLDL fraction was 0.93, just below the lower limit of severe clinical manifestations characteristic of abeta- lipoproteinemia. Most patients are totally asymptomatic A preliminary report of this study was presented to the American Heart Association Annual Meeting in Miami, Fla. 1 Abbreviations used in this paper: apoA, B, C, and E, apo- 1977. (Circulation. 1977. 57: 111-4.) lipoproteins A, B, C, and E; HDL, high density lipoprotein; Received for publication 19 June 1978 and in revised form IDL, intermediate density lipoprotein; LDL, low density lipo- 26 February 1979. protein; VLDL, very low density lipoprotein. 292 J. Clin. Invest. © The American Society for Clinical Investigation, Inc. * 0021-9738/79/07/0292/10 $1.00 Volume 64 July 1979 292-301 and the diagnosis is usually made by chance during a Hospital, San Diego, on 6 May 1976. Physical examination routine clinical work-up or in screening programs. Fat revealed a well-nourished man 5 ft 6 in. tall and weighing 171 lb. Pulse, 72/min and regular; blood pressure, 160/90. There absorption is normal or only marginally impaired; acan- was no retinal pigmentation. Hearing was normal for his age. thocytes are rarely seen; growth and development in Heart and lungs were within normal limits. The liver was infancy and childhood are almost always normal. A smooth and nontender, palpable 4 cm below the right costal few patients have had neurological signs and symptoms margin, with a total liver span of 15 cm. The spleen was not felt. Rectal examination revealed an enlarged prostate con- but the other hypobetalipoproteinemic members of sistent with benign prostatic hypertrophy. Neurological ex- these kindreds were unaffected. The nature of the re- amination, performed by Professor W. C. Wiederholt, Chair- lationship between the neurologic changes and the person of Neurosciences, was within normal limits. Specifically, hypobetalipoproteinemia remains unclear. This dis- there were no abnormal pyramidal, cerebellar, or posterior order is inherited in an autosomal dominant pattern. column signs and no peripheral neuropathy. The following laboratory values were obtained: hemoglo- Recently it has become clear that a double dose of the bin, 14.2 g/dl; hematocrit, 42.6%. Erythrocyte indices were abnormal allele causing hypobetalipoproteinemia can normal and the morphology of most cells was normal except produce a severe clinical picture not readily distin- that a rare acanthocyte was noted. Leukocytes, 4,000/mm3 with guishable from that of abetalipoproteinemia (6, 7). normal differential count. Fasting plasma glucose, 112 mg/dl; dominant inheritance of 2-h postprandial plasma glucose, 136 mg/dl. Normal values However, the clearly hypo- were found for blood urea nitrogen, uric acid, calcium, phos- betalipoproteinemia in these kindreds indicates that phorus, iron, electrolytes, creatinine, total bilirubin, alkaline homozygous hypobetalipoproteinemia represents a phosphatase, lactic dehydrogenase, glutamic oxaloacetic mutation distinct from that in abetalipoproteinemia. transaminase, glutamic pyruvic transaminase, creatine phos- In this paper we present the results of intensive phokinase, bromosulfonphthalein retention, thyroxine, and free thyroxine index. Urinalysis was negative. Plasma protein studies in an asymptomatic man in his seventh decade electrophoresis was normal. Chest x ray was normal. Abdominal with a familial hypobetalipoproteinemic syndrome dif- x ray showed multiple radiopaque shadows in the right upper ferent from those previously reported in a number of quadrant consistent with cholelithiasis; abdominal echo- respects: (a) extremely low LDL levels (4-8 mg LDL graphic studies confirmed the presence of gallstones. cholesterol/dl); (b) niormal triglyceride levels; (c) low Electrocardiogram showed a normal sinus rhythm. There was left axis deviation and evidence of old anteroseptal myo- high density lipoprotein levels; (d) mild fat malabsorp- cardial infarction. Additional questioning elicited no history tion; and (e) a chylomicron clearance defect. suggestive of infarction. A later exercise electrocardiogram (heart rate 160) elicited no symptoms and no ischemic signs. METHODS Fecal fat in a 3-d stool collection was 13 g/d (dietary fat 100 g/d). Additional measurements on four 2-d stool collec- Patient. H.J.B., a retired Navy chaplain,
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