Failure of Complete Bile Diversion and Oral Bile Acid Therapy in the Treatment of Homozygous Familial Hypercholesterolemia

Deckelbaum, Richard J.; Lees, Robert S.; Small, Donald; Hedberg, Stephen E.; Grundy, Scott M.

doi:10.1056/nejm197703032960901

Cited by 53 publications

(20 citation statements)

References 21 publications

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“…First, cholestyramine treatment increases fecal bile acid excretion in FH homozygotes to the same degree as it does in normal subjects (40). Second, complete biliary diversion increased bile acid excretion markedly in two FH homozygotes without altering the plasma cholesterol level (41). Third, feeding bile acids to patients with FH does not materially influence the plasma cholesterol level (42).…”

Section: Resultsmentioning

confidence: 99%

Metabolic Studies in Familial Hypercholesterolemia

Bilheimer¹,

Stone²,

Grundy³

1979

J. Clin. Invest.

199

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A B S T R A C T To investigate the gene-dosage effect in familial hypercholesterolemia (FH), metabolic studies were conducted in a group of well-characterized patients with either heterozygous (n = 7) or homozygous (n = 7) FH and the results were compared to those obtained in normal subjects (n = 6). 524 these seven patients is caused by variation in the plasma apoLDL synthetic rates. Consistent with this conclusion was the finding that the correlation between the plasma LDL level and the apoLDL synthetic rates in the seven FH homozygotes was 0.943.The rate of total body cholesterol synthesis determined by chemical cholesterol balance did not appear to clearly differ between normals and patients with either one or two mutant FH genes. Two of the youngest FH homozygotes exhibited cholesterol overproduction but the other five did not. No consistent abnormality of bile acid metabolism was observed in these patients. Because the daily plasma flux of cholesterol on LDL is about threefold greater than the amount of cholesterol produced per day, a significant amount ofthe cholesterol liberated from LDL degradation must be reused.

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Section: Resultsmentioning

confidence: 99%

Metabolic Studies in Familial Hypercholesterolemia

Bilheimer¹,

Stone²,

Grundy³

1979

J. Clin. Invest.

199

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“…Partial ileal bypass may be complicated by malabsorptive gastrointestinal side effects, whereas portacaval shunting may lead to hepatic encephalopathy. 22 Liver transplantation is restricted by a lack of donor organs and the need for continuous postoperative immunosuppression. 23 LDL apheresis significantly lowers LDL-C and is considered the standard of care for patients with HoFH.…”

Section: Discussionmentioning

confidence: 99%

Reduction in Mortality in Subjects With Homozygous Familial Hypercholesterolemia Associated With Advances in Lipid-Lowering Therapy

et al. 2011

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Background-Homozygous familial hypercholesterolemia is an inherited disorder caused by mutations in both low-density lipoprotein receptor alleles, which results in extremely elevated plasma low-density lipoprotein cholesterol concentrations and very early morbidity and mortality due to cardiovascular disease. Methods and Results-To evaluate the impact of advances in lipid-lowering (predominantly statin) therapy on cardiovascular disease morbidity and mortality in a large cohort of patients with homozygous familial hypercholesterolemia, the records of 149 patients (81 females, 68 males) from 2 specialized lipid clinics in South Africa were evaluated retrospectively. Homozygous familial hypercholesterolemia was diagnosed by confirmation of mutations in genes affecting low-density lipoprotein cholesterol or by clinical criteria. A Cox proportional hazard model with time-varying exposure was used to estimate the risk of death and major adverse cardiovascular events among statin-treated patients compared with statin-naive patients. The hazard ratio for benefit from lipid therapy, calculated with the Cox proportional hazards model for the end point of death, was 0.34 (95% confidence interval 0.14 -0.86; Pϭ0.02), and for the end point of major adverse cardiovascular events, it was 0.49 (95% confidence interval 0. Clinical Perspective on p 2207The frequency of FH throughout the world has been estimated at 1 in 500 people in the less severe heterozygous form and at 1 per 1 million people in the more severe homozygous form. 1 In South African white Afrikaners, there is a much higher prevalence of heterozygous and homozygous FH, estimated at 1:100 and 1:30 000, respectively. 3 This high prevalence is due to a founder effect that occurred when a limited number of LDL receptor mutations were introduced by Dutch families who settled in the Cape Province during the second half of the seventeenth century. 4 Until the 1980s, treatment of FH was limited to a low-fat diet and minimally effective lipid-modifying agents. Lipidlowering drug therapy changed radically in the 1990s with the introduction of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, or statins, a drug class that is remarkably effective in lowering LDL-C. 5 Multiple ranContinuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz. The aims of the present study were to assess the impact of modern lipid-lowering therapy, predominantly statin therapy, on all-cause and cardiovascular mortality in a large cohort of HoFH patients who have been followed up for up to 40 years at 2 specialized lipid treatment centers in South Africa. Methods PatientsThis study was a retrospective cohort design that reviewed data from July 1972, the time of inception of the first specialized lipid clinics in South Africa, to March 2009. Medical records of HoFH subjects were reviewed to establish genetic and phenotypic data, anthropometric measures, and data on cardiovascular events and lipidlowering drug...

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“…Cholestyramine treatment has been shown to reduce plasma LDL levels in individuals with heterozygous familial hypercholesterolemia by increasing the receptor-mediated elimination of LDL (44). However, plasma LDL levels in patients with homozygous (receptor-negative) familial hypercholesterolemia are not lowered even by treatment with a total bile fistula (45). In addition, suppression of bile acid biosynthesis in man, which occurs during treatment with the primary bile acid chenodeoxycholic acid (46,47), results in a slight, but significant, increase in plasma LDL levels (48,49).2 Chenodeoxycholic acid treatment in man is associated with decreased hepatic cholesterol synthesis (50), a reduced production rate of VLDL (51) (the precursor of human plasma LDL), and possibly a reduction in LDL catabolism.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Hepatic Lipoprotein Receptors in the Dog. RAPID REGULATION OF APOLIPOPROTEIN B,E RECEPTORS, BUT NOT OF APOLIPOPROTEIN E RECEPTORS, BY INTESTINAL LIPOPROTEINS AND BILE ACIDS

Angelin¹,

Raviola²,

Innerarity³

et al. 1983

J. Clin. Invest.

112

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A B S T R A C T Two distinct lipoprotein receptors can be expressed in the dog liver. One is the apolipoprotein (apo-) B,E receptor. This receptor binds apo-B-containing low density lipoproteins (LDL), as well as apo-E-containing lipoproteins, such as the cholesterol-induced high density lipoproteins (HDL,). The second hepatic lipoprotein receptor is the apo-E receptor. It binds apo-E HDLC and chylomicron remnants, but not LDL. The present studies were undertaken to determine whether short-term (acute) regulation of the two receptors can occur in response to perturbations in hepatic cholesterol metabolism. The design used three groups of experimental animals: (a) immature dogs (with both hepatic apo-B,E and apo-E receptors expressed), (b) adult dogs (with predominantly the apo-E receptor expressed and little detectable apo-B,E receptor binding activity), and (c) dogs treated with the bile acid sequestrant cholestyramine or those that have undergone biliary diversion (with apo-E receptors and induced apo-B,E receptors).In per kg) or saline were infused intravenously for 6-8 h into matched pairs of dogs. Serial liver biopsies were obtained at intervals of 1-2 h. A progressive loss of specific (calcium-dependent) binding of LDL was seen in hepatic membranes from both immature and cholestyramine-treated dogs. After 4-6 h of lymph infusion, almost no apo-B,E receptor binding could be detected. The decrease in binding of apo-E HDLC to the same membranes was much less pronounced, and could be explained by a loss of binding of HDLC to the apo-B,E receptor; there was little or no effect on apo-E receptor binding.In the second series of experiments, the effects of a diminished hepatic demand for cholesterol on lipoprotein receptor expression were studied by suppressing bile acid synthesis. The bile acid taurocholate (2-3 jmol/kg per min) was infused intravenously over a 6-h interval. This resulted in a progressive loss of LDL binding to liver membranes of immature or cholestyramine-treated dogs. The infusion of taurocholate for 6 h did not significantly alter the expression of the apo-E receptor binding activity, whereas apo-B,E receptor activity was rapidly down-regulated. Prepara The results indicate that the two canine hepatic lipoprotein receptors differ in their metabolic regulation. The apo-B,E receptor responds rapidly to changes in hepatic requirements for cholesterol. The apo-E receptor appears to be more refractory to acute regulation. The rapidity of the changes in the activity of the apo-B,E receptor (within 2-4 h) suggests that the binding activity of this receptor may be regulated by factors independent of protein synthesis.

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Failure of Complete Bile Diversion and Oral Bile Acid Therapy in the Treatment of Homozygous Familial Hypercholesterolemia

Cited by 53 publications

References 21 publications

Metabolic Studies in Familial Hypercholesterolemia

Metabolic Studies in Familial Hypercholesterolemia

Reduction in Mortality in Subjects With Homozygous Familial Hypercholesterolemia Associated With Advances in Lipid-Lowering Therapy

Regulation of Hepatic Lipoprotein Receptors in the Dog. RAPID REGULATION OF APOLIPOPROTEIN B,E RECEPTORS, BUT NOT OF APOLIPOPROTEIN E RECEPTORS, BY INTESTINAL LIPOPROTEINS AND BILE ACIDS

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