Portacaval Shunt in Four Patients With Homozygous Hypercholesterolæmia

Stein, Evan A.; Mieny, C. J.; Spitz, Lewis; Saaron, I.; Pettifor, John M.; Heimann, Klaus; Bersohn, I; Dinner, Melvyn I.

doi:10.1016/s0140-6736(75)93005-6

Cited by 58 publications

(7 citation statements)

References 6 publications

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“…The data in Table 2 (10)(11)(12)(13)(14). Previous reports also have demonstrated decreased rates ofwhole body cholesterol and bile acid synthesis (11,32) as well as decreased production of apolipoprotein B (11,31).…”

Section: Methodsmentioning

confidence: 90%

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Treatment of familial hypercholesterolemia by portacaval anastomosis: effect on cholesterol metabolism and pool sizes.

McNamara¹,

Ahrens²,

Kolb³

et al. 1983

Proc. Natl. Acad. Sci. U.S.A.

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Measurements of the key parameters of cholesterol homeostasis and the mass of the body pools of cholesterol were carried out in two patients with familial hypercholesterolemia (FH), one homozygote and one heterozygote, before and 28 and 18 months, respectively, after portacaval anastomosis (PCA). In both patients the procedure significantly reduced the plasma concentrations of total and low density lipoprotein cholesterol and the daily rate of whole body cholesterol and bile acid synthesis. In addition, PCA caused a net efflux of accumulated tissue cholesterol as demonstrated by reductions in the rapidly exchangeable and total exchangeable masses of body cholesterol. Shunt patency was verified by demonstration of increased bile acids in serum from fasting patients and from patients 2 hr after a meal and by increased plasma glucagon before and after arginine infusion. Other than a persistently increased level of serum alkaline phosphatase, liver function tests have fallen within the normal range in both patients; there has been no evidence of hepatic encephalopathy. In the homozygous patient there has also been a striking resolution in xanthoma size and distribution. These multiple effects on cholesterol homeostasis and pool sizes strongly suggest that PCA can reverse the progressive accumulation of cholesterol in body tissues of FH patients.Familial hypercholesterolemia (FH) is an autosomal dominant genetic defect resulting in decreased numbers ofcell receptors for low density lipoprotein (LDL) (1). This inborn error of metabolism is characterized by increased plasma LDL, deposition of cholesterol in subcutaneous and tendinous tissues (xanthomata), and premature cardiovascular disease (2). Analysis of plasma cholesterol decay kinetics has shown that FH patients have significantly increased body cholesterol pools (3, 4) in addition to an overproduction of LDL (5,6). Metabolic studies have demonstrated that young homozygous FH (HmFH) patients have an increased rate of cholesterol synthesis that decreases to normal rates with increasing age (7,8).Portacaval anastomosis (PCA) has been shown to cause marked reductions in plasma cholesterol concentrations in HmFH patients. This intervention, introduced in FH by Starzl et al. in 1973 (9), has been used as a treatment modality in more than 30 HmFH patients (10-14); postoperatively, most patients have experienced a striking resolution ofxanthomata along with decreases in synthesis rates of LDL and cholesterol (11).In a recent report from this laboratory (15) it was demonstrated in the rat that PCA significantly reduced plasma cholesterol and the rate ofwhole body cholesterol synthesis. It was shown also that PCA caused a decrease in net tissue cholesterol content as compared to untreated control animals. Because rats with shunts exhibited normal growth rates, it could not be determined whether the PCA caused a redistribution of body cholesterol pools or whether a net efflux of tissue cholesterol had occurred.To extend our previous studies of cholesterol homeost...

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Section: Methodsmentioning

confidence: 90%

“…This intervention, introduced in FH by Starzl et al in 1973 (9), has been used as a treatment modality in more than 30 HmFH patients (10)(11)(12)(13)(14); postoperatively, most patients have experienced a striking resolution ofxanthomata along with decreases in synthesis rates of LDL and cholesterol (11).…”

mentioning

confidence: 99%

Treatment of familial hypercholesterolemia by portacaval anastomosis: effect on cholesterol metabolism and pool sizes.

McNamara¹,

Ahrens²,

Kolb³

et al. 1983

Proc. Natl. Acad. Sci. U.S.A.

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“…122 Because FXR expression is induced by glucose, 121 because FXR activation decreases HDL cholesterol, 22 and because FXR suppresses bile acid synthesis, 37 it is tempting to speculate that the high-glucose diet increased hepatic FXR expression, which, in turn, was followed by repression of apoA-I and CYP7A1 expression. Finally, the fact that not only homozygous familial hypercholesterolemic patients [123][124][125] but also normocholesterolemic men 126,127 on total parenteral nutrition (a diet extremely rich in glucose) display a significant reduction in plasma cholesterol and a decreased excretion of bile acids suggest that glucose interference with FXR signaling is likely to constitute a novel mechanism involved in the control of plasma cholesterol levels.…”

Section: Role Of Fxr In Glucose Homeostasismentioning

confidence: 99%

The Farnesoid X Receptor

Claudel

Staels

Kuipers

2005

ATVB

439

106

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Key Words: bile acid Ⅲ FXR Ⅲ glucose metabolism Ⅲ lipid Ⅲ nuclear receptor A s a direct consequence of the obesity epidemic, 1-3 the prevalence of the metabolic syndrome is increasing at an alarming rate. 4 Almost 25% of the adult US population is currently affected, and the situation is even worse in people older than 60 years. 5 The metabolic syndrome has been defined by the National Cholesterol Education Program as a cluster of at least 3 of 5 criteria: insulin resistance and glucose intolerance, abdominal obesity, hypertension, low high-density lipoprotein (HDL) cholesterol, and hypertriglyceridemia. 6 Given the fact that the metabolic perturbation associated with the metabolic syndrome predisposes to cardiovascular diseases and stroke, 7 novel and more specific therapeutical strategies are urgently needed. Certain ligand-activated nuclear receptors provide promising new targets for this purpose. In this review, we discuss the biology of the Farnesoid X receptor (FXR, NRIH4), recently identified as a modulator of lipid and glucose homeostasis.Nuclear receptors are transcription factors that, on ligand binding by specific molecules and cofactor recruitment, regulate the expression of specific target genes. 8 FXR is highly expressed in liver and intestine 9 and was cloned during a search for new Retinoid X receptor (RXR or NR2B1) heterodimers. 9,10 Originally described as a farnesol-activated receptor interacting with RXR, and accordingly named, FXR was later identified as a Original

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“…All patients with homozygous familial hypercholesterolemia (FH) and patients with severe heterozygous FH belong to this specific group (20–22). Surgical procedures, such as portocaval shunt, ileal bypasses, and liver transplantation, can be used to circumvent the disastrous effects of severe hypercholesterolemia, but these measures are associated with a high morbidity rate (23–26).…”

mentioning

confidence: 99%

Low‐density Lipoprotein Apheresis: An Overview

Bambauer¹,

Schiel²,

Latza³

2003

Ther Apher Dial

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Atherosclerosis with myocardial infarction, stroke, and peripheral cellular disease still maintains its position at the top of morbidity and mortality statistics in industrialized nations. Established risk factors widely accepted are smoking, arterial hypertension, diabetes mellitus, and central obesity. Furthermore, there is a strong correlation between hyperlipidemia and atherosclerosis. The prognosis of patients suffering from severe hyperlipidemia, sometimes combined with elevated lipoprotein (a) (Lpa) levels, and coronary heart disease (CHD) refractory to diet and lipid-lowering drugs is poor. For such patients, regular treatment with low-density lipoprotein (LDL) apheresis is the therapeutic option. Today, there are four different LDL apheresis systems available: immunoadsorption, heparin-induced extracorporeal LDL/fibrinogen precipitation, dextran sulfate LDL adsorption and LDL hemoperfusion. Regarding the different LDL apheresis systems used, there is no significant difference with respect to the clinical outcome or concerning total cholesterol, LDL, high-density lipoprotein (HDL), or triglyceride concentrations. With respect to elevated Lpa levels, however, the immunoadsorption method seems to be the most effective. In 45 patients (25 women, 20 men) suffering from familial hypercholesterolemia resistant to diet and lipid lowering drugs, low-density lipoprotein (LDL) apheresis was performed over 95.6 +/- 44.7 months. Four different systems (Liposorber, 32 of 45, Kaneka, Osaka, Japan; Therasorb, 6 of 45, Baxter, Munich, Germany; Lipopak, 2 of 45, Pocard, Moscow, Russia; and Dali, 5 of 45, Fresenius, St. Wendel, Germany) were used. With all methods, average reductions of 57% for total cholesterol, 55.9% for LDL, 75.8% for lipoprotein a (Lpa), and 45.9% for triglycerides, and an average increase of 14.3% for HDL were reached. Severe side-effects such as shock or allergic reactions were very rare (0.3%) in all methods. In the course of treatment, an improvement in general well-being and increased performance were experienced by 44 of 45 patients. The present data demonstrate that treatment with LDL apheresis of patients suffering from familial hypercholesterolemia resistant to maximum conservative therapy is very effective and safe even in long-term application.

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Portacaval Shunt in Four Patients With Homozygous Hypercholesterolæmia

Cited by 58 publications

References 6 publications

Treatment of familial hypercholesterolemia by portacaval anastomosis: effect on cholesterol metabolism and pool sizes.

Treatment of familial hypercholesterolemia by portacaval anastomosis: effect on cholesterol metabolism and pool sizes.

The Farnesoid X Receptor

Low‐density Lipoprotein Apheresis: An Overview

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