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

Abstract

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...

Effects of Portacaval Shunt on the Cholesterol Metabolism of Genetically Hypercholesterolemic Rats (‘Rico’ Strain)

“…PCA affects the liver structure: re duction of hepatocyte number, size and smooth endothelium reticulum surface while swelling of mitochondria have been reported [7], Both blood flow and diversion of pan creatic hormones have been proposed as ex planations for the hepatic atrophy of PCA [1], Rico rats had more cholesterol in their body than control rats (table I). PCA slightly reduced cholesterol body pools in both Rico and control rats, as observed previously in Zucker and other rats [1,21] or in humans [ 12].…”

The ECK fistula in animals and humans

“…The extraordinary degree to which cholesterol homeostasis was altered by portacaval shunt in the homozygous patient 4 in our own series and the heterozygous patient 6 has been described by McNamara et al 75 Exogenous cholesterol absorption was unchanged in both patients, and bile acid synthesis was halved. Whole body cholesterol synthesis was decreased by 68% in patient 4 and by 41% in patient 6.…”

“…68,[74][75][76] Another synthetic pathway that has been well studied after portal diversion is the hepatic urea (Krebs-Henseleit) cycle, which has been shown by Reichle et al to be depressed by Eck's fistula in rats 77 and dogs 78 ; they demonstrated a reduction in several of the enzymes involved in this metabolic pathway.…”

After 40 Years of Cholesterol‐Watching

“…Portacaval anastomosis in patients with familial hypercholesteremia (21) has been shown to cause a marked reduction in plasma cholesterol levels (but not into the "normal" range), with marked reduction in cholesterol synthesis rates and net efflux of stored cholesterol. These advantages have not been of sufficient magnitude to prevent the progression of cardiovascular disease.…”