Fecal protoporphyrin excretion in erythropoietic protoporphyria: effect of cholestyramine and bile acid feeding

The effect of cholestyramine and bile acid feeding upon fecal, red blood cell, and plasma protoporphyrin levels was evaluated in a patient with erythropoietic protoporphyria and evidence of hepatic damage. After a basal period on a controlled diet, bile acids alone were administered (300-900 mg) daily for 9 days, followed by cholestyramine (12 g) plus bile acids (900 mg) daily for 7 days, and cholestyramine alone (12 g) daily for 6 days. There was no substantial change in either the red blood cell or plasma protoporphyrin concentrations during any treatment period. However, cholestyramine and cholestyramine combined with bile acids caused a threefold increase in fecal protoporphyrin excretion, whereas bile acids alone had no effect in this regard. After 1 yr of cholestyramine therapy, fecal excretion of protoporphyrin remained elevated with concurrent improvement in liver function tests and photosensitivity. This study indicates that cholestyramine but not bile acids can substantially increase protoporphyrin excretion and therefore may be capable of ameliorating the hepatotoxicity that may occur in selected patients with erythropoietic protoporphyria.     

Use and indications of cholestyramine and bile acid sequestrants

Cholestyramine is a bile acid sequestrant, like colestipol and colesevelam. These molecules are positively charged non-digestible resins that bind to bile acids in the intestine to form an insoluble complex, which is excreted in the feces. They are used mainly for the treatment of primary hypercholesterolemia and hypercholesterolemia associated with mild hypertriglyceridemia, in patients not responding to dietary treatment as well as a second line-treatment for pruritus associated with cholestatic disease, in patients with incomplete biliary obstruction. Several data indicate that modulation of bile acid homeostasis has a good clinical effect in managing diabetes mellitus and the diarrhea from bile acid malabsorption. In this review, we present the “in label” use and indication for these compounds, revisiting the other clinical applications that may benefit from the use of bile acid sequestrants in the near future.     

考来烯胺对胆汁酸合成的基因调节作用

目的研究考来烯胺促进肝内胆汁酸合成的基因调节机制。方法20只新西兰白兔分为考来烯胺组（考来烯胺每天1g/kg,灌胃2周）和对照组,每组10只。测定两组2周后的血清胆固醇水平、总胆汁酸水平、肝组织胆固醇7α-羟化酶（CYP7A1）活性及其mRNA、法尼酯衍生物X受体（FXR）的靶基因短异源二聚体伴侣受体（SHP）mRNA和胆盐输出泵（BSEP）mRNA、低密度脂蛋白受体（LDL-R）mRNA表达。结果考来烯胺组血清胆固醇水平较对照组下降10.25%,而血清总胆汁酸水平无明显改变;肝脏CYP7A1活性及其mRNA表达较对照组显著升高（P〈0.05）,FXR靶基因SHPmRNA和BSEPmRNA表达较对照组显著降低（P〈0.05）,LDL-RmRNA表达较对照组显著升高（P〈0.05）。结论考来烯胺通过抑制回肠胆汁酸重吸收,减少回流入肝脏的胆汁酸（FXR配体）,从而抑制肝内FXR,激活CYP7A1,促进肝内胆固醇转化为胆汁酸,继而维持体内胆汁酸池稳定,降低血清胆固醇水平。     

Faecal bile acid excretion in children with inflammatory bowel disease.

Faecal bile acid excretion and intestinal transit time were studied in 18 children with inflammatory bowel disease in clinical remission and with normal stools: 16 with ulcerative colitis, two with Crohn's colitis, mean age 14 years (range 10-17 years). Five healthy children, mean age 12.4 years (range 10-17 years), were studied as control subjects. Most patients were taking sulphasalazine, but none were taking steroids. Transit time was determined by carmine and did not differ between groups. Faeces were collected for 72 hours, and faecal water was prepared by centrifugation of faeces at 15,000 x g for two hours. Bile acids in total faeces and faecal water were studied using capillary gas-liquid chromatography-mass spectrometry. Faecal excretion of total bile acids, unconjugated bile acids, and glycine and taurine conjugates were significantly increased in patients as was faecal water excretion of total bile acids, particularly the taurine conjugates and cholic and chenodeoxycholic acids. Total concentrations of bile acids in faeces and faecal water were two to five times higher in patients. The children with inflammatory bowel disease in clinical remission had high excretion and concentration rates of bile acids, especially taurine conjugates, in both total faeces and faecal water, a finding of considerable interest in the pathogenesis of malignancy in these diseases.     

Cholesterol lowering with high-viscosity hydroxypropylmethylcellulose

Hydroxypropylmethylcellulose (HPMC) is a food gum having several structural and functional properties in common with hypocholesterolemic soluble fibers. The safety and cholestero-lowering efficacy of HPMC, incorporated into a National Cholesterol Education Program Step I diet, was compared with placebo in patients with mild to moderate hypercholesterolemia. After an 8-week National Cholesterol Education Program Step I dietary lead-in phase, 160 patients with low-density lipoprotein (LDL) cholesterol between 130 and 200 mg/dl and triglycerides <300 mg/dl were randomized to placebo, 2.5, 5.0, or 7.5 g/day of HPMC for a 6-week treatment period. Patients returned to the clinic every 2 weeks for lipid measurements and safety assessments. HPMC significantly lowered total, LDL, and non-high-density lipoprotein (HDL) cholesterol. LDL cholesterol concentrations (average of weeks 4 and 6) decreased by 3.0% (4.9 mg/dl), 5.9% (10.3 mg/dl), 12.1% (20.4 mg/dl), and 11.7% (20.3 mg/dl) from baseline levels in the placebo and 2.5, 5.0, and 7.5 g/day HPMC treatment groups, respectively. Statistically significant (p<0.05) reductions in LDL cholesterol were observed in the 5.0 and 7.5 g/day HPMC groups compared with placebo and 2.5 g/day HPMC treatment groups. Total and non-HDL cholesterol responses paralleled those of LDL cholesterol. There were no significant differences between the treatment groups in HDL cholesterol or triglyceride responses, incidence of adverse experiences, or gastrointestinal-related adverse experiences. These results suggest that HPMC is a well-tolerated and effective adjunct to diet for lowering LDL cholesterol in patients with mild to moderate hypercholesterolemia.     

Cholesterol and bile acid metabolism in middle-aged diabetics

Serum lipoproteins, bile and kinetics and net steroid balance were studied in 22 diet-treated and 5 insulin-treated patients with noninsulin-dependent diabetes mellitus, in 6 patients with insulin-dependent diabetes mellitus and in 15 normoglycemic controls. All subjects were middle-aged and the patients were hyperglycemic. Some of the diet-treated patients suffered from obesity and/or dyslipoproteinaemia mainly characterized by elevated levels of triglycerides and cholesterol in VLDL (very low-density lipoproteins). The diet-treated patients had enhanced fractional turnover of both cholic acid and chenodeoxycholic acid but bile acid formation was within the control range in all groups of patients. As the most significant finding net steroid balance (total cholesterogenesis) was raised in the diet-treated patients. Bile acid kinetics and net steroid balance were normal in insulin-treated patients irrespective of type of diabetes.     

Effect of cholestyramine on bile acid kinetics in patients with portal cirrhosis of the liver

The kinetics of cholic acid (C) and chenodeoxycholic acid (CD) were studied in six patients with portal liver cirrhosis. The studies were conducted both before and after 5–6 weeks of treatment with cholestyramine (12 g/day). In keeping with previous observations, the pool size and formation of C showed subnormal values during the pretreatment period, while the production of CD was within normal limits. The pool sizes of C and CD did not change upon treatment with cholestyramine, but the mean total bile acid formation increased by a factor of about 2.5. The ratio between the amounts of C and CD synthesized remained essentially unchanged. Considering the therapeutic response previously observed in normal subjects and in patients with hyper-β-lipoproteinemia, the present results suggest a selective impairment of the biosynthesis of C in patients with portal liver cirrhosis. It is suggested that the primary defect may reside in the 12α-hydroxylase enzyme system.     

The effect of cholestyramine on bile acid kinetics in healthy controls

Serum lipids and the kinetics of the two primary bile acids, cholic acid (C) and chenodeoxycholic acid (CD), were studied in six normolipidaemic subjects before and during treatment with cholestyramine (12 g/day). After therapy, total serum and low-density lipoprotein cholesterol decreased by about 15%. These changes were accompanied by significant increases in the pool size, synthesis, and fractional turnover rate (FTR) of C and in the synthesis and FTR of CD. In spite of the enhanced formation of CD, the CD pool size decreased in all subjects, on average by more than 50%. The combined pool size of C and CD remained constant, but the mean total bile acid formation increased by a factor of 2.9. It is suggested that the different responses of C and CD, with an augmented contribution of C to the total amounts of bile acid produced, reflect an enhanced hepatic cholesterogenesis and, possibly, that C and CD to some extent originate from different cholesterol precursor pools.     

Cholesterol lowering in the elderly population. Coordinating Committee of the National Cholesterol Education Program.

The incidence of coronary heart disease (CHD) peaks in the elderly population. In secondary and primary prevention trials, cholesterol-lowering therapy reduces risk for CHD in both older and younger participants. This benefit, therefore, can be extended to the elderly.     

Regulation of bile acid synthesis in humans: effect of treatment with bile acids, cholestyramine or simvastatin on cholesterol 7 alpha-hydroxylation rates in vivo

The rates of cholesterol 7 alpha-hydroxylation (the first and rate-limiting step of bile acid synthesis from cholesterol) were evaluated in vivo in patients administered bile acids with different structural properties, cholestyramine or simvastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Twenty-three subjects, with normal hepatic and intestinal functions, were studied in basal conditions and after one of the following treatment schedules, lasting 4 to 6 weeks: cholestyramine, 4 and 12 gm/day (four patients); ursodeoxycholic acid, 9 to 11 mg/kg/day (four patients); chenodeoxycholic acid, 12 to 15 mg/kg/day (five patients); deoxycholic acid, 8 to 10 mg/kg/day (four patients); and simvastatin, 40 mg/day (six patients). 7 alpha-Hydroxylation of cholesterol was assayed by measuring the increase in body water tritium after intravenous bolus of cholesterol tritiated at the 7 alpha position. Plasma bile acid composition, evaluated by gas-liquid chromatography, revealed a substantial enrichment of the recirculating pool by the administered bile acid, whereas treatment with cholestyramine decreased the content of dihydroxylated bile acids. Cholesterol 7 alpha-hydroxylation increased in a dose-related manner after cholestyramine, in parallel with a decrease of cholesterol in total plasma and low-density lipoproteins (1.006 to 1.063 gm/ml). Hydroxylation rates decreased by an average of 47% with chenodeoxycholic acid and by an average of 78% with deoxycholic acid; ursodeoxycholic acid treatment did not affect 7 alpha-hydroxylation significantly. Simvastatin markedly reduced plasma total and low-density lipoprotein-cholesterol but exerted no change on 7 alpha-hydroxylation rates.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of ethinyl estradiol and phenobarbital on bile acid synthesis and biliary bile acid and cholesterol excretion.

Bile acid synthesis calculated from respiratory (14)CO2 derived from the catabolism of [26 or 27-(14)C]cholesterol to bile acids in rats with intact enterohepatic circulations decreased 50% after 5 days of ethinyl estradiol treatment (5 mg per kg per day). Maximal derepressed bile acid synthesis, measured as biliary bile acid excretion after bile acid pool depletion, was also reduced 50% by ethinyl estradiol treatment. Because ethinyl estradiol did not alter biliary cholesterol excretion, bile contained less bile acid relative to cholesterol. Hepatic bile acid concentration was not increased by ethinyl estradiol treatment. Because the inhibitory effect of ethinyl estradiol on bile acid synthesis required 5 days of treatment it is concluded that bile acid synthesis probably was not reduced by negative feedback repression of 7alpha-hydroxylase, the rate-limiting enzyme in bile acid synthesis, which has a half-life of 2 to 3 hr. During the first 14 hr after bile duct cannulation, before bile acid pool depletion, ethinyl estradiol-treated rats excreted less than one-half as much bile acid and the same amount of cholesterol as controls. The bile acid to cholesterol ratio was therefore decreased. Rats treated simultaneously with phenobarbital and ethinyl estradiol excreted significantly more bile acid than rats treated with ethinyl estradiol alone, but biliary cholesterol excretion was not increased. The proportion of biliary bile acid relative to cholesterol was thereby restored to the control value. In contrast, after 14 hr of bile drainage and depletion of the bile acid pool, rats treated with ethinyl estradiol and those treated with phenobarbital-ethinyl estradiol excreted the same amount of bile acid. Thus, when phenobarbital is administered with ethinyl estradiol, it increases the bile acid pool size and biliary bile acid excretion, but it does not increase bile acid synthesis. The increase in pool size and biliary bile acid excretion might be due to the phenobarbital-induced increase in ileal absorption of bile acids.     

Cholesterol lowering and endothelial function

The pathophysiology of the association between cholesterol and atherosclerosis has been thought to involve the deposition, modification, and cellular uptake of cholesterol. We now believe that the process begins with vascular injury and involves inflammation and vessel remodeling. The vascular endothelium actively regulates vascular tone, lipid breakdown, thrombogenesis, inflammation, and vessel growth, all of which are important factors in the development of atherosclerosis. Endothelial dysfunction promotes atherosclerosis through vasoconstriction, monocyte and platelet adhesion, thrombogenesis, and cytokine and growth factor stimulation and release. An important component of endothelial dysfunction is reduced availability of nitric oxide, which is caused by low-density lipoproteins, especially if they are oxidized. This reduced availability appears to occur through a combination of decreased production, abnormal signaling, and increased destruction by oxygen-free radicals. Concurrently, endothelium-mediated vasoconstrictors, adhesion molecules, cytokines, growth factors, and thrombogenic factors, such as endothelin, are increased by oxidized low-density lipoprotein. Several studies have shown improvements in endothelial function with cholesterol lowering, which may explain the early and substantial reductions in major cardiovascular events associated with cholesterol lowering.     

Oral bile acid treatment and the patient with Zellweger syndrome.

The cerebrohepatorenal syndrome of Zellweger is a congenital syndrome of multiple manifestations, including hepatomegaly and liver dysfunction. Treatment is generally of a supportive nature, aimed at improving nutrition and growth, controlling the central nervous system symptoms and limiting progression of liver disease. Because the liver disease in Zellweger syndrome may be attributed to an overproduction and accumulation of cholestanoic acids, exacerbated by diminished primary bile acid synthesis, we hypothesized that primary bile acid administration would be beneficial in improving liver function by a mechanism involving down-regulation in the synthesis of these atypical bile acids. We report here the clinical and biochemical responses to primary bile acid administration in a 2-mo-old boy who was seen with the typical signs of Zellweger syndrome. Liver disease was evident from hepatomegaly and elevated serum liver enzymes and bilirubin. The diagnosis was supported by markedly elevated serum very long chain fatty acids and the bile acids dihydroxycholestanoic acid and trihydroxycholestanoic acid. Confirmation of the lack of peroxisomes was established by electron microscopy. When the patient was 6 mo old, the primary bile acids cholic acid and chenodeoxycholic acid, (100 mg each/day) were administered orally. A significant improvement in biochemical indices of liver function occurred with a normalization of the serum bilirubin and liver enzymes and a histological improvement in the extent of inflammation and bile duct proliferation and disappearance of cannalicular plugs. Serum and urinary cholestanoic acids showed a significant decrease within a few days. A striking and sustained increase in growth was observed after therapy, and an improvement in neurological symptoms was noted. In conclusion, this study indicates that primary bile acid therapy improves liver function and growth in the patient with peroxisomal dysfunction and should be considered in the supportive therapies for this condition.     

Cholesterol and bile acid metabolism in moderately advanced, stable cirrhosis of the liver.

We have selected for this study a well-defined group of patients with moderately advanced but compensated alcoholic cirrhosis. They were well-nourished and had no ascites, varices, azotemia, or encephalopathy. Liver biopsy showed little or no necrosis and inflammation despite wide-spread fibrosis. Serum bilirubin, transaminase, alkaline phosphatase, albumin and globulins were essentially normal. Biochemical evidence for liver disease was restricted to modest elevation of BSP retention, gamma GTP, serum bile acid concentrations, and urinary bile acid excretion. Except for changes in the interrelationships among the three biliary lipids, they were generally spared the abnormalities of sterol metabolism described in other patients with more advanced, more active liver disease. Thus, striking abnormalities in the metabolism of cholesterol and bile acids probably require severe reductions in functioning hepatocellular mass, major portal-systemic shunting, high disease activity, or all three to become manifest.