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The cause of the recently described syndrome of chronic watery diarrhea associated with microscopic colitis is unknown. A patient appearing to have this disorder is described here. A major pathophysiologic role for bile-salt malabsorption in her, and perhaps other such patients, was suggested by her clinicopathologic response to cholestyramine.
From a survey of the etiology of colorectal cancer, consideration of the basic pathologic characteristics of ulcerative colitis and familial polyposis of the colon suggests that they might be sister diseases. Similarities in the primary and secondary target organs and in fecal steroid metabolism might be more than coincidental. Thus, it would seem reasonable to pay particular attention to several groups of patients who are receiving therapy or have had operations that alter bile acid and/or cholesterol metabolism: 1) patients who have had jejunoileal bypass procedures for morbid obesity or hypercholesterolemia, 2) patients taking cholestyramine and/or other anti-hyperlipidemic agents, 3) patients receiving chenodeoxycholic therapy to dissolve gallstones, 4) patients taking the birth control pill, and 5) young patients who have had a cholecystectomy. Proponents of such therapy and physicians treating patients who develop colonic cancer or polypoid disease after having had such therapy are encouraged to provide accurate reports.
The influence of the intestinal bile acid content on the secretion of the exocrine pancreas and on the plasma concentrations of the relevant peptides (NT), and CCK is the subject of continuing controversy. Thus the alterations of pancreatic secretion and both hormones during variations of intestinal bile acid content were investigated. Modified Herrera fistulas were implanted in six dogs for analysis of the pancreatic secretions. Intraduodenal application of taurocholate (1.8, 3.6, or 7.2 mM) led to a marked reduction of the pancreatic secretion as well as to a simultaneous decrease of NT and CCK release after stimulation by the intraduodenal instillation of a 20% lipid emulsion. (The integrated protein secretion decreased from 20.1 +/- 1.9 g to 15.2 +/- 1.6 g, NT release dropped from 4970 to 3050 pg/180 min, and CCK from min.) cholestyramine together with the lipid emulsion had the opposite effect. The pancreatic protein as well as NT and CCK release increased. It therefore appears that there is a negative feedback relationship between the postprandial intestinal bile acid content on the one hand, and the secretion of the exocrine pancreas and the regulatory peptides NT and CCK on the other hand. This relationship is independent of any interaction between pancreatic proteases and bile acids.
We describe two cases of leflunomide-related interstitial pneumonia (IP). A 75-year-old woman with rheumatoid arthritis (RA) developed rapidly progressing IP 45 days after institution of leflunomide. She died of respiratory failure, and an autopsy revealed a mixed pattern of acute and organizing diffuse alveolar damage. A 69-year-old woman with RA also developed acute IP 3 months after institution of leflunomide. Methylprednisolone pulse therapy and cholestyramine ameliorated her IP. The implication of leflunomide in the pathogenesis of IP was suggested.
Plasma cholesterol levels are markedly reduced when doxazosin, a selective alpha 1-adrenoceptor inhibitor, is administered for several days to C57BR/cdJ mice that have been fed a high cholesterol diet. This system affords a useful model for investigating the mechanism by which selective alpha 1-adrenoceptor inhibitors decrease circulating lipid levels. The results indirectly suggest that hypercholesterolemia induced by dietary cholesterol may involve activation of the sympathetic nervous system. The basis for linkage between circulating cholesterol levels and sympathetic nervous activity, while not yet understood, may involve changes in the balance among cholesterol pathways in the liver, alteration of vasomotor tone and control of the activity of vascular endothelial lipases. An additive effect is described for cholestyramine and doxazosin, in which low density lipoprotein cholesterol is decreased by 76% by a combination of maximal doses of the 2 agents.
A variety of double-blind studies have compared the efficacy of hydroxymethylglutaryl coenzyme A reductase inhibitors (lovastatin and simvastatin) with that of control agents (cholestyramine, fibrates and probucol) in patients with type IIA or IIB primary hypercholesterolemia. Results have shown that both lovastatin and simvastatin are more effective than the standard therapies with regard to reducing total and low-density lipoprotein cholesterol. Decreases in triglycerides and increases in high-density lipoprotein cholesterol were generally greater with fibrates. Ongoing studies are assessing the benefits of lovastatin and simvastatin in reducing the incidence of mortality from coronary artery disease, as well as causing regression of coronary atheroma.
The Probucol Quantitative Regression Swedish Trial tested whether treatment of hypercholesterolemic persons with probucol for 3 years affected femoral atherosclerosis. The primary end point was the change in atheroma volume estimated as change in lumen volume of the femoral artery assessed by quantitative arteriography. Three hundred three patients with visible atherosclerosis were randomized to probucol 0.5 g, twice daily, or to placebo. All patients were given diet and cholestyramine, 8 to 16 g/day. Twenty-nine patients were excluded because of inadequate primary end point measurements. The mean age of the remaining 274 subjects (158 were men) was 55 years. Seventeen percent had intermittent claudication and 24% had angina pectoris. After 3 years, the probucol-treated patients had 17% lower serum cholesterol, 12% lower low-density lipoprotein cholesterol, 24% lower total high-density lipoprotein cholesterol, and 34% lower high-density lipoprotein2 cholesterol levels than control subjects. All lipoprotein differences between the treatment groups remained highly significant during the trial. There was no statistically significant change in lumen volume between the probucol and the control group. Furthermore, there was no difference between the treatment groups with regard to change in arterial edge roughness or amount of aorto-femoral atherosclerosis; neither were there any differences between the treatment groups with regard to change in ST-segment depressions on exercise tests or ankle/arm blood pressure (secondary end points). In the control group, lumen volume increased (p < 0.001) and roughness of the femoral artery decreased (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
A total of 429 subjects (79 women and 350 men), aged 35-75 years, have been enrolled in a randomized clinical trial of fluvastatin therapy for hypercholesterolemia. The progression and regression of atherosclerotic lesions will be assessed by quantitative angiography and positron emission tomography (PET) after 2.5 years of treatment. Patients were included in the trial if they had angiographically documented lesions that occluded 30-75% of the diameter of a major coronary vessel. Of the 429 subjects, 99 were also studied by PET at rest and during static exercise of sustained handgrip combined with administration of dipyridamole. All subjects were instructed in an American Heart Association/National Cholesterol Education Program (AHA/NCEP) Step I or Step II diet. Of the total, 107 subjects (25%) had low density lipoprotein cholesterol (LDL-C) > or = 160 mg/dL and were given cholestyramine, 8 g/day. All subjects were randomized to placebo or fluvastatin, the newest 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor to be introduced into the U.S. market. Fluvastatin is entirely synthetic and is similar in efficacy to the other available HMG-CoA reductase inhibitors. Its pharmaceutical profile (i.e., low systemic exposure) makes fluvastatin a good candidate for use in combination lipid-lowering therapy. The majority of subjects were recruited through a community campaign and the remainder through cardiac catheterization laboratories and the medical records of hospitals in the Texas Medical Center. Approximately 8,500 prospects from the community campaign were screened and 272 were randomized, a conversion rate of approximately 3%.(ABSTRACT TRUNCATED AT 250 WORDS)
Chronic obstructive liver disease and secondary hyperlipidemia developed in an immunodeficient boy. Sequential addition of cholestyramine and phenobarbital to his medical regimen, following an initial response to bile drainage, resulted in the disappearance of xanthomas and pruritus, and the restoration of normal serum concentrations of lipids and bile acids. This improvement may result from shifting the bile acid pool from the peripheral blood compartment to the enterohepatic circulation.
We describe a 49 year old woman with impressive regression of renal artery stenosing atherosclerotic lesions in response to sustained excellent control of hyperlipidemia. Initially, she had high blood pressure necessitating combined drug therapy with chlorothiazide, methyldopa and propranolol, with only moderately satisfactory control. Renal arteriography revealed a 90 per cent stenosing lesion of the right renal artery and 75 per cent narrowing of the left renal artery. Peripheral vein plasma renin was markedly increased at 32 ng/ml. With a combination of cholestyramine and clofibrate, serum lipids were maintained at normal values for several years. Increased blood pressure diminished spontaneously, and the patient has maintained normal blood pressures after discontinuation of antihypertensive therapy. Repeat renal arteriograms showed almost complete regression of the right renal artery lesion and a possible decrease in left renal artery disease. Peripheral vein plasma renin became normal at 3 ng/ml. This case illustrates that sustained control of hyperlipidemia could lead to regression of atherosclerotic nodules and impressive clinical improvement in certain patients.
The most frequent indication for treatment of hyperlipidemia is for prevention of arteriosclerosis, a suspected but unproved benefit. The cornerstone of treatment of primary hyperlipidemia is diet; drugs may be added to, but do not replace, diet. When a drug is used with any patient, its potential benefits and hazards must be carefully weighed for the given subject. The subjects should be carefully followed and observed for side effects. Plasma lipids should be monitored during the course of treatment. Five drugs have been approved by the U.S. Food and Drug Administration for the treatment of hyperlipidemia: cholestyramine, clofibrate, nicotinic acid, sodium dextrothyroxine and beta-sitosterol. The use, the actions and the side effects of each and of several nonapproved agents are discussed.
A quantitative HPLC method has been developed for measuring 3 beta-hydroxy-delta 5-C27-steroid oxidoreductase activity in rat liver microsomes. Apparent Km values of 23 and 27 microM were estimated for 5-cholestene-3 beta,7 alpha-diol and NAD+, respectively. A temperature optimum of 45 degrees C was estimated using standard assay conditions. It was observed that feeding cholesterol (2%) or cholestyramine (5%) to rats increased (twofold) specific activity. This method should prove useful in studies of the regulation of bile acid synthesis and complement the HPLC assay technique recently developed for measuring cholesterol 7 alpha-hydroxylase activity.
1. Rats were maintained in a strictly controlled environment of 12 h illumination and 12 h darkness. At regular intervals during the light/dark cycle the portal blood conjugated cholic acid and conjugated chenodeoxycholic acid concentrations were measured. The bile salt concentrations exhibited similar diurnal rhythms, the highest concentrations occurring in the middle of the dark phase. 2. The concentrations of conjugated cholic and chenodeoxycholic acids in the portal blood of rats fed a diet containing the bile salt sequestrant, cholestyramine, were significantly lower than those found in rats given a control diet. 3. During total biliary drainage the portal blood concentrations of conjugated cholic and chenodeoxycholic acids fell to a minimum 6--8 h after the start of the experiment, whereas bile salt synthesis in hepatocytes isolated from the rats was not increased until the least 13 h after the commencement of total biliary drainage. 4. These results suggest that the concentrations of bile salts in the portal blood do not affect directly the diurnal fluctuation in rates of bile salt synthesis, as the response of synthesis to a change in portal blood bile salt concentrations is too slow. 5. When the rats were given a small supplement of cholesterol in the diet to suppress hepatic cholesterologenesis prior to being subjected to total biliary drainage, the changes in the portal blood concentrations of conjugated cholic and chenodeoxycholic acids and the synthesis of the two bile salts by isolated hepatocytes were similar to those found in rats given the control diet. 6. The rise in bile salt production seen during biliary drainage may not be dependent exclusively on a preceding increase in cholesterol synthesis.
Incubation of rat liver microsomal fraction in the presence of increasing concentration of a serum preparation and the re-isolation of the treated microsomal vesicles resulted in a progressive increase in the concentration of non-esterified cholesterol, a progressive decrease in the activity of hydroxymethylglutaryl-CoA reductase and progressive changes in the characteristics of the Arrhenius plots of the enzyme. The changes in the characteristics of the Arrhenius plots of the enzyme in the serum-treated preparations are consistent with a progressive increase in the concentration of non-esterified cholesterol in the environment of the hydroxymethylglutaryl-CoA reductase in endoplasmic reiticulum vesicles. The serum-treated preparations with high non-esterified cholesterol content showed a constant activation energy between 37 and 20 degrees C, whereas the enzyme in the non-treated microsomal fraction, the buffer-treated and the lipoprotein-deficient serum-treated preparations showed breaks in the activation energy at about 29 degrees C. The microsomal fraction from rats fed on the standard, cholesterol- or cholestyramine-supplemented diet showed considerable differences in the activity of hydroxymethylglutaryl-CoA reductase and differences in the characteristics of their Arrhenius plots. However, the incubation of the microsomal fraction from the rats in the three experimental conditions with ATP and Mg2+ and the further incubation of the inactivated enzyme with a preparation of cytosolic phosphoprotein phosphatase resulted in Arrhenius plots with similar characteristics to those of the corresponding original microsomal fraction. These results suggest that changes in the concentration of non-esterified cholesterol in the endoplasmic reticular membrane are responsible for the differences in the activity of hydroxymethylglutaryl-CoA reductase in the microsomal fraction from the rats in these dietary conditions.
Rat hepatocyte monolayers were maintained for periods up to 24 h during which time their viability was greater than 85%. Using specific radioimmunoassays, the hepatocyte monolayers were shown to synthesise conjugated cholic, chenodeoxycholic and beta-muricholic acids. Feeding the bile salt sequestrant, cholestyramine, to donor animals increased synthesis of the major bile salt conjugates by the cells. Incubation of hepatocyte monolayers with bovine serum albumin decreased total synthesis of the three bile acids measured, but increased the amount of conjugated chenodeoxycholic acid detected. In order to test whether the effect of bovine serum albumin on bile salt synthesis was due to binding of bile salts, hepatocyte monolayers were incubated with antiserum to conjugated chenodeoxycholic acid. This treatment increased conjugated chenodeoxycholic acid production but had no effect on the other bile salt conjugates. It is concluded that the increase in conjugated chenodeoxycholic acid synthesis seen with bovine serum albumin and antiserum to conjugated chenodeoxycholic acid is caused by binding of the bile salt in the medium.
The activity of the soluble form of phosphatidic acid phosphatase in rat liver was stimulated about 2.5-fold by inclusion of mevinolin, a competitive hydroxymethylglutaryl-CoA reductase inhibitor, in the diet (0.1%). The stimulatory effect of mevinolin was present also after dietary addition of cholestyramine (5%) or intraperitoneal administration of ethanol. Addition of cholesterol (2%) to the diet totally abolished the stimulation by mevinolin on phosphatidic acid phosphatase. The results support a correlation between the synthesis of the rate-limiting enzyme in cholesterol biosynthesis and the activity of the apparent rate-limiting enzyme in triacylglycerol biosynthesis.
A synthetic fat-free diet, previously shown to decrease hepatic cholesterol synthesis, was utilized to manipulate cholesterol balance in vivo in female Sprague-Dawley rats. A significant 65% decrease of hepatic cholesterol synthesis compared to controls was shown after 1 week of treatment, which remained constant during the following 3 weeks. The inhibitory effect of the diet was completely abolished by cholestyramine supplementation. At week 3 of the experimental diet, bile acid synthesis was reduced by 63%, this reduction being correlated with decreased recycling frequency of the bile acid pool. Hepatic clearance of low-density lipoprotein (LDL) was slightly decreased, with no changes in plasma cholesterol, hepatic LDL-cholesterol uptake and whole body LDL-cholesterol production. When cholesterol and saturated fatty acids were supplemented to the diets in the attempt to disclose alteration in LDL transport, LDL clearance was unaffected; plasma LDL-cholesterol and hepatic LDL-cholesterol uptake were increased, as a consequence of increased LDL-cholesterol production. On the other hand, hepatic cholesterol synthesis was further suppressed; bile acid synthesis was increased by cholesterol supplementation in the fat-free group, even if to subnormal levels. These findings suggest that: (1) bile acid synthesis is decreased by feeding a synthetic fat-free diet, probably due to slower recirculation of bile acids along the entero-hepatic axis in conditions of reduced functional need; (2) consequently, a significant reduction of hepatic cholesterol synthesis is observed with no changes in LDL-cholesterol uptake; (3) further supplementation of dietary cholesterol and saturated fats is compensated for by changes in the rates of cholesterol and bile acid synthesis, but not of LDL transport. The data confirm the existence of independent regulation for hepatic sterol synthesis and LDL transport in this species.
Three branch-point enzymes of the mevalonate pathway, farnesyl pyrophosphate synthase, cis-prenyltransferase and squalene synthase were characterized in rat hepatic cytosol, microsomes and peroxisomes isolated from rats after treatment with peroxisome proliferators, inducers of the endoplasmic reticulum or modulators of lipid metabolism. Cholestyramine and phenobarbital induced primarily the cytosolic farnesyl pyrophosphate synthase, whereas clofibrate and phthalates elevated the corresponding peroxisomal activity. cis-Prenyltransferase activities in microsomes were induced 4-5-fold after clofibrate, phthalate and phenobarbital administration, but these same treatments affected the peroxisomal activity to only a limited extent. Squalene synthase activity in microsomes was completely abolished, but the peroxisomal activity was unaffected after administration of cholesterol. On the other hand, clofibrate and phthalate induced only the microsomal activities. Mevinolin treatment greatly increased peroxisomal and cytosolic farnesyl pyrophosphate synthase activities, but not the mitochondrial activity, and the cis-prenyltransferase activities were elevated in peroxisomes, but not in microsomes. These results demonstrate that the branch-point enzymes in cholesterol and dolichol biosynthesis at various cellular locations are regulated differentially and that the capacities of peroxisomes and the endoplasmic reticulum to participate in the synthesis of polyisoprenoid lipids is affected profoundly by treatment with different xenobiotics.