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PubMed1979

Effects of tristearin, triolein and safflower oil diets on cholesterol balance in rats.

Diets containing relatively homogeneous triglycerides composed of 18-carbon chain saturated, monounsaturated or polyunsaturated fatty acids were fed to rats. Cholesterol absorption and turnover were studied. Cholesterol absorption was significantly less in rats fed tristearin than in animals fed triolein or safflower oil. Cholesterol removal from plasma was fastest in rats fed tristearin and slowest with safflower oil and triolein. Plasma cholesterol levels were lowest with tristearin and highest with safflower oil. Increased cholesterol in high density lipoproteins was observed with tristearin and triolein. Lymph and hepatic cholesterol, and lymph triglycerides were highest with safflower oil, suggesting endogenous mobilization. Cholesterol production was least with triolein. Sterol synthesis was greatest with tristearin, perhaps attributable to decreased negative feedback analogous to effects of cholestyramine. Differences in lipoprotein composition observed with the various diets are important since effects on particle size and shape may influence removal mechanisms. The mechanisms underlying the different effects of dietary triglycerides on sterol absorption and metabolism remain to be elucidated.

Animals↗

PubMed1983

Chronic suppression of cholesterol 7 alpha-hydroxylase by dietary chenodeoxycholic acid in neonatal guinea pigs: its effect on subsequent bile acid metabolism in the adult.

Treatment of neonatal guinea pigs with cholestyramine persistently increases the activity of hepatic cholesterol 7 alpha-hydroxylase (CH-7 alpha), the rate-limiting enzyme of bile acid biosynthesis. In this study, we examined whether CH-7 alpha activity could be persistently inhibited by manipulations (chenodeoxycholic acid feeding) during neonatal life. Male Hartley guinea pigs (2-3 days old) were fed 0.25% chenodeoxycholic acid (CDCA)-supplemented diet for 10 days or 6 weeks. Feeding CDCA for 10 days increased plasma cholesterol [controls (C), 25 +/- 3 vs. CDCA, 34 +/- 2 mg/dl]. Bile acid pool in animals fed CDCA for 10 days was nearly fivefold greater than controls (C, 5.8 +/- 0.3 vs. CDCA, 29.1 +/- 0.9 mg/100 g body weight), whereas CH-7 alpha activity was almost completely inhibited [C, 1.83 +/- 0.4 vs. CDCA, 0.02 +/- 0.02 pmol/(mg . minute)]. Four weeks after stopping CDCA feeding, CH-7 alpha was greater in the CDCA-fed animals (C, 0.47 +/- 0.03 vs. CDCA, 0.67 +/- 0.05). This was associated with a greater bile acid pool in these animals (C, 3.0 +/- 0.2 vs. CDCA, 5.8 +/- 0.4). We conclude that CDCA fed to neonatal guinea pigs inhibits CH-7 alpha activity. This inhibition is not permanent, however, since CH-7 alpha activity increases following withdrawal from chronic CDCA feeding.

Age Factors↗

PubMed2001

Guinea pigs as models for cholesterol and lipoprotein metabolism.

Guinea pigs carry the majority of their plasma cholesterol in LDL, making them a unique animal model with which to study hepatic cholesterol and lipoprotein metabolism. In this review, the benefits and advantages of using this particular model are discussed. How dietary factors such as soluble fiber, cholesterol and fatty acids that vary in saturation and chain length affect hepatic cholesterol homeostasis and influence the synthesis, intravascular processing and catabolism of lipoproteins is reviewed. In addition, alterations in hepatic cholesterol metabolism and plasma lipoproteins as affected by treatment with cholestyramine or 3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors, exercise, marginal intake of vitamin C, ovariectomy (a model for menopause) and similarities to the human situation are addressed. A review of guinea pigs as models for early atherosclerosis development is also presented.

Animals↗

PubMed1986

Estimating the impact of risk factor modification programs.

Most studies of the etiology and prevention of disease do not adequately address the quantitative implications of their findings for the population. This report presents a method of combining observational and experimental data to estimate the overall impact of a risk factor modification program. After the terminology is introduced, the model is applied to a categoric risk factor (serum cholesterol) for coronary heart disease, with data from the Pooling Project (1964-1974) and the Lipid Research Clinics studies (1972-1983). With optimistic assumptions about the impact of cholestyramine treatment at various cholesterol levels, about 5% of the cases of coronary heart disease in middle-aged men in the United States could be prevented; more realistic assumptions reduce that estimate by more than half. The model emphasizes the importance of estimating and comparing the overall impact of available risk factor modification programs when planning public health strategies.

Adult↗

PubMed1998

Lower mevalonate pyrophosphate decarboxylase activity is caused by the reduced amount of enzyme in stroke-prone spontaneously hypertensive rat.

Spontaneously hypertensive rat (stroke-prone) (SHRSP) has a low serum cholesterol level as compared with the normotensive Wistar Kyoto rat (WKY). We previously indicated that the lower activity of mevalonate pyrophosphate decarboxylase (MPD) was responsible for the reduced cholesterol biosynthesis in the liver of SHRSP [Sawamura et al. (1992) J. Biol. Chem. 267, 6051-6055]. To elucidate the mechanism of the reduced activity, we purified liver MPD from SHRSP treated with cholestyramine and pravastatin in this study. We compared its enzymatic properties with those of the enzyme from WKY, and also measured the amounts of MPD in the crude extract of various tissues in WKY and SHRSP by Western blot analysis. Results indicated that (i) MPD of SHRSP has essentially the same properties as MPD of WKY, except for a difference in the dependency on divalent cations. (ii) The amount, as well as the activity, of MPD in the crude extract of brain and liver was reduced in SHRSP. (iii) There was no difference between SHRSP and WKY, in the ratio of the enzyme activity to the amount of MPD in the crude extract. These data led us to conclude that the lower activity of MPD was caused by the reduced amount of this enzyme in SHRSP.

Animals↗

PubMed1995

Cholesterol biosynthesis from lanosterol: regulation and purification of rat hepatic sterol 8-isomerase.

The membrane bound sterol-8-isomerase (isomerase) catalyzes the anaerobic conversion of sterol-8-ene to the sterol-7-ene isomer in eucaryotes. To examine the regulatory mechanism as well as molecular characteristics of the isomerase we investigated the consequences of alteration of the enzymic activity under various diet conditions. Feeding 5% cholesterol or 0.1% AY-9944 for a minimum of 2 days caused more than a 70% decrease in microsomal isomerase activity. Feeding 5% cholestyramine plus 0.1% lovastatin (CL-diet) for 7 days led to approximately 4.0-fold induction of the isomerase activity. In addition, diurnal variation in the enzymic activity was observed with this diet. Induction of the isomerase activity by the CL-diet was quantitatively reflected in an increase in the cholesterol synthetic rate in isolated rat hepatocytes. The isomerase was highly purified from liver of rats fed the CL-diet, and its molecular mass was determined to be 21,000 Da by denaturing sodium dodecylsulfate gel electrophoresis.

Animals↗

PubMed2003

Terbinafine-associated hepatotoxicity.

Terbinafine, an orally and topically active agent licensed for treatment of dermatophytic infection, has gained rapid worldwide acceptance in medical practice. Despite its fairly benign profile of adverse reactions, liver toxicity has occasionally been linked to terbinafine. This report describes a patient with severe cholestatic hepatitis associated with use of terbinafine. The patient was treated successfully with corticosteroids after partial response to ursodeoxycholic acid and cholestyramine. We attempt to identify risk factors for terbinafine-induced hepatotoxicity by an analytical review of all relevant literature. The mechanism underlying terbinafine hepatotoxicity could be more than just an idiosyncratic reaction. 7,7-dimethylhept-2-ene-4-ynal (TBF-A), the allylic aldehyde metabolite of terbinafine, may play a role in the pathogenesis of its hepatotoxicity. Our analysis supports monitoring patients clinically and measuring liver biochemistry through periodic blood tests, after confirming normal liver function at the onset of therapy with terbinafine. Early detection of abnormal hepatic function should prompt immediate discontinuation of this drug along with further evaluation.

Adrenal Cortex Hormones↗

PubMed2004

Microscopic colitis.

Microscopic colitis is a condition that is clinically underrecognized as a cause of chronic or intermittent diarrhea and can be diagnosed only by mucosal biopsy. Microscopic colitis is more common in middle-age to elderly women, appears to be induced by some medications, particularly nonsteroidal antiinflammatory drugs, and has been associated with autoimmune conditions and sprue. Symptomatic treatment includes cholestyramine and antidiarrheal medications. Bismuth subsalicylate, and 5-amniosalicylates are therapeutic options; however, budesonide is more effective in achieving clinical and histologic improvement and/or remission and has been studied in more randomized trials. Use of immune modulators should be restricted to more severe cases that are steroid refractory or steroid dependent. Surgical intervention should be reserved for a very highly select group of refractory cases. Diverting ileostomy or colectomy appear to be equally effective surgical alternatives for microscopic colitis, which is not a risk factor for carcinoma.

Journal Article↗

PubMedDate not supplied

Gastrointestinal radiology. A study of iopanoate metabolism and toxicity in isolated cell cultures.

Radiologists are familiar with certain toxic manifestations of biliary and urinary contrast media (ie, acute tubular necrosis in dehydrated patients with diabetes or multiple myeloma), and with the specific effects of contrast media on other diagnostic tests (ie, I uptake, PBI, etc). These have been studied because of their clinical and diagnostic impact upon patient management. It has become apparent that many subtle, though perhaps predictable, drug interactions occur. Some of these are of obvious clinical and therapeutic significance and have been studied and described in detail. The authors have tried to establish the effects of clinically used drugs on the contrast medium iopanoic acid. The fact that both drugs thus far studied - aspirin and cholestyramine - have profound laboratory effects on iopanoic acid suggests that some systematic approach to the study of the clinical pharmacology of contrast agents is desirable. Others have also observed effects of contrast media on various clinical and laboratory parameters, but most observations are isolated empirical observations, and our basic understanding of the mechanisms involved are crude at best. How might this problem be approached? Although in vivo pharmacokinetic studies in unanesthetized animals allow identification of possible drug-drug interactions in the absence of multiple clinical variables and let us do crossover studies with each animal acting as its own control, such studies are difficult, expensive, and do little to establish the mechanism of the interaction. The authors are currently approaching this problem with a more basic technique. In conjunction with colleagues in gastroenterology and pharmacy, they are studying iopanoate metabolism and aspirin-iopanoate interaction in isolated hepatocyte monolayer cultures. The preliminary data from these experiments will be presented, and the significance of these results and the potential usefulness of this model will be discussed.

Animals↗

PubMed1980

Intrahepatic cholestasis for 15 years without cirrhosis.

Whether prolonged cholestasis is followed by hepatic cirrhosis is still controversial. We have studied two unrelated children who have had cholestasis for 15 years, but neither of whom have developed cirrhosis. Both have severe growth retardation, peculiar facies, pulmonic stenosis, transitory renal tubular acidosis, and vitamin D-resistant rickets. The patients presented in infancy with hepatomegaly and direct hyperbilirubinemia; liver biopsy at that time revealed cholestasis and paucity of bile ducts. Subsequent serial liver biopsies have continued to demonstrate cholestasis, but there has been no evidence of cirrhosis. Electron microscopy has revealed swollen and blunted microvilli of the canalicular membrane of the hepatocyte. The patients have had elevated bile acids in the serum as well as a reversed ration of tri- to dihydroxy bile acids. Treatment with cholestyramine and phenobarbital has brought about symptomatic relief from severe pruritus and excoriation and has lowered the level of serum bile acids, although they are still above the normal range. These findings suggest that cholestasis accompanied by an elevated and reversed bile acid ratio does not universally cause hepatic cirrhosis.

Adolescent↗

PubMed1996

Whole-bowel irrigation as an adjunct to the treatment of chronic, relapsing Clostridium difficile colitis.

We report the successful treatment of two patients with chronic, intractable Clostridium difficile infection using whole-bowel irrigation with a polyethylene glycol solution (Golytely) as adjunctive therapy. Before this treatment, both patients had recurrent symptoms of diarrhea, weight loss, abdominal pain, and documented C. difficile toxin-positive stools despite multiple pharmacologic treatments. Each child was prescribed myriad drug therapies, including vancomycin, metronidazole, bacitracin, and rifampin. Cholestyramine and lactobacillus were also tried alone and in combination with antibiotics. In each case, symptoms recurred shortly after cessation of therapy. Whole-bowel irrigation was subsequently administered until profuse, clear liquid stools were produced. This treatment was followed by a 3-week course of oral vancomycin and lactobacillus. In both cases, the patient became asymptomatic within 3 days of therapy; they have remained symptom-free for 36 and 48 months, respectively. We suggest that whole-bowel irrigation clears active C. difficile organisms, toxins, and spores from the intestine and is effective as an adjunct to routine therapy for chronic, relapsing C. difficile infections.

Anti-Bacterial Agents↗

PubMed1989

Late gastrointestinal bleeding and protein loss after distal small-bowel resection in infancy.

Four children who underwent extensive small-bowel resection in infancy developed recurrent iron deficiency anemia due to gastrointestinal bleeding between 4 and 12 years later. The initial resections were required for multiple ileal atresia (n = 2) and gastroschisis (n = 2). Three patients have had melena and one had persistently guaiac-positive stools. Three patients had protein-losing enteropathy, and in one there was persistent hypoalbuminemia. Colonoscopy identified circumferential ulcerative lesions at the surgical anastomosis (n = 2) and at laparotomy another patient had well-defined linear ulcers close to the surgical anastomosis. Histology demonstrated focal ulceration with chronic inflammation, but did not show granulomata, crypt abscesses, or malignancy. Multiple imaging procedures and gastroduodenoscopy failed to identify an alternative bleeding source. Medical therapy including iron, antacids, sucralfate, H2 antagonists, and cholestyramine was ineffective. Two patients have undergone anastomotic resection. One experienced symptomatic recurrence 4 months after surgery. Repeat colonoscopy found ulceration at the new anastomosis with similar histology. The other patient remains asymptomatic 7 months postsurgery. Recurrent gastrointestinal hemorrhage due to anastomotic ulceration, of unknown etiology, appears to be a late complication of small-bowel resection in infancy.

Abdominal Muscles↗

PubMed1991

Congenital diabetes mellitus and fatal secretory diarrhea in two infants.

Two unrelated male infants presented with brittle insulin-dependent diabetes mellitus in the first days of life. Subsequently they each developed severe secretory diarrhea, with stool volumes of more than 100 ml/kg/day. Extensive biochemical and serological investigation failed to reveal the etiology of the diarrhea. The infants, cared for at different institutions, underwent therapeutic trials of various agents including loperamide, cholestyramine, prednisone, indomethacin, and somatostatin analogue, without response. Both infants succumbed to septicemia and malnutrition related to diarrhea and poor control of glycemia. At autopsy, both were found to have absence of islets of Langerhans in the pancreas, and diffuse dysplastic changes in small and large intestinal mucosae. In particular, the entire alimentary tract in each case was lined by epithelia most typical of foregut mucosa: secretory-type glands, absent crypts of Lieberkuhn, and absent villi. These cases are contrasted with previously-reported infants with congenital diabetes mellitus, and the possible interrelation of these two highly unusual findings, congenital diabetes mellitus and diffuse intestinal dysplasia, is examined.

Catheters, Indwelling↗

PubMed1997

Progressive familial intrahepatic cholestasis among the Arab population in Israel.

BACKGROUND: Progressive familial intrahepatic cholestasis, which constitutes a heterogeneous group of imperfectly delineated syndromes and appears to be inherited as an autosomal recessive condition, has not been hitherto reported from the Middle East, in spite of the high rate of consanguineous marriage in this region. METHODS: Sixteen affected children from six Israeli Arab families were evaluated over 30 years. All were born to consanguineous parents. RESULTS: Jaundice appeared during the first 3 weeks of life in 15 babies. When first referred, 10 had hepatomegaly and nine had splenomegaly. A progression toward cirrhosis was the rule. Serum levels of conjugated bilirubin, liver enzymes, and alkaline phosphatase were raised; gamma-glutamyl transpeptidase levels were normal in all three infants in whom it was examined, but elevated in two siblings of another family at ages 2 and 3 years. No abnormal bile acids were detected in the serum and urine of patients. Histologic examination of the liver showed giant-cell transformation, paucity of intrahepatic bile ducts, cholestasis, fibrosis, or cirrhosis. The pattern of liver pathology differed at times among affected members within the same family. Therapeutic trials with phenobarbital, cholestyramine, or ursodeoxycholic acid were ineffective. Survival of the patients was from 5 to 18 months in four families; in the other two families, three children received liver transplants, and one is awaiting liver transplantation. CONCLUSIONS: Progressive familial intrahepatic cholestasis should be included in the differential diagnosis of infants with cholestatic jaundice of unknown etiology, especially those born to consanguineous Arab parents.

Arabs↗

PubMed1988

Prevention of coronary heart disease and hypertension.

This review will concentrate on more recent evidence on the prevention of coronary heart disease and hypertension. With the evidence from lipid-lowering regimes using cholestyramine or gemfibrozil, it is clear that cardiovascular mortality can be reduced by relatively short interventions (years rather than decades). This is surprising in a disease with a long incubation period. We are also on the threshold of much more powerful intervention with the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Follow-up of the very large number of subjects screened for the Multiple Risk Factor Intervention Trial study showed that the relation between serum cholesterol and risk is linear, with no hint of a "safe" level or threshold. This is borne out with the data from rural Chinese, who show the same trend, albeit at levels of risk that are 4% of those of Western populations. The suggestion that low cholesterol levels increase cancer risk appears to result from an artifact. The best dietary interventions for cholesterol lowering are still unresolved, with recent interest in fish oil and olive oil. On the background of raised cholesterol (most Western levels could be regarded as biologically abnormal), cigarette smoking assumes very great importance. Recent evidence from the U.S. Nurses survey points out a two- or threefold increase in risk from as few as four cigarettes per day. With other risk factors the relative risk increases 20-fold. These data are particularly important given that young girls in the United Kingdom and United States currently smoke more than boys.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1994

Hyperlipidemia in renal transplant recipients: natural history and response to treatment.

The lipid profiles of 192 patients with functioning renal transplants and their etiologic associations and response to therapy, in particular simvastatin, were assessed. Hypercholesterolemia was present in 71.3% of patients within 3 years following transplantation. There were independent associations of serum cholesterol with prednisone dosage (p < 0.05), renal function (p < 0.05), and smoking (p < 0.05) in the early posttransplant period (up to 3 months posttransplant). Those patients whose immunosuppression included cyclosporin had lower serum cholesterol levels than those receiving azathioprine and prednisone (p < 0.02). Plasma triglyceride levels reflected a marked interindividual variation, and no independent correlations were observed. The presence of diabetes mellitus, hypertension (or the use of antihypertensive agents), or the form or duration of prior dialysis did not independently influence the lipid profiles. During the study period 22 patients died, 54.5% due to vascular causes. Those who died of vascular causes had higher serum cholesterol levels than those who died of other causes, which reached statistical significance at 3 years posttransplant (7.74 +/- 0.4 versus 5.5 +/- 0.52 mmol/L; p < 0.02). Cholestyramine was introduced in 30 patients, only 2 of whom continued with therapy beyond 3 months. Simvastatin was used in 43 patients, 20 of whom were receiving cyclosporin, resulting in a mean reduction in serum cholesterol of 16.5% (p < 0.001) and in serum triglycerides of 21% (p < 0.05). No clinical or biochemical evidence of muscle, liver, or renal toxicity occurred in 15.4 +/- 0.9 months of follow-up.

Adolescent↗

PubMed1985

Primary sclerosing cholangitis.

Primary sclerosing cholangitis is a chronic, cholestatic disease affecting the biliary tree. Recent data suggest an autoimmune etiology. Clinical findings, roentgenographic characteristics, and compatible liver histology will help in establishing the diagnosis. There is no known treatment for cure, though relief of symptoms may be accomplished with certain drugs, such as antibiotics for cholangitis and cholestyramine for pruritus. Death usually ensues within five to seven years after diagnosis, as a consequence of liver failure, cholangitis, and cholangiocarcinoma.

Adult↗

PubMed1997

Chronic diarrhea associated with thymoma and hypogammaglobulinemia (Good's syndrome).

We report the case of a patient with severe diarrhea and malabsorption who was subsequently found to have hypogammaglobulinemia and thymoma (Good's syndrome). The mechanism by which hypogammaglobulinemia and/or thymoma causes diarrhea is unclear. It may be related to malabsorption caused by a mucosal lesion resembling villous atrophy, which may resolve with restoration of immunologic status. Diarrhea in some patients may respond to commercial gamma globulin injections, fresh frozen plasma, or cholestyramine therapy. The etiologic relationship between thymoma and acquired hypogammaglobulinemia remains unclear. Thymectomy is generally ineffective in improving immunologic deficiencies and coexisting conditions in patients with acquired hypogammaglobulinemia. In our patient's case, severe diarrhea resolved after resection of the thymoma.

Agammaglobulinemia↗