Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024523 (malabsorption)
 7,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cholesterol balance studies were carried out twice in a young male patient with homozygous familial hypercholesterolemia. At 13 mo, cholesterol balance in this patient averaged 31.3 mg/kg per d, and bile acid excretion was 12.0 mg/kg per d; at 3 yr, results were similar, 27.3 and 15.5 mg/kg per d for cholesterol balance and bile acids, respectively. A normal boy of 3 yr was also studied for comparison with the second study in our patient. Cholesterol balance and bile acid outputs in the normal child were 11.5 and 3.3 mg/kg per d, respectively. Thus, in comparison with the normal child, the patient with homozygous familial hypercholesterolemia had a marked increase in synthesis of cholesterol and bile acids. Although synthesis of bile acids was high in this patient, the fraction of newly synthesized cholesterol converted into bile acids (40-56%) was in the normal range; this suggests that the enhanced output of bile acids was secondary to an increased synthesis of cholesterol and not to malabsorption of bile acids, which likely would have produced a higher fractional conversion. Although our patient has been studied at a younger age than any reported in the literature, two similar children 5 and 6 yr of age were also observed to have elevated cholesterol synthesis. This finding contrasts with those in older children with the homozygous as well as heterozygous forms of this disease who appear to have normal synthesis of cholesterol and bile acids. Therefore, increased synthesis of cholesterol seems to be characteristic of early homozygous familial hypercholesterolemia, and may be a manifestation of a loss of feedback inhibition of cholesterol synthesis secondary to an absence of specific cell-surface receptors for low density lipoproteins. However, as children with this disease grow older, other mechanisms may come into play to restore cholesterol synthesis to normal levels.
 ...
PMID:Elevated cholesterol and bile acid synthesis in a young patient with homozygous familial hypercholesterolemia. 46 90

Results relative to long term treatment with Colestipol (a new resin sequestering bile acids) in 23 subjects with familial hypercholesterolemia, 12 with Type II A, 8 with Type II B and 3 homozygotes are reported. The patients had previously undergone treatment with clofibrate together with a hypocholesterolemic diet. After six weeks with placebo, the patients were given 15 g/die active drug for a period of 12 months and a double dose (30 g/die) for a successive period of 4 months. During the experimental trial the same hypocholesterolemic, isocaloric diet which had been followed during the previous hypolipidemic treatment was maintained. In the entire group taken as a whole, the total mean decrease was --56,9 +/- 15 mg/dl (P less than 0,01) after 12 months of 15 g/die Colestipol and --62,8 +/- 13 mg/dl (P less than 0,01) during the following 4 months with 30 g/die Colestipol. The difference between the two periods of treatment (15 g and 30 g/die) is not statistically significant. During the active drug treatment a slight but not statistically significant triglyceride increase was observed. The increase was most marked in the Type II B patients: the triglyceride variations in this group could be partly caused by slight variations in mean body weight. Starting from a mean basal value of 3,9 +/- 0,2 mg/dl, serum uric acid showed a significant increase which was maintained throughout the entire period of treatment, reaching a peak of 5,6 +/- 0,3 mg/dl (P less than 0,001) at the twelfth month. During the experimental trial no significant modifications were observed in the hematological routine analysis and liver functional tests, no malabsorption syndrome and no signs of toxicity were seen. Most frequent side effects were constipation, nausea, metheorism which, with the exception of four cases, which were withdrawn from the study, were reported as being transitory and mild. In conclusion, since Colestipol treatment significantly lowers cholesterol levels in patients with familial hypercholesterolemia and does not manifest any toxicity or serious side effects, it can be used effectively in the long term treatment of this disease which is characterized by an elevated frequency of cardiovascular complications.
 ...
PMID:[Long term treatment of familial hypercholesterolemia with Colestipol, a new anionic exchange resin (author's transl)]. 114 65

In the past 5 years, many different mutations in the apolipoprotein (apo) B gene have been described that affect plasma cholesterol levels. More than 20 different mutations in the apoB gene have been shown to cause familial hypobetalipoproteinaemia, a condition characterized by abnormally low plasma concentrations of apoB and LDL cholesterol. Almost all of the mutations are nonsense or frameshift mutations that interfere with the translation of a full-length apoB100 molecule. Many, but not all, of these apoB gene mutations result in the synthesis of a truncated species of apoB that can be detected within the plasma lipoproteins. Familial hypobetalipoproteinaemia heterozygotes are almost always asymptomatic and have LDL cholesterol levels about one-quarter to one-third of those of unaffected family members. Several homozygotes and compound heterozygotes for familial hypobetalipoproteinaemia have been described. In these individuals, the LDL cholesterol levels are extremely low, usually less than 5 or 10 mg dl-1, and the clinical phenotype is variable, ranging from completely asymptomatic to severe problems related to intestinal fat malabsorption. One missense mutation in the apoB gene (an Arg----Gln substitution at apoB amino acid 3500) is associated with very poor binding of apoB100 to the cellular LDL receptor. This syndrome has been designated familial defective apolipoprotein B (FDB). The amino-acid substitution at residue 3500 delays the clearance of LDL from the plasma and results in hypercholesterolaemia. In some Western populations, the frequency of FDB heterozygotes appears to be as high as 1 in 500 individuals.
 ...
PMID:Apolipoprotein B gene mutations affecting cholesterol levels. 161 87

The active transport of conjugated bile acids by the ileum is responsible for the enterohepatic circulation of bile acids, a physiological process that ensures an ample supply to the intestine of these key biological surfactants, irrespective of the rate of their biosynthesis from cholesterol. The ileal bile acid transport system is a high capacity, low affinity secondary active Na+ co-transport system that differs in substrate specificity from that present in the hepatocyte. Ileal transport is homeostatically regulated by feedback inhibition of the bile acids that are transported. The enterohepatic circulation is responsible for the concentration profile present in the intestine--high concentrations in the small intestine and low concentrations in the large intestine. Loss of ileal absorption, when mild, leads to a sequence of events that result in increased concentrations in the large intestine causing diarrhea. Severe bile acid malabsorption causes decreased concentrations in the small intestine which in turn lead to fat maldigestion and fat malabsorption. The increased passage of fatty acids into the colon contributes to diarrhea. Fat maldigestion and malabsorption also causes increased absorption of dietary oxalate from the colon which causes hyperoxaluria and contributes to nephrolithiasis. In cholestatic liver disease, inappropriate upregulation of ileal bile acid transport is likely to cause retention of hepatotoxic endogenous bile acids. In familial hypercholesterolemia, efficient bile acid absorption contributes to downregulation of LDL receptors and the maintenance of elevated plasma cholesterol levels; upregulation of bile acid transport during bile acid sequestrant therapy could diminish its efficacy. Efforts are in progress to develop a suitable bile acid analogue to be administered orally for conditions of bile acid deficiency in the small intestine.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Biological and medical aspects of active ileal transport of bile acids. 206 93

Biliary and fecal bile acid composition was studied in 13 patients 3-12 years after a partial ileal bypass operation and in 10 unoperated controls, all with heterozygous familial hypercholesterolemia. Three operated patients were taking cholestyramine. The relative amount of cholic acid in the bile was decreased at the expense of chenodeoxycholic acid in the operated subjects. Chenodeoxycholic acid content of the bile correlated negatively with the fractional cholesterol absorption, suggesting that in compromised absorption chenodeoxycholic acid is absorbed more efficiently than cholic acid. Despite a ninefold increase in total bile acid synthesis the cholic/chenodeoxycholic acid synthesis ratio was not significantly different in the operated and control subjects. However, the lower the chenodeoxycholic acid synthesis the higher was the proportion of deoxycholic acid in the bile and feces, suggesting regulation of chenodeoxycholic acid synthesis by deoxycholic acid. Ileal exclusion had increased the proportion of primary bile acids in the feces from below 10 to over 50%. Despite increased fecal water excretion the concentration of fecal total and dihydroxy bile acids was higher in the operated than in control subjects. However, the fecal concentration of the potentially cancer-promoting bile acids, deoxycholic acid and lithocholic acid, was not increased in the operated subjects. In the operated subjects, fecal water output was positively correlated with total bile acid and chenodeoxycholic acid synthesis. It is concluded that the severe bile acid malabsorption caused by ileal exclusion activates the synthesis of both primary bile acids in similar amount. However, after ileal exclusion the relative amount of cholic acid in the bile is decreased, obviously because loss of ileal absorption predominantly affects the absorption of cholic acid.
 ...
PMID:Fecal and biliary bile acid composition after partial ileal bypass operation. 339 74

Factors regulating the metabolism of plant sterols (sitosterol and campesterol) and their serum levels were studied in sixteen patients with heterozygous familial hypercholesterolemia. Eight patients had undergone an ileal bypass operation, resulting in slight fat and severe bile acid malabsorption and in lowered serum cholesterol concentration, but normal fractional cholesterol absorption. Serum plant sterol concentrations (mg/dl) were similar in the two groups, but expressed per milligram of cholesterol were higher in the operated patients. Fecal excretion (equal with intake) and biliary secretion (reflecting absorption) of the plant sterols were similar in the two groups and were significantly correlated with the serum plant sterol content, which also correlated positively with the fractional cholesterol absorption in the control but not in the operated group. The estimated fractional absorption of the plant sterols was similar in the two groups, but that of sitosterol (3.5%) was lower than that of campesterol (9.1%). Our study shows that serum plant sterols are associated with fractional cholesterol absorption even in patients with familial hypercholesterolemia. However, after ileal exclusion dietary intake of the plant sterols is the main regulator of their serum levels.
 ...
PMID:Effect of ileal exclusion on plant sterol metabolism in familial hypercholesterolemia. 344 23

Cholesterol and bile acid metabolism and vitamin B12 were studied in 19 patients with heterozygous familial hypercholesterolemia in an 8-yr follow-up (3-12 yr after ileal bypass operation), and in 11 unoperated controls. Absorption of cholesterol and vitamin B12 were decreased by the operation, but improved slowly, and at 8 yr cholesterol absorption was normal. Cholesterol excretion as fecal neutral steroids was not increased by the operation, and at 8 yr the flux of endogenous cholesterol to the gut was similar in the operated and control patients. Cholesterol absorption was positively correlated with mouth to anus transit time in the unoperated patients. Fecal bile acid excretion was increased immediately after the operation and continued to increase even after the second postoperative year. In the operated patients fecal excretion of fat, water, and dry matter were positively correlated with fecal bile acid excretion. Our study suggests that adaptive changes occur slowly after ileal bypass, resulting in gradual normalization of cholesterol absorption, despite continuing bile acid malabsorption, and that the intestinal transit time is related to steroid absorption even under physiologic conditions.
 ...
PMID:Adaptation of cholesterol and bile acid metabolism and vitamin B12 absorption in the long-term follow-up after partial ileal bypass. 394 24

Sitosterolemia is a genetic disorder characterized by sitosterol accumulation in plasma and clinically accelerated atherosclerosis. Under a condition of metabolic control with a 30% fat, low-sitosterol diet, we compared the effects of monotherapy and dual-drug treatment with lovastatin and cholestyramine on plasma sterol parameters and endogenous cholesterol synthesis in a homozygous sitosterolemic patient with concomitant heterozygous familial hypercholesterolemia (FH), her obligate heterozygous father, and hyperlipidemic control subjects. We found that for both the sitosterolemic homozygote and heterozygote, cholestyramine plus lovastatin dual therapy proved not to be superior to either drug treatment alone. In the homozygous patient, cholestyramine accounted for the decrease of plasma sterol (ie, lovastatin was ineffective), whereas in the heterozygote, lovastatin represented the margin of difference (ie, low-dose cholestyramine was relatively ineffective). Thus, the best treatment option for this homozygote child and her heterozygote father appears to be monotherapy with cholestyramine and lovastatin, respectively. Stimulation by bile acid malabsorption produced a dramatic decrease of plasma sterols in the homozygote, without increasing endogenous cholesterol synthesis, but this therapy was ineffective in the heterozygote. Decreasing endogenous cholesterol synthesis with lovastatin was effective in the heterozygote, but ineffective in the homozygote. In suspected sitosterolemia, a poor sterol response to lovastatin and a dramatic response to cholestyramine may differentiate homozygous from heterozygous and other familial forms of hyperlipidemia.
 ...
PMID:Sitosterolemia: opposing effects of cholestyramine and lovastatin on plasma sterol levels in a homozygous girl and her heterozygous father. 863 39

Statins effectively inhibit cholesterol synthesis and are currently the most commonly used drugs for the treatment of hypercholesterolemia. However, patients with familial hypercholesterolemia and those unwilling to take, or who cannot tolerate statins, and patients with combined hyperlipidemia require a combination treatment. Statins combined with cholesterol malabsorption, caused, e.g., by plant stanol esters or ezetimibe (Schering-Plough Corp/Merck & Co Inc), or with bile acid malabsorption, caused by bile acid binding resins or guar gum, inhibit compensatory increases in cholesterol synthesis and effectively lower LDL cholesterol levels. Combination therapy of statins with fibrates should be controlled by lipidology experts. Recent information on indications and advantages of combining statins with n-3 fatty acids, hormone replacement therapy, or niacin, will also be discussed.
 ...
PMID:Combination therapy with statins. 1249 7

Patients with severe malabsorption have abnormal lipid metabolism with low plasma cholesterol and frequently high triglyceride (TG) levels. The mechanisms behind these abnormalities and the respective roles of malabsorption itself and of the parenteral nutrition given to these patients are unclear. We measured endogenous lipids synthesis (cholesterol synthesis and hepatic lipogenesis) and the expression (mRNA concentrations in circulating mononuclear cells) of regulatory genes of cholesterol metabolism in 10 control subjects and 22 patients with severe malabsorption receiving (n = 18) or weaned of parenteral nutrition (n = 4). Patients had low plasma cholesterol (P < 0.01) and raised TG (P < 0.05) levels. Both fractional and absolute cholesterol synthesis (P < 0.001) and hepatic lipogenesis (P < 0.01) were increased. These abnormalities are independent of parenteral nutrition since they were present in patients receiving or weaned of parenteral nutrition. No relation between hepatic lipogenesis and plasma TG levels was found, suggesting that other metabolic abnormalities participated in hypertriglyceridemia. HMG-CoA reductase and LDL receptor mRNA levels were decreased (P < 0.05) in patients on long-term parenteral nutrition. HMG-CoA reductase mRNAs were normal in weaned patients.Severe malabsorption induces large increases of cholesterol synthesis and hepatic lipogenesis independently of the presence of parenteral nutrition. These abnormalities are probably due to the malabsorption of bile acids.
 ...
PMID:Stimulation of cholesterol synthesis and hepatic lipogenesis in patients with severe malabsorption. 1270 Mar 39


1