Effect of potassium-magnesium citrate on upper gastrointestinal mucosa.

BACKGROUND: Potassium supplements may cause mucosal damage of the gastrointestinal tract. AIM: To evaluate the effect of a new potassium supplement, potassium-magnesium citrate (K-Mag), on upper gastrointestinal mucosa and to compare it with an older potassium supplement, potassium citrate (Urocit-K). METHODS: A randomized and double-blind study was conducted utilizing 36 healthy adults. Subjects were randomized into three groups: K-Mag (70 mmol/day K, 35 mmol/day citrate and 17.6 mmol/day Mg); Urocit-K (70 mmol/day K and 23.4 mmol/day citrate), and placebo. All subjects took 5 tablets b.d. of the allocated drug and 2 mg t.d.s. of glycopyrrolate for 7 days. On day 8, stool was examined for occult blood, a symptom score was calculated and an oesophagogastroduodenoscopy was performed. Mucosal lesions were scored at five anatomic sites. RESULTS: Demographic characteristics and symptom score were similar in the three groups (< 10% with more than mild symptoms). There were no significant differences in the endoscopic scores at any site examined nor in the total scores among the three groups. Erosion or ulcers were found in 180% of K-Mag, 23% of Urocit-K and 17% of the placebo group. CONCLUSION: Short-term use of K-Mag does not appear to induce lesions in the upper gastrointestinal mucosa and its oral tolerance is similar to Urocit-K or placebo.

Treatment of severe steatorrhea with ox bile in an ileectomy patient with residual colon.

Patients with ileectomy can present with severe steatorrhea due to bile acid depletion. While exogenous bile acid would seem to be ideal therapy for this condition, it is not often used because it is thought that the bile acid would be malabsorbed and would enter the colon, producing a secretory diarrhea. This report describes a patient who had an ileectomy and partial right colon resection for Crohn's disease and then developed severe steatorrhea due to bile acid malabsorption. Although steatorrhea was reduced from 134 to 9 g/24 hr with chronic ingestion of ox bile extract, stool weight did not increase with ox bile (stool weight 669 g/24 hr before therapy and 507 g/24 hr after therapy). In this patient, oral bile acid supplementation reduced fat excretion markedly, but did not aggravate diarrhea, even though the colon was still present. This result may have been due to impaired solubility of bile acid in fecal fluid due to an acid pH or to binding of bile acid with particles of solid stool. Ingestion of ox bile extract does not necessarily increase stool weight in patients with defective fat absorption due to bile acid malabsorption and can be tried with caution in an effort to diminish steatorrhea.

Comparison of endogenous and radiolabeled bile acid excretion in patients with idiopathic chronic diarrhea.

Fecal recovery of radioactivity after ingestion of a bolus of radiolabeled bile acid is abnormally high in most patients with idiopathic chronic diarrhea. To evaluate the significance of this malabsorption, concurrent fecal excretion of both exogenous radiolabeled bile acid and endogenous (unlabeled) bile acid were measured in patients with idiopathic chronic diarrhea. Subjects received a 2.5-microCi oral dose of taurocholic acid labeled with 14C in the 24th position of the steroid moiety. Endogenous bile acid excretion was measured by a hydroxysteroid dehydrogenase assay on a concurrent 72-h stool collection. Both radiolabeled and endogenous bile acid excretion were abnormally high in most patients with chronic diarrhea compared with normal subjects, even when equivoluminous diarrhea was induced in normal subjects by ingestion of osmotically active solutions. The correlation between radiolabeled and endogenous bile acid excretion was good. However, neither radiolabeled nor endogenous bile acid excretion was as abnormal as is typically seen in patients with ileal resection, and none of these diarrhea patients responded to treatment with cholestyramine with stool weights less than 200 g. These results suggest (a) that this radiolabeled bile acid excretion test accurately reflects excess endogenous bile acid excretion; (b) that excess endogenous bile acid excretion is not caused by diarrhea per se; (c) that spontaneously occurring idiopathic chronic diarrhea is often associated with increased endogenous bile acid excretion; and (d) that bile acid malabsorption is not likely to be the primary cause of diarrhea in most of these patients.

Inappropriate hepatic cholesterol synthesis expands the cellular pool of sterol available for recruitment by bile acids in the rat.

These studies test the hypothesis that a major determinant of excessive biliary cholesterol secretion is a level of hepatic sterol synthesis that is inappropriately high relative to the needs of the liver cell for preserving cholesterol balance. Biliary cholesterol secretion was measured in vivo in two models after loading the hepatocyte with sterol by two different mechanisms. In the first model, cholesterol was delivered physiologically to the liver in chylomicron remnants. This resulted in a sixfold increase in cholesteryl ester content and marked suppression of cholesterol synthesis, but biliary cholesterol secretion remained essentially constant. In the second model, 3-hydroxy-3-methyl-glutaryl CoA reductase levels in the liver were markedly increased by chronic mevinolin (lovastatin) administration. Withdrawal of the inhibitor resulted in a sudden fivefold increase in the rate of sterol synthesis in the liver of the experimental animals that was inappropriately high for cellular needs. This excessive synthesis, in turn, was accompanied by a fivefold increase in the cholesteryl ester content, enrichment of microsomal membranes with cholesterol and, most importantly, by a threefold increase in the rate of biliary sterol secretion. As the rate of sterol synthesis gradually returned to normal over 48 h, the cholesterol ester content, the lipid composition of the microsomal membranes, and rate of cholesterol secretion into bile also returned to baseline values. These results further support the concept of functional compartmentalization of cholesterol in the hepatocyte. Derangements that cause an inappropriately high rate of sterol synthesis in the endoplasmic reticulum may lead to an expansion of that pool of cholesterol that is recruitable by bile acids and, hence, to greater situation of the bile.

Bile salt hydrophobicity influences cholesterol recruitment from rat liver in vivo when cholesterol synthesis and lipoprotein uptake are constant.

These studies were undertaken to characterize the role of bile salt hydrophobicity in determining the rate of cholesterol recruitment from the liver. Using an in vivo rat model in which the acquisition of hepatic cholesterol from chylomicron remnants, low-density lipoproteins, and de novo synthesis was measured and kept constant, it was found that the amount of sterol recruited from the liver cell increased progressively as the liver was probed with a constant infusion of progressively more hydrophobic bile salts. The absolute secretion rate of both cholesterol and phospholipid increased nearly 50% as the hydrophobic index of the bile salts traversing the liver increased from 1.7 to 4.5, but the ratio of cholesterol to phospholipid secreted in bile remained nearly constant. Thus, when cholesterol entry into the hepatocyte via lipoproteins and de novo cholesterol synthesis is constant, the mass of cellular cholesterol recruited into the bile is directly proportional to the hydrophobic-hydrophilic balance of the secreted bile salts.

Cholesterol gallstone disease: the current status of nonsurgical therapy.

Gallstone disease is a common disease that appears to be related to a Western diet. The underlying pathogenesis is a subtle alteration in the liver such that excessive cholesterol is extracted from the liver cell by bile acids undergoing an enterohepatic recirculation. Gallstone disease progresses through well-defined stages, beginning with a bile supersaturated with cholesterol and proceeding to crystal formation, stone growth, and finally symptoms caused by impaction of a stone in either the cystic duct or the common bile duct. The natural history is that most stones never cause symptoms. Stones that cause symptoms have been present for an average of 12 years. The treatment of truly asymptomatic stones should be observation. Ultrasonography of the right upper quadrant is the gold standard for the diagnosis of stones in the gallbladder. Endoscopic retrograde cholangiopancreatography (ERCP) is the gold standard for the diagnosis of stones in the common bile duct. Oral cholecystogram (OCG) helps select patients who have noncalcified, floating stones that may be dissolved with bile acids or methyl tertiary butyl ether (MTBE). Therapy with chenodiol has been a disappointment because of a low complete response rate. The ideal candidate for attempted dissolution with chenodiol would be a thin woman with hypercholesterolemia and a small number of symptomatic, small, floating, radiolucent gallstones. Ursodeoxycholic acid (Urso), when it is available, will have all of the attributes of chenodiol and virtually none of the side effects. Rapid dissolution of gallstones with MTBE shows great promise of being a generally available means of dissolving gallstones. Extracorporeal shock wave lithotripsy also shows promise, but its general availability may be limited by the cost of the equipment needed. As of now, the treatment of choice for symptomatic gallstones remains cholecystectomy, unless there is a compelling reason not to operate.

Renal cell carcinoma in the Wistar-Lewis rat: a model for studying the mechanisms of cholesterol acquisition by a tumor in vivo.

Renal adenocarcinoma implanted into isogeneic Wistar-Lewis rats closely resembles human renal cancer. This paper characterizes the tumor's growth rate, metastatic potential, and its light and electron microscopic appearance. Additionally, for the first time, the pathways through which a tumor acquires the cholesterol needed for growth were quantified in vivo. Two 1-mg pieces of renal carcinoma were implanted beneath the renal capsule of 80 Wistar-Lewis rats. Of the implanted tumors 95% "took" and grew rapidly, doubling every 2.6 days initially. Growth slowed, however, to a doubling time of 8.3 days by the fifth wk. Twenty rats underwent surgical resection of the primary tumor 5 wk after implantation. Of these, 85% subsequently developed lung metastases. Histologically, the tumor had a clear-cell appearance due to the presence of large vacuoles, some of which contained glycogen. The esterified cholesterol content of the tumor was 3-fold higher than normal kidney during the initial period of rapid tumor growth and increased to a 14-fold elevation by 12 wk. The normal kidney in vivo had a high rate of uptake of cholesterol carried in low density lipoproteins and a low rate of de novo sterol synthesis. In contrast, the renal carcinoma lost most of its low density lipoprotein uptake activity and, instead, acquired the cholesterol needed for growth by a 5-fold increase in the rate of de novo cholesterol synthesis. This model may prove valuable in both testing therapeutic strategies directed against human renal cancer and understanding the regulation of cholesterol homeostasis in a growing cancer.

Bile acids regulate hepatic low density lipoprotein receptor activity in the hamster by altering cholesterol flux across the liver.

The effect of different bile acids on receptor-dependent and receptor-independent low density lipoprotein (LDL) uptake in the liver and intestine was investigated. When fed at the 0.1% level for three weeks, cholic acid and chenodeoxycholic acid suppressed hepatic cholesterol synthesis in the rat by 80% and 50%, respectively, while ursodeoxycholic acid had no effect. In contrast, hepatic cholesteryl ester levels, rates of hepatic LDL transport, and concentrations of plasma LDL-cholesterol were not affected by bile acid feeding in this species. Cholic acid and chenodeoxycholic acid also suppressed hepatic cholesterol synthesis in the hamster. However, since basal rates of hepatic cholesterol synthesis in this species, as in man, are very low, the absolute reduction in hepatic synthesis could not compensate for the change in hepatic sterol balance induced by bile acid feeding. Hence, in the hamster the feeding of cholic acid and chenodeoxycholic acid increased hepatic cholesteryl ester levels 660% and 39%, respectively, reduced hepatic receptor-dependent LDL uptake by 50% and 32%, respectively, and elevated plasma LDL-cholesterol levels by 160% and 50%, respectively. Ursodeoxycholic acid feeding did not alter any of these processes, and none of the bile acids changed the rate of hepatic receptor-independent LDL transport. In the intestine, none of the bile acids altered rates of cholesterol synthesis or LDL uptake. When cholic acids, chenodeoxycholic acid, or ursodeoxycholic acid was infused continuously for 8 hr in supranormal amounts into control hamsters or rats or into animals pretreated with cholestyramine, there were no changes in LDL transport or any other parameter of hepatic cholesterol metabolism. Thus, these studies indicated that cholic acid and chenodeoxycholic acid have no acute, direct effect on rates of receptor-dependent LDL transport or cholesterol synthesis but do alter these processes indirectly by inducing changes in cholesterol balance across the liver. Ursodeoxycholic acid, in contrast, does not affect these processes either directly or indirectly and so causes no change in plasma LDL levels.

Low density lipoprotein-receptor activity is lost in vivo in malignantly transformed renal tissue.

Mammalian cells can acquire cholesterol through two tightly regulated pathways, namely de novo cholesterol synthesis and receptor-mediated endocytosis of circulating low density lipoprotein (LDL). Malignant cells growing in vitro acquire cholesterol through both mechanisms but the quantitative importance of these pathways to a cancer growing in vivo is not known. Using the Lewis rat renal carcinoma model, this study measured the rate of cholesterol acquisition via both pathways in vivo in both normal and malignant renal tissue. In contrast to normal kidney, after malignant transformation, LDL-receptor activity disappeared entirely and the cancer acquired the cholesterol needed for growth by a 5-fold increase in the rate of cholesterol synthesis.