Hans Fromm

Breath test for altered bile-acid metabolism

Summary Increased bacterial deconjugation of bile acids was agsessed by measuring 14 CO 2 specific activity of breath samples taken at intervals after a meal containing cholyl-glycine-l- 14 C (glycocholic acid). In all of 5 patients with conditions associated with stasis and bacterial overgrowth in the small intestine, and in 17 of 19 patients with ileal resection and documented severe bile acid malabsorption, 14 CO 2 specific activity was strikingly higher at two or four hours than in eighteen healthy control subjects. Measurement of fecal 14 C, in addition to breath 14 CO 2 , permitted complete separation of bile-acid malabsorption from bacterial overgrowth and also identified the 2 false-negatives who had a negative breath test despite severe bile-acid malabsorption. The breath test is a rapid, simple, tubeless outpatient procedure for detecting increased deconjugation of bile acids in intestinal disease.

Acquired Hyperoxaluria, Nephrolithiasis, and Intestinal Disease: Description of a Syndrome

Abstract In seven patients with resection of the distal ileum, calcium oxalate nephrolithiasis and increased urinary excretion of oxalate (64 to 135 mg per 24 hours) developed. Cholestyramine therapy (4 g four times a day) lowered the 24-hour urinary excretion of oxalate to normal in the four patients in whom it was used. Urinary excretion of oxalate was measured in an additional 42 patients with various types of intestinal disorders without evidence of nephrolithiasis. Five of 18 patients with ileal resection, two of seven with bacterial over-growth, and six of 15 with miscellaneous conditions, including nontropical sprue and cirrhosis, had hyperoxaluria.

Acquired Hyperoxaluria, Nephrolithiasis, and Intestinal Disease

Abstract In seven patients with resection of the distal ileum, calcium oxalate nephrolithiasis and increased urinary excretion of oxalate (64 to 135 mg per 24 hours) developed. Cholestyramine therapy (4 g four times a day) lowered the 24-hour urinary excretion of oxalate to normal in the four patients in whom it was used. Urinary excretion of oxalate was measured in an additional 42 patients with various types of intestinal disorders without evidence of nephrolithiasis. Five of 18 patients with ileal resection, two of seven with bacterial over-growth, and six of 15 with miscellaneous conditions, including nontropical sprue and cirrhosis, had hyperoxaluria.

Comparative efficacy and side effects of ursodeoxycholic and chenodeoxycholic acids in dissolving gallstones. A double-blind controlled study.

In a double-blind controlled study of ursodeoxycholic acid (400 and 800 mg/day) and chenodeoxycholic acid (375 and 750 mg/day), in comparison with placebo, ursodeoxycholic acid was significantly more effective than chenodeoxycholic acid in dissolving gallstones after 12 mo of treatment. Although there continued to be better dissolution during ursodeoxycholic acid treatment (dissolution complete in 30% and partial in another 30% of the patients) than during chenodeoxycholic acid treatment (dissolution complete in 7% and partial in 40%) at 24 mo, this difference between the treatment groups was no longer statistically significant. The incidence of floating stones was significantly higher in the patients who dissolved their stones than in those who did not (p less than 0.001). The three failures of dissolution of floating stones during bile acid treatment were associated with chenodeoxycholic acid therapy--two of them with the 750-mg and the third with the 375-mg doses. Gallstone dissolution with ursodeoxycholic acid occurred in spite of a rise in biliary cholesterol saturation, which was consistent with a nonmicellar mechanism of cholelitholysis. Furthermore, more than threefold serum elevations of L-alanine aminotransferase were observed only during chenodeoxycholic acid therapy. They occurred in 2 patients treated with 375 and 750 mg/day, respectively. The enzyme levels normalized after discontinuation of chenodeoxycholic acid and have remained normal for 13 and 8 mo, respectively, after the institution of treatment with 800 mg/day of ursodeoxycholic acid. There was no correlation between the liver tests and biliary levels of lithocholic acid. Of all the symptoms studied, only constipation showed changes that approached statistical significance (p = 0.0681). There was a significant improvement of constipation in the combined chenodeoxycholic acid groups when they were compared with the combined ursodeoxycholic acid groups. The total bile acid pool expanded significantly in both the chenodeoxycholic acid and in the 800-mg ursodeoxycholic acid treatment groups. The marked increases of biliary ursodeoxycholic acid and chenodeoxycholic acid, respectively, indicated compliance with the treatment in all but 1 bile acid-treated patient. Neither serum triglycerides nor serum cholesterol showed significant changes in any of the treatment groups. The study shows that ursodeoxycholic acid dissolves gallstones faster and with fewer side effects than chenodeoxycholic acid. The results of the study are also consistent with the view that ursodeoxycholic acid is cholelitholytic at a lower dose than is chenodeoxycholic acid.

Sensitivity and Specificity in Tests of Distal Ileal Function: Prospective Comparison of Bile Acid and Vitamin B12 Absorption in Ileal Resection Patients

Abstract Bile acid and vitamin B 12 absorption were compared prospectively in 22 patients with distal ileal resection, 7 with similar diarrhea but apparently normal ileal function, 5 with the stagnant loop syndrome, and 3 with steatorrhea due to digestive abnormalities. Also studied were 18 healthy control subjects. A test meal containing glycine- 14 C-labeled glycocholate, 3 H-ring-labeled taurocholate, vitamin B 12 - 57 Co with intrinsic factor, and 51 CrCl 3 as nonabsorbable marker was administered to fasting patients. Bile acid absorption was assessed by appearance of 14 CO 2 in breath and by fecal excretion of 14 C or 3 H; B 12 absorption was measured by excretion of 57 Co in urine (Schilling test). Based on fecal excretion of 3 H, nearly all patients with ileal resection had unequivocal bile acid malabsorption. Measurement of 14 CO 2 in breath was less sensitive since four false negatives were identified. Measurement of both 14 CO 2 and fecal 14 C was as sensitive as measurement of fecal 3 H. Of the 14 patients with resections less than 100 cm, 4 had normal Schilling tests, despite nearly all having bile acid malabsorption; both tests were equivocal or abnormal in patients with larger resections. In patients with similar diarrhea but no evidence of ileal dysfunction, bile acid malabsorption was not present, since the ratio of fecal bile acid radioactivity to marker radioactivity was significantly smaller than in patients with ileal resection; B 12 absorption was normal. The breath test appears to be a useful screening test for the detection of the stagnant loop syndrome. Its interpretation is uncertain in patients with ileal dysfunction, since such patients may also have bile acid malabsorption. Thus, the clinical value of the breath test or measurement of bile acid absorption in such patients probably can only be determined by future studies which relate test results to therapeutic response.

Gallstone dissolution treatment with a combination of chenodeoxycholic and ursodeoxycholic acids: Studies of safety, efficacy and effects on bile lithogenicity, bile acid pool, and serum lipids

Sixteen patients with radiolucent gallstones were treated with a combination of chenodeoxycholic and ursodeoxycholic acids for an average of 19 months. Liver tests remained normal in all patients. In nine of 15 patients (60%), in whom the gallbladder visualized during an oral cholecystogram, gallstones dissolved after one year, in eight of them, partially, and in the remaining one, completely. After two years, partial dissolution became complete in three patients, and partial dissolution occurred in 1 additional patient. Changes in lithogenic index and bile acid pool size were statistically not significant. Biliary content of chenodeoxycholic acid increased significantly from 25.7±3.53 to 45.2±3.31 (mean±se)% and that of ursodeoxycholic acid from 2.6±0.52 to 34.6±2.45%. There were no discernible changes in serum triglycerides, total cholesterol, and HDL cholesterol. The findings suggest that the chenodeoxycholic-ursodeoxycholic acid combination provides a safe and efficacious treatment for some cholesterol gallstones.

Comparative formation of lithocholic acid from chenodeoxycholic and ursodeoxycholic acids in the colon.

The comparative rate of formation of lithocholic acid from chenodeoxycholic acid and its 7 beta epimer, ursodeoxycholic acid, was studied in human subjects and in a rhesus monkey. [24-14C]Chenodeoxycholic acid and [24-14C]ursodeoxycholic acid were incubated in vitro, under anaerobic conditions, in fecal samples from 7 control and 7 asymptomatic gallstone subjects. The incubations were carried out for 0, 0.5, 1, 4, and 12 h. In addition, the labeled precursors were instilled into the colon of 4 asymptomatic gallstone patients and a rhesus monkey in which a bile duct fistula had been created. Radioactive metabolites were analyzed by thin-layer chromatography in the in vitro fecal incubates and in the in vivo colonic aspirates, stool, and bile. The biotransformation of the unlabeled material was analyzed by gas-liquid chromatography in the in vitro incubates and in the in vivo fecal samples of the rhesus monkey. There was no statistical difference between chenodeoxycholic and ursodeoxycholic acids in their rate of biotransformation to lithocholic acid, when the total group of 14 subjects was compared. However, among these 14, a subgroup of 4 subjects (2 controls and 2 with gallstones) was identified in whom the rate of degradation to lithocholic acid was significantly faster for chenodeoxycholic than for ursodeoxycholic acid. Increases in the concentrations of the precursors led to a decrease in the rate, but not a change in the comparative pattern of lithocholic acid formation. At the lower concentrations, the conversion of both bile acids to lithocholic acid was almost complete after 12 h. In the in vivo studies, the formation of lithocholic acid from chenodeoxycholic and ursodeoxycholic acids was comparable both in the 4 human subjects and in the rhesus monkey. The results of this study indicate that, in most cases, the risk of liver damage from lithocholic acid formation should be similar for both epimers. However, there appears to be a small population in which this risk could be higher during chenodeoxycholic acid than during ursodeoxycholic acid treatment due to a more rapid formation of lithocholic acid.

Successful Outpatient Treatment of Gallstones with Piezoelectric Lithotripsy

Excerpt The application of extracorporeal shock-wave lithotripsy to the treatment of gallstones has followed its promising results in the treatment of urinary calculi (1, 2). First-generation spark...

Changes in G protein expression account for impaired modulation of hepatic cAMP formation after BDL

The regulation of cAMP synthesis by hormones and bile acids is altered in isolated hamster hepatocytes 2 days after bile duct ligation (BDL) [Y. Matsuzaki, B. Bouscarel, M. Le, S. Ceryak, T. W. Gettys, J. Shoda, and H. Fromm. Am. J. Physiol. 273 (Gastrointest. Liver Physiol. 36): G164-G174, 1997]. Therefore, studies were undertaken to elucidate the mechanism(s) responsible for this impaired modulation of cAMP formation. Hepatocytes were isolated 48 h after either a sham operation or BDL. Both preparations were equally devoid of cholangiocyte contamination. Although the basal cAMP level was not affected after BDL, the ability of glucagon to maximally stimulate cAMP synthesis was decreased by approximately 40%. This decreased glucagon effect after BDL was not due to alteration of the total glucagon receptor expression. However, this effect was associated with a parallel 50% decreased expression of the small stimulatory G protein alpha-subunit (GsalphaS). The expression of either the large subunit (GsalphaL) or the common beta-subunit remained unchanged. The expression of Gialpha2 and Gialpha3 was also decreased by 25 and 46%, respectively, and was associated with the failure of ANG II to inhibit stimulated cAMP formation. Therefore, alterations of the expression of GsalphaS and Galphai are, at least in part, responsible for the attenuated hormonal regulation of cAMP synthesis. Because cAMP has been reported to stimulate both bile acid uptake and secretion, impairment of cAMP synthesis and bile acid uptake may represent an initial hepatocellular defense mechanism during cholestasis.The regulation of cAMP synthesis by hormones and bile acids is altered in isolated hamster hepatocytes 2 days after bile duct ligation (BDL) [Y. Matsuzaki, B. Bouscarel, M. Le, S. Ceryak, T. W. Gettys, J. Shoda, and H. Fromm. Am. J. Physiol. 273 ( Gastrointest. Liver Physiol. 36): G164-G174, 1997]. Therefore, studies were undertaken to elucidate the mechanism(s) responsible for this impaired modulation of cAMP formation. Hepatocytes were isolated 48 h after either a sham operation or BDL. Both preparations were equally devoid of cholangiocyte contamination. Although the basal cAMP level was not affected after BDL, the ability of glucagon to maximally stimulate cAMP synthesis was decreased by ∼40%. This decreased glucagon effect after BDL was not due to alteration of the total glucagon receptor expression. However, this effect was associated with a parallel 50% decreased expression of the small stimulatory G protein α-subunit (GsαS). The expression of either the large subunit (GsαL) or the common β-subunit remained unchanged. The expression of Giα2and Giα3was also decreased by 25 and 46%, respectively, and was associated with the failure of ANG II to inhibit stimulated cAMP formation. Therefore, alterations of the expression of GsαSand Giα are, at least in part, responsible for the attenuated hormonal regulation of cAMP synthesis. Because cAMP has been reported to stimulate both bile acid uptake and secretion, impairment of cAMP synthesis and bile acid uptake may represent an initial hepatocellular defense mechanism during cholestasis.

New Breath Test for Bile Acid Deconjugation

Bile acids are secreted from the liver as conjugates with glycine and taurine, and, in health, the majority of the bile acid pool is absorbed from the ileum without bacterial deconjugation. In cond...