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Hepatic and Renal Toxicity Among Patients Ingesting Sheep Bile as an Unconventional Remedy for Diabetes Mellitus -- Saudi Arabia, 1995

A recent report of acute hepatic and renal toxicity associated with drinking bile from fish (grass carp) (1) alerted epidemiologists in Saudi Arabia to the possibility of similar risks associated with an existing practice of drinking sheep bile. To assess the prevalence and adverse effects of this practice, in 1995 the Field Epidemiology Training Program of the Ministry of Health of Saudi Arabia initiated an investigation in Al-Wadein village (1995 population: 5640) in the Asir Region of Saudi Arabia where a traditional healer had advised patients with diabetes to drink raw sheep bile as a treatment for their diabetes. This report presents the findings of the investigation, which demonstrate gastrointestinal, hepatic, and renal toxicity associated with ingestion of sheep bile.

Initial reviews of all 73 patients with adult-onset diabetes mellitus who were registered at the two primary health-care centers in the village identified 30 men aged 53-78 years who reported using unconventional medicine as diabetes therapy. These 30 were interviewed about underlying illnesses, ingestion of sheep bile, and subsequent illnesses. Three local hospitals provided information about serum chemistries obtained from annual examinations during the year preceding ingestion of bile (baseline), during acute illnesses that occurred immediately following reported ingestion, and 2 months after ingestion.

Of the 30 men, 14 (including five on hemodialysis for chronic renal failure) reported that they had tried the prescribed regimen of drinking sheep bile to cure diabetes once during a 4-year period. The traditional healer had advised a single regimen of 1-2 15-mL doses of bile before breakfast for 30 consecutive days for all patients. Two patients discontinued this regimen after the first 15-mL dose because of severe nausea. Others continued for 2-7 days, ingesting 30 mL-210 mL of bile until more severe symptoms caused them to discontinue the regimen.

All 14 patients reported onset of nausea and anorexia immediately after ingesting the bile, and 12 who ingested greater than 15 mL also reported vomiting with diarrhea within 36 hours after the first dose; none reported fever. All 14 sought medical treatment, and 12 were hospitalized for gastrointestinal symptoms during the week after drinking bile. One patient became oliguric, and one patient became comatose. Cultures of stool specimens from 13 patients were negative for bacterial pathogens.

The 14 patients sought care for acute gastrointestinal disease within 1 week of beginning bile treatments. Mean serum alanine aminotransferase (ALT) levels for the 14 had increased from a baseline of 32 U/L (range: 23 U/L-57 U/L) to 289 U/L (range: 56 U/L-497 U/L) (pless than 0.001, paired t-test). In comparison, among the 16 patients who used unconventional medicines other than bile treatments, the baseline mean ALT levels were 27 U/L (range: 15 U/L-42 U/L) (pless than 0.01, t-test). Other serum levels (bilirubin, aspartate aminotransferase, and alkaline phosphatase) also were elevated in patients using sheep bile. The absolute difference between baseline and postingestion serum ALT was higher in direct relation to higher doses of ingested bile (r=0.88; 95% confidence interval {CI}=0.76-0.94). Tests for hepatitis infection (immunoglobulin M antibody to hepatitis A virus, hepatitis B surface antigen, and antibody to hepatitis C virus) were negative. Serum ALT remained elevated (mean: 54 U/L; range: 26 U/L-249 U/L) 2 months after acute illness (pless than 0.01, paired t-test).

Among patients who had ingested bile, the mean serum creatinine increased from a baseline of 4.0 mg/100 mL (range: 0.6 mg/100 mL-10.4 mg/100 mL) to a postingestion level of 8.0 mg/100 mL (range: 1.9 mg/100 mL-20 mg/100 mL) (pless than 0.001, paired t-test). Serum sodium levels declined from a baseline of 139 meq/L (range: 135 meq/L-142 meq/L) to 131 meq/L (range: 127 meq/L-140 meq/L) (pless than 0.001, paired t-test). The absolute difference between baseline and postingestion serum creatinine increased (r=0.6; 95% CI=0.3-0.8) and serum sodium decreased (r=-0.38; 95% CI=-0.66 to -0.01) in direct relation to dose of ingested bile. Biochemical indicators of renal toxicity returned to baseline levels in each of the patients 2 weeks after seeking treatment for the acute illness.

Each of the 14 patients had discontinued use of insulin or oral hypoglycemic agents during the bile treatment. Compared with a baseline of 196 mg/100 mL (range: 150 mg/100 mL-270 mg/100 mL) before ingestion of bile, the mean blood glucose (random blood sugar) during acute illness was 253 mg/100 mL (range: 180 mg/100 mL-357 mg/100 mL) (pless than 0.001, paired t-test). However, the absolute difference between baseline and exposure serum glucose levels was unrelated to the volume of bile ingested (r=0.01; 95% CI= -0.36 to 0.38).

None of the attending physicians for the 14 patients had obtained histories of bile ingestion or suspected bile toxicity. Following the investigation, the Ministry of Health contacted all medical facilities to ask physicians to identify and report any incidents of ingestion of bile.

Reported by: MS Al-Qahtani, MBBS, Field Epidemiology Training Program, Ministry of Health, Kingdom of Saudi Arabia.

Editorial Note

Editorial Note: The gastrointestinal, hepatic, and renal toxicity in the patients in Saudi Arabia is consistent with known cytotoxic effects of bile acids (2,3), and ingestion of bile acid as therapy for cholelithiasis has been associated with diarrhea and mild elevations in serum transaminases (4). Although renal toxicity has not been documented previously in persons who ingest bile acids, exposure in dogs has been associated with decreased inulin clearance and a natriuretic effect (5). Exogenous administration of bile acids will saturate the enterohepatic cycle and result in increased levels of circulating serum bile acids (6). The cytotoxicity of individual bile acids reflects levels of hydrophobicity; chenodeoxycholic and deoxycholic acids are more cytotoxic than cholic acid (3). The minimum 15-mL dose of sheep bile contains an estimated average 271 mg of bile acids (including 47% deoxycholic, 25% chenodeoxycholic, 23% cholic, and 5% lithocholic acids) -- the equivalent of 36% of the maximum daily dose of bile acids used for treating cholelithiasis and 9% of the total bile acid pool (3.0 g) in adults (4,7). The toxic component of grass carp bile, associated previously with similar toxic reactions, probably was 5-alpha-cyprinol (1,8), an alcohol sulfate of a bile acid with physiologic function of a bile acid in lower vertebrates (9).

The investigation described in this report indicates the potential for direct toxicity associated with unconventional treatment of diabetes. In addition, because these patients discontinued conventional treatment of diabetes, control of blood sugar levels was impaired. Unconventional therapy for diabetes may be common; an estimated 34% of adults in the United States have used unconventional therapy for any health problem during a 12-month period (10). Because patients are unlikely to offer spontaneous, unsolicited histories of unconventional therapy, physicians who manage patients with diabetes and other chronic or recurrent diseases should actively seek information from patients to identify unconventional therapies.

References

  1. CDC. Acute hepatitis and renal failure following ingestion of raw carp gallbladders -- Maryland and Pennsylvania, 1991 and 1994. MMWR 1995;44:565-6.

  2. Heaton KW. Bile salts in health and disease. Edinburgh: Churchhill Livingstone, 1972:116-24.

  3. Sagawa H, Tazuma S, Kajiyama G. Protection against hydrophobic bile salt-induced cell membrane damage by liposomes and hydrophilic bile salts. Am J Physiol 1993;264(5 pt 1):G835-G839.

  4. Schoenfield LJ, Lachin JM. Chenodiol (chenodeoxycholic acid) for dissolution of gallstones: the National Cooperative Gallstone Study. Ann Intern Med 1981;95:257-82.

  5. Alon U, Berant M, Mordechovitz D, Better OS. The effect of intrarenal infusion of bile on kidney function in the dog. Clin Sci 1982;62:431-3.

  6. De Barros SG, Balistreri WF, Soloway RD, Weiss SG, Miller PC, Soper K. Response of total and individual serum bile acids to endogenous and exogenous bile acid input to the enterohepatic circulation. Gastroenterology 1982;82:647-52.

  7. Bobowiec R. Effects of the intravenous infusion of sodium salts of bile acids on bile flow and bile acids of sheep {Polish}. Annales Universitatis Mariae Curie-Sklodowska, DD Medicina Veterinaria, 1984;39:29-42.

  8. Yip LL, Chow CL, Yung KH, Chiu KW. Toxic material from the gallbladder of the grass carp (Ctenopharyngodon idellus). Toxicon 1981;19:567-9.

  9. Hazelwood GAD. Bile salt evolution. J Lipid Res 1967;8:535.

  10. Eisenberg DM, Kessler RC, Foster C, Norlock FE, Calkins DR, Delbanco TL. Unconventional medicine in the United States: prevalence, costs, and patterns of use. N Engl J Med 1993; 328:246-52.




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