- Email: [email protected]
Benign Recurrent Intrahepatic Cholestasis: Treatment With S-Adenosylmethionine
GASTROENTEROLOGY 1989;96:1354-7
BRIEF REPORTS
Benign Recurrent Intrahepatic Cholestasis: Treatment With S-Adenosylmethionine GREGORY T. EVERSON, DENNIS AHNEN, PHILLIP C. HARPER, and EDWARD L. KRAWITT Division of Gastroenterology and Hepatobiliary Center, University of Colorado School of Medicine, Denver, Colorado and University of Vermont Medical College, Burlington, Vermont
S-Adenosylmethionine (800 mg i.v. per day) was used to treat two brothers and a brother and sister from each of two kindreds with benign recurrent intrahepatic cholestasis. Symptoms, rQutine tests of liver function, concentrations of total bile acids, and the oral clearances of [11,12- 2 HJchenodeoxycholic acid and [24- 13 C]cholic acid were determined before and after treatment with S-adenosylmethionine. S-Adenosylmethionine did not ameliorate symptoms or biochemical parameters of cholestasis but reduced bile acid clearances in 3 of 4 subjects. Transaminase levels in both subjects of one kindred rose during treatment. These limited, preliminary observations suggest that S-adenosylmethionine may be ineffective in the therapy of benign recurrent intrahepatic cholestasis and may be hepatotoxic in some patients.
B
enign recurrent intrahepatic cholestasis (BRIC) was first described in 1959 as a disorder of unknown etiology characterized by intermittent episodes of extreme jaundice and pruritus (1,2). Treatment of the cholestasis of BRIC with cholestyramine, phenobarbital, and charcoal hemoperfusion has been variably effective (3-7). S-Adenosylmethionine (SAMe) has been used in the treatment of a wide variety of psychiatric and liver diseases (8-10) and has been reported to ameliorate intrahepatic cholestasis of pregnancy (11). Thus, the specific aim of this study was to assess the efficacy of SAMe in reversing cholestasis in BRIC.
Materials and Methods This study was approved by the Human Subjects Committees and Clinical Research Centers of both the University of Colorado Medical Center and the University of Vermont College of Medicine. S-Adenosylmethionine
was supplied by Dr. Georgio Stramentinoli of BioResearch, Inc. (Milan, Italy) and its use authorized by the U.S. Food and Drug Administration under IND No. 21,224.
Subjects Two brothers (A and B) and a brother (Y) and sister (Z) from two separate families were studied. Three were icteric and one anicteric at the time of study. All subjects had a similar duration of disease although the age of onset of cholestasis in the Vermont subjects (3 and 1 yr old) was much earlier than that of the Colorado subjects (10 and 22 yr old). Each subject underwent 12 days of study: a 3-day control period followed by a 9-day treatment period. The treatment period was further divided into initial 4-day (Tl) and late 5-day (T2) intervals. During the control period, 100 ml of 0.9% saline was infused every 6 h. During the treatment period, 200 mg of SAMe was infused in 100 ml of 0.9% saline every 6 h. Subjects kept a diary of the severity of their symptoms, and aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, y-glutamyl transpeptidase, bilirubin, and serum bile acids were measured daily. The hepatic clearances of [l1,12- 2 H]chenodeoxycholic acid (CDCA) and [24-13C]cholic acid (CA) were determined on the first day of the control period and the last day of the treatment period. The absolute serum concentration of each labeled bile acid was measured by isotope dilution mass spectrometry (12) and oral clearance (CIa) calculated from Cl o = Dose/AUC,
(1)
where AUC is the area under the serum concentration versus time curve (13,14).
Abbreviations used in this paper: BRIC, benign recurrent intrahepatic cholestasis; CA, cholic acid; CDCA, chenodeoxycholic acid; 'Y-GT, 'Y-glutamyl transpeptidase; SAMe, S-adenosylmethionine. © 1989 by the American Gastroenterological Association 0016-5085/89/$3.50
May 1989
TREATMENT OF FAMILIAL CHOLEST ASIS
1355
Table 1. Response of Each Subject to S-Adenosylmethionine Treatment a Colorado subjects Subject A
Symptoms b Pruritus Sleeplessness Biochemistry" Bili (mg/ml) Alk phos (IU/L) y-GT (IU/L) AST (lUlL) ALT (IUlL)d Total serum bile acid (J.tM) Fasting Postprandial Clearances (mllkg. min)e [11.12- 2 HjCDCA [24-"3C]CA
Vermont subjects Subject Y
Subject B
Subject Z
C
T1
T2
C
T1
T2
C
T1
T2
C
T1
T2
7.5 0.0
5.3 0.3
4.8 0.3
2.1 0.0
1.0 0.0
0.0 0.0
2.8 1.0
1.5 1.0
2.3 1.0
4.8 0.5
1.5 1.0
2.0 1.0
4.9 4.0 1.3 5.6 10.9
4.2 3.7 1.4 5.7 9.7
3.5 3.5 1.3 6.2 11.5
0.7 2.2 0.6 1.0 0.9
0.7 1.9 0.6 0.8 0.9
0.7 1.9 0.6 0.8 1.2
3.3 1.7 0.5 0.9 1.8
3.0 1.9 0.5 1.2 2.4
3.0 1.8 0.5 1.1 3.1
2.9 0.9 0.3 1.0 1.9
2.8 0.9 0.2 1.4 2.2
2.7 0.9 0.3 1.5 2.8
307 368
350 371
312 406
5 6
0 4
0 7
129 286
165 347
223 337
111 146
142 170
126 10!6
23 ----"- 14 16 ----"- 11
17----- 11 19----- 14
2 5 ------- 24 2 8 ------- 12
15 ----"- 13 8---- 9
Data are given as the mean value of the study interval. Alk phos. alkaline phospatase; ALT. alanine aminotransferase; AST. aspartate aminotransferase; Bili. total bilirubin; CA. cholic acid: CDCA. chenodeoxycholic acid; y-GT. y-glutamyl transferase. a S-Adenosylmethionine (200 mg Lv. every 6 h) was given thrO\~ghout the treatment period. C, control period (3 days); T1. first 4 days of S-adenosylmethionine; T2, last 5 days of S-adenosylmethionine. b Symptoms were graded by severity where 0 = no symptom and 10 = most severe. Expressed as a multiple of the upper limit of normal. d In both of the Vermont subjects the alanine aminotransferase level rose considerably during S-adenosylmethionine treatment. Values rapidly returned to their pretreatment levels after S-adenosylmethionine was discontinued. e The clearances of isotope-labeled bile acids were determined on the first day of the control period and after 9 days of S-adenosylmethionine treatment. G
Results Results are presented in Table 1. Symptoms Pruritus scores decreased from the control period to the early treatment period (T1) in all 4 subjects but did not decrease further with continued treatment. However, daily fluctuations in pruritus scores were considerable. For example, the pruritus score in subject A dropped from 10 to 6 during the control period of saline infusion (no SAMe). No subject had a change in sleep pattern during the period of SAMe treatment, and no adverse reactions to SAMe were reported. Serum Bilirubin and Liver Enzymes Total bilirubin levels decreased in all 3 jaundiced subjects (subjects A, Y, and Z), but levels had been declining in all three subjects before the study, and the rate of decline was not altered by SAMe. There was no consistent change in alkaline phosphatase, y-glutamyl transpeptidase or in alanine or aspartate aminotransferases during use of SAMe. One unusual characteristic, common to all subjects, was the finding of near normal (Denver patients) or depressed (Vermont patients) levels of y-glutamyl transpeptidase despite either marked jaundice or
twofold to 20-fold elevations in alkaline phosphatase. The liver-specific isozyme of y-glutamyl transpeptidase was not measured in any patient. Levels of alanine and aspartate aminotransferase increased in subjects Y and Z during treatment with SAMe and returned to pretreatment levels after completion of the study, once SAMe had been discontinued. Concentrations of Serum Bile Acids The fasting and postprandial concentrations of total serum bile acid were not altered by SAMe administration. In all subjects serum levels of bile acid rose after meals, suggesting that even in these markedly cholestatic subjects a portion of the bile acid pool was stored in the gallbladder or intestin~ during fasting. Hepatic Clearance of Bile Acids Labeled With Stable Isotopes Serum concentrations of labeled bile acids rose 30-60 min after their oral administration. Peak concentrations occurred between 1 and 2 h and by 6 h only low concentrations were detectable. The clearance of CDCA and CA decreased 21% and 37%, respectively, during SAMe administration (CDCA clearance; 20 ± 5 vs. 16 ± 6 mllkg . min; CA clearance, 18 ± 8 vs. 11 ± 2 mllkg . min). The decrease in
1356 EVERSON ET A1.
clearance was not associated with any other alteration in liver tests.
Discussion Benign recurrent intrahepatic cholestasis is a rare inherited disorder (1,2). As the underlying biochemical abnormality is not known, treatment is empiric. Existing therapies for the pruritus of cholestasis include bile acid binding resins, such as cholestyramine, and microsomal enzyme inducers, such as phenobarbital or rifampin (1-7,15). All, except rifampin, have been used in treatment of BRIC, but the clinical response has been incomplete, transient, or unsatisfactory. S-Adenosylmethionine has been used to treat a wide variety of liver disorders in both animal models of hepatic injury and in humans. One controlled trial demonstrated that SAMe was effective in reversing intrahepatic cholestasis of pregnancy (11). Animal studies have also suggested that SAMe may reverse cholestasis induced by ethinyl estradiol (16). Thus, we postulated that SAMe might also reverse cholestasis in subjects with BRIC. In our study, SAMe was given intravenously to ensure 100% bioavailability of the administered compound. A 9-day course of treatment was chosen because, in the only controlled trial of SAMe, this length of time was sufficient to observe a beneficial effect (11). S-Adenosylmethionine did not significantly improve any measurement of hepatic function in our subjects. The decrease in bilirubin was due to the normal fluctuation in the underlying disease and not related to SAMe therapy. The only major improvement in pruritus (subject A) occurred during the first 3 days of study, during infusion of saline without SAMe. Thus, a 9-day course of SAMe, 800 mg i.v. per day, did not resolve or improve cholestasis in our subjects with BRIC. Our subjects with BRIC had basal rates of clearance of orally administered unconjugated bile acid (CDCA: 15-25 mllkg. min; CA: 8-28 mllkg. min) that were similar to rates we have measured in other subjects without hepatocellular dysfunction (unpublished data; CDCA: 17 ± 7 mllkg . min; CA: 25 ± 10 mllkg . min). Thus, the clearance of unconjugated bile acid is not markedly altered by the cholestatic state in subjects with BRIe. S-Adenosylmethionine therapy decreased the hepatic clearance of CDCA by 21 % and that of CA by 37%. The mechanism of the reduction in clearance was not definee!.. In addition to the reduction in clearance, SAMe increased serum transaminase levels in subjects Y and Z, suggesting a hepatotoxic effect of SAMe in these individua.ls. As the members of only one of the kiildreds had elevations in aspartate aminotransferase and alanine ami-
GASTROENTEROLOGY Vol. 96, No.5, Part 1
notransferase, hepatotoxicity might be a manifestation of the unique metabolic abnormality underlying the cholestatic state. In summary, SAMe therapy was evaluated in 4 subjects from two kindreds with BRIC. Normal or low levels of y-glutamyl transferase during periods of intense cholestasis was a feature characteristic of all subjects. S-Adenosylmethionine (800 mg i.v. per day for 9 days) was ineffective in reversing symptoms or biochemical measures of cholestasis. Bile acid clearance decreased and hepatic transaminase levels increased, suggesting that SAMe may be hepatotoxic in some patients with BRIC.
References 1. Summers kill WHJ, Walshe JM. Benign recurrent intrahepatic "obstructive" jaundice. Lancet 1959;ii:686-90. 2. Summers kill WHJ. The syndrome of benign recurrent cholestasis. Am J Med 1965;38:298-305. 3. Williams R, Cartter MA, Sherlock S, Scheuer PI. Hill KR. Idiopathic recurrent cholestasis: a study of the functional and pathological lesions in four cases. Quart J Med 1964;33:38799. 4. Spiegel EL, Schubert W, Perrin E, Schiff 1. Benign recurrent intrahepatic cholestasis, with response to cholestyramine. Am J Med 1965;39:682-8. 5. Stiehl A, Thaler MM, Admirand WHo The effects of phenobarbital on bile salts and bilirubin in patients with intrahepatic and extrahepatic cholestasis. N Engl J Med 1972;286: 858-61. 6. LaRusso NF, Dickson ER, Pineda AA. Case report: plasmaperfusion and studies of copper metabolism in benign recurrent cholestasis. Novel procedures in a rare syndrome. Mayo Clin Proc 1980;55:450-4. 7. Lauterburg BH, Pineda AA, Dickson ER, Baldus WP, Taswell HF. Plasma perfusion for the treatment of intractable pruritus of cholestasis. Mayo Clin Proc 1978;53:403-7. 8. Fiaccadori F, DiPadova C, Ghinelli F, Magnani G, Pelosi G, Dacchini D. Effects of S-adenosyl-L-methionine (SAMe) on alcoholic liver disease in humans. Hepatology 1982;2:153A. 9. Mazzanti R. Arcangeli A, Salvadori G. On the anti-steatosic effect of S-adenosyl-L-methionine in various chronic liver diseases (multicenter study). Curr Ther Res 1979;25:25-34. 10. Frezza M, DiPadova C, and the Italian Study Group for SAMe in Liver Disease. Multicenter placebo controlled clinical trial of intravenous and oral S-adenosylmethionine (SAMe) in cholestatic patients with liver disease. Hepatology 1987;7: 1105. 11. Frezza M, Pozzato G, Chiesa L, Stramentinoli G, DiPadova C. Reversal of intrahepatic cholestasis of pregnancy in women after high dose S-adenosyl-L-methionine administration. Hepatology 1984;4:274-8. 12. Everson GT. Steady-state kinetics of serum bile acids in healthy human subjects: single and dual isotope techniques using stable isotopes and mass spectrometry. J Lipid Res 1987;28:238-52. 13. Greenblatt DJ, Koch-Weser J. Drug therapy: clinical pharmacokinetics. Part I. N Engl J Med 1975;293:702-5. 14. Greenblatt DJ, Koch-Weser J. Drug therapy. Clinical pharmacokinetics. Part II. N Engl J Med 1975;293:964-70. 15. Ghent CN, Carruthers SG. Treatment of pruritus in primary biliary cirrhosis with rifampin. Results of a double-blind,
May 1989
crossover, randomized trial. Gastroenterology 1988;94:48893. 16. Stramentinoli G, DiPadova C, Gualano M, Rovagnati P, GalliKienle M. Ethynylestradiol-induced impairment of bile secretion in the rat: protective effects of S-adenosyl-L-methionine and its implication in estrogen metabolism. Gastroenterology 1981;80:154-8.
Received April 4, 1988. Accepted November 10, 1988. Address requests for reprints to: Gregory T. Everson, M.D., Division of Gastroenterology, University of Colorado School of Medicine, 4200 East Ninth Avenue (Box B-158). Denver, Colorado 80262. These studies were supported by the Clinical Research Centers of the University of Colorado School of Medicine (RR-00051) and
TREATMENT OF FAMILIAL CHOLESTASIS
1357
the University of Vermont Medical College (RR 109) from the General Clinical Research Centers Program of the Division of Research Resources, National Institutes of Health. Dr. Everson was supported by an National Institutes of Health Clinical Investigator Award (NIH 1 K08 DKOl156) during the period of conduct of these studies. Additional support for the gas chromatography/ mass spectrometry of bile acids was obtained through the Hepatobiliary Center of the University of Colorado Health Sciences Center (USPHS DK 34914). The authors acknowledge the excellent technical assistance of Robert Farrell and the excellent nursing support provided by the Clinical Research Centers of the University of Colorado School of Medicine and the University of Vermont College of Medicine. They also thank Dr. Georgio Stramentinoli of Bioresearch, Inc., for supplying the S-adenosylmethionine used in these studies and Teresa Boulay for transcribing and preparing the manuscript.
BRIEF REPORTS
Benign Recurrent Intrahepatic Cholestasis: Treatment With S-Adenosylmethionine GREGORY T. EVERSON, DENNIS AHNEN, PHILLIP C. HARPER, and EDWARD L. KRAWITT Division of Gastroenterology and Hepatobiliary Center, University of Colorado School of Medicine, Denver, Colorado and University of Vermont Medical College, Burlington, Vermont
S-Adenosylmethionine (800 mg i.v. per day) was used to treat two brothers and a brother and sister from each of two kindreds with benign recurrent intrahepatic cholestasis. Symptoms, rQutine tests of liver function, concentrations of total bile acids, and the oral clearances of [11,12- 2 HJchenodeoxycholic acid and [24- 13 C]cholic acid were determined before and after treatment with S-adenosylmethionine. S-Adenosylmethionine did not ameliorate symptoms or biochemical parameters of cholestasis but reduced bile acid clearances in 3 of 4 subjects. Transaminase levels in both subjects of one kindred rose during treatment. These limited, preliminary observations suggest that S-adenosylmethionine may be ineffective in the therapy of benign recurrent intrahepatic cholestasis and may be hepatotoxic in some patients.
B
enign recurrent intrahepatic cholestasis (BRIC) was first described in 1959 as a disorder of unknown etiology characterized by intermittent episodes of extreme jaundice and pruritus (1,2). Treatment of the cholestasis of BRIC with cholestyramine, phenobarbital, and charcoal hemoperfusion has been variably effective (3-7). S-Adenosylmethionine (SAMe) has been used in the treatment of a wide variety of psychiatric and liver diseases (8-10) and has been reported to ameliorate intrahepatic cholestasis of pregnancy (11). Thus, the specific aim of this study was to assess the efficacy of SAMe in reversing cholestasis in BRIC.
Materials and Methods This study was approved by the Human Subjects Committees and Clinical Research Centers of both the University of Colorado Medical Center and the University of Vermont College of Medicine. S-Adenosylmethionine
was supplied by Dr. Georgio Stramentinoli of BioResearch, Inc. (Milan, Italy) and its use authorized by the U.S. Food and Drug Administration under IND No. 21,224.
Subjects Two brothers (A and B) and a brother (Y) and sister (Z) from two separate families were studied. Three were icteric and one anicteric at the time of study. All subjects had a similar duration of disease although the age of onset of cholestasis in the Vermont subjects (3 and 1 yr old) was much earlier than that of the Colorado subjects (10 and 22 yr old). Each subject underwent 12 days of study: a 3-day control period followed by a 9-day treatment period. The treatment period was further divided into initial 4-day (Tl) and late 5-day (T2) intervals. During the control period, 100 ml of 0.9% saline was infused every 6 h. During the treatment period, 200 mg of SAMe was infused in 100 ml of 0.9% saline every 6 h. Subjects kept a diary of the severity of their symptoms, and aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, y-glutamyl transpeptidase, bilirubin, and serum bile acids were measured daily. The hepatic clearances of [l1,12- 2 H]chenodeoxycholic acid (CDCA) and [24-13C]cholic acid (CA) were determined on the first day of the control period and the last day of the treatment period. The absolute serum concentration of each labeled bile acid was measured by isotope dilution mass spectrometry (12) and oral clearance (CIa) calculated from Cl o = Dose/AUC,
(1)
where AUC is the area under the serum concentration versus time curve (13,14).
Abbreviations used in this paper: BRIC, benign recurrent intrahepatic cholestasis; CA, cholic acid; CDCA, chenodeoxycholic acid; 'Y-GT, 'Y-glutamyl transpeptidase; SAMe, S-adenosylmethionine. © 1989 by the American Gastroenterological Association 0016-5085/89/$3.50
May 1989
TREATMENT OF FAMILIAL CHOLEST ASIS
1355
Table 1. Response of Each Subject to S-Adenosylmethionine Treatment a Colorado subjects Subject A
Symptoms b Pruritus Sleeplessness Biochemistry" Bili (mg/ml) Alk phos (IU/L) y-GT (IU/L) AST (lUlL) ALT (IUlL)d Total serum bile acid (J.tM) Fasting Postprandial Clearances (mllkg. min)e [11.12- 2 HjCDCA [24-"3C]CA
Vermont subjects Subject Y
Subject B
Subject Z
C
T1
T2
C
T1
T2
C
T1
T2
C
T1
T2
7.5 0.0
5.3 0.3
4.8 0.3
2.1 0.0
1.0 0.0
0.0 0.0
2.8 1.0
1.5 1.0
2.3 1.0
4.8 0.5
1.5 1.0
2.0 1.0
4.9 4.0 1.3 5.6 10.9
4.2 3.7 1.4 5.7 9.7
3.5 3.5 1.3 6.2 11.5
0.7 2.2 0.6 1.0 0.9
0.7 1.9 0.6 0.8 0.9
0.7 1.9 0.6 0.8 1.2
3.3 1.7 0.5 0.9 1.8
3.0 1.9 0.5 1.2 2.4
3.0 1.8 0.5 1.1 3.1
2.9 0.9 0.3 1.0 1.9
2.8 0.9 0.2 1.4 2.2
2.7 0.9 0.3 1.5 2.8
307 368
350 371
312 406
5 6
0 4
0 7
129 286
165 347
223 337
111 146
142 170
126 10!6
23 ----"- 14 16 ----"- 11
17----- 11 19----- 14
2 5 ------- 24 2 8 ------- 12
15 ----"- 13 8---- 9
Data are given as the mean value of the study interval. Alk phos. alkaline phospatase; ALT. alanine aminotransferase; AST. aspartate aminotransferase; Bili. total bilirubin; CA. cholic acid: CDCA. chenodeoxycholic acid; y-GT. y-glutamyl transferase. a S-Adenosylmethionine (200 mg Lv. every 6 h) was given thrO\~ghout the treatment period. C, control period (3 days); T1. first 4 days of S-adenosylmethionine; T2, last 5 days of S-adenosylmethionine. b Symptoms were graded by severity where 0 = no symptom and 10 = most severe. Expressed as a multiple of the upper limit of normal. d In both of the Vermont subjects the alanine aminotransferase level rose considerably during S-adenosylmethionine treatment. Values rapidly returned to their pretreatment levels after S-adenosylmethionine was discontinued. e The clearances of isotope-labeled bile acids were determined on the first day of the control period and after 9 days of S-adenosylmethionine treatment. G
Results Results are presented in Table 1. Symptoms Pruritus scores decreased from the control period to the early treatment period (T1) in all 4 subjects but did not decrease further with continued treatment. However, daily fluctuations in pruritus scores were considerable. For example, the pruritus score in subject A dropped from 10 to 6 during the control period of saline infusion (no SAMe). No subject had a change in sleep pattern during the period of SAMe treatment, and no adverse reactions to SAMe were reported. Serum Bilirubin and Liver Enzymes Total bilirubin levels decreased in all 3 jaundiced subjects (subjects A, Y, and Z), but levels had been declining in all three subjects before the study, and the rate of decline was not altered by SAMe. There was no consistent change in alkaline phosphatase, y-glutamyl transpeptidase or in alanine or aspartate aminotransferases during use of SAMe. One unusual characteristic, common to all subjects, was the finding of near normal (Denver patients) or depressed (Vermont patients) levels of y-glutamyl transpeptidase despite either marked jaundice or
twofold to 20-fold elevations in alkaline phosphatase. The liver-specific isozyme of y-glutamyl transpeptidase was not measured in any patient. Levels of alanine and aspartate aminotransferase increased in subjects Y and Z during treatment with SAMe and returned to pretreatment levels after completion of the study, once SAMe had been discontinued. Concentrations of Serum Bile Acids The fasting and postprandial concentrations of total serum bile acid were not altered by SAMe administration. In all subjects serum levels of bile acid rose after meals, suggesting that even in these markedly cholestatic subjects a portion of the bile acid pool was stored in the gallbladder or intestin~ during fasting. Hepatic Clearance of Bile Acids Labeled With Stable Isotopes Serum concentrations of labeled bile acids rose 30-60 min after their oral administration. Peak concentrations occurred between 1 and 2 h and by 6 h only low concentrations were detectable. The clearance of CDCA and CA decreased 21% and 37%, respectively, during SAMe administration (CDCA clearance; 20 ± 5 vs. 16 ± 6 mllkg . min; CA clearance, 18 ± 8 vs. 11 ± 2 mllkg . min). The decrease in
1356 EVERSON ET A1.
clearance was not associated with any other alteration in liver tests.
Discussion Benign recurrent intrahepatic cholestasis is a rare inherited disorder (1,2). As the underlying biochemical abnormality is not known, treatment is empiric. Existing therapies for the pruritus of cholestasis include bile acid binding resins, such as cholestyramine, and microsomal enzyme inducers, such as phenobarbital or rifampin (1-7,15). All, except rifampin, have been used in treatment of BRIC, but the clinical response has been incomplete, transient, or unsatisfactory. S-Adenosylmethionine has been used to treat a wide variety of liver disorders in both animal models of hepatic injury and in humans. One controlled trial demonstrated that SAMe was effective in reversing intrahepatic cholestasis of pregnancy (11). Animal studies have also suggested that SAMe may reverse cholestasis induced by ethinyl estradiol (16). Thus, we postulated that SAMe might also reverse cholestasis in subjects with BRIC. In our study, SAMe was given intravenously to ensure 100% bioavailability of the administered compound. A 9-day course of treatment was chosen because, in the only controlled trial of SAMe, this length of time was sufficient to observe a beneficial effect (11). S-Adenosylmethionine did not significantly improve any measurement of hepatic function in our subjects. The decrease in bilirubin was due to the normal fluctuation in the underlying disease and not related to SAMe therapy. The only major improvement in pruritus (subject A) occurred during the first 3 days of study, during infusion of saline without SAMe. Thus, a 9-day course of SAMe, 800 mg i.v. per day, did not resolve or improve cholestasis in our subjects with BRIC. Our subjects with BRIC had basal rates of clearance of orally administered unconjugated bile acid (CDCA: 15-25 mllkg. min; CA: 8-28 mllkg. min) that were similar to rates we have measured in other subjects without hepatocellular dysfunction (unpublished data; CDCA: 17 ± 7 mllkg . min; CA: 25 ± 10 mllkg . min). Thus, the clearance of unconjugated bile acid is not markedly altered by the cholestatic state in subjects with BRIe. S-Adenosylmethionine therapy decreased the hepatic clearance of CDCA by 21 % and that of CA by 37%. The mechanism of the reduction in clearance was not definee!.. In addition to the reduction in clearance, SAMe increased serum transaminase levels in subjects Y and Z, suggesting a hepatotoxic effect of SAMe in these individua.ls. As the members of only one of the kiildreds had elevations in aspartate aminotransferase and alanine ami-
GASTROENTEROLOGY Vol. 96, No.5, Part 1
notransferase, hepatotoxicity might be a manifestation of the unique metabolic abnormality underlying the cholestatic state. In summary, SAMe therapy was evaluated in 4 subjects from two kindreds with BRIC. Normal or low levels of y-glutamyl transferase during periods of intense cholestasis was a feature characteristic of all subjects. S-Adenosylmethionine (800 mg i.v. per day for 9 days) was ineffective in reversing symptoms or biochemical measures of cholestasis. Bile acid clearance decreased and hepatic transaminase levels increased, suggesting that SAMe may be hepatotoxic in some patients with BRIC.
References 1. Summers kill WHJ, Walshe JM. Benign recurrent intrahepatic "obstructive" jaundice. Lancet 1959;ii:686-90. 2. Summers kill WHJ. The syndrome of benign recurrent cholestasis. Am J Med 1965;38:298-305. 3. Williams R, Cartter MA, Sherlock S, Scheuer PI. Hill KR. Idiopathic recurrent cholestasis: a study of the functional and pathological lesions in four cases. Quart J Med 1964;33:38799. 4. Spiegel EL, Schubert W, Perrin E, Schiff 1. Benign recurrent intrahepatic cholestasis, with response to cholestyramine. Am J Med 1965;39:682-8. 5. Stiehl A, Thaler MM, Admirand WHo The effects of phenobarbital on bile salts and bilirubin in patients with intrahepatic and extrahepatic cholestasis. N Engl J Med 1972;286: 858-61. 6. LaRusso NF, Dickson ER, Pineda AA. Case report: plasmaperfusion and studies of copper metabolism in benign recurrent cholestasis. Novel procedures in a rare syndrome. Mayo Clin Proc 1980;55:450-4. 7. Lauterburg BH, Pineda AA, Dickson ER, Baldus WP, Taswell HF. Plasma perfusion for the treatment of intractable pruritus of cholestasis. Mayo Clin Proc 1978;53:403-7. 8. Fiaccadori F, DiPadova C, Ghinelli F, Magnani G, Pelosi G, Dacchini D. Effects of S-adenosyl-L-methionine (SAMe) on alcoholic liver disease in humans. Hepatology 1982;2:153A. 9. Mazzanti R. Arcangeli A, Salvadori G. On the anti-steatosic effect of S-adenosyl-L-methionine in various chronic liver diseases (multicenter study). Curr Ther Res 1979;25:25-34. 10. Frezza M, DiPadova C, and the Italian Study Group for SAMe in Liver Disease. Multicenter placebo controlled clinical trial of intravenous and oral S-adenosylmethionine (SAMe) in cholestatic patients with liver disease. Hepatology 1987;7: 1105. 11. Frezza M, Pozzato G, Chiesa L, Stramentinoli G, DiPadova C. Reversal of intrahepatic cholestasis of pregnancy in women after high dose S-adenosyl-L-methionine administration. Hepatology 1984;4:274-8. 12. Everson GT. Steady-state kinetics of serum bile acids in healthy human subjects: single and dual isotope techniques using stable isotopes and mass spectrometry. J Lipid Res 1987;28:238-52. 13. Greenblatt DJ, Koch-Weser J. Drug therapy: clinical pharmacokinetics. Part I. N Engl J Med 1975;293:702-5. 14. Greenblatt DJ, Koch-Weser J. Drug therapy. Clinical pharmacokinetics. Part II. N Engl J Med 1975;293:964-70. 15. Ghent CN, Carruthers SG. Treatment of pruritus in primary biliary cirrhosis with rifampin. Results of a double-blind,
May 1989
crossover, randomized trial. Gastroenterology 1988;94:48893. 16. Stramentinoli G, DiPadova C, Gualano M, Rovagnati P, GalliKienle M. Ethynylestradiol-induced impairment of bile secretion in the rat: protective effects of S-adenosyl-L-methionine and its implication in estrogen metabolism. Gastroenterology 1981;80:154-8.
Received April 4, 1988. Accepted November 10, 1988. Address requests for reprints to: Gregory T. Everson, M.D., Division of Gastroenterology, University of Colorado School of Medicine, 4200 East Ninth Avenue (Box B-158). Denver, Colorado 80262. These studies were supported by the Clinical Research Centers of the University of Colorado School of Medicine (RR-00051) and
TREATMENT OF FAMILIAL CHOLESTASIS
1357
the University of Vermont Medical College (RR 109) from the General Clinical Research Centers Program of the Division of Research Resources, National Institutes of Health. Dr. Everson was supported by an National Institutes of Health Clinical Investigator Award (NIH 1 K08 DKOl156) during the period of conduct of these studies. Additional support for the gas chromatography/ mass spectrometry of bile acids was obtained through the Hepatobiliary Center of the University of Colorado Health Sciences Center (USPHS DK 34914). The authors acknowledge the excellent technical assistance of Robert Farrell and the excellent nursing support provided by the Clinical Research Centers of the University of Colorado School of Medicine and the University of Vermont College of Medicine. They also thank Dr. Georgio Stramentinoli of Bioresearch, Inc., for supplying the S-adenosylmethionine used in these studies and Teresa Boulay for transcribing and preparing the manuscript.