GASTROENTEROLOGY 1990;96:1013-1016
Rifampin Relieves Pruritus in Children With Cholestatic Liver Disease HARRY A. CYNAMON, JOEL M. ANDRES, and R. PETER IAFRATE Department Department
of Pediatrics, University of Florida, and Division of Gastroenterology of Pharmacy Services, Shands Hospital, Gainesville, Florida
Chronic cholestatic liver disease in children frequently results in severe intractable pruritus. Current forms of therapy, including cholestyramine, are usually ineffective. Therefore, a 6-wk, double-blind, crossover study was designed to test the ability of rifampin to relieve pruritus in children with chronic cholestasis. Rifampin proved effective in alleviating pruritus in all five children tested compared with a placebo-treated group. After the 6-wk study period, rifampin was continued for 6 mo, and its effectiveness was maintained. No complications resulted from rifampin use. This study and a similar study in older patients with primary biliary cirrhosis suggest that a highly effective form of therapy is available for treatment of severe pruritus in patients with chronic cholestasis. These patients must be carefully selected and frequently monitored.
P
ruritus in children and adults with chronic cholestasis is difficult to treat and is a cause of significant morbidity (1). Cholestyramine is an effective antipruritic only if adequate concentrations of bile acids are present in the small intestine. In randomized single-blind crossover and double-blind placebocontrolled trials, respectively, terfenadine (21, and intravenous naloxone (3) have lessened the severe pruritus of some adult patients with cholestasis, especially those with primary biliary cirrhosis. Other therapies, including plasmapheresis (4), phototherapy (5), and external diversion of bile (6) have been evaluated in uncontrolled or single-blind trials. Rifampin was recently reported to relieve pruritus in nine adult patients with primary biliary cirrhosis in a doubleblind, crossover trial (7). Therefore, the effect of rifampin on pruritus in children with various forms of chronic cholestasis was studied in a similar doubleblind, crossover fashion.
and
Patients and Methods Five children, aged l-17 yr, with chronic cholestatic liver disease were studied. Informed consent was obtained from legal guardians with prior approval by the Institutional Review Board at the University of Florida. Persistent pruritus interfering with sleep was present in 4 patients for 5 or more yr and for 2 mo in a l-yr-old patient. Four of the 5 children had no relief of pruritus or improvement in sleep pattern (no response] when taking cholestyramine (up to 16 g/day). The fifth patient was not given cholestyramine because there was no detectable biliary flow. All 5 patients had persistent pruritus not relieved by other forms of antipruritic therapy such as phenobarbital, antihistamines, and charcoal. All antipruritic medications were discontinued at least 1 mo before the study period. Clinical features and prior antipruritic therapies are summarized in Table 1. The patients received 14 days of rifampin suspension in a dose of 10 mg/kg per day (maximum 300 mg each day; divided into two doses) or a placebo in a double-blind, crossover pattern. The placebo consisted of carmine red, eggshell-yellow dyes, cherry syrup, and lactose to mimic the taste, color, and consistency of rifampin suspension. Patients were informed that the color of their urine or stool may be affected by either medication. A 14-day washout period was employed between courses of treatment of either suspension (7). Treatment order was random. An independent pharmacist coded the active drug and placebo. Medication bottles were returned to the pharmacist to monitor compliance. At the end of the 6-wk trial period, patients who preferred rifampin to placebo were offered the option of continuing rifampin for 6 additional months. Blood studies were conducted at the beginning of the study and 2 and 6 wk later. These tests included complete blood count, creatinine, urea nitrogen, calcium, phosphorus, albumin, prothrombin time, alanine and aspartate aminotransferase (ALT and AST), total and conjugated bilirubin, and total serum bile acids. For those patients continuing in the chronic phase of the Abbreviations used in this paper: AIT, alanine aminotransferase; AST, aspartate amino transferase. 0 1990 by the American Gastroenterological Association 0016-5065/90/63.00
1014
CYNAMON ET AL.
GASTROENTEROLOGY
Vol. 98. No. 4
Table 1. Clinical Data of Patients Before Rifampin Treatment Patient no.
Age I Yrl
Diagnosis
1
17
Intrahepatic
cholestasis
2
14
Intrahepatic
cholestasis
3
10
NSPIBD
Prior therapy Charcoal Diphenhydramine Cholestyramine Phenobarbital Cholestyramine Hydroxyzine Cholestyramine Hydroxyzine
Response
Total bile acids
None None None None Minimal None Minimal
4
9
NSPIBD
Cholestyramine
None None
5
1
Biliary atresia
Hydroxyzine
None
NSPIBD, nonsyndromic
298
44
208
84
145
251
193
17 157 o-35
357 o-13
Normal range (NM)
Bilirubin
variety of paucity of the interlobular bile ducts.
study, blood testing was performed every 2 mo. Children were fasted for at least 8 h on each occasion that serum for bile acid analysis was obtained. Total bile acids were quantified by an enzymatic method (8). This method does not permit fractionation of bile acids. All other blood tests were carried out in the Clinical Laboratory of the University of Florida employing standard methods. The severity of pruritus was assessed at the onset of the study and 2, 4, and 6 wk later by a self-administered questionnaire ($10). The questionnaire was also completed every 2 mo at the time of blood testing during the 6-mo phase of the study. The statements were (a] “I never itch”; [b] “I itch rarely but never complain”; (c) “I itch occasionally with mild annoyance”: [d) “1 itch often: it may be severe, but I can be active or rest easily”; (e) “I itch often; it may be severe and interferes with rest but not activity”; and [f) “I always itch; it is severe and interferes with both rest and activity.” These six statements were arranged in nine paired response alternatives. The sequence of paired statements was randomized at each study period. The patient or parent was instructed to select the statement in each pair that was closest to the truth. Responses were then ranked using an itching scale of 1 (no itching) to 10 [severe and constant itching). Inconsistent responses were noted to determine patient comprehension. The same parent completed the questionnaire at each session for children less than 12 years of age. Patients 1, 2, and 5 received rifampin before the placebo. To compare rifampin and placebo data, biochemical assessments and pruritus scores were analyzed by Student’s paired t-test. A p value to.05 was considered significant.
response per reporting session. The overall compliance was greater than 90%. There were no significant changes in blood count or biochemical tests throughout the study. Serum bile acid levels did not significantly change as levels increased and decreased with rifampin usage. Patient 3 initially had a total bilirubin concentration of 251 PM (normal, 2-18 PM) with a conjugated fraction of 184 PM; the total bilirubin level decreased to 174 PM [conjugated fraction, 106 PM) after 2 wk of rifampin. After an additional 6 mo of rifampin the total bilirubin was 80 PM. In two other patients followed for 6 mo (patients 4 and 5), there was a small increase in total bilirubin (5-10 PM). Patient 1 had no change in total bilirubin after 6 mo. All patients and/or their parents elected to continue rifampin after the 6-wk trial. Prolonged relief from
““1
Results All patients or their parent stated a preference for rifampin compared to placebo. This was verified by a substantial decrease in pruritus score [Figure 1) for each patient during rifampin therapy (p = O.OOl), but not while taking placebo (p = 0.78). There were no inconsistent questionnaire responses from patients 1, 2, and 3. Patients 4 and 5 averaged one inconsistent
WEEKS
Figure 1. Pruritus scores (higher values indicate more severe pruritus) for individual patients who received (A)the active drug rifampin before placebo and (B) placebo before rifampin. A washout period was used between treatments. A11patients experienced a marked decline in pruritus while taking rifampln (p = O.OOl), but not with placebo (p = 0.78).
April1990
pruritus was accomplished in four children, and they maintained the same or lower pruritus score. Patient 2 was dropped from the chronic phase of the study after noncompliance with the protocol. Biochemical tests remained unchanged during the 6 additional months of rifampin therapy except for the aminotransferases of patient 3. When the ALT level increased to 177 U/L (normal, O-35 U/L) from a baseline value of 57 U/L (bilirubin was unchanged], rifampin was then prescribed in a single dose of 5 mg/kg. The lower rifampin dose resulted in an increased pruritus score (from 4 to 7) but no change in the ALT level. The pruritus score improved (from 7 to 4) when he was returned to the prior dose, and the serum ALT declined to 128U/L.
Discussion This is the first study in children to show the effectiveness of rifampin in relieving the pruritus of cholestatic liver disease. When analyzed together, our results and those of a similar study in adults with primary biliary cirrhosis (7) indicate that rifampin is effective in alleviating severe pruritus in patients with a variety of cholestatic disorders. Both studies involved a small number of patients but used a comparable double-blind, crossover design and measured the degree of pruritus. Our study was extended 6 mo beyond the initial trial with continued relief of pruritus without significant alteration of biochemical tests of liver or renal function. While on rifampin, all children experienced marked improvement in life style. For example, those who had difficulty with sleeping at night now awaken only rarely. For children, the dose of 10 mg/kg was chosen based upon the amount of drug shown to be effective in adults with primary biliary cirrhosis (7). In one patient, the dose was reduced to 5 mg/kg; this resulted in a return of his previous severe degree of pruritus. As a group, all patients showed a decrease in serum bilirubin concentration after 6 wk; however, this was never statistically significant and not confirmed after 6 mo on rifampin. Patients in both studies were free of side effects from rifampin. For example, no bacterial infections were observed during the course of this study, even though the emergence of resistant organisms is a concern for patients on prolonged rifampin therapy. Drug hepatitis associated with rifampin has almost always occurred during concurrent use of a second antitubercuOther previously reported side effects, lous drug (11,12). such as gastrointestinal disturbance, dizziness, mental confusion, muscular weakness, and hypersensitivity reactions were not observed in this study population. Despite this, patients must be carefully selected for rifampin treatment and then monitored on a frequent
RIFAMPIN RELIEVES PRURITUS IN CHILDREN
1015
basis. Furthermore, the safety of long-term use of rifampin should be determined. The mechanism of pruritus in cholestatic liver disease is not precisely understood (7,13,14). Other investigators have hypothesized that pruritus associated with liver disease is caused by high hepatic concentrations of bile acids that cause release of an unidentified pruritogen (7). Therefore, rifampin should be an effective form of treatment because it inhibits bile acid uptake into the hepatocyte (15). Recently, partial external diversion of bile has been proposed as treatment for children with intrahepatic cholestasis (6). This approach was not as effective for children with arteriohepatic dysplasia (6,161 as for those with progressive intrahepatic cholestasis. With surgical diversion of bile, cholestasis and pruritus were relieved in patients with progressive intrahepatic cholestasis, but the number of patients, as in the current study, was small. No clear trend in serum bilirubin or total bile acids were noted in children treated with rifampin. It is premature to draw any definite conclusions regarding the modification of liver disease after either the surgical or medical approach to the problem of pruritus in patients with severe cholestasis. It is suggested that these patients only be considered for surgery (external biliary diversion) if rifampin is not efficacious or is not well tolerated. References I. Garden JM, Ostrow JD. Roenigk HH Jr. Pruritus in hepatic cholestasis. Pathogenesis and therapy. Arch Dermato11985;121: 1415-1420. 2. Duncan JS, Kennedy HJ, Triger DR. Treatment of pruritus due to chronic obstructive liver disease. Br Med J 1984;289:22. 3. Summerfield JA. Naloxone modulates the perception of itch in man. Br J Clin Pharmaco11980;10:180-182. 4. Lauterburg BH, Pineda AA, Burgstaler EA, Taswell HF. Dickson ER, Carlson GL. Treatment of pruritus of cholestasis by plasma perfusion through USP-charcoal-coated glass beads. Lancet 1980;1:53-55. 5. Maggiore G, Grifeo S, De Giacomo C, Scotta MS. Phototherapy for pruritus in chronic cholestasis of childhood. Eur J Pediatr 1982;139:90-91. 6. Whitington PF, Whitington GL. Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis. Gastroenterology 1988;95:130-136. 7. Ghent CN, Carruthers SG. Treatment of pruritus in primary biliary cirrhosis with rifampin. Gastroenterology 1988;94:488493. 8. Mashige F, Imai K, Osuga T. A simple and sensitive assay of total serum bile acids. Clin Chim Acta 1976;70:79-86. 9. Ingham JG. Quantitative evaluation of subiective symptoms. Proc R Sot Med 1969;62:492-494. 10. Pederson JA, Matter BJ, Czerwinski AW, Llach F. Relief of idiopathic generalized pruritus in dialysis patients treated with activated oral charcoal. Ann Intern Med 1980;93:446-448. 11.Lees WA, Asgher B, Hashem MA. Jaundice after rifampin. Br J Dis Chest 1970;64:94-95.
1016 CYNAMON ET AL.
12. O’Brien PJ. Long MW, Cross FS, Lyle MA, Snider DE. Hepatotoxicity from isoniazid and rifampin among children treated for tuberculosis. Pediatrics 1983;72:491-499. 13. Ghent CN, Bloommer JR, Klatskin G. Elevations in skin tissue levels of bile acids in human cholestasis: relation to serum levels and to pruritus. Gastroenterology 1977;73:1125-1130. 14. Ghent CN. Pruritus of cholestasis is related to effects of bile salts on the liver, not the skin. Am J Gastroenterol1987;82:117-118. 15. Galeazzi R, Lorenzini I, Orlandi F. Rifampicin-induced elevations of serum bile acids in man. Dig Dis Sci 1980;25:108-112.
GASTROENTEROLOGY
Vol. 98. No. 4
16. Alagille D, Odievre M, Gautier M, Dommergues JP. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur. J Pediatr 1975;86:63-73.
Received November 29.1988. Accepted September 4,1989. Address requests for reprints to: Joel M. Andres, M.D., University of Florida, Department of Pediatrics, Box J-296, JHMHC, Gainesville, Florida 32610.
Rifampin Relieves Pruritus in Children With Cholestatic Liver Disease HARRY A. CYNAMON, JOEL M. ANDRES, and R. PETER IAFRATE Department Department
of Pediatrics, University of Florida, and Division of Gastroenterology of Pharmacy Services, Shands Hospital, Gainesville, Florida
Chronic cholestatic liver disease in children frequently results in severe intractable pruritus. Current forms of therapy, including cholestyramine, are usually ineffective. Therefore, a 6-wk, double-blind, crossover study was designed to test the ability of rifampin to relieve pruritus in children with chronic cholestasis. Rifampin proved effective in alleviating pruritus in all five children tested compared with a placebo-treated group. After the 6-wk study period, rifampin was continued for 6 mo, and its effectiveness was maintained. No complications resulted from rifampin use. This study and a similar study in older patients with primary biliary cirrhosis suggest that a highly effective form of therapy is available for treatment of severe pruritus in patients with chronic cholestasis. These patients must be carefully selected and frequently monitored.
P
ruritus in children and adults with chronic cholestasis is difficult to treat and is a cause of significant morbidity (1). Cholestyramine is an effective antipruritic only if adequate concentrations of bile acids are present in the small intestine. In randomized single-blind crossover and double-blind placebocontrolled trials, respectively, terfenadine (21, and intravenous naloxone (3) have lessened the severe pruritus of some adult patients with cholestasis, especially those with primary biliary cirrhosis. Other therapies, including plasmapheresis (4), phototherapy (5), and external diversion of bile (6) have been evaluated in uncontrolled or single-blind trials. Rifampin was recently reported to relieve pruritus in nine adult patients with primary biliary cirrhosis in a doubleblind, crossover trial (7). Therefore, the effect of rifampin on pruritus in children with various forms of chronic cholestasis was studied in a similar doubleblind, crossover fashion.
and
Patients and Methods Five children, aged l-17 yr, with chronic cholestatic liver disease were studied. Informed consent was obtained from legal guardians with prior approval by the Institutional Review Board at the University of Florida. Persistent pruritus interfering with sleep was present in 4 patients for 5 or more yr and for 2 mo in a l-yr-old patient. Four of the 5 children had no relief of pruritus or improvement in sleep pattern (no response] when taking cholestyramine (up to 16 g/day). The fifth patient was not given cholestyramine because there was no detectable biliary flow. All 5 patients had persistent pruritus not relieved by other forms of antipruritic therapy such as phenobarbital, antihistamines, and charcoal. All antipruritic medications were discontinued at least 1 mo before the study period. Clinical features and prior antipruritic therapies are summarized in Table 1. The patients received 14 days of rifampin suspension in a dose of 10 mg/kg per day (maximum 300 mg each day; divided into two doses) or a placebo in a double-blind, crossover pattern. The placebo consisted of carmine red, eggshell-yellow dyes, cherry syrup, and lactose to mimic the taste, color, and consistency of rifampin suspension. Patients were informed that the color of their urine or stool may be affected by either medication. A 14-day washout period was employed between courses of treatment of either suspension (7). Treatment order was random. An independent pharmacist coded the active drug and placebo. Medication bottles were returned to the pharmacist to monitor compliance. At the end of the 6-wk trial period, patients who preferred rifampin to placebo were offered the option of continuing rifampin for 6 additional months. Blood studies were conducted at the beginning of the study and 2 and 6 wk later. These tests included complete blood count, creatinine, urea nitrogen, calcium, phosphorus, albumin, prothrombin time, alanine and aspartate aminotransferase (ALT and AST), total and conjugated bilirubin, and total serum bile acids. For those patients continuing in the chronic phase of the Abbreviations used in this paper: AIT, alanine aminotransferase; AST, aspartate amino transferase. 0 1990 by the American Gastroenterological Association 0016-5065/90/63.00
1014
CYNAMON ET AL.
GASTROENTEROLOGY
Vol. 98. No. 4
Table 1. Clinical Data of Patients Before Rifampin Treatment Patient no.
Age I Yrl
Diagnosis
1
17
Intrahepatic
cholestasis
2
14
Intrahepatic
cholestasis
3
10
NSPIBD
Prior therapy Charcoal Diphenhydramine Cholestyramine Phenobarbital Cholestyramine Hydroxyzine Cholestyramine Hydroxyzine
Response
Total bile acids
None None None None Minimal None Minimal
4
9
NSPIBD
Cholestyramine
None None
5
1
Biliary atresia
Hydroxyzine
None
NSPIBD, nonsyndromic
298
44
208
84
145
251
193
17 157 o-35
357 o-13
Normal range (NM)
Bilirubin
variety of paucity of the interlobular bile ducts.
study, blood testing was performed every 2 mo. Children were fasted for at least 8 h on each occasion that serum for bile acid analysis was obtained. Total bile acids were quantified by an enzymatic method (8). This method does not permit fractionation of bile acids. All other blood tests were carried out in the Clinical Laboratory of the University of Florida employing standard methods. The severity of pruritus was assessed at the onset of the study and 2, 4, and 6 wk later by a self-administered questionnaire ($10). The questionnaire was also completed every 2 mo at the time of blood testing during the 6-mo phase of the study. The statements were (a] “I never itch”; [b] “I itch rarely but never complain”; (c) “I itch occasionally with mild annoyance”: [d) “1 itch often: it may be severe, but I can be active or rest easily”; (e) “I itch often; it may be severe and interferes with rest but not activity”; and [f) “I always itch; it is severe and interferes with both rest and activity.” These six statements were arranged in nine paired response alternatives. The sequence of paired statements was randomized at each study period. The patient or parent was instructed to select the statement in each pair that was closest to the truth. Responses were then ranked using an itching scale of 1 (no itching) to 10 [severe and constant itching). Inconsistent responses were noted to determine patient comprehension. The same parent completed the questionnaire at each session for children less than 12 years of age. Patients 1, 2, and 5 received rifampin before the placebo. To compare rifampin and placebo data, biochemical assessments and pruritus scores were analyzed by Student’s paired t-test. A p value to.05 was considered significant.
response per reporting session. The overall compliance was greater than 90%. There were no significant changes in blood count or biochemical tests throughout the study. Serum bile acid levels did not significantly change as levels increased and decreased with rifampin usage. Patient 3 initially had a total bilirubin concentration of 251 PM (normal, 2-18 PM) with a conjugated fraction of 184 PM; the total bilirubin level decreased to 174 PM [conjugated fraction, 106 PM) after 2 wk of rifampin. After an additional 6 mo of rifampin the total bilirubin was 80 PM. In two other patients followed for 6 mo (patients 4 and 5), there was a small increase in total bilirubin (5-10 PM). Patient 1 had no change in total bilirubin after 6 mo. All patients and/or their parents elected to continue rifampin after the 6-wk trial. Prolonged relief from
““1
Results All patients or their parent stated a preference for rifampin compared to placebo. This was verified by a substantial decrease in pruritus score [Figure 1) for each patient during rifampin therapy (p = O.OOl), but not while taking placebo (p = 0.78). There were no inconsistent questionnaire responses from patients 1, 2, and 3. Patients 4 and 5 averaged one inconsistent
WEEKS
Figure 1. Pruritus scores (higher values indicate more severe pruritus) for individual patients who received (A)the active drug rifampin before placebo and (B) placebo before rifampin. A washout period was used between treatments. A11patients experienced a marked decline in pruritus while taking rifampln (p = O.OOl), but not with placebo (p = 0.78).
April1990
pruritus was accomplished in four children, and they maintained the same or lower pruritus score. Patient 2 was dropped from the chronic phase of the study after noncompliance with the protocol. Biochemical tests remained unchanged during the 6 additional months of rifampin therapy except for the aminotransferases of patient 3. When the ALT level increased to 177 U/L (normal, O-35 U/L) from a baseline value of 57 U/L (bilirubin was unchanged], rifampin was then prescribed in a single dose of 5 mg/kg. The lower rifampin dose resulted in an increased pruritus score (from 4 to 7) but no change in the ALT level. The pruritus score improved (from 7 to 4) when he was returned to the prior dose, and the serum ALT declined to 128U/L.
Discussion This is the first study in children to show the effectiveness of rifampin in relieving the pruritus of cholestatic liver disease. When analyzed together, our results and those of a similar study in adults with primary biliary cirrhosis (7) indicate that rifampin is effective in alleviating severe pruritus in patients with a variety of cholestatic disorders. Both studies involved a small number of patients but used a comparable double-blind, crossover design and measured the degree of pruritus. Our study was extended 6 mo beyond the initial trial with continued relief of pruritus without significant alteration of biochemical tests of liver or renal function. While on rifampin, all children experienced marked improvement in life style. For example, those who had difficulty with sleeping at night now awaken only rarely. For children, the dose of 10 mg/kg was chosen based upon the amount of drug shown to be effective in adults with primary biliary cirrhosis (7). In one patient, the dose was reduced to 5 mg/kg; this resulted in a return of his previous severe degree of pruritus. As a group, all patients showed a decrease in serum bilirubin concentration after 6 wk; however, this was never statistically significant and not confirmed after 6 mo on rifampin. Patients in both studies were free of side effects from rifampin. For example, no bacterial infections were observed during the course of this study, even though the emergence of resistant organisms is a concern for patients on prolonged rifampin therapy. Drug hepatitis associated with rifampin has almost always occurred during concurrent use of a second antitubercuOther previously reported side effects, lous drug (11,12). such as gastrointestinal disturbance, dizziness, mental confusion, muscular weakness, and hypersensitivity reactions were not observed in this study population. Despite this, patients must be carefully selected for rifampin treatment and then monitored on a frequent
RIFAMPIN RELIEVES PRURITUS IN CHILDREN
1015
basis. Furthermore, the safety of long-term use of rifampin should be determined. The mechanism of pruritus in cholestatic liver disease is not precisely understood (7,13,14). Other investigators have hypothesized that pruritus associated with liver disease is caused by high hepatic concentrations of bile acids that cause release of an unidentified pruritogen (7). Therefore, rifampin should be an effective form of treatment because it inhibits bile acid uptake into the hepatocyte (15). Recently, partial external diversion of bile has been proposed as treatment for children with intrahepatic cholestasis (6). This approach was not as effective for children with arteriohepatic dysplasia (6,161 as for those with progressive intrahepatic cholestasis. With surgical diversion of bile, cholestasis and pruritus were relieved in patients with progressive intrahepatic cholestasis, but the number of patients, as in the current study, was small. No clear trend in serum bilirubin or total bile acids were noted in children treated with rifampin. It is premature to draw any definite conclusions regarding the modification of liver disease after either the surgical or medical approach to the problem of pruritus in patients with severe cholestasis. It is suggested that these patients only be considered for surgery (external biliary diversion) if rifampin is not efficacious or is not well tolerated. References I. Garden JM, Ostrow JD. Roenigk HH Jr. Pruritus in hepatic cholestasis. Pathogenesis and therapy. Arch Dermato11985;121: 1415-1420. 2. Duncan JS, Kennedy HJ, Triger DR. Treatment of pruritus due to chronic obstructive liver disease. Br Med J 1984;289:22. 3. Summerfield JA. Naloxone modulates the perception of itch in man. Br J Clin Pharmaco11980;10:180-182. 4. Lauterburg BH, Pineda AA, Burgstaler EA, Taswell HF. Dickson ER, Carlson GL. Treatment of pruritus of cholestasis by plasma perfusion through USP-charcoal-coated glass beads. Lancet 1980;1:53-55. 5. Maggiore G, Grifeo S, De Giacomo C, Scotta MS. Phototherapy for pruritus in chronic cholestasis of childhood. Eur J Pediatr 1982;139:90-91. 6. Whitington PF, Whitington GL. Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis. Gastroenterology 1988;95:130-136. 7. Ghent CN, Carruthers SG. Treatment of pruritus in primary biliary cirrhosis with rifampin. Gastroenterology 1988;94:488493. 8. Mashige F, Imai K, Osuga T. A simple and sensitive assay of total serum bile acids. Clin Chim Acta 1976;70:79-86. 9. Ingham JG. Quantitative evaluation of subiective symptoms. Proc R Sot Med 1969;62:492-494. 10. Pederson JA, Matter BJ, Czerwinski AW, Llach F. Relief of idiopathic generalized pruritus in dialysis patients treated with activated oral charcoal. Ann Intern Med 1980;93:446-448. 11.Lees WA, Asgher B, Hashem MA. Jaundice after rifampin. Br J Dis Chest 1970;64:94-95.
1016 CYNAMON ET AL.
12. O’Brien PJ. Long MW, Cross FS, Lyle MA, Snider DE. Hepatotoxicity from isoniazid and rifampin among children treated for tuberculosis. Pediatrics 1983;72:491-499. 13. Ghent CN, Bloommer JR, Klatskin G. Elevations in skin tissue levels of bile acids in human cholestasis: relation to serum levels and to pruritus. Gastroenterology 1977;73:1125-1130. 14. Ghent CN. Pruritus of cholestasis is related to effects of bile salts on the liver, not the skin. Am J Gastroenterol1987;82:117-118. 15. Galeazzi R, Lorenzini I, Orlandi F. Rifampicin-induced elevations of serum bile acids in man. Dig Dis Sci 1980;25:108-112.
GASTROENTEROLOGY
Vol. 98. No. 4
16. Alagille D, Odievre M, Gautier M, Dommergues JP. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur. J Pediatr 1975;86:63-73.
Received November 29.1988. Accepted September 4,1989. Address requests for reprints to: Joel M. Andres, M.D., University of Florida, Department of Pediatrics, Box J-296, JHMHC, Gainesville, Florida 32610.
