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Ursodeoxycholic acid for the treatment of home parenteral nutrition-associated cholestasis
GASTROENTEROLOGY 1991;101:250-253
Ursodeoxycholic Acid for the Treatment of Home Parenteral Nutrition-Associated Cholestasis A Case Report KEITH D. LINDOR and JAN BURNES Division of Gastroenterology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota
Severe cholestasis associated with long-term home parenteral nutrition is rare, and no treatment is known to be effective. This study shows a case of a patient who developed jaundice while receiving long-term home parenteral nutrition. Causes of jaundice, other than the patient’s parenteral feedings, were excluded. The patient’s jaundice did not respond to alterations in his parenteral feeding program or to metronidazole. Ursodeoxycholic acid (600 mg/day) led to a prompt and sustained improvement in his hyperbilirubinemia. When ursodeoxycholic acid was stopped, the patient again became jaundiced, but this resolved with reinstitution of ursodeoxycholic acid. This case suggests that ursodeoxycholic acid may be an effective treatment for home parenteral nutrition-associated cholestasis and should be evaluated further in patients with cholestasis associated with parenteral feeding.
A
bnormalities in liver tests frequently complicate the use of parenteral nutrition, particularly when treatment is initiated (1,2). Although these abnormalities are usually transient, a few cases are reported of patients with severe, progressive liver disease while on long-term home parenteral feeding programs (3,4). Some of these patients die of liver failure (3). To date, no effective therapy exists for management of this rare problem once it occurs, although a number of treatments have been tried (5-8). In this study, we report on one patient treated with ursodeoxycholic acid who had a marked and sustained improvement in liver biochemistries.
small bowel biopsy suggested celiac sprue. He initially responded to gluten withdrawal; but, shortly afterwards, he was referred to the Mayo Clinic because of continued abdominal cramping and abdominal pain. Abdominal supine and upright films showed a small bowel obstruction, and he underwent abdominal exploration during which 14 cm of jejunum were resected because of diffuse large-cell lymphoma of the small bowel complicating celiac sprue. At that time, there was no other evidence of intraabdominal lymphoma. A computerized tomographic (CT) scan of the abdomen, a bone marrow examination, and a lymphangiogram were negative. He received 400~1 rads of radiation therapy to the abdomen. Following treatment, he initially did well on a gluten-free diet. However, 3 years later, he noted the onset of bloating and night sweats. A CT of the abdomen suggested a recurrence of his lymphoma. He was reexplored where recurrent lymphoma was discovered within the mesentery with direct extension into several loops of bowel. The mass and 52 cm of jejunum were removed. Postoperatively, he developed a wound dehisence that eventually closed. He received six cycles of methotrexate, Adriamycin, cyclophosphamide, and vincristine. One year later, he developed nausea, vomiting, and weight loss. A CT scan showed a dilated stomach and small bowel, but no definite evidence of recurrent disease was noted. He did not respond to conservative management and underwent exploration for a third time. No recurrent tumor was found, but many adhesions were noted and lysed. Postoperatively, he could not tolerate oral or tubal feedings. Therefore, a Hickman catheter was placed, and total parenteral nutrition (TPN) was begun. His weight normalized over the next 2 years on home parenteral nutrition (HPN). Attempts to resume oral intake met with nausea and pain, and his intake was limited to one to two cups of coffee per day, without any solid food. Computerized tomography and small bowel x-ray examina-
Case Report The patient, a 52-year-old man, presented in 1982 to a local hospital with crampy abdominal pain, weight loss, and diarrhea. He was found to have fat malabsorption, and a
Abbreviations used in this paper: CT, computerized tomography; HPN, home parenteral nutrition. o 1991 by the American Gastroenterological Association
0016-5085/91/$3.00
July 1991
tion showed no evidence for recurrence. His nightly HPN formula contained 2250 kcallday, which supplied 46 kcal . kg’ day-’ and 1.8 g protein . kg-’ . day-’ at a nonprotein kilocalorie-to-nitrogen ratio of 14O:l with 25% of his calories from fat (1.05 g fat. kg-’ . day-‘). However, 2 months later he returned because of jaundice associated with malaise and pruritus. His liver tests were formerly characterized by mild elevations of alkaline phosphatase and minimal elevations of aspartate aminotransferase (AST) with normal bilirubin levels until the time of the onset of jaundice. Serological tests for hepatitis A, B, and C were negative including hepatitis B core antibody, surface antigen, and surface antibody. Tests for cytomegalovirus and Epstein-Barr virus showed evidence of past exposure but no evidence of a recent or acute infection. Ultrasonography of the liver and biliary system found a normal liver and gallbladder with no duct dilatation. A retrograde cholangiography was normal, and a liver biopsy specimen [Figure 1) showed hepaticocanilicular cholestasis and scattered foamy macrophages with centrilobular hemosiderin deposits. There was minimal fatty change on the liver biopsy. These histological changes were thought to be compatible with TPN-induced cholestasis. Sepsis was excluded. The TPN was reduced from approximately 2250 calories/day to 1440 calories/day with an increase in the percentage of calories supplied by fat from 25% to 40% of total calories (1.06 g fat . kg-’ . day-‘), and metronidazole treatment, 250 mg t.i.d., was begun. His weight dropped 6 kg over 3 months with the reduction in calories. His bilirubin level ranged from 168 to 298 p,mol/L (9.8 to 17.4 mg/dL) with metronidazole treatment. His TPN was increased because of weight reduction and lack of any effect on the bilirubin. His bilirubin remained elevated at 253 kmol/L (14.8 mg/dL). At this point, metronidazole treatment was stopped 3 months after it was begun, and treatment with ursodeoxycholic
Figure 1. Photomicrograph of liver biopsy specimen showing hepatocanalicular cholestasis, scattered foamy macrophages, and minimal fatty changes. A special stain for iron (not shown) showed deposition of hemosiderin and ferritin.
URSO FOR HPN-INDUCED CHOLESTASIS
251
acid, 600 mg/day in two divided doses PO, was begun. Within 3 weeks, his bilirubin level had dropped to 144 pmol/L (8.4 mg/dL). Two months later, his bilirubin level was 34 p,mol/L (2.0 mg/dL) and eventually reached a level of 17 pmol/L (1.0 mg/dL). His alkaline phosphatase level remained elevated, and his AST became nearly normal. He felt considerably better, and the pruritus that he had experienced had resolved. The ursodeoxycholic acid was discontinued after 2 months of normal bilirubin levels; however, shortly after discontinuation, the bilirubin level rose to 68 p,mol/L (4 mg/dL). At that time, the ursodeoxycholic acid treatment was resumed, the bilirubin level had returned to normal, and the AST and alkaline phosphatase levels were near normal while on ursodeoxycholic acid treatment. A repeat liver biopsy was not considered justified because of his near complete biochemical normalization and the absence of specific diagnostic features on his initial biopsy sample. These results are summarized in Figure 2.
Discussion The origin of cholestasis associated with parenteral nutrition is undefined, and no treatment is known to be clearly effective. Some reported evidence suggests that biliary stasis and increased formation of toxic bile acid metabolites during TPN may contribute to cholestasis (9). It appears that severe cholestasis is more apparent in patients who have undergone massive intestinal resection (4); however, our patient had a total of < 100 cm of intestine removed and would not be categorized as having had massive resection. It has been suggested that absorption of bacterial toxins from a nonused intestine, such as occurs in the
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jejunal loop syndrome, may be important. Therefore, metronidazole treatment has been used for a few patients, although the effects have been quite variable (5). Phenobarbital has been used in children, although the effects of the barbiturate seem unpredictable and are not well described in adults (6,7). Ursodeoxycholic acid is the 7-p epimer of chenodeoxycholic acid and it is widely used for gallstone dissolution. It has an excellent safety profile with minimal side effects. Abnormalities in liver tests or diarrhea experienced by patients taking chenodeoxycholic acid are rarely encountered by patients receiving ursodeoxycholic acid (10). Furthermore, ursodeoxycholic acid has been reported to be beneficial for patients with primary biliary cirrhosis, a disease of chronic cholestasis involving interlobular and septal bile ducts. Patients with this disease receiving the drug have experienced clinical, biochemical, and a trend towards histological improvement (11). Ursodeoxycholic acid has also been used in the treatment of primary sclerosing cholangitis and chronic active hepatitis, although the data supporting its use in these diseases is incomplete. The mechanism by which ursodeoxycholic acid may exert its beneficial effects in patients with liver disease is unknown. It is thought to be a choleretic agent, it may replace bile
Figure 2. Levels of serum bilirubin, alkaline phosphatase, and AST, respectively, over time and relationship to use of ursodeoxycholic acid. Shaded urea represents normal range, and black bars indicate periods of ursodeoxycholic acid treatment.
acids that are toxic to the liver, and there is some suggestion that ursodeoxycholic acid may have direct protective effects on liver cell membranes. Because of the finding of prominent cholestasis on liver biopsy and the well-established safety profile of ursodeoxycholic acid, a therapeutic trial seemed reasonable. Our patient’s prompt and salutary response to this drug was remarkable. The patient did not have any evidence of lymphomatous involvement of the liver or recurrent lymphoma. He did not have primary biliary cirrhosis or primary sclerosing cholangitis, liver diseases associated with celiac sprue. Other causes of liver disease were excluded, and the relapse with withdrawal of the drug and the improvement of liver tests with reintroduction suggest that ursodeoxycholic acid is a drug that should be tested more formally in patients with this unusual condition of cholestasis associated with long-term HPN. References Sheldon GF, Petersen SR, Sanders R. Hepatic dysfunction during hyperalimentation. Arch Surg 1978;113:504-508. Lindor KD, Fleming CR, Abrams A, Hirschkorn MA. Liver function values in adults receiving total parenteral nutrition. JAMA 1979;241:2398-2400. Bowyer BA, Fleming CR, Ludwig J, Petz J, McGill DB. Does
July 1991
4.
5.
6. 7.
8.
long-term home parenteral nutrition in adult patients cause chronic liver disease? JPEN 1985;9:11-17. Stank0 RT, Nathan G, Mendelow H, Adibi SA. Development of hepatic cholestasis and fibrosis in patients with massive loss of intestine supported by prolonged pare&era1 nutrition. Gastroenterology 1987;92:197-202. Lambert JR, Thomas SM. Metronidazole prevention of serum liver enzyme abnormalities during total parenteral nutrition. JPEN 1985;9:501-503. South M, King A. Parenteral nutrition-associated cholestasis: recovery following phenobarbitone. JPEN 1987;11:208-209. Gleghorn EE, Merritt RJ, Subramanian N, Ramos A. Phenobarbital does not prevent total parenteral nutrition-associated cholestasis in noninfected neonates. JPEN 1986;10:282-283. Bowyer BA, Miles JM, Haymond MW, Fleming CR. L%arnitine therapy in home parenteral nutrition patients with abnormal liver tests and low plasma carnitine concentrations. Gastroenterology 1988;94:434-438.
URSO FOR HPN-INDUCED
CHOLESTASIS
253
9. Whitington PF. Cholestasis associated with total parenteral nutrition in infants. Hepatology 1985;5:693-696. 10. Bachrach WH, Hofmann AF. Ursodeoxycholic acid in the treatment of cholesterol choielithiasis, Part II. Dig Dis Sci 1982;27:833-856. 11. Leuschner U, Fischer H, Kurtz W, Guldautuna S, Hubner K, Hellstern A, Gatzen M, Leuschner M. Ursodeoxycholic acid in primary biliary cirrhosis: results of a controlled double-blind trial. Gastroenterology 1989;97:1268-1274.
Received July 24,199O. Accepted February 11.1991. Address requests for reprints to: Keith D. Lindor, M.D., Mayo Clinic, Division of Gastroenterology, Rochester, Minnesota 55905. The authors thank the patient’s local physician, Dr. Leroy Mueller, for his help in following the patient’s course, and Dr. C. R. Fleming for his thoughtful suggestions in the preparation of the manuscript.
Ursodeoxycholic Acid for the Treatment of Home Parenteral Nutrition-Associated Cholestasis A Case Report KEITH D. LINDOR and JAN BURNES Division of Gastroenterology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota
Severe cholestasis associated with long-term home parenteral nutrition is rare, and no treatment is known to be effective. This study shows a case of a patient who developed jaundice while receiving long-term home parenteral nutrition. Causes of jaundice, other than the patient’s parenteral feedings, were excluded. The patient’s jaundice did not respond to alterations in his parenteral feeding program or to metronidazole. Ursodeoxycholic acid (600 mg/day) led to a prompt and sustained improvement in his hyperbilirubinemia. When ursodeoxycholic acid was stopped, the patient again became jaundiced, but this resolved with reinstitution of ursodeoxycholic acid. This case suggests that ursodeoxycholic acid may be an effective treatment for home parenteral nutrition-associated cholestasis and should be evaluated further in patients with cholestasis associated with parenteral feeding.
A
bnormalities in liver tests frequently complicate the use of parenteral nutrition, particularly when treatment is initiated (1,2). Although these abnormalities are usually transient, a few cases are reported of patients with severe, progressive liver disease while on long-term home parenteral feeding programs (3,4). Some of these patients die of liver failure (3). To date, no effective therapy exists for management of this rare problem once it occurs, although a number of treatments have been tried (5-8). In this study, we report on one patient treated with ursodeoxycholic acid who had a marked and sustained improvement in liver biochemistries.
small bowel biopsy suggested celiac sprue. He initially responded to gluten withdrawal; but, shortly afterwards, he was referred to the Mayo Clinic because of continued abdominal cramping and abdominal pain. Abdominal supine and upright films showed a small bowel obstruction, and he underwent abdominal exploration during which 14 cm of jejunum were resected because of diffuse large-cell lymphoma of the small bowel complicating celiac sprue. At that time, there was no other evidence of intraabdominal lymphoma. A computerized tomographic (CT) scan of the abdomen, a bone marrow examination, and a lymphangiogram were negative. He received 400~1 rads of radiation therapy to the abdomen. Following treatment, he initially did well on a gluten-free diet. However, 3 years later, he noted the onset of bloating and night sweats. A CT of the abdomen suggested a recurrence of his lymphoma. He was reexplored where recurrent lymphoma was discovered within the mesentery with direct extension into several loops of bowel. The mass and 52 cm of jejunum were removed. Postoperatively, he developed a wound dehisence that eventually closed. He received six cycles of methotrexate, Adriamycin, cyclophosphamide, and vincristine. One year later, he developed nausea, vomiting, and weight loss. A CT scan showed a dilated stomach and small bowel, but no definite evidence of recurrent disease was noted. He did not respond to conservative management and underwent exploration for a third time. No recurrent tumor was found, but many adhesions were noted and lysed. Postoperatively, he could not tolerate oral or tubal feedings. Therefore, a Hickman catheter was placed, and total parenteral nutrition (TPN) was begun. His weight normalized over the next 2 years on home parenteral nutrition (HPN). Attempts to resume oral intake met with nausea and pain, and his intake was limited to one to two cups of coffee per day, without any solid food. Computerized tomography and small bowel x-ray examina-
Case Report The patient, a 52-year-old man, presented in 1982 to a local hospital with crampy abdominal pain, weight loss, and diarrhea. He was found to have fat malabsorption, and a
Abbreviations used in this paper: CT, computerized tomography; HPN, home parenteral nutrition. o 1991 by the American Gastroenterological Association
0016-5085/91/$3.00
July 1991
tion showed no evidence for recurrence. His nightly HPN formula contained 2250 kcallday, which supplied 46 kcal . kg’ day-’ and 1.8 g protein . kg-’ . day-’ at a nonprotein kilocalorie-to-nitrogen ratio of 14O:l with 25% of his calories from fat (1.05 g fat. kg-’ . day-‘). However, 2 months later he returned because of jaundice associated with malaise and pruritus. His liver tests were formerly characterized by mild elevations of alkaline phosphatase and minimal elevations of aspartate aminotransferase (AST) with normal bilirubin levels until the time of the onset of jaundice. Serological tests for hepatitis A, B, and C were negative including hepatitis B core antibody, surface antigen, and surface antibody. Tests for cytomegalovirus and Epstein-Barr virus showed evidence of past exposure but no evidence of a recent or acute infection. Ultrasonography of the liver and biliary system found a normal liver and gallbladder with no duct dilatation. A retrograde cholangiography was normal, and a liver biopsy specimen [Figure 1) showed hepaticocanilicular cholestasis and scattered foamy macrophages with centrilobular hemosiderin deposits. There was minimal fatty change on the liver biopsy. These histological changes were thought to be compatible with TPN-induced cholestasis. Sepsis was excluded. The TPN was reduced from approximately 2250 calories/day to 1440 calories/day with an increase in the percentage of calories supplied by fat from 25% to 40% of total calories (1.06 g fat . kg-’ . day-‘), and metronidazole treatment, 250 mg t.i.d., was begun. His weight dropped 6 kg over 3 months with the reduction in calories. His bilirubin level ranged from 168 to 298 p,mol/L (9.8 to 17.4 mg/dL) with metronidazole treatment. His TPN was increased because of weight reduction and lack of any effect on the bilirubin. His bilirubin remained elevated at 253 kmol/L (14.8 mg/dL). At this point, metronidazole treatment was stopped 3 months after it was begun, and treatment with ursodeoxycholic
Figure 1. Photomicrograph of liver biopsy specimen showing hepatocanalicular cholestasis, scattered foamy macrophages, and minimal fatty changes. A special stain for iron (not shown) showed deposition of hemosiderin and ferritin.
URSO FOR HPN-INDUCED CHOLESTASIS
251
acid, 600 mg/day in two divided doses PO, was begun. Within 3 weeks, his bilirubin level had dropped to 144 pmol/L (8.4 mg/dL). Two months later, his bilirubin level was 34 p,mol/L (2.0 mg/dL) and eventually reached a level of 17 pmol/L (1.0 mg/dL). His alkaline phosphatase level remained elevated, and his AST became nearly normal. He felt considerably better, and the pruritus that he had experienced had resolved. The ursodeoxycholic acid was discontinued after 2 months of normal bilirubin levels; however, shortly after discontinuation, the bilirubin level rose to 68 p,mol/L (4 mg/dL). At that time, the ursodeoxycholic acid treatment was resumed, the bilirubin level had returned to normal, and the AST and alkaline phosphatase levels were near normal while on ursodeoxycholic acid treatment. A repeat liver biopsy was not considered justified because of his near complete biochemical normalization and the absence of specific diagnostic features on his initial biopsy sample. These results are summarized in Figure 2.
Discussion The origin of cholestasis associated with parenteral nutrition is undefined, and no treatment is known to be clearly effective. Some reported evidence suggests that biliary stasis and increased formation of toxic bile acid metabolites during TPN may contribute to cholestasis (9). It appears that severe cholestasis is more apparent in patients who have undergone massive intestinal resection (4); however, our patient had a total of < 100 cm of intestine removed and would not be categorized as having had massive resection. It has been suggested that absorption of bacterial toxins from a nonused intestine, such as occurs in the
252
LINDOR AND BURNES
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GASTROENTEROLOGY
Vol. 101, No. 1
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jejunal loop syndrome, may be important. Therefore, metronidazole treatment has been used for a few patients, although the effects have been quite variable (5). Phenobarbital has been used in children, although the effects of the barbiturate seem unpredictable and are not well described in adults (6,7). Ursodeoxycholic acid is the 7-p epimer of chenodeoxycholic acid and it is widely used for gallstone dissolution. It has an excellent safety profile with minimal side effects. Abnormalities in liver tests or diarrhea experienced by patients taking chenodeoxycholic acid are rarely encountered by patients receiving ursodeoxycholic acid (10). Furthermore, ursodeoxycholic acid has been reported to be beneficial for patients with primary biliary cirrhosis, a disease of chronic cholestasis involving interlobular and septal bile ducts. Patients with this disease receiving the drug have experienced clinical, biochemical, and a trend towards histological improvement (11). Ursodeoxycholic acid has also been used in the treatment of primary sclerosing cholangitis and chronic active hepatitis, although the data supporting its use in these diseases is incomplete. The mechanism by which ursodeoxycholic acid may exert its beneficial effects in patients with liver disease is unknown. It is thought to be a choleretic agent, it may replace bile
Figure 2. Levels of serum bilirubin, alkaline phosphatase, and AST, respectively, over time and relationship to use of ursodeoxycholic acid. Shaded urea represents normal range, and black bars indicate periods of ursodeoxycholic acid treatment.
acids that are toxic to the liver, and there is some suggestion that ursodeoxycholic acid may have direct protective effects on liver cell membranes. Because of the finding of prominent cholestasis on liver biopsy and the well-established safety profile of ursodeoxycholic acid, a therapeutic trial seemed reasonable. Our patient’s prompt and salutary response to this drug was remarkable. The patient did not have any evidence of lymphomatous involvement of the liver or recurrent lymphoma. He did not have primary biliary cirrhosis or primary sclerosing cholangitis, liver diseases associated with celiac sprue. Other causes of liver disease were excluded, and the relapse with withdrawal of the drug and the improvement of liver tests with reintroduction suggest that ursodeoxycholic acid is a drug that should be tested more formally in patients with this unusual condition of cholestasis associated with long-term HPN. References Sheldon GF, Petersen SR, Sanders R. Hepatic dysfunction during hyperalimentation. Arch Surg 1978;113:504-508. Lindor KD, Fleming CR, Abrams A, Hirschkorn MA. Liver function values in adults receiving total parenteral nutrition. JAMA 1979;241:2398-2400. Bowyer BA, Fleming CR, Ludwig J, Petz J, McGill DB. Does
July 1991
4.
5.
6. 7.
8.
long-term home parenteral nutrition in adult patients cause chronic liver disease? JPEN 1985;9:11-17. Stank0 RT, Nathan G, Mendelow H, Adibi SA. Development of hepatic cholestasis and fibrosis in patients with massive loss of intestine supported by prolonged pare&era1 nutrition. Gastroenterology 1987;92:197-202. Lambert JR, Thomas SM. Metronidazole prevention of serum liver enzyme abnormalities during total parenteral nutrition. JPEN 1985;9:501-503. South M, King A. Parenteral nutrition-associated cholestasis: recovery following phenobarbitone. JPEN 1987;11:208-209. Gleghorn EE, Merritt RJ, Subramanian N, Ramos A. Phenobarbital does not prevent total parenteral nutrition-associated cholestasis in noninfected neonates. JPEN 1986;10:282-283. Bowyer BA, Miles JM, Haymond MW, Fleming CR. L%arnitine therapy in home parenteral nutrition patients with abnormal liver tests and low plasma carnitine concentrations. Gastroenterology 1988;94:434-438.
URSO FOR HPN-INDUCED
CHOLESTASIS
253
9. Whitington PF. Cholestasis associated with total parenteral nutrition in infants. Hepatology 1985;5:693-696. 10. Bachrach WH, Hofmann AF. Ursodeoxycholic acid in the treatment of cholesterol choielithiasis, Part II. Dig Dis Sci 1982;27:833-856. 11. Leuschner U, Fischer H, Kurtz W, Guldautuna S, Hubner K, Hellstern A, Gatzen M, Leuschner M. Ursodeoxycholic acid in primary biliary cirrhosis: results of a controlled double-blind trial. Gastroenterology 1989;97:1268-1274.
Received July 24,199O. Accepted February 11.1991. Address requests for reprints to: Keith D. Lindor, M.D., Mayo Clinic, Division of Gastroenterology, Rochester, Minnesota 55905. The authors thank the patient’s local physician, Dr. Leroy Mueller, for his help in following the patient’s course, and Dr. C. R. Fleming for his thoughtful suggestions in the preparation of the manuscript.