Benign recurrent intrahepatic cholestasis
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《美国医学杂志》
1 Department of Pediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
2 Department of Pathology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
Abstract
Benign recurrent intrahepatic cholestasis (BRIC) is a rare cause of cholestasis in children. The disease may start in infancy or early childhood. Jaundice persists or recurs throughout life but does not lead to chronic liver disease or cirrhosis. Treatment is mostly symptomatic. The condition has not been reported in Indian children. We report an interesting case of BRIC in a 9-year-old boy who had recurrent episodes of jaundice since when he was 1 yr old.
Keywords: BRIC; Cholestasis; Jaundice; Cirrhosis
Cholestatic jaundice in children is commonly due to acute viral hepatitis or is drug induced. However, conditions like chronic hepatitis, Wilson's disease, alpha-1 antitrypsin deficiency and liver disease associated with chronic inflammatory bowel disease are also considered in the differential diagnosis. Rare causes include syndromes of intrahepatic cholestasis with familial patterns of occurrence.[1] These familial cholestatic syndromes share many clinical similarities with onset in infancy or early childhood. These persist or recur throughout life. At one end of the spectrum is Byler's disease which is a progressive familial intrahepatic cholestasis (PFIC) culminating in cirrhosis during teenage years. At the other end is benign recurrent intrahepatic cholestasis (BRIC) which as the name suggests has a benign course and does not lead to chronic liver disease or cirrhosis. There have been isolated case reports of BRIC in pediatric patients in foreign literature[2],[3] but none from India. However, there is one case report in an adult patient.[4] We report an interesting case of BRIC in a 9-year- old boy.
Case Report
A 9-year-old boy presented to our out-patient department with complaints of recurrent episodes of jaundice and dark coloured urine since he was 1 year old. The child also had pruritus along with jaundice. The interval between the episodes was variable, occurring every 1 to 1 years and lasting from 2 to 3 weeks. The child was asymptomatic in between the episodes. He had approximately 6 episodes of jaundice prior to the present episode that required only symptomatic treatment and no hospitalization. Liver function tests done during 4 of these episodes showed conjugated hyperbilirubinemia each time (range 2.9-4.5 mg/dl) with high alkaline phosphatase level (range 760-940 IU). Viral markers for hepatitis A, B and ultrasonography of abdomen done three times were normal. He was a student of class III with average intelligence and frequent absenteeism due to jaundice.
On examination, the child had icterus without pallor, pedal edema or signs of vitamin deficiencies. There were no signs of liver failure in the form of spider angiomas, palmar erythema or thenar atrophy. Liver was just palpable in right hypochondrium with a span of 9 cm. Spleen was not palpable and there was no evidence of free fluid in the abdomen. Rest of the systemic examination was non contributory. His anthropometric parameters were within normal limits with average height and weight. Investigations revealed hemoglobin of 10.5 g/dl with normal total and differential count. Total bilirubin was 3.4 mg% with a direct component of 2.9 mg%. Alkaline phosphatase was elevated with a value of 844 IU. Liver enzymes including ALT, AST and gamma glutamyl transpeptidase (GGT) were within normal limits. Serum proteins, albumin globulin ratio and prothrombin time were also normal.Ultrasonography of abdomen showed normal echotexture of liver. Viral markers for hepatitis A and B were negative and serum ceruloplasmin was within normal limits. Endoscopic retrograde cholangio Pancreatography (ERCP) was normal. In view of the above findings, a possibility of recurrent cholestasis was kept and a liver biopsy was performed. The biopsy showed preserved lobular architecture with marked cholestasis within hepatocytes with some portal inflammation Figure1. The child was given symptomatic treatment and he improved within 2 weeks with complete normalization of serum bilirubin and alkaline phosphatase level. As the child had no evidence of chronic or progressive liver disease and other possible causes of jaundice were excluded, a diagnosis of benign recurrent intrahepatic cholestasis was made. At 6 months follow-up the child continues to be symptom free.
Discussion
Benign recurrent intrahepatic cholestasis is a rare disorder of unknown etiology characterized by intermittent episodes of cholestasis with normal extra hepatic biliary tree. The attacks can start at any age and last from weeks to months.[5] In a large series of patients the age of presentation varied from 1 to 59 yr and duration of icteric phase was also variable lasting from weeks to months.[6] In our patient, the first attack started at the age of 1 and each episode lasted for 2 to 3 weeks. In such cases, during icteric phase serum bilirubin, bile acids and alkaline phosphatase are elevated but gamma glutamyl transferase level is characteristically low or normal. Occasionally alanine aminotransferase (ALT) and aspartate aminofransferase (AST) levels may be markedly elevated but usually there is only mild elevation. In the present case the liver enzymes including (GGT) were within normal limits at the time of presentation but previous reports did show some elevation of enzymes. Progressive familial intrahepatic cholestasis (PFIC) is another liver disease which is characterized by cholestasis with normal gamma glutamyl transferase level which starts in infancy and progresses to cirrhosis, liver failure and death unless a liver transplantation is performed. Conversely, long term follow up of a number of patients with BRIC has shown that the disease follows a benign course and there is no progression to chronic liver disease.[7],[8] In the present case, even after 8 years there was no evidence of cirrhosis. However, a recent report has suggested that few patients may start with clinical symptoms of BRIC and may progress to PFIC [9]. In view of this new evidence, patients with benign recurrent cholestasis need a regular follow up.
Treatment of the condition is purely symptomatic. There are conflicting reports regarding the use of cholestyramine and ursodeoxycholic acid. One report suggested that cholestyramine therapy shortened the duration of icteric phase and ursodeoxycholic acid ameliorated the symptoms of pruritus if present.[2] However, another report has suggested that no treatment was successful in shortening the duration of symptoms.[6] Some recent reports have shown a beneficial role of rifampicin in remission of cholestasis.[10],[11] In the present case, the child was given a trial of ursodeoxycholic acid which provided symptomatic relief with decrease in pruritus. Child made an uneventful recovery within 3 weeks. He is on regular follow up for 6 months and has not suffered another attack.
References
1. Whitington PE, Emerick KM, Suchy FJ. Familial hepatocellular cholestasis. In Suchy FJ, Sokol RJ, Balistreri WF, eds. Liver disease in children. 2nd edn. Philadelphia; Lippincott William and Wilkins 2001; 315-323.
2. Drees K, a Zaben A, al Amir A, Abdulla A. Benign recurrent intrahepatic cholestasis in a Saudi child. Ann Trop Pediatr 1999; 19: 215-217.
3. Liu CJ, Kao JH, Chen PJ, Lai MY, Mao TL, Wang TH, Chen DS. Benign recurrent intrahepatic cholestasis. J Formos Med Assoc 1997; 96: 370-373.
4. Samal SC, Kashyap R. Benign recurrent intrahepatic cholestasis. J Assoc Phy India 1995 ; 43: 569 - 570.
5. Summerskill WHJ, Walshe JM. Benign recurrent intrahepatic obstructive jaundice. Lancet 1959; 2: 686 - 690.
6. Brenard R, Genhel AP, Benhamou JP. Benign recurrent intrahepatic cholestasis: a report of 26 cases. J Clin Gastroenterol 1989; 11: 546-551.
7. Nakamuta M, Sakamoto S, Miyata Y,Sato M, Nawata H. Benign recurrent intrahepatic cholestasis: a long term follow up. Hepatogastroenterology 1994; 41: 287-289.
8. Bijleveld CM, Vonk RJ, Kuipers F, Havinga R, Fernandes J. Benign recurrent intrahepatic cholestasis: a long term follow-up study of two patients. Hepatology 1989; 9: 532-537.
9. van Ooteghem NA, Klomp LW, van Berge- Henegouwen GP, Houwen RH. Benign recurrent intrahepatic cholestasis progressing to Progressive familial intrahepatic cholestasis: low GGT cholestasis is a clinical continuum. J Hepatol 2002;36: 439-443.
10. Balsells F, Wyllie R, Steffen R, Kay M. Benign recurrent intrahepatic cholestasis: improvement of pruritus and shortening of symptomatic phase with rifampicin therapy: a case report. Clin Pediatr (Phila) 1997; 36: 483-485.
11. Cancado EL, Leito RM, Carrilho FJ, Laudanna AA. Unexpected clinical remission of cholestasis after rifampicin therapy in patients with normal or slightly increased levels of GGt. Am J Gastroenterol 1998; 93: 1510-1517.(Gupta V, Kumar M, Bhatia )
2 Department of Pathology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
Abstract
Benign recurrent intrahepatic cholestasis (BRIC) is a rare cause of cholestasis in children. The disease may start in infancy or early childhood. Jaundice persists or recurs throughout life but does not lead to chronic liver disease or cirrhosis. Treatment is mostly symptomatic. The condition has not been reported in Indian children. We report an interesting case of BRIC in a 9-year-old boy who had recurrent episodes of jaundice since when he was 1 yr old.
Keywords: BRIC; Cholestasis; Jaundice; Cirrhosis
Cholestatic jaundice in children is commonly due to acute viral hepatitis or is drug induced. However, conditions like chronic hepatitis, Wilson's disease, alpha-1 antitrypsin deficiency and liver disease associated with chronic inflammatory bowel disease are also considered in the differential diagnosis. Rare causes include syndromes of intrahepatic cholestasis with familial patterns of occurrence.[1] These familial cholestatic syndromes share many clinical similarities with onset in infancy or early childhood. These persist or recur throughout life. At one end of the spectrum is Byler's disease which is a progressive familial intrahepatic cholestasis (PFIC) culminating in cirrhosis during teenage years. At the other end is benign recurrent intrahepatic cholestasis (BRIC) which as the name suggests has a benign course and does not lead to chronic liver disease or cirrhosis. There have been isolated case reports of BRIC in pediatric patients in foreign literature[2],[3] but none from India. However, there is one case report in an adult patient.[4] We report an interesting case of BRIC in a 9-year- old boy.
Case Report
A 9-year-old boy presented to our out-patient department with complaints of recurrent episodes of jaundice and dark coloured urine since he was 1 year old. The child also had pruritus along with jaundice. The interval between the episodes was variable, occurring every 1 to 1 years and lasting from 2 to 3 weeks. The child was asymptomatic in between the episodes. He had approximately 6 episodes of jaundice prior to the present episode that required only symptomatic treatment and no hospitalization. Liver function tests done during 4 of these episodes showed conjugated hyperbilirubinemia each time (range 2.9-4.5 mg/dl) with high alkaline phosphatase level (range 760-940 IU). Viral markers for hepatitis A, B and ultrasonography of abdomen done three times were normal. He was a student of class III with average intelligence and frequent absenteeism due to jaundice.
On examination, the child had icterus without pallor, pedal edema or signs of vitamin deficiencies. There were no signs of liver failure in the form of spider angiomas, palmar erythema or thenar atrophy. Liver was just palpable in right hypochondrium with a span of 9 cm. Spleen was not palpable and there was no evidence of free fluid in the abdomen. Rest of the systemic examination was non contributory. His anthropometric parameters were within normal limits with average height and weight. Investigations revealed hemoglobin of 10.5 g/dl with normal total and differential count. Total bilirubin was 3.4 mg% with a direct component of 2.9 mg%. Alkaline phosphatase was elevated with a value of 844 IU. Liver enzymes including ALT, AST and gamma glutamyl transpeptidase (GGT) were within normal limits. Serum proteins, albumin globulin ratio and prothrombin time were also normal.Ultrasonography of abdomen showed normal echotexture of liver. Viral markers for hepatitis A and B were negative and serum ceruloplasmin was within normal limits. Endoscopic retrograde cholangio Pancreatography (ERCP) was normal. In view of the above findings, a possibility of recurrent cholestasis was kept and a liver biopsy was performed. The biopsy showed preserved lobular architecture with marked cholestasis within hepatocytes with some portal inflammation Figure1. The child was given symptomatic treatment and he improved within 2 weeks with complete normalization of serum bilirubin and alkaline phosphatase level. As the child had no evidence of chronic or progressive liver disease and other possible causes of jaundice were excluded, a diagnosis of benign recurrent intrahepatic cholestasis was made. At 6 months follow-up the child continues to be symptom free.
Discussion
Benign recurrent intrahepatic cholestasis is a rare disorder of unknown etiology characterized by intermittent episodes of cholestasis with normal extra hepatic biliary tree. The attacks can start at any age and last from weeks to months.[5] In a large series of patients the age of presentation varied from 1 to 59 yr and duration of icteric phase was also variable lasting from weeks to months.[6] In our patient, the first attack started at the age of 1 and each episode lasted for 2 to 3 weeks. In such cases, during icteric phase serum bilirubin, bile acids and alkaline phosphatase are elevated but gamma glutamyl transferase level is characteristically low or normal. Occasionally alanine aminotransferase (ALT) and aspartate aminofransferase (AST) levels may be markedly elevated but usually there is only mild elevation. In the present case the liver enzymes including (GGT) were within normal limits at the time of presentation but previous reports did show some elevation of enzymes. Progressive familial intrahepatic cholestasis (PFIC) is another liver disease which is characterized by cholestasis with normal gamma glutamyl transferase level which starts in infancy and progresses to cirrhosis, liver failure and death unless a liver transplantation is performed. Conversely, long term follow up of a number of patients with BRIC has shown that the disease follows a benign course and there is no progression to chronic liver disease.[7],[8] In the present case, even after 8 years there was no evidence of cirrhosis. However, a recent report has suggested that few patients may start with clinical symptoms of BRIC and may progress to PFIC [9]. In view of this new evidence, patients with benign recurrent cholestasis need a regular follow up.
Treatment of the condition is purely symptomatic. There are conflicting reports regarding the use of cholestyramine and ursodeoxycholic acid. One report suggested that cholestyramine therapy shortened the duration of icteric phase and ursodeoxycholic acid ameliorated the symptoms of pruritus if present.[2] However, another report has suggested that no treatment was successful in shortening the duration of symptoms.[6] Some recent reports have shown a beneficial role of rifampicin in remission of cholestasis.[10],[11] In the present case, the child was given a trial of ursodeoxycholic acid which provided symptomatic relief with decrease in pruritus. Child made an uneventful recovery within 3 weeks. He is on regular follow up for 6 months and has not suffered another attack.
References
1. Whitington PE, Emerick KM, Suchy FJ. Familial hepatocellular cholestasis. In Suchy FJ, Sokol RJ, Balistreri WF, eds. Liver disease in children. 2nd edn. Philadelphia; Lippincott William and Wilkins 2001; 315-323.
2. Drees K, a Zaben A, al Amir A, Abdulla A. Benign recurrent intrahepatic cholestasis in a Saudi child. Ann Trop Pediatr 1999; 19: 215-217.
3. Liu CJ, Kao JH, Chen PJ, Lai MY, Mao TL, Wang TH, Chen DS. Benign recurrent intrahepatic cholestasis. J Formos Med Assoc 1997; 96: 370-373.
4. Samal SC, Kashyap R. Benign recurrent intrahepatic cholestasis. J Assoc Phy India 1995 ; 43: 569 - 570.
5. Summerskill WHJ, Walshe JM. Benign recurrent intrahepatic obstructive jaundice. Lancet 1959; 2: 686 - 690.
6. Brenard R, Genhel AP, Benhamou JP. Benign recurrent intrahepatic cholestasis: a report of 26 cases. J Clin Gastroenterol 1989; 11: 546-551.
7. Nakamuta M, Sakamoto S, Miyata Y,Sato M, Nawata H. Benign recurrent intrahepatic cholestasis: a long term follow up. Hepatogastroenterology 1994; 41: 287-289.
8. Bijleveld CM, Vonk RJ, Kuipers F, Havinga R, Fernandes J. Benign recurrent intrahepatic cholestasis: a long term follow-up study of two patients. Hepatology 1989; 9: 532-537.
9. van Ooteghem NA, Klomp LW, van Berge- Henegouwen GP, Houwen RH. Benign recurrent intrahepatic cholestasis progressing to Progressive familial intrahepatic cholestasis: low GGT cholestasis is a clinical continuum. J Hepatol 2002;36: 439-443.
10. Balsells F, Wyllie R, Steffen R, Kay M. Benign recurrent intrahepatic cholestasis: improvement of pruritus and shortening of symptomatic phase with rifampicin therapy: a case report. Clin Pediatr (Phila) 1997; 36: 483-485.
11. Cancado EL, Leito RM, Carrilho FJ, Laudanna AA. Unexpected clinical remission of cholestasis after rifampicin therapy in patients with normal or slightly increased levels of GGt. Am J Gastroenterol 1998; 93: 1510-1517.(Gupta V, Kumar M, Bhatia )