Clinical and biochemical findings in progressive familial intrahepatic cholestasis

Clinical and biochemical findings in progressive familial intrahepatic cholestasis

258 HEPATOLOGYElsewhere Whitington PF, Freese DK, Alonso EM, Schwarzenberg SJ, Sharp HL. Clinical and biochemical findings in progressive familial in...

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258 HEPATOLOGYElsewhere

Whitington PF, Freese DK, Alonso EM, Schwarzenberg SJ, Sharp HL. Clinical and biochemical findings in progressive familial intrahepatic cholestasis. J Pediatr Gastroenterol Nutr 1994; 18:134-141. ABSTRACT

SHmmary: The clinical findings in 33 patients with progressive f~rni|ial intrahepatic cholestasis (PFIC) are presented. Symptoms developed almost invariably before 6 months of age with severe pruritus and moderate jaundice. Other clinical findings included wheezing and nosebleeds, fat-soluble vitamin deficiency states, and cholelithiasis. Lower values for T-glutamyl transpeptidase, averaging 15 IU/L before the administration of phenobarbital, and cholesterol, which averaged 156 mg/dl, are helpful in distinguishing PFIC from other pediatric cholestatic liver diseases. Autosomal recessive inheritance is probable. Twenty-six patients are alive at 12.9 ± 6.7 years of age, all having had successful surgical treatment, either partial biliary diversion (n = 17) or orthotopic liver transplantation (n -- 10). Seven patients died at a mean age of 3.9 ± 2.4 years, as a result of liver failure in two, hepatocellular carcinoma in two, and complications of liver transplantation in three. Key Word~ Byler disease--Ductal paucity--Surgical therapy for cholestatic liver disease--T-Glutamyl transpeptidase. COMMENTS

Cholestatic liver disorders constitute a large part of chronic liver disease in infancy and childhood. Disorders without significant cholestasis, such as chronic viral hepatitis and autoimmune hepatitis, occur in children, but are less common t h a n they are in adults, or may not be manifest until adolescence or adulthood. Thus, pediatric hepatologists are often confronted with the diagnosis and m a n a g e m e n t of children with cholestatic syndromes. The majority of infants under 3 months of age with significant cholestasis have extrahepatic biliary atresia, which continues to be the most common indication for liver transplantation in pediatrics. Other disorders of the extrahepatic biliary tree, such as choledochal cyst, primary sclerosing cholangitis, and Caroli's disease, occur much less frequently. Intrahepatic cholestasis, defined as that which occurs in the absence of extrahepatic obstruction, represents about one third of cases of childhood cholestatic liver disease. 1 The challenge has been to tease out specific entities within this broad category. The lack of specific diagnostic tests or histological findings for any of these disorders has hampered efforts at exact definition. The first efforts in this regard took advantage of the familial nature of some of these entities, and genetic patterns and causes were sought. This work led to the description of Alagille syndrome, or arteriohepatic dysplasia, an autosomal dominant condition in which cholestasis is associated with intrahepatic bile duct paucity, cardiovascular abnormalities, short stature,

HEPATOLOGYJanuary 1995 vertebral abnormalities, and other physical findings. 2'3 The recent identification of a deletion defect on the short arm of chromosome 20 in some families with Alagille syndrome 4'~ confirms this disorder as a distinct entity and will eventually allow for understanding of its pathogenesis. Other clinical entities, identified in specific ethnic groups, have not been as well defined. These include Byler's disease, North American Indian cholestasis, Greenland Eskimo cholestasis, and Norwegian cholestasis. Children who are not members of these ethnic groups and who have sporadic or familial cholestasis associated with intrahepatic bile duct paucity, are classified as having nonsyndromic bile duct paucity. Recently, some cases of intrahepatic cholestasis with severe liver disease, which might otherwise have been classified as familial intrahepatic cholestasis, have been found to be caused by inborn errors of bile acid metabolism6; enzyme deficiencies have been detected, and effective therapy has been instituted in some instances. In these two reports, the authors present their experience with a large series of patients with, for lack of a more specific term, progressive familial intrahepatic cholestasis (PFIC). By using specific clinical criteria and excluding known causes of intrahepatic cholestasis, they attempt to define and delineate the histological and clinical characteristics of this group of children. The importance of this work is that strict definition of a subgroup of childhood cholestasis will allow for more precise study of the natural history, prognosis, pathogenesis, and eventual t r e a t m e n t of this disease or syndrome. This work is a retrospective review of the records of these 33 children, and the authors used a control group consisting of children with other cholestatic disorders, such as extrahepatic biliary atresia and Alagille syndrome. It should be stated that this diagnosis, PFIC, is not clearly distinguishable from what has been called Byler's disease, and Byler's disease m a y be simply PFIC as it occurred in one particular well studied kindred. 7 Some of the reported experience with Byler's disease may, in fact, be applicable to this broader group of patients. Alternatively, they m a y be two different disorders that share a phenotype. This distinction will not be clarified until specific diagnostic or genetic markers are identified. The first article describes the histologic findings in 84 liver biopsy specimens from 28 children with PFIC. Sequential biopsy specimens were available in 26 of the patients, so that histopathologic progression of the disorder could be described. Although some of the findings such as early hepatocellular and canalicular cholestasis and pseudoacinar transformation ofhepatocytes s have been previously reported, other observations, such as postinfantile giant cell transformation, and early degeneration of bile duct epithelium leading to bile duct paucity, have not heretofore been as clearly defined. Of particular interest is the fairly unusual develop-

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HEPATOLOGYElsewhere 259

mental pattern of hepatic fibrosis: the early lesion is bile duct obstruction or injury. In most cholestatic liver one of pericentral sclerosis, which was noted to pro- diseases, GGTP levels are greatly elevated. Normal segress via a lacy deposition of collagen within the lob- rum levels of GGTP are otherwise reported only in beules, and bridging to the portal areas, so that late in nign recurrent intrahepatic cholestasis, 11 which is the process a more typical pattern of biliary cirrhosis characterized by episodes of cholestasis with complete was evident. This pattern of progression is not that resolution in between episodes, and normal liver histolobserved in biliary obstruction, either at the intralobu- ogy. The normal serum values of this enzyme in PFIC lar or extrahepatic level, and the authors think that may indicate that hepatocytes are the main target of this pattern is specific to PFIC. The rate of progression the injury, that there is a primary deficiency of this was highly variable among the patients but fairly re- enzyme, or that there is an underlying transport defect producible. Thus, although initial liver biopsy speci- that precludes secretion of this enzyme from liver to mens may not be diagnostic of this disorder, they pro- serum; data regarding hepatic content of GGTP in pose that this histological progression is recognizable PFIC are conflictingJ2 Nonetheless, it is hoped that this almost unique biochemical feature will provide and predictive. The second article, again in an attempt to more accu- clues to pathogenesis. Normal serum cholesterol values rately define PFIC within the broad category of intra- are observed in PFIC, in contrast to the elevated values hepatic cholestasis of childhood, describes clinical and in other cholestatic conditions. It is intriguing to note biochemical findings in the 33 patients. To some extent, that lipid and GGTP secretion are physiologically rethe data rely on circular reasoning: the case definition lated and dependent on bile acid secretion) 3'14 includes early onset (before 6 months of age) of chronic The role of bile acid metabolism in the pathogenesis cholestasis without anatomic, metabolic or infectious of PFIC remains a field of active research. Investigators cause, associated with low/normal serum levels of ~/- have postulated a defect in bile acid transport, possibly glutamyl transpeptidase (GGTP) and cholesterol, the at the level of the canaliculus. The consequent accumulatter of which are then reported as characteristic of lation of bile acids may cause membrane injury; dePFIC. Yet the validity of these findings is somewhat creased secretion of cholesterol, other lipids, and intuitive from the familial pattern in many of the pa- GGTP; as well as impairment of other cellular functients, the relative consistency of clinical traits, and tions. Secondarily, changes in glutathione secretion the clear distinction of these clinical and biochemical caused by an effect on GGTP may perpetuate or aggracharacteristics from those of the other childhood chole- vate the cholestasis, since glutathione secretion is restatic disorders studied, including primary sclerosing sponsible for much of the bile-acid-independent porcholangitis, extrahepatic biliary atresia, and Alagille tion of bile flow. This theory is somewhat substantiated by the observed improvement in both biochemical and syndrome. Evidence for fat-soluble vitamin malabsorption, histological manifestations of PFIC in children who unmanifest by rickets and peripheral neuropathy, was dergo partial biliary diversion, creation of a conduit common, as were cholelithiasis and intractable pruri- from gallbladder to skin, which removes approximately tus, but these findings can be explained by severe 50% of the bile acid pool. 15 Although the ratio of prichronic cholestasis. More unique clinical observations mary bile acids is abnormal in PFIC and abnormal included airway symptoms (wheezing and cough) in 10 amounts of minor bile acids are detected, no bile acid children, which resolved with successful therapy of the pattern has been found characteristic or diagnostic of liver disease in 9, and recurrent, severe epistaxis with- this disorder. Ursodeoxycholic acid therapy has met out thrombocytopenia or coagulopathy in more than with variable success in improving symptoms in chilhalf of the patients. These symptoms are not exhibited dren with PFICJ ~ in other forms of childhood cholestasis, although they These authors have described both histological and remain unexplained in PFIC. Failure of linear growth clinical findings in the largest series reported to date (height less than the fifth percentile) was an almost of children with PFIC, in an attempt to more clearly universal finding. Although the authors did not present define a subgroup of patients with chronic intrahepatic growth data from either cholestatic controls or unaf- cholestasis. These children have severe unremitting fected siblings of the PFIC patients, the severity and cholestasis, usually beginning early in life, with normal frequency of the growth failure in this group of children GGTP and cholesterol levels, respiratory symptoms, is compelling, and almost certainly is an intrinsic com- epistaxis and significant growth failure. A typical patponent of the syndrome. tern of histological progression of the liver disease is The normal serum levels of GGTP and cholesterol described. Whether this definition is valid, and indeed reported by these authors have been described pre- indicates specific diagnostic criteria, remains to be viously in patients with PFIC. 9'~° GGTP, which cata- seen. Interpretation of studies of natural history, proglyzes the transfer of gammaglutamyl groups from glu- nosis, and therapeutic interventions rely heavily on actathione and other peptides, is found primarily in the curate and careful case definition. It is hoped that furcanalicular membrane domain ofhepatocytes, and bile ther attempts to tightly characterize this disorder will duct epithelial cells. Its synthesis is inducible by drugs, lead to the discovery of the primary pathogenetic mechincluding phenobarbital and ethanol; hormones; and anism(s) and perhaps even the underlying genetic



defect. I n t h e m e a n t i m e , p e d i a t r i c g a s t r o e n t e r o l o g i s t s w e l c o m e t h e c o n t i n u e d efforts a t s h e d d i n g light into t h e b l a c k box of childhood cholestatic liver disease. IAN D. A. D'AGATA, MD MAUREEN M. JONAS, MD

Center for Childhood Liver Disease Combined Program in Gastroenterology Children's Hospital Boston, MA REFERENCES 1. Balistreri WF. Interrelationship between the infantile cholangiopathies and paucity of the intrahepatic bile ducts. Balistreri WF, Stocker JT, eds. In Pediatric hepatology. New York: Hemisphere Publishing Cerp, 1990:1-18. 2. Alagille D, Habib EC, and Thomassin N. L'atresie des voies biliaires intrah~patiques perm~ables chez l'enfant: h propos de 25 observations. J Paris Pediatr 1969;30:1-18. 3. Watson GH, Miller V. Arteriohepatic dysplasia: familial pulmonary stenosis with neonatal liver disease. Arch Dis Child 1973; 48:459-466. 4. Schnittger S, Hofers C, Heidman P, Beermann F, Hansmann I. Molecular and cytogenetic analysis of an interstitial 20p deletion associated with syndromic intrahepatic ductular hypoplasia (Alagille syndrome). Hum Genet 1989;83:239-244. 5. Zhang F, Deleuze JF, Aurias A, Dutrillaux M, Hugon RN, Alagille D, Thomas G, Hadchouel M. Internal deletion of the short arm of chromosome 20 in arteriohepatic dysplasia (Alagille syndrome). J Pediatr 1990; 116:73-77. 6. Setchell KDR, Street JM. Inborn errors of bile acid synthesis. Semin Liv Dis 1987;7:85-99. 7. Clayton RJ, Iber FL, Ruebner BH. Byler's disease: fatal familial intrahepatic cholestasis in an Amish kindred. J Pediatr 1965; 67:1026-1028. 8. OdiSvre M, Gautier M, Hadchouel M, Alagille D. Severe familial intrahepatic cholestasis. Arch Dis Child 1973;48:806-812. 9. Ballow M, Margolis CZ, Schachtel B, Hsia Y. Progressive familial intrahepatic cholestasis. Pediatrics 1973;51:998-1007. 10. Maggiore G, Bernard O, Hadchouel M, Lemonnier A, Alagille D. Diagnostic value of serum gammaglutamyltranspeptidase activity in liver disease in children. J Pediatr Gastroenterol Nutr 1991; 12:21-26. 11. Summerskill WHJ, Oxen DM. Benign recurrent intrahepatic "obstructive" jaundice. Lancet 1959;2:686-690. 12. Chobert MN, Bernard O, Bulle F, Lemonnier A, Gueallaen G, and Alagille D. High hepatic gammaglutamyltranspeptidase (GGT) with normal serum GGT in children with progressive idiopathic cholestasis. J Hepatol 1989;8:22-25. 13. O'Maille ER, Kozmary SV, Hofmann AF, Gurantz D. Differing effects of norcholate and chelate on bile flow and biliary lipid secretion in the rat. Am J Physiol 1984;246:G67-71. 14. Galan AI, Roman ID, Munoz ME, Cava F, Gonzales-Buitrago JM, Esteller A, Jimenez R. Inhibition of biliary lipid and protein secretion by cyclosporin A in the rat. Biochem Pharmcol 1992;44:1105-1111. 15. Whitington PR, Whitington GL. Partial external division of bile for the therapy of intractable pruritus associated with intrahepatic cholestasis. Gastroenterology 1988; 95:130-136. 16. Balistreri WF, A-Kader HH, Ryckman FC, Heubi JE, Setchell KDR. Ursodeoxycholic acid therapy in pediatric patients with chronic cholestasis. In Lentze MJ and Rachen J, eds. Paediatric cholestasis. Dondrecht, the Netherlands: Kluwer Academic Publishers, 1992:333-343.


Rolles K, Burroughs AK, Davidson BR, Karatapanis S, Prentice HG, Hamon MD. Donor-specific b o n e m a r -

HEPATOLOGYJanuary 1995 row infusion a f t e r orthotopic liver t r a n s p l a n t a t i o n . L a n c e t 1994;263-265. ABSTRACT Donor-specific b o n e m a r r o w infusion after organ grafting can induce tolerance in animals. In this randomized, controlled study w e s h o w it has n o benefit in patients u n d e r g o i n g liver transplantation. Of 25 patients, 9 received b o n e m a r r o w 5 days after a 10 day course of a n t i t h y m o c y t e g l o b , lin, l m m u n o s u p p r e s s i o n w a s maintained w i t h cyclosporin only. An average o f 3.0 rejection episodes per patient was seen in the b o n e m a r r o w group c o m p a r e d to 3.1 in the controls. Cbimerism w a s not found in peripheral blood or bone m a r r o w of recipients using erythrocyte antigen markers, PCR for donor class II DNA or T-probe in-situ hybridisation in one female recipient of male liver and bone marrow.

COMMENTS T h e s h o r t r e p o r t t h a t a p p e a r e d in Lancet b y Rolles, et al, r e p o r t s a series of p a t i e n t s w h o u n d e r w e n t liver t r a n s p l a n t a t i o n u n d e r s e q u e n t i a l t h e r a p y w i t h antit h y m o c y t e globulin followed b y cyclosporine. I n n i n e p a t i e n t s , c r y o p r e s e r v e d d o n o r bone m a r r o w w a s inf u s e d 5 d a y s a f t e r a 10 d a y course of a n t i t h y m o c y t e , t h a t b e g a n on t h e d a y of t r a n s p l a n t a t i o n . T h e s e pat i e n t s w e r e c o m p a r e d w i t h 16 o t h e r liver r e c i p i e n t s w h o did not receive t h e bone m a r r o w infusion. T h e investig a t i o n e x a m i n e d clinical o u t c o m e s of p a t i e n t a n d g r a f t survival, t h e incidence of rejection (including s e v e r i t y of rejections), as well as t h e p r e s e n c e of p e r i p h e r a l a n d bone m a r r o w c h i m e r i s m following t r a n s p l a n t a t i o n . T h e i n v e s t i g a t o r s concluded t h a t infusion of bone m a r r o w (at 2-3 x l 0 s d o n o r b o n e m a r r o w cells p e r kilog r a m ) did not affect t h e incidence of a c u t e rejections d u r i n g t h e first y e a r a f t e r t r a n s p l a n t a t i o n . I n addition, u s i n g flow c y t o m e t r y a n d p o l y m e r a s e c h a i n r e a c t i o n of p e r i p h e r a l blood a n d bone m a r r o w , t h e i n v e s t i g a t o r s failed to show h e m a t o l y m p h o i d c h i m e r i s m in t h e recipi e n t s of bone m a r r o w u p to 100 d a y s a f t e r t r a n s p l a n t a tion. T h e i n v e s t i g a t o r s conclude t h a t t h i s series does not j u s t i f y e v e n t u a l w i t h d r a w a l of i m m u n o s u p p r e s s i o n in h o p e s of a c h i e v i n g donor-specific u n r e s p o n s i v e n e s s . T h e principle l i m i t a t i o n of t h i s r e p o r t is t h e v e r y h i g h incidence of rejection in b o t h t h e d o n o r specific bone m a r r o w infusion g r o u p a n d t h e control group. All b u t 1 of t h e 25 t o t a l p a t i e n t s e x p e r i e n c e d a cellular rejection episode. T h e 96% incident of rejection is a t l e a s t 20% to 30% h i g h e r t h a n t h e incidence of rejections n o t e d in o t h e r l a r g e series in liver t r a n s p l a n t a t i o n . 1 A l t h o u g h t h e a u t h o r s s t a t e t h a t "basic i m m u n o s u p p r e s s i v e regim e n w a s a d e q u a t e , " t h e r e l a t i v e l y low level of cyclosporine levels achieved, w i t h o u t t h e u s e of induction steroid t h e r a p y , a n d a v e r y h i g h incidence of rejection w i t h i n t h e first 4 w e e k s a f t e r t r a n s p l a n t a t i o n , s u g g e s t t h a t o p t i m a l i m m u n o s u p p r e s s i o n w a s not achieved. W h e t h e r this h i g h incidence of rejection adv e r s e l y affected t h e s u b s e q u e n t lack of d e m o n s t r a t i o n of h e m a t o l y m p h o i d c h i m e r i s m is subject to debate.