Dig Dis Sci DOI 10.1007/s10620-014-3220-5

STANFORD MULTIDISCIPLINARY SEMINARS

Complications Following Liver Transplantation for Progressive Familial Intrahepatic Cholestasis Jennifer Berumen • Elyssa Feinberg • Tsuyoshi Todo • C. Andrew Bonham • Waldo Concepcion • Carlos Esquivel

 Springer Science+Business Media New York 2014

Case Presentation and Evolution A 9-year-old girl with genetically confirmed progressive familial intrahepatic cholestasis Type 1 (PFIC 1) was evaluated for neonatal jaundice. Due to persistent jaundice with pruritus, she underwent biliary diversion with cholecysto-jejunostomy at 8 months of age. Although postoperatively the pruritus initially resolved, she had other manifestations of PFIC, including persistent diarrhea. Over several years, the jaundice and pruritus returned, becoming progressively more severe. Relief from pruritus was not obtained despite the prescription of multiple medications, including diphenhydramine, rifampicin, and cholestyramine, resulting in a decrease in her quality of life. Due to continuing severe, intolerable pruritus, she received a reduced size (left lobe) liver transplant with a choledocho– choledocho biliary anastomosis at age 7 years. Shortly after transplantation, liver function improved and pruritus resolved. Nevertheless, her chronic diarrhea worsened. At age 9, she developed cholangitis that was treated successfully with antibiotics. Magnetic resonance cholangiopancreatography (MRCP) revealed a stricture at her native common bile duct at the level of the ampulla accompanied by delayed bile excretion (Fig. 1). At endoscopic retrograde cholangiopancreatography (ERCP), these findings were confirmed (Fig. 2), and the stricture was dilated and stented. Although she improved after the procedure, she developed two more episodes of cholangitis over the ensuing 8 months requiring repeated ERCP and dilation. During her last episode of cholangitis, liver biopsy J. Berumen (&)  E. Feinberg  T. Todo  C. A. Bonham  W. Concepcion  C. Esquivel Stanford, CA, USA e-mail: [email protected]

revealed rejection and hepatic steatosis (Fig. 3). After treatment for the cholangitis with antibiotics and the rejection with pulse steroids, she underwent Roux-en-Y choledocho-jejunostomy and liver biopsy shortly after at age 9. Since her native common bile duct was strictured at the ampulla, whereas the donor’s common bile duct was patent, but dilated, the jejunum was anastomosed to the healthy donor bile duct. Postoperatively, although some liver-related biochemical tests were abnormal, a biopsy was reported as showing up to 50 % steatosis (Fig. 4) with no evidence of rejection. At present, biliary obstruction is resolved and rejection is treated adequately, though steatosis persists. Persistent severe diarrhea is being treated with rifaximin and occasional loperamide. She has had no recurrence of pruritus.

Discussion PFIC is a cluster of rare bile canalicular disorders that typically progress to liver cirrhosis, but are distinctly characterized by hyperbilirubinemia and pruritus [1]. The syndrome, first described in 1965, is now classified as three named subtypes, all with autosomal recessive transmission. PFIC 1 has been linked to a mutation in the ATP8B1 gene, which encodes the FIC1 protein, which stabilizes membranes in order to facilitate phospholipid transmembrane translocation. FIC1 is also expressed in liver, small intestine, pancreas, and other epithelialized tissues. The defect results in cholestasis and cirrhosis, jaundice with significant pruritus, and extrahepatic manifestations including diarrhea, pancreatitis, short stature, and sensorineural defects. PFIC 2 is linked to a defect in the ABCB11 gene, which encodes a protein essential for the function of the bile salt export pump (BSEP). Loss of BSEP function is

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Fig. 1 MRCP shows normal intrahepatic bile ducts, but significantly dilated common bile duct to the level of the ampulla, indicating an ampullary stricture

Fig. 2 ERCP shows a dilated common bile duct to the level of the ampulla

Fig. 3 Portal and central mixed inflammatory infiltrate with predominantly lymphocytes showing acute cellular portal and central rejection and moderate steatosis

associated with bile salt retention and manifests as cholestasis progressing to cirrhosis. PFIC 2 in particular is associated with the development of early hepatocellular carcinoma (HCC), with the need for frequent surveillance

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Fig. 4 Decreased inflammatory infiltrate, but increase in steatosis up to 50 %

and transplant if HCC develops. PFIC 3 is linked to a mutation in the ABCB4 gene that encodes a protein termed MDR3, which facilitates hepatocyte phosphatidylcholine translocation. Decrement of MDR3 function is associated with accumulation of toxic micelles, which damage hepatocytes. Children with PFIC 3 are usually diagnosed during their teenage years, typically initially manifesting as cirrhosis with portal hypertension [2]. The diagnosis of PFIC is typically made when evaluating an infant or child for conjugated hyperbilirubinemia. Typical screening tests are completed, including the newborn screening tests to rule out metabolic diseases. Extrahepatic obstruction is ruled out with imaging or cholangiography, and then, hepatocellular sources are investigated first with lab values. PFIC 1 and 2 have a low gamma-glutamyl transpeptidase (GGT), whereas PFIC 3 is associated with a high GGT. All may have an elevated alkaline phosphatase and serum 50 nucleotidase. Significantly decreased bile acid concentrations are present in bile. Liver biopsy is commonly done and in PFIC may confirm the diagnosis: hepatocellular and canalicular cholestasis with pseudoacinar transformation are present

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Fig. 5 a Partial external biliary diversion: Cholecysto-jejunostomy with a segment of jejunum attached to the gallbladder to create a stoma. b Partial internal biliary diversion: Cholecystojejunocolic anastomosis with a segment of jejunum attaching directly the colon to

the gallbladder. c Ileal exclusion: Terminal ileum is bypassed completely by attaching the jejunum in continuity directly with the colon, leaving the ileum as a blind end

in PFIC 1 and 2, whereas expanded portal areas with proliferation of interlobular bile ducts plugged with bile are present in PFIC 3. Other disorders (including Alagille’s, congenital hepatic fibrosis) are also considered, and if no definitive diagnosis is made, genetic evaluation will reveal the specific mutation and type of PFIC. Over time, all lesions characteristically progress to fibrosis and cirrhosis, and occasionally late diagnosis can be made if the child presents with overt cirrhosis [3]. Treatment of PFIC is initially supportive, using medications to treat pruritus, including rifampicin, hydroxyzine, diphenhydramine, ursodiol, cholestyramine, and even phenobarbital. Surgical treatment may involve biliary diversion procedures (Fig. 5) meant to bypass the enterohepatic circulation of bile, in order to decrease the bile acid storage pool. This is thought to improve pruritus and in some cases may delay the progression to cirrhosis, thus improving outcomes. Surgical therapy centers on diverting biliary flow by either attaching a free segment of jejunum to the gallbladder to drain bile to an external stoma (Fig. 5a), or directly to the colon (Fig. 5b) [4]. Although Ileal bypass (Fig. 5c) can also be effective, it is riskier for children; hence, partial biliary bypass is preferred. Nonetheless, if significant fibrosis or cirrhosis is present, biliary diversion will not be successful and should not be performed [5]. Liver transplantation is indicated for cirrhosis and hepatocellular carcinoma, but also for significant uncontrolled pruritus severely impairing quality of life. Living donor liver transplantation can also be an option, although inferior outcomes were reported from some, but not all cases of PFIC 1 compared with outcomes reported from deceased donors [6]. PFIC 2 and 3 are essentially ‘‘cured’’ by liver transplant, since those diseases are confined to the liver, but with PFIC 1, extrahepatic manifestations can cause significant morbidity even after transplantation.

Transplant can often exacerbate diarrhea in PFIC 1 for unknown reasons, with persistent issues including pancreatitis, short stature, and sensorineural deafness. Hepatic steatosis commonly occurs in the transplanted graft in PFIC 1 recipients, which can progress to fibrosis, cirrhosis, and the need for re-transplantation [7]. The patient described has these findings, including worsening of diarrhea, short stature, and now hepatic steatosis that is at present only manifest as liver enzyme abnormalities. The stricture of her native common bile duct is believed related to PFIC affecting her small intestine or bile duct.

Key Points •







PFIC is a group of bile canalicular transport disorders with autosomal recessive inheritance causing cholestasis and eventual cirrhosis PFIC1 has multiple extrahepatic manifestations, including diarrhea, pancreatitis, short stature, and sensorineural defects PFIC 2 and 3 are resolved with transplant, but with PFIC 1, the extrahepatic manifestations continue and diarrhea can worsen With PFIC 1, significant steatosis often occurs after transplant and can eventually result in progressive liver failure and cirrhosis

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Dig Dis Sci 2. Jacquemin E. Progressive familial intrahepatic cholestasis. Genetic basis and treatment. Clin Liver Dis. 2000;4:753–763. 3. Davit-Spraul A, Gonzales E, Baussan C, Jacquemin E. Progressive familial intrahepatic cholestasis. Orphanet J Rare Dis. 2009;4:1. doi:10.1186/1750-1172-4-1. 4. Bustorff-Silva J, Sbraggia Neto L, Olı´mpio H, et al. Partial internal biliary diversion through a cholecystojejunocolonic anastomosis— a novel surgical approach for patients with progressive familial intrahepatic cholestasis: a preliminary report. J Pediatr Surg. 2007;42:1337–1340. 5. Schukfeh N, Metzelder ML, Petersen C, et al. Normalization of serum bile acids after partial external biliary diversion indicates an

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excellent long-term outcome in children with progressive familial intrahepatic cholestasis. J Pediatr Surg. 2012;47:501–505. doi:10. 1016/j.jpedsurg.2011.08.010. 6. Hori T, Egawa H, Takada Y, et al. Progressive familial intrahepatic cholestasis: a single-center experience of living-donor liver transplantation during two decades in Japan. Clin Transplant. 2011;25:776–785. doi:10.1111/j.1399-0012.2010.01368.x. 7. Aydogdu S, Cakir M, Arikan C, et al. Liver transplantation for progressive familial intrahepatic cholestasis: clinical and histopathological findings, outcome and impact on growth. Pediatr Transplant. 2007;11:634–640.

Complications following liver transplantation for progressive familial intrahepatic cholestasis.

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