EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Progressive familial intrahepatic cholestasis is a heterogeneous group of autosomal recessive disorders, and liver transplant is the only curative treatment. A biliary diversion operation for disruption of enterohepatic circulation in patients with progressive familial intrahepatic cholestasis type 1 without cirrhosis is another option. We present a pediatric patient with progressive familial intrahepatic cholestasis type 1 who underwent liver transplant due to end-stage liver disease. After transplant, diarrhea and growth retardation complications resolved after partial external biliary diversion surgery.

Key words : Bile acid, End-stage liver disease, Growth retardation, Hepatic steatosis

Introduction
Progressive familial intrahepatic cholestasis (PFIC) includes a heterogeneous group of autosomal recessive disorders that usually appear with cholestasis in the first 6 to 12 months of life and progress to liver failure in early childhood or adolescence. Liver transplant is the best treatment modality for growth failure, intractable pruritus, and end-stage liver disease in patients with PFIC. However, the use of surgery to disrupt the enterohepatic circulation is a good therapeutic option for patients with PFIC type 1 (PFIC1) without cirrhosis.¹

We present a patient with PFIC1 who underwent liver transplant for end-stage liver disease. The patient had persistent diarrhea and growth retardation after liver transplant. These complications resolved after partial external biliary diversion (PEBD) surgery.

Case Report
A 1-month-old girl was admitted to our clinic with jaundice and acholic stools. Prenatal, natal, and postnatal histories were unremarkable. The patient had consanguineous parents, and there was no family history of liver disease. On physical examination, her weight was 4.220 grams and height was 58 cm. Her liver was 9 cm palpable below the right costal margin. Laboratory tests revealed the following: hemoglobin of 10.2 g/dL, white blood cell count of 15.500 × 10³, platelet count of 569.000 × 10³, aspartate aminotransferase of 247 U/L, alanine aminotransferase of 301 U/L, gamma-glutamyltransferase of 21 U/L, alkaline phosphatase of 662 U/L, total bilirubin of 16.9 mg/dL, direct bilirubin of 8.7 mg/dL, albumin 3.49 of g/dL, and international normalized ratio of 0.85. The patient’s serum bile acid level was 71.2 μmol/L (normal range, 0-10 μmol/L). The serologies for TORCH syndrome were negative, and metabolic tests were within normal limits. Cystic fibrosis and alpha-1 antitrypsin deficiency were ruled out. No pathological findings were found in vertebral radiography, echocardiography, or eye examinations. Doppler ultrasonography was normal, and hepatomegaly was detected by abdominal ultrasonography. Liver biopsy showed intrahepatic cholestasis. Ursodeoxycholic acid and fat-soluble vitamin supplementation were initiated. Homozygous deletion in the ATP8B1 gene (NM_005603 exon 23-28) was detected within the whole exon sequence, which resulted in diagnosis of PFIC1 in the patient.

When the patient was 2.5 years of age, PEBD was recommended because of chronic watery diarrhea, severe itching, and growth retardation. However, her parents declined permission for the procedure for cosmetic reasons. Her symptoms did not improve despite the medical treatment, which included rifampicin and cholestyramine.

At age of 3 years, the patient received liver transplant from a deceased donor. Watery diarrhea worsened during week 2 posttransplant. Mycophenolate mofetil was discontinued for possible gastrointestinal side effects; in addition, we did not observe any positive effects on stool number and consistency. The patient required recurrent hospitalization for severe diarrhea, dehydration, and metabolic acidosis. A liver biopsy was performed for elevated transaminases.

At month 7 posttransplant, PEBD was again discussed with the parents because of the severe risk of liver steatosis shown in the patient. The parents did not want PEBD because of the stoma appearance and the idea that quality of life would decrease with an ostomy bag. After a follow-up period with percutaneous biliary tube drainage to observe whether symptoms would improve, weight gain and decreased defecation frequency were observed. At month 19 posttransplant, the patient underwent PEBD. After PEBD, a rapid relief from diarrhea was observed. A summary of clinical and laboratory results is presented in Table 1.

Discussion
Progressive familial intrahepatic cholestasis is a group of diseases caused by genetic mutations that affect the transport of bile salts. The common feature of all PFIC patients is the development of cholestasis with characteristic itching and jaundice symptoms as a result of cutaneous and intrahepatic accumulation of bile acids. Continuous bile acid accumulation in the liver can cause fibrosis and eventually cirrhosis in PFIC patients.¹

Type 1 PFIC is caused by mutations in the ATP8B1 gene associated with a defect in intestinal bile acid absorption.² The ATP8B gene encodes a P-type ATPase that functions as a flippase for phosphatidylserine in the canalicular membrane of hepatocytes. This protein is also expressed in enterocytes, the apical membrane of cholangiocytes, and acinar cells of the pancreas, which leads to extrahepatic symptoms such as diarrhea, pancreatitis, poor growth, and deafness.³ Extrahepatic symptoms may persist or develop after liver transplant in patients with PFIC1.⁴

Treatment is aimed to control symptoms in all PFIC subtypes. A diet rich in medium-chain fatty acids, fat-soluble vitamins, ursodeoxycholic acid, antihistamines, cholestyramine, phenobarbital, and rifampicin is used for nutritional rehabilitation and to help with severe itching.^5,6 Bile adsorptive resin may be useful for intractable diarrhea in patients with PFIC1.⁷

Biliary diversion surgery is generally preferred for interruption of enterohepatic circulation in patients with PFIC1 without cirrhosis. In PEBD, a free jejunal ring is placed between the gallbladder and the skin. The effect of PEBD in PFIC1 is still unclear. It is thought that by directing bile partially out, it causes a decrease in the bile salt pool in the circulation, thus decreasing the bile salts entering the enterohepatic circulation.^8,9 The success rate of PEBD on clinical and laboratory findings (intractable diarrhea, pruritus, intrahepatic fibrosis, cholestasis, improvement in liver function) of patients has been reported to be 75% to 80%.^10-12

In general, parents do not want PEBD because of the stoma appearance and the idea that the quality of life would decrease with an ostomy bag. Wassman and colleagues reported that the health-related quality of life of patients with PFIC after PEBD was similar to that shown after liver transplant.¹³

Liver transplant is the main and definitive treatment method for PFIC patients who have severe itching, growth retardation, and liver cirrhosis. However, diarrhea exacerbation and graft steatosis causing graft loss have been reported after liver transplant in patients with PFIC.14 After liver transplant, increased bile absorption in the liver increases bile flow to the intestine, yet bile is not absorbed due to the intestinal ATP8B gene. This is thought to be the main reason for persistent diarrhea, inadequate weight gain, and consequently graft steatosis after liver transplant.¹⁵

Miyagawa-Hayashino and colleagues reported that refractory diarrhea developed in 8 of 11 patients with a diagnosis of PFIC1 who underwent liver transplant, which is similar to that shown in our patient. Seven patients also had steatohepatitis in this series.¹⁶

Although some studies have reported encouraging results with PEBD in patients with PFIC1, there are very few reports on biliary diversion after liver transplant. Shanmugam and colleagues reported 1 patient who had steatohepatitis and refractory diarrhea who was effectively treated with internal biliary diversion.¹⁷ The positive effects of PEBD on the natural course of disease, diarrhea posttransplant, and graft steatosis were reported by Jankowska and colleagues.¹⁸

Conclusions
We recommend PEBD primarily in patients with PFIC1 who have not developed severe complications, such as life-threatening itching, growth retardation, severe steatohepatitis, and cirrhosis. After these severe complications develop, liver transplant is the only option for curative treatment. Biliary diversion surgery should be recommended as a treatment option in children with PFIC1 who have developed severe diarrhea and graft steatosis after liver transplant. Biliary diversion procedures during transplant surgery may also be considered individually in patients with PFIC1.

Volume: 20 Issue: 5 May 2022 - Supplement - 3

FULL TEXT