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


Long-Term Outcomes of Patients With Progressive Familial Intrahepatic Cholestasis After Biliary Diversion

Objectives: Progressive familial intrahepatic cholesta-sis is a heterogeneous group of genetic disorders characterized by disrupted bile homeostasis. Patients with this disease typically present with cholestasis and pruritus early in life and often progress to end-stage liver disease. The clinical symptoms that patients with progressive familial intrahepatic cholestasis encounter are usually refractory to medical treatment. Although the effects of biliary diversion surgery on native liver survival are not exactly known, this procedure may provide a positive impact on pruritus and laboratory parameters in these patients.
Materials and Methods: We retrospectively evaluated the clinical and laboratory characteristics of patients with progressive familial intrahepatic cholestasis who underwent partial external biliary diversion between 2002 and 2020 at our center. Diagnosis of progressive familial intrahepatic cholestasis was made by clinical, biochemical, and histopathological characteristics as well as genetic testing.
Results: Nine patients were included in the study. Five patients required liver transplant during follow-up, with 4 having liver transplant as a result of end-stage liver disease (median interval of 5 years). In 1 patient, partial external biliary diversion was performed 1.5 years after liver transplant for severe diarrhea, metabolic acidosis, and hepatic steatosis. Four patients did not require liver transplant during follow-up (median follow-up time of 7.6 years). Pruritus responded well to partial external biliary diversion in all patients. Among laboratory values evaluated 6 months after biliary diversion, only albumin showed significant improvement.
Conclusions: Partial external biliary diversion had favorable results on long-term follow-up. This procedure can provide the relief of pruritus and delay the requirement for liver transplant in patients with progressive familial intrahepatic cholestasis. In our view, partial external biliary diversion should be considered the first-line surgical management for patients with this disease.

Key words : Liver transplantation, Partial external biliary diversion

Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of genetic disorders characterized by disrupted bile homeostasis.1 The presentation of disease in infancy or early childhood is severe cholestasis and cirrhosis. Liver transplantation (LT) is considered for curative treatment of intractable pruritus and end-stage liver disease. Three types of PFIC have been revealed based on distinct mutations of genes that encode proteins involved in the formation and bile flow in the liver (PFIC1, PFIC2, and PFIC3).1 There is no consensus in the literature on the optimal treatment for PFIC. Ursodeoxycholic acid is used for symptom relief and to counter the detrimental effects of cholestasis. Rifampicin, cholestyramine, and antihistamines are the other medical treatment options. However, medical treatment often fails.2 In the past, LT was considered the only surgical approach for patients with PFIC.3 Surgical biliary diversion treatments are strategies to resolve pruritus and delay the progression of liver damage. The results of published reports have shown that biliary diversion surgery may improve growth and liver histology and may reduce symptoms, particularly pruritus.1,4

Although partial external biliary diversion (PEBD) is considered an effective treatment for PFIC, because of the rarity of PFIC, there are scarce available data to evaluate PEBD regarding surgical complications, the requirement for LT, and clinical outcomes.Here, we have presented the long-term results of patients with PFIC who were seen at our center and who received PEBD.

Materials and Methods
We retrospectively assessed 9 patients with PFIC who underwent PEBD between 2002 and 2020 at our center.

The diagnosis of PFIC was made according to clinical criteria, biochemical findings, histopathology, and genetic testing. All other causes of cholestasis such as biliary atresia, Alagille syndrome, alpha-1 antitrypsin deficiency, and cystic fibrosis were excluded. Intractable pruritus existed in all of the study patients. All patients underwent PEBD as described by Gun and colleagues.5 Age at diagnosis, sex, type of PFIC, age at PEBD surgery, and liver function tests were recorded. Clinical outcomes of the surgery such as improvement in pruritus and nutritional status and biochemical changes, indications for LT, and patient survival were also recorded.

Among our study patients, indications for LT were refractory pruritus unresponsive to PEBD, growth retardation, worsening liver function, cirrhosis, and hepatocellular carcinoma. We considered the response to PEBD as optimal when effective in slowing the progression of liver disease and effective in relief of pruritus. These outcomes meant that the patient did not require LT.

Statistical analyses
We used the SPSS version 22.0 software package (SPSS Inc.) for statistical analyses. The results of the Kolmogorov-Smirnov test showed that the data did not have normal distribution. Therefore, nonparametric statistical methods were used to analyze the data, including the Wilcoxon test for quantitative data and the sign test for qualitative data. Statistical significance was defined as P < .05.

Of 9 pediatric patients in our study, 6 patients had PFIC2, 2 had PFIC1, and 1 had PFIC3. Preoperative liver biopsies showed mild to moderate portal fibrosis associated with cholestasis and lobar degeneration, except in 1 patient who underwent PEBD after LT. All patients did not respond to medical treatment before PEBD. The median age at the time of PEBD was 4.3 years (range, 0.8-17 y). The median follow-up after PEBD was 6 years (range, 0.5-12.4 y). One patient with PFIC1 underwent PEBD 18 months after LT due to intractable diarrhea unresponsive to cholestyramine, metabolic acidosis, growth retardation, transaminase elevation, and hepatic steatosis.

After PEBD, dramatic improvements in diarrhea, growth velocity, and liver function tests were documented. Partial internal biliary diversion (PIBD) was converted to PEBD after 1 year of refractory pruritus in 1 patient with PFIC3. None of the patients had surgical or long-term complications of PEBD, such as cholangitis, intestinal adhesions, or electrolyte imbalance. Patient characteristics are shown in Table 1.

Pruritus resolved in all patients after PEBD. Liver biochemistry parameters of patients before and after PEBD are given in Table 2. Compared with results shown before PEBD, serum albumin level increased (P = .041) and biliru-bin levels moderately decreased (P = .22) over the 6 months after PEBD. In 4 patients (59.5%) with PFIC2, clinical and laboratory findings completely improved after PEBD, and there was no need for LT during the follow-up (median follow-up time of 7.6 years). In our study group, 2 patients (with PFIC1 and PFIC2) underwent LT after PEBD surgery.

Indications for LT were cirrhosis in 3 patients and hepatocellular carcinoma in 1 patient. The median age at LT was 7.8 years (range, 3-8.5 y). The median interval between PEBD and LT was 5 years (range, 3-7 y). One patient died after LT as a result of graft hepatic artery thrombosis-related graft failure. One patient refused to use immunosuppressive medications after LT, and chronic rejection occurred. The patient is on a wait list for transplant. Other LT recipients have normal liver function without any symptoms on follow-up.

In our study, PEBD surgery was found to be a highly effective and safe treatment option for patients with PFIC. It also provided clinical and biochemical benefits as well as reduction or delay in the need for LT.

Different operative techniques have been used to treat PFIC, such as PEBD or PIBD and ileal exclusion. All of these procedures aim to interrupt the enterohepatic cycle of excess bile acids from the ileum and thus to reduce the accumulation of bile acids.6 In PIBD, stoma is prevented and the patient is more comfortable than in PEBD. In an Indian study of PIBD, 9 of 12children with a median follow-up time of 30 months were reported to be relieved of pruritus with a significant decrease in bile salts.7 However, some series reported a symptom recurrence rate of up to 50% in patients who have had PIBD.8 In our series, all patients underwent PEBD. In 1 patient, PIBD was chosen initially due to cosmetic preference. However, 18 months later, PIBD reversed to PEBD due to severe and persistent pruritus. The pruritus was resolved, with PEBD providing a favorable outcome in this patient.

Aggravation of diarrhea and malabsorption in LT recipients have been documented in patients with PFIC1 undergoing LT as a consequence of the interaction between the transplanted liver and native bowel.9,10 After LT, the defective bile salt excretion is aggravated by the restored bile flow from the liver graft. Hence, the already defective intestinal epithelium is relatively more exposed to bile acid in the posttransplant course compared with before LT. This leads to the development of refractory diarrhea and allograft steatohepatitis with malabsorption.11

Our patient with PFIC1 had recurrent hospital admissions due to diarrhea, electrolyte imbalance, and metabolic acidosis. Although cholestyramine was administered, the results were unsatisfactory. During follow-up, transaminase elevation persisted and marked steatosis was observed in liver biopsy. The patient underwent PEBD 1.5 years after LT due to refractory diarrhea and hepatic steatosis. After PEBD, diarrhea resolved and a dramatic improvement of liver functions was documented. Our results showed that PEBD may be considered a valuable treatment option in patients with PFIC1 who develop severe diarrhea and graft steatosis following LT, as suggested in a limited number of reports.12,13

In an analysis of long-term results of PEBD, biochemical findings showed reductions in bilirubin and serum bile acid levels.14 In their study of the long-term outcomes of PEBD in 7 patients diagnosed with PFIC, Halaweish and Chwals reported that LT was required in 2 patients and 2 patients died as a result of dehydration-related complications in association with gastroenteritis. Four patients had stoma-related complications in their series. Three patients were symptomfree and did not require LT during follow-up.15 Schukfeh and associates investigated long-term outcomes and complications after PEBD. They found clinical improvements, shown as a decrease in pruritus and normalization of bile acids, in a 1-year follow-up. They also reported that the presence of cirrhosis at the time of PEBD may be predictable for unfavorable outcomes.16 In our series, 9 patients underwent PEBD. Our results showed no significant difference in aspartate aminotransferase, alanine aminotransferase, and bilirubin levels before and after PEBD. Interestingly, the significant improvement in albumin levels was observed 6 months after PEBD surgery. This finding suggested a positive effect of PEBD on malnutrition. Pruritus responded well to PEBD in all of the patients. Four of the patients had no further complaints of pruritus and showed stable liver functions (mean follow-up time of 7.6 years).

Four patients underwent LT after PEBD (median interval of 5 years). Three underwent LT due to progressive disease. A period of 5 years of symptom-free survival for these patients with their own livers is an indication that PEBD surgery should be considered in patients with PFIC. One of the patients in our study had hepatic nodules that were compatible with hepatocellular carcinoma and underwent LT. One patient died after LT as a result of hepatic artery thrombosis-related graft failure. One patient, who is now on a wait list for retransplant, refused to use immunosuppressive drugs after LT and rejection occurred. Other LT recipients have continued to show normal graft functions with no symptoms on follow-up.

Because the effectiveness of PEBD on relief of pruritus and delay in the need for LT due to cholestatic liver disease is rather unpredictable, a predictor may help select patients who will have a more successful response to PEBD. So far, there are a limited number of studies suggesting that patients with certain genetic types of disease benefit from PEBD.17,18 In our study, the patients who did not require LT and who responded well to the surgery had PFIC2. Our results suggested that PFIC2 may be a prognostic factor for a favorable long-term outcome.

Limitations of our study included the low number of patients as a result of the rarity of the disease. The retrospective nature of the study was also a limitation, and no precise grading of itching could be performed as a result of retrospective data.

We found that PEBD had favorable results on long-term follow-up, and it delayed or canceled the requirement of LT and provided relief from pruritus in pediatric patients with PFIC. Based on this, we suggest that PEBD should be considered for first-line surgical management of patients with PFIC.


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Volume : 20
Issue : 5
Pages : 76 - 80
DOI : 10.6002/ect.PediatricSymp2022.O26

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From the 1Department of Pediatric Gastroenterology and the 2Transplantation Center, Gazi University, Ankara, Turkey
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflictsof interest.
Corresponding author: Hakan öztürk, Department of Pediatric Gastroenterology, Gazi University, Ankara, Turkey
Phone: +90 505 220 23 70