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Liver transplantation in tight junction protein‐2 deficiency associated liver disease

To the editor, Progressive familial intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders characterized by defects in transportation and/or excretion of bile components resulting in progressive liver disease.[1,2] Patients with certain types of PFIC may also develop extrahepatic manifestations.[1] Conventionally, three types of PFICs are described in the literature. Several other types of PFICs have been proposed as a result of advances in immunopathology and the emergence of genetic analysis. The relatively better defined of the newer types of PFIC (e.g., PFIC type IV [PFICIV]) involves a defect in tight junction protein2 (TJP2).[2] Liver disease in these patients occurs due to bile extravasation into the paracellular spaces of canalicular margins. The resulting injury to the hepatocytes and cholangiocytes results in chronic cholestatic injury that culminates in endstage liver disease. Furthermore, TJP2 defects have been associated with extrahepatic manifestations such as lung involvement and hearing impairment.[1,2] Although the natural history and pathophysiology of this disease are being increasingly elucidated, its therapeutic and prognostic implications, especially with regard to liver transplantation (LT), remain undescribed. We present our experience of four patients with PFICIV who underwent LT. Of a total of 510 pediatric LTs performed by our unit, 50 patients with a diagnosis of PFIC underwent LT. Of these, four children (three males and one female) aged between 2 and 7 years (two children— 7 years of age, other two— 2 years and 4 years, respectively) were diagnosed with PFICIV and underwent LT (Table 1). All patients had a genetic diagnosis of PFICIV (a compound heterozygous mutation in one patient and a homozygous mutation in three patients). A history of infantile cholestasis (two patients at 1 month of age and one patient each at 3 and 5 months, respectively) was common to all the children. Three of them had intense pruritus (except patient 4) with significant lichenification of the skin. Three patients (except patient 3) also had advanced cirrhosis with portal hypertension at presentation. Patient 1 had previously undergone a biliary diversion procedure, despite which she continued to have pruritus and progressive liver disease. None of the patients had any extrahepatic manifestations at presentation. Biochemically, all except one patient had normal gammaglutamyl transpeptidase (GGT) levels. Three patients underwent a living donor LT (LDLT), while one patient underwent a deceased donor splitLT (DDLT). Three of the liver allografts were left lateral segments (n = 2 for LDLT and n = 1 for split DDLT). One child received a left lobe graft. All recipients except one had an uneventful postoperative period. This patient developed recurrent pneumothorax on the 5th day after LT, which required intercostal drainage (ICD) on two separate occasions. Pneumothorax resolved with this management, and the ICD was removed on the 25th day after LT. On a median followup of 18.5 months (range 5– 58 months), all the recipients remained well with a normal graft function. Severely stunted growth was a striking feature of all our patients except one (Patient 4); all of them had a remarkable improvement in their Z scores following LT (Table 1). None of the patients developed any extrahepatic manifestations or disease recurrence. Explanted livers were grayish brown (1 patient) to greenish (3 patients; Figure 1A). Pathological findings were bridging fibrosis and cirrhotic transformation (Figure 1B), variable portal/septal inflammation, bile ductular proliferation with ductular bile plugs (Figure 1C), hepatocellular ballooning with clarification of cytoplasm and Mallory– Denk bodies (Figure 1D; in two patients), intracellular and canalicular bilirubinostasis with rosetting and apoptosis (Figure 1E), variable lobular inflammation, spotty necrosis, patchy steatosis (in one patient), hepatocellular copper deposition (Figure 1F), focal hepatocellular dysplasia, hepatocellular carcinoma (HCC; in one patient), and decreased Received: 20 January 2022 | Accepted: 17 May 2022