Your Health and Fitness Partner: Androxal & FitHub

48uep6bbphidcol2|ID

48uep6bbphidvals|1902

48uep6bbph|2000F98CTab_Articles|Fulltext

Progressive familial intrahepatic cholestasis (PFIC), also known as Byler disease, has been described as a group of childhood autosomal recessive disorders that present with hepatocellular cholestasis. It constitutes between 10-15% of the causes of cholestasis in pediatric patients^1,2 and is the cause of 10-15% of liver transplants in this population.Three genotypes of PFIC have been commonly described and are associated with mutations in hepatocellular transport system genes (PFIC 1, 2, and 3). PFIC 1 is secondary to a mutation in ATP8B1 gene that codes an amino-phospholipid transporter, PFIC 2 is due to a mutation in ABCB11 gene that codes a bile salt export protein, and PFIC 3 due to a mutation in the ABCB4 gene that codes for a canalicular phospholipid export pump (MDR3). These genotypes have different clinical, biochemical, and genetic characteristics. Patients suffering from PFIC 1 and 2 present in the neonatal period or early infancy, as it appears in the first months of life; meanwhile, PFIC3 may arise later in infancy, in childhood or even during young adulthood². There are few case reports of PFIC 4 to date.^3,4

A 3.5 year-old male child, first by birth order, born of non-consanguineous marriage presented with recurrent jaundice since three months of age along with pruritis. There was no history of clay stools or dark urine. At three months of age, he had an intracerebral hemorrhage for which he was managed with craniectomy with hematoma evacuation. He subsequently suffered from epilepsy and delayed development. He was on phenobarbitone and levetiracetam for the same. The latest convulsion was at 18 months of age. On presentation to us, height was 92 cm (10 th percentile), and weight was 12 kg (10th-20th percentile). There was icterus with mild hepatomegaly. He had a bony defect over the right parietal bone. Other systems were normal. Investigations showed alanine aminotransferase (AST) 24U/L, aspartate aminotransferase (ALT) 25U/L, total bilirubin 19.1 mg/dL, direct bilirubin 18.5 mg/dL, gamma-glutamyl transferase (GGTP) 43U/L, partial thromboplastin time (PTT) 32.7 seconds, prothrombin time (PT) 12.2 seconds and INR of 1. Abdominal ultrasound showed mild hepatosplenomegaly with normal hepatic echotexture and biliary system without focal lesions and a normal doppler scan. HIV, Hepatitic C ELISA, and HBsAg were negative. Serum ceruloplasmin was 37.8 mg/dl (Normal range- 30-40 mg/dl). Antinuclear antibody (ANA), anti double-stranded DNA (dsDNA), anti-liver kidney muscle (LKM), and anti-smooth muscle antibodies (ASMA) were negative. Alfa fetoprotein (AFP) was below 0.2 ng/ml. Magnetic retrograde cholangiopancreatography (MRCP) revealed distended gall bladder with no inclusion defect in the gall bladder and no dilatation of the biliary system. Histopathological examination of a percutaneous liver biopsy revealed maintained architecture, and inflammatory infiltrates in the portal tract, ballooning of hepatocytes, mild intrahepatic cholestasis without bile duct proliferation. Because of persistent jaundice and cholestasis and low GGTP, genetic testing was done, which revealed homozygous mutations in the TJP2 (+) of exon 2 (c.157 c >4) confirming the diagnosis of progressive familial intrahepatic cholestasis (PFIC) type 4. He was started on fat-soluble vitamin supplements along with ursodeoxycholic acid (UDCA) and cholestyramine for pruritis. The child is on regular follow up. At 5 years of age, his investigations show AST 26U/L, ALT 30U/L, total bilirubin 0.6 mg/dL, direct bilirubin 0.4 mg/dL, GGTP 51U/L, total protein concentration of 7.3 gm%. He has no portal hypertension on the doppler, and his serum AFP continued to remain normal.  

PFIC is characterized by conjugated hyperbilirubinemia and low GGT in PFIC 1 or PFIC 2, while high levels of GGT in PFIC 3.¹ It is essential to type the PFIC as the course of the disease and outcome varies. PFIC 1 is associated with extrahepatic manifestations in the form of sensorineural hearing loss, persistent diarrhea, cholecystitis, pancreatitis, failure to thrive, short stature, elevated sweat chloride concentration, respiratory symptoms and delayed sexual development¹. PFIC 2 is characterized by a more severe course and a need for an early liver transplant. It is also associated with HCC.1 Patients with PFIC 3 present with jaundice, pruritus, and hepatosplenomegaly with onset beyond infancy. The progression to cirrhosis is slow.¹ There have been only 14 cases of PFIC-4 reported in the literature.^3,4 Sambrotta et al. on follow up found that nine patients out of 12 required liver transplant, 2 had stable liver disease, and one died.⁴ Zhou et al. reported hepatocellular carcinoma (HCC) occurring in 2 patients at 24-26 months of age.³ Similarly, our patient presented with recurrent jaundice and pruritis since three months of age and had normal GGTP. He is on regular follow up and has not developed HCC but has stable liver disease. Though he had an intracranial hematoma at three months of age, he did not have any further bleeding episodes though recurrent unexplained hematomas have been reported in one patient.⁴

PFIC 1 is characterized histopathologically by maintained lobular architecture and canalicular cholestasis; while PFIC 2 has deranged lobular architecture with canalicular and hepatocellular cholestasis, and PFIC3 shows diffusehepatocellular cholestasis and portal fibrosis¹. Percutaneous liver biopsy in our child revealed maintained architecture and mild intrahepatic cholestasis. We could not perform electron microscopy to be able to comment on the type of bile.

Genetic testing in our child revealed homozygous mutations in the TJP2 (+) of exon 2(c.157 c >4) confirming the diagnosis (PFIC) type 4. Homozygous mutations in the TJP2 gene were identified in 12 patients from 8 families with progressive familial intrahepatic cholestasis-4.⁴ The transmission pattern in the families was consistent with autosomal recessive inheritance.4 Biallelic TJP2 truncating mutations were found in two cases of PFIC 4, and TJP2 deficiency was hypothesized to predispose to HCC development in early childhood.³ 

The management of PFIC comprises medical and surgical modalities. Medical therapy involves the administration of choleretics, such as ursodeoxycholic acid (UDCA), cholestyramine, and phenobarbital. Nontransplant surgical interventions such as partial external biliary diversion, ileal bypass, and partial internal biliary diversion (PIBD) are also useful in PFIC1 and PFIC2 patients. These interventions base their effect on interrupting enterohepatic circulation, thereby inhibiting bile salt toxicity. In patients failing these measures, liver transplantation remains the only option.¹