IllnessCholestasis, progressive familial intrahepatic; differential diagnosis

NGS +

Progressive familial intrahepatic cholestasis (PFIC) leads to decreased bile secretion, resulting in liver disease and eventually liver failure. Symptoms typically begin in infancy with severe pruritus, jaundice, failure to thrive, portal hypertension and hepatosplenomegaly. The three autosomal recessively inherited types include PFIC1, PFIC2 and PFIC3. Each type has a different genetic cause. Patients with PFIC1 may have short stature, deafness, diarrhea, pancreatitis as well as low blood levels of fat-soluble vitamins, they usually develop liver failure before adulthood. The severe symptoms of PFIC2 are commonly associated only with liver disease and lead to liver failure within the first few years of life. These patients are also at increased risk of developing hepatocellular carcinoma. In most people with PFIC3, signs and symptoms of liver disease do not appear until later in infancy or early childhood, and rarely in early adulthood. In PFIC3, liver failure may occur in childhood or adulthood. Bi-allelic mutations in the ATP8B1, ABCB11 and ABCB4 genes can cause PFIC. The ATP8B1 gene and protein are responsible for bile acid homeostasis and prevent PFIC1. Mutations in the ABCB11 gene lead to the accumulation of bile salts in liver cells, their damage and PFIC2. Mutations in the ABCB4 gene lead to a lack of phospholipids available for bile acid binding and cause PFIC3. Some PFIC patients lack mutations in the aforementioned genes. Hence, the cause remains unknown. Although there are no recent comprehensive studies on molecular genetic diagnosis of PFIC as such, the general yield in neonatal and infantile cholestasis with appropriate panels or exome sequencing ranges from 60 to >80%. Negative DNA test results do not exclude the clinical diagnosis.

Reference: https://www.ncbi.nlm.nih.gov/books/NBK1297/

• Allelic: Cholestasis, benign recurrent intrahepatic (ATP8B1)
• Allelic: Cholestasis, intrahepatic, of pregnancy, 1 (ATP8B1)
• Allelic: Cholestasis, intrahepatic, of pregnancy, 3 (ABCB4)
• Allelic: Gallbladder disease 1 (ABCB4)
• Allelic: Hypercholanemia, familial (TJP2)
• Allelic: Keratoderma-ichthyosis-deafness syndrome, AR (VPS33B)
• Arthrogryposis, renal dysfunction + cholestasis 1 (VPS33B)
• Bile acid conjugation defect 1 (BAAT)
• Cholestasis, benign recurrent intrahepatic, 2 (ABCB11)
• Cholestasis, progressive familial intrahepatic 1 (ATP8B1)
• Cholestasis, progressive familial intrahepatic 12 (VPS33B)
• Cholestasis, progressive familial intrahepatic 2 (ABCB11)
• Cholestasis, progressive familial intrahepatic 3 (ABCB4)
• Cholestasis, progressive familial intrahepatic 4 (TJP2)
• Cholestasis, progressive familial intrahepatic 5 (NR1H4)
• Cholestasis, progressive familial intrahepatic 6 (SLC51A)
• Cholestasis, progressive familial intrahepatic 7, +/- hearing loss (USP53)
• Cholestasis, progressive familial intrahepatic 8 (KIF12)
• Cholestasis, progressive familial intrahepatic 9 (ZFYVE19)
• Dubin-Johnson syndrome (ABCC2)
• Hypercholanemia, familial (BAAT)
• Microvillus inclusion disease (MYO5B)
• Smith-Lemli-Opitz syndrome (DHCR7)