Liver & intrahepatic bile ducts

• Incidence is ~1 in 50,000 - 100,000 people worldwide (J Clin Exp Hepatol 2014;4:25)
• Age at diagnosis is typically ≤ 20 years of age
• M = F
• Genetic mutation: autosomal recessive inheritance (see Etiology)

• Autosomal recessive disorder is associated with mutation of ATP8B1 and ABCB11 genes
• Nonsense and missense mutations in those genes will lead to partial protein expression for bile canalicular protein transport (complete deletion of protein expression will show a severe form of cholestasis, which is known as primary familial intrahepatic cholestasis [types 1 and 2]) (Hepatology 2009;50:1597)
• Defective ATP8B1 gene is located on chromosome 18 and encodes F1C1, which causes impaired bile salt excretion, while defective ABCB11 gene is located on chromosome 2, which causes impaired functioning of the canalicular pump, leading to cholestasis

• Favorable; prognosis is good and does not usually lead to fibrosis

• 21 year old man presented with pruritis and jaundice (Case Rep Gastrointest Med 2020;2020:2894293)
• 27 year old man presented with complaints of jaundice for 2 weeks (J Clin Diagn Res 2016;10:OD01)
• 27 year old Hispanic woman presented with jaundice, pruritus and weakness for 4 weeks (ACG Case Rep J 2020;7:e00412)
• 29 year old man presented with severe jaundice (World J Hepatol 2020;12:64)

Contributed by Pierre Russo, M.D.

• Mutation in ATP8B1 gene that is located on chromosome 18 and encodes F1C1, which causes impaired bile salt excretion due to partial protein expression
• Mutation in ABCB11 gene is located on chromosome 2, which causes impaired functioning of the canalicular pump, leading to cholestasis
• Rare cases have been associated with TJP2 gene mutation (JPGN Rep 2021;2:e087)

• Liver, biopsy:
  • Liver parenchyma with mild cholestasis (canalicular and intracellular); no fibrosis (see comment)
  • Comment: The patient's history of recurrent attacks of jaundice and pruritis are noted. Sections show liver core biopsies with bland cholestasis (both canalicular and intracytoplasmic). No associated inflammation, bile ductular reaction or bile duct loss is seen. No fibrosis is seen.

• Diagnosis is usually by excluding other causes of cholestasis in young patients with disease recurrence
• Progressive familial intrahepatic cholestasis (Clin Res Hepatol Gastroenterol 2019;43:20):
  • Severe form of cholestasis that leads to chronic liver disease
  • Autosomal recessive disease
  • Mutations in the same genes involved in BRIC (genes are either deleted or have frameshift mutations rather than missense mutations leading to complete loss of canalicular protein pump synthesis and manifested in a severe clinical presentation)
• Intrahepatic cholestasis of pregnancy (StatPearls: Pregnancy Intrahepatic Cholestasis [Accessed 26 June 2023]):
  • Associated with pregnancy
  • Symptoms and enzymes return to normal following delivery and recur with subsequent pregnancies
• Extrahepatic biliary atresia (J Pediatr Surg 1999;34:1706):
  • Presents as neonatal cholestasis
  • Ultrasound: absence of the gallbladder and the triangular cord sign
  • Cholangiography is confirmatory
• Late infancy with pruritus:
  • Alagille syndrome, nonsyndromic bile ductular paucity
  • Sclerosing cholangitis (primary / secondary)
  • Alpha-1 antitrypsin deficiency
  • Cystic fibrosis
• Bile acid synthetic defects:
  • Present with cholestasis and normal GGT
  • Serum bile acid concentration is low or absent
  • Pruritus is mild or absent
  • Response to bile acid therapy is good
• Drug induced cholestasis:
  • Antimicrobials or acetaminophen may impair bile flow through hepatocellular damage, resulting in episodic cholestasis

What statement is true regarding benign recurrent intrahepatic cholestasis (BRIC)?

1. Biliary tree usually shows severe strictures by radiology
2. Frameshift mutation or deletion in ATP8B1 gene or ABCB11 genes
3. Liver parenchyma with cirrhosis
4. Normal serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
5. Usually associated with cystic fibrosis

D. Normal serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Serum ALT and AST are usually normal in cases of BRIC. Answers A and C are incorrect because BRIC is not usually associated with advanced liver disease / cirrhosis or abnormal biliary tree by imaging. Answer B is incorrect because the mutated genes show missense mutations and not frameshift mutations. Answer E is incorrect because BRIC is not usually associated with cystic fibrosis.

Comment Here

Reference: Benign recurrent intrahepatic cholestasis