Progressive Familial Intrahepatic Cholestasis (PFIC)

Rare and severe type of cholestasis liver disease, beginning in infancy and progressing to cirrhosis before adolescence.

Cholestasis Progressive Familial Intrahepatic type I (PFIC I; Byler Disease; Fatal Intrahepatic Cholestasis): with low level of gamma-glutamyl transferase (GGT); gene ATP8B1 (previously termed FIC 1) mapped on 18q21.

Cholestasis Progressive Familial Intrahepatic type II (PFIC II): with a low level of GGT; gene ABCB11 (previously termed BSEP) mapped on 2q24.

Cholestasis Progressive Familial Intrahepatic type III (PFIC III; MDR 3 Deficiency; Progressive Intrahepatic Cholestasis with Elevated Serum Gamma-Glutamyltransferase Syndrome): with a high level of GGT; gene MDR3 mapped on 7q21.1.

Cholestasis Progressive Familial Intrahepatic type IV

First described by Clayton, in 1965, in an Amish descendant of Jacob Byler.

The exact frequency is unknown in the United States and internationally. Fewer than 200 patients have been reported for the low-GGT PFIC, whereas less than 20 are known in the high-GGT PFIC type. It is a lethal medical condition in childhood if not treated. Males and females are affected equally.

Autosomal recessive (majority of patients), also autosomal dominant with variable penetrance, or sporadic. Type II is found in the Middle East, Greenland, and Sweden.

Type I seems to be caused by a defect in bile salt synthesis. Type II seems to be caused by defective bile salt secretion. Type III is caused by a mutation in MDR3 protein, which mediates the translocation of phosphatidylcholine across the canalicular membrane of the hepatocyte.

Symptoms of cholestasis (pruritus and jaundice) appear in the first few months of life. Serum GGT activity is low to normal in type I and type II, and elevated in type III. Cholesterol serum is normal. Cholangiography shows normal morphology of intraand extrahepatic ducts. Liver biopsy in type I and type II is characterized by the absence of true proliferation of ducts within the liver and only periportal biliary metaplasia of hepatocytes. In type III, liver histology is characterized by ductular proliferation and inflammatory infiltrate.

Initially, episodes of severe cholestasis followed by intervals of good health. Pruritus is typically severe (more than the degree of bilirubinemia). Evolution is characterized by growth retardation, hepatomegaly, and then cirrhosis, hepatic failure, and death early during the childhood if not treated. Hepatocellular carcinoma may be present at age 2 years. Consequences of cholestasis (neurological anomalies caused by vitamin E deficiency, skin excoriations because of pruritus, rickets because of vitamin D deficiency, epistaxis as a result of coagulopathy or thrombocythemia). Pancreatic anomalies in type II may be present. In type III, symptoms appear later with a slower evolution. Jaundice is less visible and pruritus less intense.

Obtain a complete medical history of cholestatic episodes and their frequency and clinical consequences: if of prolonged duration, inquire about parenteral fat-soluble vitamins supplementation (deficiency of vitamin D: rickets, osteomalacia; vitamin K: coagulation disorders; vitamin E: ataxia, peripheral neuropathy; vitamin A: retinopathy). Serum levels: bilirubin, bile acids, alkaline phosphatase, transaminases. Coagulation profile: if prolonged, prothrombin time (PT); parenteral vitamin K should be given several days prior to surgery.

During prolonged cholestatic episodes, in cases of vitamin K deficiency, regional anesthesia is inadvisable until correction of the PT by administration of fresh-frozen plasma (FFP). With vitamin D deficiency, patients are more susceptible to fractures, thus careful positioning and padding is required. High bilirubin levels may be associated with increased risk of postoperative renal failure and generous pre- and intraoperative hydration is recommended.

During cholestatic episodes, albumin and alpha-1 acid glycoprotein levels remain within normal range. Phase I and phase II hepatic metabolic reactions are not significantly affected, but the use of anesthetic agents with minimal hepatotoxicity is advisable. Morphine should be titrated cautiously (morphine glucuronide may cumulate, particularly in case of postoperative renal insufficiency, because of inadequate hydration, as mentioned previously).

Crigler-Najjar Syndrome: Inherited disorder of bilirubin metabolism, in which the bilirubin cannot be converted into its water-soluble form, bilirubin glucuronide, because of a lack of the functional enzyme bilirubin glucuronyltransferase; this causes jaundice and multiple organ malfunctions. Clinically, neonates have jaundice and neurological manifestations, including severe brain and nerve damage, seizures, and death from bilirubin toxicity.

Gilbert Syndrome: Benign inherited disorder (allelic to Crigler-Najjar syndrome) characterized by chronic jaundice (unconjugated hyperbilirubinemia) but that does not lead to particular complications and is not a progressive disorder.

Hanot Disease: Chronic mesenchymatous hepatitis with perilobar cholestasis as a result of bile duct obstruction by giant peripheral lymphoid follicles.

Benign Recurrent Intrahepatic Cholestasis: Caused by mutations in ATP8B1, never cirrhosis. The hallmark of this medical condition is cholestasis, elevated bilirubin, bile acids, and alkaline phosphatase. Patients present with severe pruritus.

Intrahepatic Cholestasis of Pregnancy: Caused by an impairment of bile secretion in the liver. As the bile backs up in the liver, the level of bile acids increases in the bloodstream. These bile acids are deposited in the skin causing the intensive itching. Chomesterol, triglyceride, and bilirubin levels are also increased.