EASL Clinical Practice Guidelines

Genetic cholestatic liver diseases

Cystic fibrosis-associated liver disease

Cystic fibrosis-associated liver disease (CFALD) was observed in up to 27% of patients with CF during long-term follow-up as defined by hepatomegaly, persistent elevation of at least two serum liver tests and abnormal findings on ultrasound [160] and may manifest as neonatal cholestasis, hepatic steatosis, focal or multilobular cirrhosis. Complications of CFALD represent today the second most frequent cause of disease-related death in patients with CF.

Diagnosis

Diagnostic criteria for CFALD are not well defined. CF-related hepatomegaly is found in a third of CF patients and may be caused by CFALD or as a consequence of cor pulmonale with liver congestion. Serum liver tests (AP, ALT, AST, bilirubin) are recommended at yearly intervals in CF patients [161]. Elevation above 1.5× ULN of serum liver tests should induce control after 3–6 months and when persisting should prompt further investigations to more closely evaluate liver damage (prothrombin time, albumin) and exclude other causes of liver disease (e.g., drugs, toxins, infections, biliary atresia, gallstones, antitrypsine deficiency, autoimmune hepatitis, PSC or other causes of bile duct obstruction). Ultrasound may reveal signs of CFALD such as hepatomegaly or bile duct alterations [161]. Liver biopsy is controversially discussed due to the focal nature of fibrosis/cirrhosis in many cases.

Therapy

No therapy of proven benefit for the long-term prognosis of CFALD exists. Optimization of nutritional state in cholestatic patients to avoid vitamin deficiency and malnutrition is recommended, but not of proven efficacy.

UDCA at doses of 20–30 mg/kg/d has been shown to consistently improve serum liver tests [[162], [163]], to stimulate impaired biliary secretion, to improve histological appearance (over 2 years) [164] and nutritional status. The optimal dose of UDCA and its impact on survival in CF remain to be established.

Treatment of complications of cirrhosis is not different from other liver diseases. Medical treatment of portal hypertension with beta blockers and/or endoscopic treatment of varices has not been adequately evaluated in CFALD whereas elective shunt surgery in portal hypertensive patients has allowed long-term survival in a case series [165]. Outcome of liver transplantation is comparable to that for other end-stage liver diseases.

Recommendations

  1. CFALD affects a third of patients with CF during long-term follow-up, but is not well defined. It may be disclosed by detection of hepatomegaly (III/C2), annual performance of serum liver tests (III/C2), and, if abnormal, ultrasound of the liver (III/C2).
  2. UDCA (20–30 mg/kg/d) improves serum liver tests (I/C1) and histological parameters (III/C1) in CFALD. No medical therapy of proven long-term benefit exists in CFALD (III/C2). Liver transplantation is the treatment of choice in end-stage CFALD (III/B1).

Progressive familial intrahepatic cholestasis

Classification

Progressive familial intrahepatic cholestasis (PFIC) summarizes a group of three inherited cholestatic diseases which may start early after birth or at young age and may rapidly progress to end-stage disease [166]. Mutations in canalicular transporter genes of the ATP-binding cassette (ABC) transporters are responsible for these rare disorders.

PFIC type 1 (formerly “Byler disease”) typically presents in the neonatal period with signs and symptoms (pruritus!) of liver disease. Elevation of serum transaminases, bilirubin and bile acids is contrasted by low levels of γGT (in contrast to biliary atresia and Alagille syndrome). Liver histology reveals fibrosis, but no bile duct proliferation. Most patients develop end-stage liver disease before the end of the first decade of life. Diarrhea, pancreatitis, failure to thrive, and hearing deficits are extrahepatic manifestations of this genetic defect caused by mutations in the ATP8B1 gene which encodes a phospholipid (phosphatidylserine?) flippase, FIC1 [[167], [168]].

PFIC type 2 (formerly “Byler syndrome”) presents like PFIC type 1 in early childhood with clinical and biochemical signs and symptoms of progressive liver disease, but low levels of γGT. Histology reveals portal inflammation and giant cell hepatitis. Electron microscopic studies show coarse granular bile in PFIC1 and amorphous bile in PFIC2. PFIC2 is caused by mutations in the ABCB11 gene which encodes the canalicular bile salt export pump, ABCB11/BSEP [169]. The course of PFIC2 is complicated by development of hepatocellular carcinoma at considerable rates [170] making liver transplantation an attractive treatment option.

PFIC type 3 typically presents in the first years of childhood with progressive cholestasis [171], although disease manifestation and cirrhosis in adulthood has also been described most recently [95]. In contrast to PFIC1 and PFIC2, γGT is usually markedly elevated in PFIC3 and histology reveals, in addition to portal inflammation and fibrosis/cirrhosis, massive bile duct proliferation. PFIC3 may be associated with intrahepatic gallstone disease. PFIC3 is caused by mutations in the ABCB4 gene which encodes the canalicular phospholipid transporter, ABCB4/MDR3 [171].

Therapy

No medical therapy of proven benefit for the long-term prognosis of PFIC exists. Supplementation with medium chain triglycerides and fat-soluble vitamins is generally recommended in children. UDCA has been reported to improve biochemical tests in almost 50% of patients with PFIC3 [172], but generally does not affect PFIC1 and PFIC2. Rifampicin may alleviate pruritus. Partial biliary diversion and ileal exclusion have been reported in case series to improve signs and symptoms of particularly PFIC1 and also PFIC2 [[173], [174]]. Liver transplantation is the recommended treatment of end-stage disease in PFIC.

Recommendations

  1. PFIC type 1, 2 and 3 are rare chronic progressive cholestatic disorders of early childhood and adolescence. PFIC type 1 and 2 are characterized by low γGT, severe pruritus and various extrahepatic manifestations.
  2. No medical therapy of proven benefit for the long-term prognosis of PFIC exists (III/C2). UDCA improves serum liver tests in a part of PFIC3 patients (III/C2). Rifampicin may alleviate pruritus (III/C2). Partial biliary diversion has shown beneficial clinical and biochemical effects in PFIC1 and PFIC2 (III/C2). Liver transplantation is recommended for end-stage disease (III/B1).

Benign recurrent intrahepatic cholestasis

Benign recurrent intrahepatic cholestasis (BRIC) type 1 and 2 are acute cholestatic disorders of adolescence and adulthood and represent the benign forms of PFIC1 and PFIC2 mainly caused by missense mutations in the ATP8B1 and ABCB11 genes [[166], [171]]. BRIC is characterized by acute episodes of cholestasis, jaundice and severe pruritus caused by unknown factors which after weeks or months completely resolve to start again after an asymptomatic period of months to years. BRIC1 like PFIC1 may be accompanied by pancreatitis, whereas BRIC2 may be accompanied by gallstone disease [166]. Liver fibrosis has been described in cases of BRIC indicating a continuum between BRIC and PFIC in some cases [175].

No effective medical therapy of BRIC exists. UDCA and rifampicin have been anecdotally reported to affect the course of BRIC as has nasobiliary drainage [176].

Recommendations

  1. BRIC is characterized by acute episodes of cholestasis, jaundice and severe pruritus which after weeks to months completely resolve (III/C1).
  2. No evidence-based treatment of BRIC is known. Treatment attempts with UDCA, rifampicin or nasobiliary drainage are still experimental (III/C2).

Alagille syndrome

Alagille syndrome is an autosomal dominant multiorgan disease of children and adolescents which is characterized by chronic progressive cholestasis with ductopenia without relevant inflammatory changes in liver histology [177]. The extrahepatic signs and symptoms with involvement of nearly every organ system including heart, kidney, skeleton, central nervous system and a typical facies with hypertelorism, deep-set eyes and a flat nasal bridge may lead to the diagnosis of Alagille syndrome in young cholestatic patients suffering from often severe itch. The disease is caused by mutations in the JAG1 gene in 70% of patients. No effective medical treatment exists. Anecdotally, partial biliary diversion has been reported to cause relief from severe pruritus.

Recommendations

  1. Alagille syndrome is characterized by cholestasis with pruritus and ductopenia at early age in combination with various extrahepatic stigmata and symptoms indicating multiorgan involvement as a consequence of JAG1 mutations (III/C2).
  2. No effective medical treatment is known (III/C2).