Primary biliary cholangitis (ORPHA:186)
A rare autoimmune cholestatic liver disease characterized by autoimmune mediated damage of small intrahepatic bile ducts leading to cholestasis, fibrosis, and potential cirrhosis.
Epidemiology
Primary biliary cholangitis (PBC) incidence rates range from 0.33 to 5.8 per 100,000 inhabitants/year and prevalence rates range from 1.91 to 40.2 per 100,000 inhabitants Women are predominantly affected with a sex ratio of 9:1.
Clinical description
Onset is generally in the 4th to 6th decades of life. Many patients are asymptomatic at diagnosis and are identified incidentally. The initial presenting manifestations include fatigue (80%) and pruritus (20-70%), both of which fluctuate throughout the disease course. Pruritus is prominently on the palms and soles with worsening at night and can have significant impact on quality of life (occupational ability, depression, obsessive-compulsive disorder). Right upper quadrant discomfort is found less commonly. In late stages, xanthomas and xanthelasmas may develop. Osteopenia and osteoporosis with a risk of fractures are also found, along with hyperlipidemia, hypercholesterolemia, and vitamin deficiencies (vitamin A, D and rarely E). Complications related to cirrhosis include portal hypertension (with spider nevi, hyperpigmentation, palmar erythema, ascites, intra-abdominal varices), splenomegaly, muscle wasting, peripheral edema, and hepatocellular carcinoma. Neurological complications include impaired concentration and memory and disturbed sleep. Concomitant autoimmune disorders are common and include Sjögren's syndrome, CREST syndrome, autoimmune thyroid disease, rheumatoid arthritis and Raynaud syndrome, and often correlate with the autonomic dysfunction observed.
Etiology
The liver damage is due to T-cell-mediated destruction of small bile duct epithelial cells causing ductopenia and persistent cholestasis. The exact etiology is currently unknown; however, it is currently believed to involve a combination of environmental factors (e.g. toxins, chemical substances, smoking and infectious agents), genetic predisposition and loss of immune tolerance.
Diagnostic methods
In adult patients with cholestasis (elevated alkaline phosphatase (ALP) and/or gammaglutamyltransferase (GGT)), PBC can be suspected after excluding obstructive jaundice by abdominal ultrasound and systemic diseases. Diagnosis can be made when disease-specific autoantibodies are detected (i.e. antimitochondrial autoantibodies (AMA titer>1:40) and anti-nuclear autoantibodies (ANA) anti-sp100 and anti-gp210). A liver biopsy is recommended when PBC-specific antibodies are absent, autoimmune hepatitis (AIH) or non-alcoholic steatohepatitis (NASH) are suspected, or when other systemic co-morbidities are present and may have a role in the differential diagnosis of cholestasis.
Differential diagnosis
Differential diagnoses include autoimmune hepatitis, primary sclerosing cholangitis, alcoholic and non-alcoholic steatohepatitis and drug-induced hepatotoxicity.
Genetic counseling
Whilst a causal gene has not been identified, first-degree relatives have a higher risk of developing the disease.
Management and treatment
The aim of treatment is to reduce symptoms and slow disease progression. Ursodeoxycholic acid (UDCA) at dosage of 13-15 mg/kg/day is highly effective in improving transplant-free survival, although has limited effect in treating fatigue and pruritus. In patients with inadequate response (25%‐40%), obeticholic acid should be added. Response to UDCA is evaluated, after a period of 6 to 24 months of treatment, based on changes in bilirubin, transaminases and ALP. Patients with advanced disease should be screened for hepatocellular carcinoma, esophageal varices and considered for liver transplant (LT). Cholestyramine is the first line treatment for pruritus; for intolerant or refractory patients rifampin is indicated.
Prognosis
LT-free survival of patients with normal or near-normal liver biochemistry on UDCA is similar to that of the general population, whereas it is significantly reduced in those with abnormal liver biochemistry on treatment. After liver transplant, the recurrence of disease rate may be as high as 18 percent at five years, and up to 30 percent at 10 years. There is no consensus on risk factors for recurrence of the disease. HCC is infrequent in PBC; however, lack of UDCA-response after 12 months of therapy and male sex are associated with increased risk of developing HCC.

                            Last update: 
                            July 2020


                            - Expert reviewer(s): 
                            Dr Marco CARBONE  - Dr Laura CRISTOFERI  - Dr Alessio GERUSSI  - Pr Pietro INVERNIZZI | RARE-LIVER*


                                * European Reference Network