European Association for the Study of the Liver. EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. J Hepatol. 2017 Jul;67(1):145-172. doi: 10.1016/j.jhep.2017.03.022. Epub 2017 Apr 18. PubMed PMID: 28427765.
Lindor KD, Bowlus CL, Boyer J, Levy C, Mayo M. Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases. Hepatology. 2019 Jan;69(1):394-419. doi: 10.1002/hep.30145. Epub 2018 Nov 6. PubMed PMID: 30070375.
Definition, Etiology, PathogenesisTop
Primary biliary cholangitis (PBC) (also referred to as primary biliary cholangiopathy; previously primary biliary cirrhosis) is a chronic autoimmune liver disease of unknown etiology characterized by cholestasis caused by destruction of small intrahepatic bile ducts.
Most patients are women in their fifth and sixth decades of life. The disease does not occur in children.
1. Symptoms: Chronic fatigue (in ~60% of patients; often the only symptom; not significantly aggravated by increased physical activity and not alleviated by rest), pruritus (in ~50%; may precede other symptoms by many months or years; initially limited to hands and feet). Less common symptoms include oral and conjunctival dryness and constant or intermittent moderate right epigastric pain.
2. Signs: Hepatomegaly (<30% of patients), xanthomata, jaundice (in advanced disease). In late stages of the disease signs of cirrhosis may be present. Signs of other autoimmune diseases may coexist, such as Sjögren syndrome, autoimmune thyroid disease, rheumatoid arthritis, systemic sclerosis, pernicious anemia, celiac disease, and systemic lupus erythematosus.
3. Natural history: The course is unpredictable. In many untreated patients the progression of the disease is minimal for 10 or even 20 years, while in others cirrhosis develops within a few years despite treatment. A mortality risk score for PBC developed at the Mayo Clinic may assist in predicting short-term outcomes (available at mayoclinic.org).
1. Laboratory tests:
1) Blood biochemical tests: Elevated serum alkaline phosphatase (ALP) and gamma-glutamyl transferase (transpeptidase) (GGT) levels (the most common abnormality at diagnosis), elevated serum aminotransferase levels, hyperbilirubinemia (in more advanced disease), hypercholesterolemia (in 50%-90% of patients).
2) Immunologic tests:
a) Elevated serum IgM levels.
b) Positive antimitochondrial autoantibodies (AMAs) (90%-95% of patients).
c) Antinuclear antibodies (ANAs) (including those specific for PBC: anti-glycoprotein-210 [anti-gp210] and/or anti-Sp100), smooth muscle antibodies (SMAs), or both (in 20%-30% of patients).
2. Ultrasonography should be the first-line imaging study to differentiate intrahepatic from extrahepatic cholestasis. Subsequently magnetic resonance cholangiopancreatography (MRCP) or, if MRCP is not available or contraindicated, computed tomography (CT) can be performed to exclude biliary occlusion. Endoscopic ultrasonography (EUS) may be an alternative to MRCP to evaluate distal biliary disease.
3. Histologic examination of liver biopsy specimens can be used for establishing the diagnosis of PBC, histologic staging, and diagnosing cirrhosis or coexisting autoimmune hepatitis, but it is not required for PBC diagnosis. Typical findings include atrophy of the bile ducts (ductopenia) and inflammatory infiltrates in periportal zones.
4. Elastography is useful in assessing the severity of fibrosis.
The diagnosis of PBC is made in patients who meet ≥2 out of the 3 following criteria: elevated serum ALP level, positive AMAs (titer ≥1:40) or other antibodies typical for PBC (anti-gp210 or anti-Sp100) if AMAs are negative, and typical histologic features of liver biopsy specimen(s).
Primary or secondary sclerosing cholangitis, drug-induced cholestasis, overlap syndrome including autoimmune hepatitis, cholestasis in the course of sarcoidosis, idiopathic syndromes presenting with ductopenia and cholestasis.
1. Moderate physical activity and regular weight-bearing exercise may reduce chronic fatigue and decrease the risk of osteoporosis.
2. In patients with dry oral mucosa and conjunctivae, recommend frequent sipping of water and using artificial tears.
3. No pharmacotherapy can achieve radical cure. To slow down the progression of the disease, use ursodeoxycholic acid (UDCA) (INN ursodiol) 13 to 15 mg/kg once daily or in 2 divided doses.Evidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Poupon RE, Lindor KD, Cauch-Dudek K, Dickson ER, Poupon R, Heathcote EJ. Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology. 1997 Sep;113(3):884-90. PubMed PMID: 9287980. In patients who had an inadequate response (defined by various scoring systems, such as Toronto criteria: ALP >1.67 × upper limit of normal [ULN] after 24 months of UDCA therapy), add second-line therapy: obeticholic acid (OCA), if available, in the initial dose of 5 mg once daily and then titrated to 10 mg according to tolerability at 6 months (do not exceed 10 mg bid; this drug may exacerbate pruritus). Patients not tolerating UDCA treatment can be switched to OCA. In patients with decompensated liver cirrhosis (Child-Pugh class B or C), the starting oral dose must not exceed 5 mg once weekly. Bezafibrate therapy may be considered as add-on therapy in patients with an inadequate response to UDCA,Evidence 2Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Corpechot C, Chazouillères O, Rousseau A, et al. A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis. N Engl J Med. 2018 Jun 7;378(23):2171-2181. doi: 10.1056/NEJMoa1714519. PubMed PMID: 29874528. (although European guidelines predate the main study of that drug and therefore did not formally recommend this therapy at the time of publication).
4. Management of pruritus.
5. Management of chronic fatigue: The only current recommendation from the European Association for the Study of the Liver (EASL) guideline is to seek and treat associated and alternative causes of fatigue (particularly anemia, hypothyroidism, and sleep disturbances) and to develop coping strategies.
6. Liver transplantation is indicated in patients with symptomatic liver failure and features of portal hypertension who do not respond to medical treatment as well as in those with persistent and refractory pruritus, severe chronic fatigue markedly affecting daily activities, hepatocellular carcinoma (HCC) secondary to cirrhosis, or markers of disease severity (eg, persistent elevated bilirubin of 50 micromol/L [3 mg/dL]; or a high Model for End-Stage Liver Disease and Serum Sodium Concentration [MELDNa] score, eg, >15; available at mdcalc.com).
1. Osteoporosis: Prophylaxis and treatment are necessary (see Osteoporosis). Measurements of bone mineral density every 2 years are indicated.
2. Deficiency of fat-soluble vitamins (A, D, E, and K) due to malabsorption in advanced PBC (chronic hyperbilirubinemia): Administer appropriate vitamin supplements.
3. HCC develops almost exclusively in patients with cirrhosis (~4% of women and ~20% of men). The incidence of HCC in patients with diagnosed PBC is 0.36 per 100 person-years.
In asymptomatic patients and in those who were diagnosed early and treated with UDCA, the mean survival time can be close to that of the general population. Ninety-five percent of patients with a good response to UDCA survive 14 years without the need for liver transplantation. In patients with persistent hyperbilirubinemia not treated with liver transplantation, the mean survival time is up to 5 years. In patients with persistent hyperbilirubinemia treated with liver transplantation, the 5-year survival rate is ~85%. In addition to MELDNa, other scores that can be useful in estimating prognosis are the GLOBE score at globalpbc.com and the UK-PBC Risk Score Calculator at uk-pbc.com.