Primary biliary cirrhosisK74.3

Primary biliary cirrhosis is an autoimmunological (Webb GJ et al. 2015), chronic, cholestatic liver disease characterized by non-purulent, destructive cholangitis of the peripheral bile ducts with consecutive fibrosis and potential cirrhosis.

PBC can be considered as a late stage cirrhotic autoimmunological primary biliary cholangitis (K83.0). The pioneering serological diagnostic criterion is the antimitochondrial antibodies(AMA) detectable in 95% of affected patients (Carey EJ et al. 2015).

Incidence in Europe: 8- 14/100.000 inhabitants. Incidence seems to be increasing. About 1% of all cases of cirrhosis.

Questionable autoimmune disease. Discussed are hormonal and genetic influences, drugs, infections with viruses, fungi or bacteria as well as environmental influences. One study pointed out that E2 derivatives in which lipoic acid was replaced by octin-7-carboxylic acid, a compound used industrially as a methyl ester as a fragrance and flavour (violet), the modified E2 had a much stronger antigenic effect. Allergies to the methyl ester are known. Cosmetic articles containing this substance have to be labelled EU-wide ("METHYL 2-OCTYNOATE").

w:m=9:1; onset of disease: > 40 years. Familial clustering is known. First-degree relatives and patients with native sprue (celiac disease) have an increased risk of developing PBC (Webb GJ et al. 2015).

Asymptomatic in the early stages (not infrequently incidental laboratory findings). Onset with non-specific symptoms such as fatigue and exhaustion (70-90 % of patients), unclear upper abdominal complaints, weight loss. Not infrequently, xanthelasma (in about 20 % of patients) or (more rarely) eruptive xanthomas are the first early symptoms.

Later, agonizing pruritus (20-70 %, well before the onset of icterus), icterus. Furthermore, accompanying rheumatoid symptoms, autoimmunological thyroid diseases(Hashimoto's thyroiditis - 20%) and sicca symptoms (Sjögren's syndrome 70%). Furthermore, signs of maldigestion with fatty stools and possible vitamin A, D, E and K deficiency may occur. In women, there is a tendency to recurrent urinary tract infections (20% of affected women).

In the late stages of the disease, complications typical of cirrhosis develop, such as ascites, oesophageal varices, fundus varices, hepatic encephalopathy and liver carcinoma.

Sonography: Liver in early stages often inconspicuous or fatty liver-like. In later stages the liver may be enlarged, in the final stage of cirrhosis the surface is often bumpy or wavy.

Increased cholestasis parameters, antimitochondrial antibodies (AMA) 95% of cases positive (specific are anti-M2 antibodies. Target antigen= E2 subunit of the pyruvate dehydrogenase complex - PDC-E2). ANA (50%) mostly low titre. IgM usually strongly elevated. Hypercholesterolemia.

St I: Lymphoplasmacellular infiltration of the portal fields with destruction of the bile duct epithelium

St II: Bile duct proliferation with pseudogallenous ducts

St III: obliteration of the portal fields, moth feeding (pice. meal) necroses + sinking of small bile ducts.

St IV: Cirrhosis (mostly micronodular), macroscopic dark green liver

It is important to clearly distinguish PBC from other autoimmune diseases such as autoimmune hepatitis or primary sclerosing cholangitis. In up to 10% of cases, mixed forms of e.g. PBC and autoimmune hepatitis can also occur (so-called overlap syndrome).

Causal therapy is not known.

Omission of all potential liver noxae (alcohol, medication); all patients should be vaccinated against HA/HB if the virus status is negative. Additional hepatitis infections lead to a severe course with increased mortality.

Drug therapy with ursodeoxycholic acid (UDCA), dosage: 13-15mg/KG/day. Patients treated with ursodesoxycholic acid have a better life expectancy than those who are untreated (Bowlus CL et al. 2014). Colestyramine binds bile acids and lowers cholesterol levels.

PBC is a chronic insidious disease that can often go undetected clinically for years. Untreated, in 10 to 12 years it develops into a complete cirrhosis of the liver with decreasing liver function (Bowlus CL et al. 2014). In stage IV (cirrhosis), as with cirrhosis of other causes, there is an increased risk of developing hepatocellular carcinoma.

Healing is not possible even under drug therapy. 10-year survival time after diagnosis about 65%. Mean survival time (without liver transplantation) 10-20 years.

Primary biliary cirrhosis and comorbidities:

• Autoimmune thyroiditis (Hashimoto) 20%
• Sjögren Sydrome (70%)
• Autoimmune hepatitis (10%) (K75.4)
• CREST syndrome (10%) (M34.1)
• systemic scleroderma (21%).
• Rheumatoid arthritis (M06.99)
• IgG4-related retroperitoneal fibrosis (case description Huang X et al. 2018) (N13.5)
• Primary Myelofibrosis (case description Lu C et al. 2018)
• Xanthelasma (H02.6)
• Eruptive xanthomas (E75.5)
• Steatorrhoea (K90.4)
• Vitamin deficiency
• Celiac disease (increased risk of PBC in patients with celiac disease) (K90.0)

Bowlus CL et al (2014) The diagnosis of primary biliary cirrhosis. Autoimmune Rev 13:441-444.

Carey EJ et al. (2015) Primary biliary cirrhosis. Lancet 386: 1565-1575.

Marí-Alfonso B et al (2015) Prognostic implications of extra-hepatic clinical manifestations, autoimmunity and microscopic nail capillaroscopy in patients with primary biliary cirrhosis. Med Clin (Barc) 146:8-15.

Huang X et al (2018) IgG4-related retroperitoneal fibrosis overlapping with primary biliary cirrhosis and primary Sjögren's syndrome: A case report. Medicine (Baltimore) 97:e11303.

Lu C et al (2018) Primary myelofibrosis but not autoimmune myelofibrosis accompanied by Sjögren's syndrome and primary biliary cirrhosis in a patient with trisomy 8 mosaic: a case report and literature review. Clin Exp Rheumatol PMID: 29745886

Webb GJ et al (2015) The immunogenetics of primary biliary cirrhosis: A comprehensive review. J Autoimmune 64:42-52.