Cholangitis, Primary Biliary

Essentials of Diagnosis

• Occurs in middle-aged women

• Often asymptomatic

• Elevated serum alkaline phosphatase, IgM, and cholesterol; positive antimitochondrial antibodies (AMA)

• Characteristic liver biopsy

• In later stages, can present with fatigue, jaundice, features of cirrhosis, xanthelasma, xanthomata, steatorrhea

General Considerations

• Chronic disease of the liver characterized by autoimmune destruction of small intrahepatic bile ducts and cholestasis

• The designation "primary biliary cholangitis" has been proposed instead of primary biliary cirrhosis because many patients do not have cirrhosis

• Insidious in onset

• Occurs usually in women aged 40–60

• Often detected by the chance finding of elevated serum alkaline phosphatase levels

• It may be associated with

  • Sjögren syndrome

  • Autoimmune thyroid disease

  • Raynaud syndrome

  • Scleroderma

  • Hypothyroidism

  • Gluten enteropathy

• Infection with Novospingobium aromaticivorans and Chlamydophila pneumoniae may trigger or cause primary biliary cholangitis; other triggers include viruses, lactobacillus vaccination, and xenobiotics

• Risk factors include

  • History of urinary tract infections

  • Smoking

  • Hormone replacement therapy

  • Use of hair dye

• Patients with a clinical and histologic picture of primary biliary cholangitis but with no AMA are said to have AMA-negative primary biliary cholangitis ("autoimmune cholangitis"), which has been associated with

  • Lower serum IgM levels

  • Greater frequency of smooth muscle antibodies and antinuclear antibodies

Demographics

• Estimated incidence and prevalence rates in the United States

  • In women: 4.5 and 65.4 per 100,000, respectively

  • In men: 0.7 and 12.1 per 100,000, respectively

Symptoms and Signs

• Many are asymptomatic for years

• The onset of clinical illness is insidious and is heralded by fatigue and pruritus

• With progression, physical examination reveals hepatosplenomegaly

• Xanthomatous lesions may occur in the skin and tendons and around the eyelids

• Jaundice, steatorrhea, and signs of portal hypertension are late findings, although occasional patients have esophageal varices despite an early histologic stage

• Autonomic dysfunction, including orthostatic hypotension, associated with fatigue, and cognitive dysfunction appear to be common

• The risk of low bone density, osteoporosis, and fractures is increased, as in patients with other forms of chronic liver disease

Differential Diagnosis

• Chronic biliary tract obstruction (stone or stricture)

• Carcinoma of the bile ducts

• Primary sclerosing cholangitis

• Sarcoidosis

• Cholestatic drug toxicity (eg, chlorpromazine)

• Chronic hepatitis

• Some patients have overlapping features of primary biliary cholangitis and autoimmune hepatitis

Laboratory Tests

• Blood cell counts are normal early in the disease

• Liver biochemical tests reflect cholestasis with elevation of serum alkaline phosphatase, cholesterol (especially high-density lipoproteins and lipoprotein X), and, in later stages, bilirubin

• Antimitochondrial antibodies (AMA)

  • Directed against pyruvate dehydrogenase or other 2-oxo-acid enzymes in mitochondria

  • Present in 95% of patients

  • Titer > 1:40 in serum

• Serum IgM levels are elevated

• Antinuclear antibodies directed against the nuclear pore complex may be detected in specialized laboratories has high specificity, and predicts progression to liver failure

• Anti-centromere antibodies predict progression to cirrhosis and portal hypertension

Imaging

• Baseline ultrasonography should be obtained

Diagnostic Procedures

• Liver biopsy

  • Not necessary for diagnosis unless AMAs are absent

  • However, it permits histologic staging

    • Stage I: portal inflammation with granulomas

    • Stage II: bile duct proliferation, periportal inflammation

    • Stage III: interlobular fibrous septa

    • Stage IV: cirrhosis

Medications

• Ursodeoxycholic acid (13–15 mg/kg/day in one or two doses)

  • Preferred medical treatment because it lacks toxicity

  • Can be continued during pregnancy

  • Has been shown to slow the progression of disease (particularly early-stage disease), stabilize histology, improve long-term survival, reduce the risk of developing esophageal varices, and delay (and possibly prevent) the need for liver transplantation even in the absence of liver biochemical test improvement

  • Complete normalization of liver biochemical tests occurs in 20% within 2 years and 40% within 5 years

• Obeticholic acid

  • Approved for the treatment of primary biliary cholangitis in patients with an incomplete response or intolerance to ursodeoxycholic acid

  • Dosage:

    • Started at 5 mg orally daily and increased to 10 mg daily at 6 months if tolerated, based on the decline in serum alkaline phosphatase and bilirubin levels

    • In patients with Child-Pugh class B or C cirrhosis, the initial dose is 5 mg weekly

  • Pruritus is the principal side effect

  • Expensive; may not be cost-effective

• Bezafibrate (not available in the United States) and fenofibrate

  • Activate peroxisome proliferator-activated receptors (PPARs)

  • Inhibit bile acid synthesis

  • Have shown promise as second-line agents

  • May improve symptoms, liver biochemical test levels, and fibrosis

• Colchicine (0.6 mg twice daily) and methotrexate (15 mg/wk) may improve symptoms and levels of serum alkaline phosphatase and bilirubin

• Methotrexate may also improve liver histology, but overall response rates have been disappointing

• Penicillamine, corticosteroids, and azathioprine are not beneficial

• Budesonide may improve liver histology but worsens bone density

• Mycophenolate mofetil, rituximab, and seladelpar (a peroxisome proliferator-activated receptor delta agonist) are under study

• For pruritus

  • Cholestyramine (4 g) in water or juice three times daily may be beneficial

  • Rifampin, 150–300 mg twice daily orally, is inconsistently beneficial

  • Opioid antagonists (eg, naloxone, 0.2 mcg/kg/min by intravenous infusion, or naltrexone, starting at 12.5 mg/day orally) may help

  • The 5-HT3 serotonin receptor antagonist ondansetron, 4 mg three times a day as needed orally, and the selective serotonin uptake inhibitor sertraline, 75–100 mg/day orally, may also provide some benefit

  • Plasmapheresis or extracorporeal albumin dialysis may be needed for refractory pruritus

• Modafinil, 100–200 mg/day orally, may improve daytime somnolence

• Deficiencies of vitamins A, D, and K may occur if steatorrhea is present and be aggravated when cholestyramine or colestipol is administered

• Calcium supplementation (500 mg three times daily) may help prevent osteomalacia but is of uncertain benefit in osteoporosis

Surgery

• For patients with advanced disease, liver transplantation is the treatment of choice

Prognosis

• Among asymptomatic patients, at least one-third will become symptomatic within 15 years

• An increase in liver stiffness of > 2.1 kilopascals per year indicates an adverse prognosis

• Ursodeoxycholic acid has been shown to

  • Slow the progression of disease

  • Stabilize histology

  • Improve long-term survival

  • Reduce the risk of developing esophageal varices

  • Delay (and possibly prevent) the need for liver transplantation

• Without liver transplantation, survival averages 7–10 years once symptoms develop

• In advanced disease, adverse prognosis is indicated by

  • Older age

  • High serum bilirubin

  • Edema

  • Low serum albumin

  • Prolonged prothrombin time

  • Variceal hemorrhage

• The risk of hepatocellular carcinoma appears to be increased

• Liver transplantation

  • Should be considered when the MELD-Na score is at least 15, total serum bilirubin at least 6, or Mayo risk score at least 7.8

  • Associated with a 1-year survival rate of 85–90%

• The disease recurs in the graft in 20% of patients by 3 years, but this does not seem to affect survival

When to Refer

• For liver biopsy

• For liver transplant evaluation

When to Admit

• Gastrointestinal bleeding

• Stage 3–4 hepatic encephalopathy

• Worsening kidney function

• Severe hyponatremia

• Profound hypoxia