COMMENTARY

Finding the Patient With Primary Biliary Cirrhosis

Rowen K. Zetterman, MD

Disclosures

February 27, 2015

In This Article

Primary biliary cirrhosis (PBC) is a chronic progressive disorder of presumed autoimmune cause that appears to be increasing in case frequency in parallel with a rising incidence of other autoimmune conditions. PBC typically affects women more than men, presents during midlife, and is uncommon before age 25 years or after age 65 years. Patients may be asymptomatic and identified only because of abnormal liver tests or such symptoms as itching or fatigue.

Pathogenesis

The cause of PBC is unknown. Although PBC may have a multifactorial basis, the association with other apparent autoimmune disorders, such as celiac sprue,[1] Sjögren syndrome, and multiple sclerosis, suggests that autoimmunity plays a substantial role.[2]

Infectious etiologies have been associated with PBC and may serve as a potential trigger in patients predisposed to autoimmune disease. The association of PBC with a history of urinary tract infections[3] was suggested by the finding of bacteriuria in 19% of patients with PBC compared with only 5% of other patients. Escherichia coli bacteria were identified in 70% of patients with PBC and coexisting urinary tract infections; this association has also been described by others.[4] Other infectious agents have been implicated in the pathogenesis of PBC, including mycobacteria and Novosphingobium aromaticivorans.[5,6] However, no definite cause and effect for infections and PBC has been established.

Because clustering of PBC cases has been observed in certain geographic regions, environmental factors have been suggested as an etiology. A study from England found a higher incidence of PBC among people living in lower socioeconomic households associated with overcrowding.[7] Other studies have found higher numbers of cases near Superfund hazardous waste sites for hydrocarbons.[8] If people move from a high-risk to a lower-risk area, the risk for PBC diminishes.

Clinical Features

PBC is an uncommon disorder, with a prevalence of up to 40 cases per 100,000 population.[7,9] In The Netherlands, an incidence of 1.9 cases and a prevalence of 13.2 cases per 100,000 population have been reported.[10]

The diagnosis of PBC is typically established between the ages of 30 and 60 years.

PBC develops in all races, and 90% of cases occur in women, with a concurrence within families. Antimitochondrial antibodies (AMAs) are found in approximately 20% of family members of a first-degree relative diagnosed with PBC,[11] and 5%-9% of these family members will also have PBC.[12] Mother/daughter pairs and sisters with concurrent PBC are seen. Monozygotic twins have a 60% concurrence of PBC, although the risk for concurrence in dizygotic twins is low.[13]

Given the increased likelihood of AMAs and concurrence of disease in family members of patients with PBC, the question of whether they should be routinely screened has been raised, but such screening is currently not recommended. However, a physician should be vigilant in identifying such symptoms as pruritus, fatigue, dark urine, or jaundice, and in following up abnormal liver tests in family members of a patient with PBC.

The presentation of PBC can range from an abnormal serum alkaline phosphatase level in an asymptomatic person to unexplained pruritus, overt jaundice, or an initial presentation with advanced liver disease. Pruritus and fatigue are early symptoms that usually precede the development of jaundice by many years. PBC is typically a slowly progressive disease that may lead to cirrhosis and liver failure within 10 years of diagnosis.[14]

Pruritus develops in up to 75% of patients with PBC.[15] What causes the itching in patients with cholestasis is yet to be determined. Clinical evidence of itching includes excoriation of extremities, a butterfly rash over the back in the regions that the patient can reach and scratch, and prurigo nodularis. Itching is often diurnal and can have a distressing impact on quality of life and impair sleeping. Refractory, unremitting pruritus has been used as an indication for liver transplantation.[16]

Chronic fatigue may also be distressing in patients and impair daily living activities. Such patients may describe needing to nap after simple activities, such as child care, preparing a meal, or washing the dishes. Fatigue is often out of proportion to the severity of the underlying liver disease. No clear treatment for fatigue is available.

Other disorders associated with PBC include sicca complex, causing dry eyes and dry mouth in 45%-70% of patients.[17] Up to 9% of patients with Sjögren syndrome will have concurrent PBC[18] and should be evaluated in the presence of an abnormal alkaline phosphatase level.

Scleroderma occurs in 10% of patients with PBC.[17] Patients with both scleroderma and PBC are more likely to die of the complications of scleroderma than PBC.[19]

Celiac disease, Hashimoto thyroiditis, pancreatic insufficiency (perhaps related to autoimmune pancreatitis), hyperlipidemia, and hepatic osteodystrophy/osteoporosis are frequently observed with PBC. Interstitial lung disease with lymphocytic infiltrates, interstitial fibrosis, or pulmonary granulomas can occasionally be present.[20]

Hepatopulmonary syndrome producing impaired arterial oxygenation owing to ventilation/perfusion mismatch in the pulmonary parenchyma can cause hypoxemia and cyanosis.[20] Patients may present with dyspnea that is worse when upright and improved when lying supine (platypnea) and have an alveolar-arterial oxygenation difference > 15 mm Hg. Patients with hepatopulmonary syndrome should be considered for oxygen therapy and liver transplantation.

Portopulmonary hypertension is the finding of pulmonary arterial hypertension in the setting of portal hypertension.[20] Patients present with dyspnea after minimal exertion and have pulmonary arterial pressures > 25 mm Hg at rest associated with a pulmonary vascular resistance > 240 dyne/s/cm-5.

Progressive liver disease with cirrhosis can lead to portal hypertension with ascites, hepatic encephalopathy, and esophagogastric varices. Varices can even develop in patients who lack cirrhosis, as a consequence of presinusoidal portal fibrosis that impairs portal blood flow.[21] These patients may also have high alkaline phosphatase levels and thrombocytopenia.

Although hepatocellular carcinoma (HCC) is less likely to develop in patients with PBC than in those with many other end-stage hepatic disorders, it does occur, and patients with PBC should be regularly screened for HCC.[22] Men with PBC may be a greater risk of developing HCC than women. Non-Hodgkin lymphoma may also develop in patients with PBC.[23]

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