UDCA is the only therapy approved by the U.S. Food and Drug Administration for the treatment of PBC. The mechanism of action of UDCA remains unknown. It is a choleretic agent. It has been shown to slow progression of disease in patients with early-stage disease and is highly effective as monotherapy in 25–30% of patients. As is seemingly true with all therapies used for PBC, UDCA is not as effective in advanced disease. There is clearly a point in the natural history of PBC where sufficient numbers of bile ducts are destroyed and the condition has passed the point of reversibility. The appropriate dosage of UDCA is 13–15 mg/kg/day split into two doses. It is well tolerated with the most common side effect being diarrhea.
Although many hepatologists do not recommend consideration of any therapy beyond UDCA (Figure 51–2), there is a growing consensus that it is important for the clinician to differentiate between patients who have responded to UDCA and those who have not; studies have shown that patients with a biochemical and histological response to UDCA have a better prognosis than those who do not respond. These data support a more aggressive approach to management in these selected patients who are at a higher risk of disease progression and in young patients with early-stage disease with the ultimate goal of improving outcomes (Figure 51–3). If patients have an incomplete biochemical or histologic response to UDCA, the use of alternative therapies including colchicine, methotrexate, and budesonide should be considered.
Treatment of primary biliary cirrhosis (PBC). The most widely accepted algorithm is illustrated. Ursodeoxycholic acid (UDCA) is initiated and patients are then monitored for progression of disease and complications. The only other active intervention in this algorithm is referral of patients for transplantation when their liver disease has decompensated. LFTs, liver function tests.
Treatment of primary biliary cirrhosis (PBC): a stepwise approach. This algorithm highlights the use of the baseline histologic staging to direct treatment as well as monitor the response to therapy. It also reflects the reality that ursodeoxycholic acid (UDCA) monotherapy is effective in only a minority of patients and that there are subsets of patients who respond to colchicine, methotrexate (MTX), or budesonide, but there is no way to predict response. LFTs, liver function tests.
In contrast to some studies that failed to show a benefit of colchicine, several prospective double-blind trials found that colchicine improved biochemistry profiles, symptoms (pruritus), and histologic findings. A meta-analysis reported that colchicine delayed the need for transplantation and reduced the incidence of major complications.
Methotrexate has been shown in some studies to improve biochemical and histologic findings in patients with an incomplete response to UDCA monotherapy. Other studies have failed to show any benefit of methotrexate, either alone or in combination with UDCA. One 10-year study suggested that patients with early-stage disease were most likely to benefit from methotrexate.
Short duration, randomized, placebo-controlled trials of budesonide have shown that it improves biochemical and histologic findings in PBC. Longer trials will be needed to assess the impact on survival and ensure osteopenia is not an issue. Budesonide is contraindicated in patients with cirrhosis.
Figure 51–3 highlights the stepwise approach for patients with stage 1–3 disease. This approach is based on the observation that clinical response to medical therapy varies greatly from patient to patient and that a significant percentage of patients will progress on UDCA monotherapy. In this approach, histology is a critical component in decision making, both in determining whether to add additional agents to UDCA and whether to continue those agents. The severity of the portal inflammation is typically the major deciding factor in determining whether to add additional therapies.
Liver transplantation is the only effective therapy for patients with end-stage PBC. These patients have post-transplant outcomes that exceed most other indications. Disease recurrence has been reported—30% at year 10 in one series—but it is exceedingly rare to lose a graft to recurrent disease.
Corpechot C, Abenavoli L, Rabahi N, et al. Biochemical response to ursodeoxycholic acid and longterm prognosis in primary biliary cirrhosis. Hepatology
Corpechot C, Carrat F, Bahr A, et al. The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis. Gastroenterology.
Kuiper EM, Hansen BE, de Vries RA, et al. Improved prognosis of patients with primary biliary cirrhosis that have a biochemical response to ursodeoxycholic acid. Gastroenterology
Lindor K. Ursodeoxycholic acid for the treatment of primary biliary cirrhosis. N Engl J Med.
As with primary therapy, management of pruritus is most effective when one proceeds in a logical and stepwise fashion. Cholestyramine is effective in more than 90% of patients and should be the first-line agent. The starting dosage is typically 4 g, two to three times a day, and some improvement of symptoms is usually seen within 2–4 days. Tolerance can be an issue, with gastrointestinal side effects (unpleasant taste and constipation) being prominent. It is critical to educate patients regarding the need to separate the dosing of cholestyramine from other medications. The second-line agent for pruritus is rifampin; a dosage of 150 mg twice daily is well tolerated and has little risk of toxicity. Oral opioid receptor antagonists are a reasonable third-line agent. Sertraline, 75–100 mg a day was shown of benefit in one study of pruritus in patients with cholestatic hepatitis. Antihistamines have little role aside from use as a sleep aid. Plasmapheresis has been effective in truly refractory cases.
This symptom can be incapacitating, even in patients with early-stage disease. Modafinil has been shown to be effective in two small, uncontrolled pilot trials and in personal experience. Controlled trials are awaited. The dosage is 100–200 mg/day.
Approximately one third of patients with PBC develop osteoporosis, which can manifest before the onset of jaundice. Bone density should be checked every 2 years in patients with PBC and osteopenia managed aggressively. While benefit has not been proven, these patients should be on calcium (1500 mg a day) and vitamin D (1000 IU/day) supplementation. Alendronate has been shown to be beneficial in two trials and estrogen replacement in two studies of postmenopausal women; however, this benefit needs to be weighed against the increased risk of vascular disease and cancer.
Although serum lipids are often elevated in PBC, patients seemingly do not have an increased risk of atherosclerosis. This finding is explained partly by the presence of high levels of high-density lipoprotein and partly by the presence of a subfraction of low-density lipoproteins, called lipoprotein X, that has anti-atherogenic properties. Thus, it is rare that PBC patients require lipid-lowering agents. However, statin drugs can be used safely, if indicated, so long as standard monitoring for hepatotoxicity is performed.
Fat Soluble Vitamin Deficiency
Deficiency of fat-soluble vitamins occurs in patients with PBC, particularly those with advanced stage disease. Vitamin A deficiency can occur in up to one third of patients and cases of night blindness have been reported. Fat-soluble vitamin levels should be checked every 2 years and supplemented as needed.