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Many randomized controlled trials (RCTs) of a number of different agents have been performed in patients with PBC. Because PBC is such a slowly progressive disease, it takes many years with large numbers of patients to perform an adequately powered trial of a new therapy. Unfortunately, most of the studies in PBC have been significantly underpowered and of short duration and have lacked valid end points, making the results very difficult to interpret. As a compromise, meta-analyses have been performed combining the raw data from numerous small trials. Although generally a reasonable strategy, it is important to ensure that all trials included are of similar quality; this has not always been the case.

A variety of different types of agents have been used to treat PBC. Because it is thought to be an autoimmune disease, many different immunosuppressive agents have been tried. In addition, antifibrotic and anticholestatic agents have been studied to see if they may slow down disease progression. Because of the likely need for very prolonged therapy to combat this slowly progressive disease, long-term complications of therapy are critical to consider. It is imperative to ensure that such complications are not worse than the disease itself.

Immunosuppressive agents that have been studied in PBC include azathioprine, cyclosporine, MTX, prednisolone, chlo-rambucil, thalidomide, and budesonide (Table 121-2). None of these agents have been shown to be useful in a properly conducted RCT. MTX has probably received the most attention because of early promising pilot studies. In the only RCT, no benefit was seen, and, in fact, the patients taking MTX had higher serum bilirubin values and Mayo risk scores with a trend to worsened survival at the end of 5 years, suggesting that MTX may, in fact, be toxic in PBC.

D-Penicillamine and colchicine have been studied to see if they may reduce fibrogenesis in PBC. There have been eight RCTs of D-penicillamine, but the results have been uniformly disappointing, with significant adverse effects and no survival benefit. Colchicine has been studied in three small RCTs. Although two of the three studies showed an improvement in liver synthetic function (ie, albumin and bilirubin), the benefit on histology or survival is doubtful.

Ursodeoxycholic Acid

UDCA is a hydrophilic bile acid that appears to have its effect by reducing exposure of hepatocyte membranes to the toxic effects of retained endogenous hydrophobic bile acids. It also reduces bile acid absorption in the terminal ileum and up-regulates the canalicular transporter Mrp2, which may explain its pronounced effect on serum bilirubin levels. UDCA was first studied in the early 1980s, and now a total of 16 RCTs have been performed and analyzed in multiple meta-analyses. The most recent meta-analysis comes from the Cochrane Library in which Gluud and Christensen combined the data from all of these rather heterogeneous studies; treatment periods ranged from 6 months to 4 years, with a daily dose of UDCA from 7.7 to 15 mg/kg, and there was a range of disease severity. In addition, the majority of the trials (11 of 16) were of poor methodologic quality. Attempting to take all of this into consideration, the authors concluded that there was no survival benefit at 2 years, but patients who received UDCA for 4 years or longer had a significant delay to time for liver transplantation. Examining liver

TABLE 121-2. Disease-Modifying Agents in Primary Biliary Cirrhosis

Agent

Trials

Benefits

Adverse Effects

Comment

Azathioprine

1 uncontrolled, 1 RCT

Only seen after adjustment for baseline factors

Underpowered, high dropout rates, survival benefit of months after adjust for baseline factors only—questionable

Cyclosporine

2 pilot, 1 RCT

Only seen after adjust for baseline factors

Renal 9%, HTN 11%

Unequal groups at baseline, survival benefit seen after adjust baseline factors only—significant adverse events

Methotrexate

1 pilot, 1 RCT

Decreased ALP, no history or survival benefit

Higher Mayo risk score and bilirubin in treated patients, questionable toxicity in PBC

Prednisolone

2 RCTs

Reduced bilirubin

Significant osteoporosis

Decreased bilirubin at 3 yr, addition of bisphosphonate stabilized bone loss

Chlorambucil

1 pilot

Decreased ALP

30% dropout, BM suppression

High toxicity and very small study (13 patients)

Thalidomide

1 RCT

No

Only 6-mo study in 18 patients; no benefit seen

Budesonide

2 RCTs

Improved histology in early disease

Osteoporosis

Initial trial showed histology benefit; second study worse Mayo score and osteoporosis? 2° to shunting past liver

D-Penicillamine

8 RCTs

No

+++

High withdrawal rates; no benefit

Colchicine

3 RCTs

Two-thirds improved albumin/bilirubin 32% dropout in

1 study

All underpowered, high dropout; may be promising; needs further study

UDCA

16 RCTs

Survival improved at 4 yr and maybe at 2 yr

Minimal

Most recent meta-analysis less encouraging results, but questionable study inclusion

ALP = alkaline phosphatase; BM = bone marrow; HTN = hypertension; PBC = primary biliary cirrhosis; RCT = randomized controlled trial; UDCA = ursodeoxycholic acid.

ALP = alkaline phosphatase; BM = bone marrow; HTN = hypertension; PBC = primary biliary cirrhosis; RCT = randomized controlled trial; UDCA = ursodeoxycholic acid.

histology, UDCA does not reduce existing fibrosis but does appear to slow its progression.

Based on the data to date, UDCA is the only treatment that has any effect on long-term outcome in PBC. Currently, a study is ongoing looking at the combination of UDCA with MTX, and small studies looking at other combinations have been performed in the past. Until these data are available, UDCA remains the mainstay of treatment for this disease. The major advantage to UDCA is that, in addition to being moderately effective, it is harmless. Rarely, patients report gastrointestinal intolerance with diarrhea or constipation, and, curiously, UDCA occasionally makes pruritus worse. Some important considerations about UDCA therapy are that the dosing is (15 mg/kg, which can be taken once daily), AMAs may disappear on therapy, and enzymes will remain elevated (albeit less elevated) in up to 50% of patients. Although patients may progress on UDCA (even if liver tests return to and remain normal) and it is tempting to try additional therapies, it is important to consider that none have been shown effective and most are associated with at least moderate adverse effects. Although this is rather conservative advice, until better data are available supporting other treatments, we would not advocate their use.

In patients who progress to liver failure despite treatment, liver transplantation remains the only alternative. Fortunately, patients with PBC tend to do extremely well, with > 70% with 5-year survival and > 60% with 10-year survival. Although

PBC can recur in the new liver, this is uncommon and usually inconsequential. To date, no transplantations have been done for recurrent PBC, although this may be misleading because it can be difficult to differentiate between chronic ductopenic rejection and recurrent PBC.

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