Histological staging is used for stratification and as-
A number of therapies for PBC have been investisessment of treatment efficacy in therapeutic trials for gated in clinical trials although none has been shown to primary biliary cirrhosis (PBC). Knowledge of the rate be totally effective. [10][14] Most recently, ursodeoxycholic of progression of the histological changes would be helpacid and methotrexate have shown promise; 18-21 howful in the design (duration) and conduct of clinical trials. ever, further evaluation will be necessary before the The histological stages were recorded for liver biopsies efficacy of these drugs given alone or in combination is performed annually on 222 patients during a randomestablished.
ized, placebo-controlled clinical trial in which therapy
Assessment of hepatic histological stage is often used
with D-penicillamine (DPCA) was shown to be ineffecin survival models as well as in evaluation of treatment tive. These data were analyzed using a Markov model to efficacy in therapeutic trials for PBC. Histological stagdescribe the time course of histological progression in PBC. At study entry, 15 patients were stage I, 56 were ing systems have been developed by Scheuer, 22 Popper stage II, 96 were stage III, and 55 were stage IV. Histologand Schaffner, 23 and Ludwig et al. Histological stage ical progression was observed after 1 year in 41%, 43%, provides prognostic information 4 but the rate of histoand 35% of the patients, and after 2 years in 62%, 62%, logical progression in PBC has not been reported. This and 50% of the patients who were stage I, stage II, and information would be helpful in clinical trial design stage III at entry, respectively. After 4 years biopand in assessing prognosis and therapeutic benefit. sies showed cirrhosis in 31% and 50% of the patients in Therefore, we analyzed specimens from serial biopsies stage I and stage II at entry, respectively. A minority in a large number of patients who received ineffective (20%) of the precirrhotic patients showed histological therapy (placebo or penicillamine) to determine the stability; sustained histological regression was rarely time course over which patients progressed through observed (2%). Our data suggest that a majority of patients with PBC will progress histologically within 2 the histological stages of PBC. years. The distribution of histological stages over time PATIENTS AND METHODS may be helpful in determining the number of patients and length of time necessary to appreciate a treatment Beginning in 1974, 312 patients with clinical and biochemieffect on histological progression in clinical trials for cal evidence of PBC were enrolled in a double-blinded, pla-PBC. (HEPATOLOGY 1996;23:52-56.) cebo-controlled, randomized clinical trial of D-penicillamine (DPCA). The study protocol, that was approved by the institutional review board of the Mayo Clinic, Rochester, MN, stipu-Abbreviations: PBC, primary biliary cirrhosis; DPCA, D-penicillamine. From the Division of 1 Gastroenterology and Internal Medicine, 2 Depart-sults have been reported previously. 11