Hepatobiliary Disorder

Sequential steps in causality assessment are outlined in Fig. 1. Complete clinical data, including serial laboratory test results together with the local ULN values, were extracted from the clinical records and entered into a 65-page case report form (CRF). To exclude conditions that can mimic drug-induced liver disease, the patients and their medical records were screened for previous liver disease, alcohol use, serological and virological evidence of hepatitis A, B, or C infection, autoantibodies, ceruloplasmin, alpha-1-antitrypsin, ferritin, and iron; additionally, results of imaging studies were reviewed. Patients who had not been fully evaluated when they were first identified underwent testing for any missing laboratory data at enrollment. Liver biopsy was not required for adjudication purposes, but if it was performed as part of routine clinical care, the results were collected and made available to reviewers. To facilitate adjudication, the extensive database was summarized in an abbreviated CRF that included such key elements as the date of onset of liver injury, complete information about all medications taken within 6 months of onset of the event, the presence of symptoms and signs of liver disease, pertinent past medical history, complete laboratory tests, imaging and liver biopsy results, and serial results for ALT, AST, AP, serum bilirubin, and the prothrombin time or INR.
In addition to the short CRF summary, a succinct case summary called the clinical narrative was completed by the study investigator who enrolled the subject. The narrative provided detailed information on the history and chronology of the illness with dates of drug initiation and liver disease onset, pertinent features of the liver disease, and the time to improvement or recovery. The narrative also included information on past use of the implicated agent and significant concomitant drugs, the past medical history, the extent of alcohol use, whether there had been an episode of hypotension, and information on the course of the illness, including hospitalization, a history of hepatic decompensation or organ failure, and death or liver transplantation. Finally, the investigator provided a rationale for ascribing the event to a specific medication or medications without offering a personal view on the estimated strength of the association.

The PHS II was a randomized, double-blind, placebo-controlled, 2×2×2×2 factorial trial evaluating the balance of risks and benefits of vitamin E (400 IU synthetic α-tocopherol or its placebo on alternate days; BASF Corporation), vitamin C (500 mg synthetic ascorbic acid or its placebo daily; BASF Corporation), and a multivitamin (Centrum Silver or its placebo daily; Wyeth Pharmaceuticals) in the prevention of cancer and CVD among 14,641 male physicians aged ≥50 years.37 (link) A fourth randomized component, β-carotene (50 mg Lurotin or placebo on alternate days; BASF Corporation), was scheduled to stop in March 2003, while the Data and Safety Monitoring Board recommended that the vitamin E, C, and multivitamin components continue.
The PHS II study design has previously been described.37 (link) Recruitment, enrollment, and randomization of men into PHS II occurred in two phases (Figure 1). Starting in July 1997, 18,763 living PHS I participants38 (link), 39 (link) were invited to participate in PHS II. Men were ineligible if they reported a history of cirrhosis, active liver disease, were on anticoagulants, or reported a serious illness that might preclude participation. Men with a history of myocardial infarction (MI), stroke, or cancer were eligible to enroll in PHS II. Subjects also must have been willing to forego during the course of PHS II any current use of multivitamins or individual supplements containing more than 100% of the RDA of vitamin E, vitamin C, β-carotene, or vitamin A. A total of 7,641 (41%) willing participants from PHS I were randomized into PHS II and retained their original β-carotene treatment assignment.
In 1999, invitational letters and baseline questionnaires were mailed to 254,597 US male physicians aged ≥50 years identified from a list provided by the American Medical Association, excluding PHS I participants. Between July 1999 and July 2001, 42,150 men completed a baseline questionnaire. Of these, 16,743 participants were willing to participate in PHS II, of whom 11,128 were eligible following the same eligibility criteria as PHS I participants. A 12-week run-in period excluded non-compliers who typically emerge during the first several months of participation.40 (link) Of 11,128 physicians who entered the run-in phase, 7,000 (63%) willing and eligible men took at least two-thirds of their pills and were randomized into PHS II.
Thus, 14,641 men (7,641 from PHS I and 7,000 new physicians) were randomized into PHS II in blocks of 16, stratified by age, prior diagnosis of CVD, prior diagnosis of cancer, and, for the 7,641 PHS I participants, their original β-carotene treatment assignment. Men were randomly assigned to vitamin E or its placebo, to vitamin C or its placebo, and to active or placebo β-carotene and multivitamin. There were 754 (5.1%) men with prevalent CVD (nonfatal MI and stroke) randomized into PHS II. All participants provided informed consent and the Institutional Review Board at Brigham and Women’s Hospital approved the research protocol.