In this clinicopathological study, we have examined the prevalence of biochemical and histological graft abnormalities in 116 patients who have lived for longer than five years since orthotopic liver transplantation (mean, 8.4 years [range, 5.2-19.5 years]). In each patient, the protocol biopsy was carried out in addition to full clinical, biochemical, and immunological evaluation. The renal function was preserved in most patients (mean creatinine, 86 mu mol/L [0.95 mg%]) with only 35% showing any degree of impairment, and only one patient with pretransplant renal failure required dialysis, Forty one (35%) of the patients had normal biochemical liver function tests (LFTs); 19 of these patients had histologic abnormalities. Of the remaining 75 patients with abnormal LFTs, 65 were found to have histological abnormalities on liver biopsy. Some of the 84 patients with an abnormal histology had more than one finding but were placed into 6 categories according to the main change as follows: chronic hepatitis in 27; primary biliary cirrhosis-like changes in 8; cholangitis in 15; structural anomalies in 26; chronic rejection in 2; mild acute cellular rejection in 1; and miscellaneous in 5. The recurrence of B, C, or autoimmune hepatitis accounted for 14 cases of chronic hepatitis, whereas, in 13 cases, no cause could be detected. The latter cases included 8 patients who had liver transplants for primary biliary cirrhosis (PBC), leaving suboptimally treated rejection or disease recurrence as possible causes. Characteristic histological features of PBC were observed in 8 additional cases that had liver transplantations for this disease. Of the 26 cases with structural anomalies, various types of occlusive vasculopathy were detected during pre- or posttransplantation in 12 cases. All but one of these were maintained on azathioprine, the only possible etiological factor in the 14 other cases, 5 of whom showed stabilization or clinical and histological improvement following withdrawal of the drug, De-novo malignancy was seen in 3.4% of cases, causing mortality in only one patient to date. This study demonstrates an unexpectedly high prevalence of histological abnormalities that is found often in the presence of normal biochemical liver-function in liver grafts of long-term survivors. Although graft loss at this time is rare, protocol liver biopsies at 5 years, and thereafter at 2-year intervals, may allow for earlier beneficial therapeutic intervention.
