Patricia A. Sheiner

Hepatitis C is the most common cause of end-stage liver disease leading to liver transplant. The disease can recur after transplant, resulting in clinical hepatitis in up to 75% of patients and severe disease in approximately 7%. Treatment of rejection with steroid boluses and treatment of steroid-resistant rejection with OKT3 have both been shown to increase the incidence of recurrent hepatitis C. The use of OKT3 for steroid-resistant rejection is reportedly associated with more severe recurrence. The calcineurin inhibitors tacrolimus and cyclosporine have not been conclusively associated with different rates or severity of recurrence. Viral levels rise 10- to 15-fold after transplant and appear to be associated with the use of immunosuppression. Studies suggest that high viral levels, either pretransplant or early after transplant, may be associated with severe recurrent disease. Although the role of genotype is still unclear, genotype 1b is known to be associated with a poorer prognosis in nontransplanted patients and a lesser response to treatment than other genotypes. Furthermore, some reports suggest that after transplant, recurrent disease may progress more rapidly in patients with genotype 1. Treatment options after recurrence remain poor. Neither interferon nor ribavirin alone provides any true benefit. Combination therapy appears to have a better short-term outcome but may be poorly tolerated, and long-term benefits are unknown. Prophylaxis with combination therapy may be a better option but requires further study. Finally, retransplantation for recurrent hepatitis C is complicated not by rapid recurrence of disease in the new allograft but by high perioperative mortality that may be predicted by the presence of renal failure or sepsis preretransplant.

Publications about liver transplantation (LTX) for autoimmune hepatitis (AIH) have started to emerge, but many issues remain unresolved. We reviewed data on 32 patients transplanted for AIH to determine how pretransplantation and posttransplantation characteristics correlate with recipient outcome, including disease recurrence. Recipients were 37± 14 years old; 30 of 32 were women. Most had chronic disease (8 ± 6 years); 25% had fulminant failure. The majority had ascites (91%), jaundice (88%), elevated prothrombin time (18 ± 3 seconds), and hypoalbuminemia (2.7 ± 0.6 g/dL). All had hypergammaglobulinemia (3.0 ± 1.0 g/dL) and autoantibodies (72% antinuclear, 74% smooth muscle). Only one was HLA A1-B8-DR3 positive. Other autoimmune disorders affected 25% of patients; half improved after transplantation. Actuarial survival was 81% at 1 and 2 years posttransplantation. There was a high frequency of rejection (75% of recipients had 1.7 ± 0.8 episodes), and 39% of rejections required OKT3. Among 24 recipients with long-term follow-up (27 ± 14 months), histologically proven recurrent AIH occurred in 25%, 15 ± 2 months posttransplantation; half (3 patients) required retransplantation 11 ± 3 months after diagnosis. After retransplantation 2 of 3 patients had re-recurrence within 3 months; 1 received a third LTx. Recurrence occurred in 6 of 18 patients transplanted for chronic disease vs. 0 of 6 transplanted as fulminants (P = not significant [NS]). Patients with and without recurrence had similar rejection profiles. In summary, results of LTx for AIH are excellent. However, AIH patients have a high frequency of rejection and often require OKT3. Furthermore, severe recurrent AIH sometimes develops, particularly in chronic versus fulminant AIH patients and in those already retransplanted for recurrence. Multicenter studies could elucidate the best posttransplantation immunosuppressive regimens for AIH patients.

Background. Short-term outcomes of liver transplantation are well reported. Little is known, however, about long-term results in liver recipients surviving ≥5 years. We sought to analyze long-term complications in liver recipients surviving ≥5 years after transplant, to assess their medical condition and to compare findings to the general population. Methods. We analyzed the chart and database records of all patients (n=139) who underwent liver transplantation at a major transplant center before January 1, 1991. Outcome measures included the presence of diabetes, hypertension, heart, renal or neurological disease, osteoporosis, incidence of de novo malignancy or fracture, or other pathology, body mass index, serum cholesterol and glucose, liver function, blood pressure, frequency of laboratory and clinic follow-up, current pharmacological regimen, and late rejection episodes. Results. Ninety-six patients (70%) survived ≥5 years. Compared to numbers expected based on U.S. population rates, transplant recipients had significantly higher overall prevalences of hypertension (standardized prevalence ratio [SPR]=3.07, 95% confidence interval [CI], 2.35–3.93) and diabetes (SPR=5.99, 95% CI, 4.15–8.38), and higher incidences of de novo malignancy (standardized incidence ratio [SIR]=3.94, 95% CI, 2.09–6.73), non-Hodgkin’s lymphoma (SIR=28.56, 95% CI, 7.68–73.11), non-melanoma skin cancer (estimated SIR≥3.16) and fractures in women (SIR=2.05, 95% CI, 1.12–3.43). Forty-one of 87 (47.1%) patients were obese, and 23 patients (27.4%) had elevated serum cholesterol levels (≥240 mg/dl, 6.22 mmol/L), compared to 33% and 19.5% of U.S. adults, respectively. Prevalences of heart or peptic ulcer disease were not significantly higher. Conclusions. Liver transplantation is being performed with excellent 5-year survival. Significant co-morbidities exist, however, which appear to be related to long-term immunosuppression.

In liver transplant (LTx) recipients, gut-associated bacterial and fungal organisms produce significant postoperative morbidity and mortality. We sought to assess the role of selective digestive decontamination (SDD) in preventing postoperative infections in a large single-center cohort of liver recipients transplanted under two non-simultaneous protocols. In 212 consecutive patients transplanted between 1/1/91 and 7/31/92, SDD (gentamicin 80 mg, polymyxin B 100 mg, nystatin suspension 10 mL) was employed, starting after induction of anesthesia and continued until POD 21 (SDD Group). In 157 consecutive patients transplanted between 1/1/93 and 12/31/93, SDD was not used (non-SDD Group). Both groups received IV vancomycin and cefotaxime prophylaxis. All culture-positive infections within the first 30 days post-LTx were recorded and classified as bacterial or fungal. Infection-related mortality (patients who died of infectious complications without any technical complication) was recorded. Groups did not differ in patient demographics, United Network for Organ Sharing (UNOS) status, use of veno-venous bypass, total/warm ischemia, or length of ICU stay. Infections developed in fewer SDD patients (56/212; 26%) than non-SDD patients (69/157; 44%) (p<0.001). The incidence of gram-negative infection was less in the SDD group (11% vs. 26%, p<0. 001) as was gram-positive infection (16% vs. 26%, p<0.001). Among patients who developed infection, there was no difference between groups in infections per patient. Primary graft non-function (PNF) developed in 20 SDD patients (7/20 had infections) and 8 non-SDD patients (6/8 had infections) (p=0.06). There were no differences in incidence of fungal infections or of infection-related mortality between groups. In the SDD group, there were fewer abdominal (p<0. 001), lung (p<0.001), wound (p<0.01), and urinary tract infections (p<0.05). Use of SDD in liver recipients early after transplant was associated with significantly fewer infections in the early postoperative period.

Nearly 2000 liver transplants have been performed over the past 12 years at Mount Sinai, with a recent exponential growth in living donor surgeries. Living-donor liver transplantation has emerged as an important option for our patients with end-stage liver disease. We are only beginning to recognize fully the advantages that 'scheduled' liver transplantation can offer. In this era of severe cadaver organ shortages, living donation offers patients the option of liver replacement in a timely fashion, before life-threatening complications of hepatic failure and/or carcinoma progression prohibit transplantation. The next era of transplantation at Mount Sinai will bring significant increases in the number of transplants performed with living donors, with projections of over 50% of the total transplants each year expected to involve living donations. We are committed to offering this option while recognizing that donor safety remains paramount and cannot be overemphasized. Proper donor and recipient selection, as well as surgical experience are imperative to success with this technically demanding procedure. Recurrent disease after transplantation, particularly with hepatitis C, remains a challenge clinically. Further investigations into the pathogenesis of the rapid progression of recurrent hepatitis C need to be addressed. Living donor transplantation could be an important option for these patients and would allow timely transplantation and the potential for improved survival in patients with hepatocellular carcinoma.

Organ transplant recipients are at higher risk for developing lymphoid tumors, skin carcinomas, and sarcomas. Whether liver transplant recipients are at higher risk for developing more common cancers is unclear. All patients with a history of malignancy prior to liver transplantation and those who developed malignancy, either de novo or recurrent, after transplantation were identified retrospectively. The following parameters were examined: age at diagnosis; indication for transplant; interval from transplant to tumor diagnosis; tumor treatment received; predisposing factors for the development of cancer; immunosuppression regimen, including the use of OKT3; number and treatment of rejection episodes; and survival. Of 888 patients, 29 (3.2%) had 31 previous malignancies; of these 29 patients, 4 developed a recurrence in the posttransplant period. Thirty-nine patients (4.3%) developed 43 de novo nonlymphoid malignancies. Alcoholic cirrhotic patients had a significantly higher incidence of de novo carcinomas. Except for skin carcinomas, tumors did not occur with greater frequency than in the general population, and recurrent tumors were not more aggressive than reported for that disease. One patient had an unrecognized renal cell carcinoma at the time of transplant that progressed rapidly; this patient died 64 days after transplantation. With current immunosuppressive regimens, liver transplant patients do not appear to be at an increased risk for developing nonlymphoid solid organ tumors. However, longer follow-up will be necessary to confirm these results.

The hepatotoxic effects of isoniazid have been well described, but there have been no reports on the incidence of isoniazid-induced liver disease in patients who have received an orthotopic liver transplant. We retrospectively reviewed the records of 13 patients who received isoniazid after liver transplantation for either chemoprophylaxis or as part of a multidrug regimen for the treatment of Mycobacterium tuberculosis infection. Five of the 13 patients developed biochemical and histologic evidence of isoniazid hepatotoxicity. All five patients were on a multidrug regimen which included the administration of rifampin. No hepatotoxicity occurred in patients who received isoniazid alone or in conjunction with ethambutol for chemoprophylaxis. In conclusion, the incidence of isoniazid hepatotoxicity increased when the drug was used in conjunction with rifampin for the treatment of M. tuberculosis infection.