Current concepts on cytomegalovirus infection after liver transplantation

Cytomegalovirus (CMV) is the most common viral pathogen that negatively impacts on the outcome of liver transplantation. CMV cause febrile illness often accompanied by bone marrow suppression, and in some cases, invades tissues including the transplanted allograft. In addition, CMV has been significantly associated with an increased predisposition to allograft rejection, accelerated hepatitis C recurrence, and other opportunistic infections, as well as reduced overall patient and allograft survival. To negate the adverse effects of CMV on outcome, its prevention, whether through antiviral prophylaxis or preemptive therapy, is regarded as an essential component to the medical management of liver transplant patients. Two recent guidelines have suggested that antiviral prophylaxis or preemptive therapy are similarly effective in preventing CMV disease in modest-risk CMV-seropositive liver transplant recipients, while antiviral prophylaxis is the preferred strategy over preemptive therapy for the prevention of CMV disease in high-risk recipients [CMV-seronegative recipients of liver allografts from CMV-seropositive donors (D+/R-)]. However, antiviral prophylaxis has only delayed the onset of CMV disease in many CMV D+/R- liver transplant recipients, and at least in one study, such occurrence of late-onset primary CMV disease was significantly associated with increased mortality after liver transplantation. Therefore, optimized strategies for prevention are needed, and aggressive treatment of CMV infection and disease should be pursued. The standard treatment of CMV disease consists of intravenous ganciclovir or oral valganciclovir, and if feasible, one should also reduce the degree of immunosuppression. In one recent controlled clinical trial, valganciclovir was found to be as effective and safe as intravenous ganciclovir for the treatment of mild to moderate CMV disease in solid organ (including liver) transplant recipients. In this article, the authors review the current state and the future perspectives of prevention and treatment of CMV disease after liver transplantation.     

Risk factors of cytomegalovirus infection after living donor liver transplantation

BACKGROUND/AIMS: Cytomegalovirus (CMV) infection is one of the most common infectious diseases complicating liver transplantation. Data regarding the incidence and results after CMV infection or disease after living donor liver transplantation, however, are limited. METHODOLOGY: A total of 169 patients who underwent living donor liver transplantation in. our department were enrolled in the study. All of the patients were preemptively treated with intravenous ganciclovir (10mg/kg/d) when the pp65 antigenemia assay was positive. The incidence of CMV infection and disease, and risk factors for CMV infection were evaluated. RESULTS: The incidence of CMV infection and CMV disease was 44% and 3%, respectively. Acute rejection was significantly associated with CMV infection. CONCLUSIONS: The incidence of CMV disease was low, suggesting that our strategy might be effective for preventing the development of CMV disease.     

Low incidence of cytomegalovirus disease in liver transplant recipients receiving sirolimus primary immunosuppression with 3-day corticosteroid taper

BACKGROUND: Cytomegalovirus (CMV) disease is the most common infection following liver transplantation, occurring in approximately 20% of recipients. In liver transplant recipients, CMV is associated with a higher cost following transplantation, subsequent infections, and recurrent hepatitis C. Since we have initiated a prednisone-free immunosuppressive regimen in January 2000, we have noted an extremely low incidence of CMV disease in our cohort of liver transplant recipients. We report our findings here. METHODS: All 150 patients transplanted between January 2000 and December 2002 with tacrolimus (or cyclosporin A) and sirolimus, and 3-day corticosteroid taper were retrospectively analyzed. Recipients who were CMV IgG negative with a CMV IgG-positive donor ("CMV mismatch") received conventional prophylactic therapy with intravenous and oral ganciclovir. The incidence of CMV disease (defined as positive tissue culture or positive immunohistochemical stain of affected tissue or CMV-DNA >3000 associated with clinical symptoms) was recorded for each patient. RESULTS: The proportion of "CMV mismatches" (donor CMV IgG positive, recipient CMV IgG negative) was 15%. The mean total number of days of ganciclovir prophylaxis (intravenous and/or oral) administered to "CMV mismatch" patients was 45.6 days. The incidence of CMV disease in patients receiving sirolimus primary immunosuppression was 2%. The mean time to diagnosis of CMV disease was 139 days. CONCLUSIONS: (1) The incidence of CMV disease is very low using a prednisone-free, sirolimus immunosuppressive regimen. (2) Two possible explanations for this finding include appropriate prophylaxis with ganciclovir and low levels of immunosuppression including the absence of prednisone.     

Management of cytomegalovirus infection and disease in liver transplant recipients

Cytomegalovirus(CMV) is one of the most common viral pathogens causing clinical disease in liver transplant recipients, and contributing to substantial morbidity and occasional mortality. CMV causes febrile illness often accompanied by bone marrow suppression, and in some cases, invades tissues including the transplanted liver allograft. In addition, CMV has been significantly associated with an increased predisposition to acute and chronic allograft rejection, accelerated hepatitis C recurrence, and other opportunistic infections, as well as reduced overall patient and allograft survival. To negate the adverse effects of CMV infection on transplant outcome, its prevention, whether through antiviral prophylaxis or preemptive therapy, is an essential component to the management of liver transplant recipients. Two recently updated guidelines have suggested that antiviral prophylaxis or preemptive therapy are similarly effective in preventing CMV disease in modest-risk CMV-seropositive liver transplant recipients, while antiviral prophylaxis is the preferredstrategy over preemptive therapy for the prevention of CMV disease in high-risk recipients [CMV-seronegative recipients of liver allografts from CMV-seropositive donors(D+/R-)]. However, antiviral prophylaxis has only delayed the onset of CMV disease in many CMV D+/Rliver transplant recipients, and such occurrence of lateonset CMV disease was significantly associated with increased all-cause and infection-related mortality after liver transplantation. Therefore, a search for better strategies for prevention, such as prolonged duration of antiviral prophylaxis, a hybrid approach(antiviral prophylaxis followed by preemptive therapy), or the use of immunologic measures to guide antiviral prophylaxis has been suggested to prevent late-onset CMV disease. The standard treatment of CMV disease consists of intravenous ganciclovir or oral valganciclovir, and if feasible, reduction in pharmacologic immunosuppression. In one clinical trial, oral valganciclovir was as effective as intravenous ganciclovir for the treatment of mild to moderate CMV disease in solid organ(including liver) transplant recipients. The aim of this article is to provide a state-of-the art review of the epidemiology, diagnosis, prevention, and treatment of CMV infection and disease after liver transplantation.     

Cytomegalovirus infection in liver-transplanted children

Cytomegalovirus (CMV) infection is a common complication of liver trans-plantation in children. The CMV serostatus of recipients and donors is the primary risk factor, and prophylaxis or pre-emptive strategies are recommended for high-risk patients. Graft rejection, coinfection and Epstein-Bar virus reactivation, which can lead to post-transplant lymphoproliferative disease, are indirect effects of CMV infection. Assessment of CMV infection viral load should be routinely performed upon clinical suspicion. However, tissue-invasive CMV disease is not associated with CMV viraemia and requires confirmation by tissue pathology. Oral valganciclovir and intravenous ganciclovir are equivalent treatments, and the duration of treatment depends on factors including CMV viral load, tissue pathology, and clinical response. Risk stratification by donor and recipient status prior to transplantation and post-transplantation antiviral prophylaxis or pre-emptive therapy are recommended. Adult guidelines have been established but additional study of the effectiveness of the preventive guidelines in children is needed. This review summarizes the burden, risk factors, clinical manifestations, laboratory evaluation, treatment, and prevention of CMV infection in children after liver transplantation.     

Cytomegalovirus infection/disease after hematopoietic stem cell transplantation

Cytomegalovirus (CMV) disease has historically been a main cause of death after allogeneic hematopoietic stem cell transplantation (HSCT). Since the introduction of prophylactic or preemptive therapy against CMV, the incidence of CMV disease has been successfully reduced. However, breakthrough CMV disease, particularly CMV gastrointestinal disease, remains one of the major infectious complications. Administration of an antiviral agent, ganciclovir, is often associated with myelotoxicity in HSCT recipients, and delayed immune reconstitution against CMV. Delayed immune reconstitution is a possible cause of the increasing incidence of late (more than 3 months after transplant) CMV disease after HSCT in this era of preemptive therapy. Foscarnet and valganciclovir are the available alternatives to intravenous ganciclovir. Foscarnet is not myelotoxic and has a toxicity profile different from ganciclovir. Valganciclovir, a prodrug of ganciclovir, has a higher bioavailability than oral ganciclovir and could be of clinical use, particularly in the outpatient setting or for patients requiring long-term antiviral therapy. Recent technological developments have enabled the visualization and isolation of CMV-specific T cells. Using these techniques, an individualized approach could be conducted based on each patient’s immune reconstitution against CMV. In this review, we summarize the recent progress and current knowledge of CMV infection and disease after allogeneic HSCT.     

Deficiency of cytomegalovirus (CMV)-specific CD8+ T cells in patients presenting with late-onset CMV disease several years after transplantation

Abstract: Cytomegalovirus (CMV) is a major cause of morbidity and mortality among transplant recipients. The routine use of anti-CMV prophylaxis has modified the epidemiology of post-transplant CMV infection by delaying the onset of clinical disease. While the majority of delayed-onset CMV disease still occurs during the first year after transplant, reports of late-onset CMV disease presenting many years after transplantation are increasing. Here, we describe 2 CMV-seropositive transplant recipients who presented with late-onset CMV disease at 8 and 11 years after transplantation. To determine whether CMV disease occurring at a very late period after transplantation is related to immune competence, we assessed global and CMV-specific cellular immunity by evaluating the activation capability of CD8+ T cells to a mitogenic stimulus and by quantitative and functional analysis (as assessed by intracellular cytokine production and degranulation) of CMV-specific CD8+ T cells. In both patients, we demonstrated the absence or marked deficiency of CMV-specific T-cell immunity despite CMV seropositivity, and in one patient, a partial defect in the immune response to phorbol myristate acetate and ionomycin suggesting impaired global immune competence. Hence, our data suggest that late-onset CMV disease occurring many years after transplantation remains related to defects in the immune competence of patients. Measurement of CMV-specific cellular immune competence may therefore provide an additional tool to screen for patients at high risk of developing late-onset CMV disease. The clinical utility of this assay, however, will need to be evaluated in larger prospective studies.     

Cytomegalovirus infection after liver transplantation： Current concepts and challenges

Cytomegalovirus （CMV） is a common viral pathogen that influences the outcome of liver transplantation. In addition to the direct effects of CMV syndrome and tissue-invasive diseases, CMV is associated with an increased predisposition to acute and chronic allograft rejection, accelerated hepatitis C recurrence, and other opportunistic infections, as well as reduced overall patient and allograft survival. Risk factors for CMV disease are often interrelated, and include CMV D＋/R- serostatus, acute rejection, female gender, age, use of high-dose mycophenolate mofetil and prednisone, and the overall state of immunity. In addition to the role of CMV-specific CD4＋ and CD8＋ T lymphocytes, there are data to suggest that functionality of the innate immune system contributes to CMV disease pathogenesis. In one study, liver transplant recipients with a specific polymorphism in innate immune molecules known as Toll-like receptors were more likely to develop higher levels of CMV replication and clinical disease. Because of the direct and indirect adverse effects of CMV disease, its prevention, whether through antiviral prophylaxis or preemptive therapy, is an essential component in improving the outcome of liver transplantation. In the majority of transplant centers, antiviral prophylaxis is the preferred strategy over preemptive therapy for the prevention of CMV disease in CMV-seronegative recipients of liver allografts from CMV-seropositive donors （D＋/R-）. However, the major drawback of antiviral prophylaxis is the occurrence of delayed-onset primary CMV disease. In several prospective and retrospective studies, the incidence of delayed-onset primary CMV disease ranged from 16% to 47% of CMV D＋/R- liver transplant recipients.Current data suggests that delayed-onset CMV disease is associated with increased mortality after liver transplantation. Therefore, optimized strategies for prevention and novel drugs with unique modes of action are needed. Currently, a randomized controlled clinical trial is being perf     

Immunohistochemically proven cytomegalovirus end-organ disease in solid organ transplant patients: clinical features and usefulness of conventional diagnostic tests

We studied the main clinical features, outcome, and laboratory parameters in a group of solid organ transplant (SOT) patients with immunohistochemically proven cytomegalovirus (CMV) disease. Confirmed CMV cases were obtained through databases. Demographics, clinical data, transplantation type, immunosuppressive regimens, donor and recipient CMV serostatus, therapy, outcome and laboratory results, pp65 antigenemia, and qualitative polymerase chain reaction (PCR) for CMV were analyzed. From 1995 to 2004, 31 cases with complete medical records were identified. Disease appeared between 24 and 2538 days after transplantation but most cases presented in the first 100 days. Gastrointestinal CMV disease was the most frequent form (71%), while thrombocytopenia was present in 50% of cases, and leukopenia was less common (35.5%). CMV pp65 antigenemia was positive in 58% of patients, but its sensitivity increased to 71% if performed during the first 6 months. A qualitative CMV PCR technique gave similar results during this period (71.4%). Most patients were treated with intravenous ganciclovir (n=25; 80.6%). In 4 cases (19.4%), use of foscarnet alone or a sequential regimen with ganciclovir-foscarnet was deemed necessary. Surgical procedures were necessary in 5 patients (16%). The death rate reached 13%. CMV end-organ disease can be a life-threatening infection in SOT patients. Gastrointestinal disease was the most frequent end-organ disease. CMV antigen detection is best suited for the early period after transplantation.     

Human herpesvirus 6 infections after liver transplantation

Human herpesvirus 6 （HHV-6） infections occur in 〉 95% of humans. Primary infection, which occurs in early childhood as an asymptomatic illness or manifested clinically as roseola infantum, leads to a state of subclinical viral persistence and latency. Reactivation of latent HHV-6 is common after liver transplantation, possibly induced and facilitated by allograft rejection and immunosuppressive therapy. Since the vast majority of humans harbor the virus in a latent state, HHV-6 infections after liver transplantation are believed to be mostly due to endogenous reactivation or superinfection （reactivation in the transplanted organ）. In a minority of cases, however, primary HHV-6 infection may occur when an HHV-6 negative individual receives a liver allograft from an HHV-6 positive donor. The vast majority of documented HHV-6 infections after liver transplantation are asymptomatic. In a minority of cases, HHV-6 has been implicated as a cause of febrile illness with rash and myelosuppression, hepatitis, pneumonitis, and encephalitis after liver transplantation. In addition, HHV-6 has been associated with a variety of indirect effects such as allograft rejection, and increased predisposition and severity of other infections including cytomegalovirus （CMV）, hepatitis C virus, and opportunistic fungi. Because of the uncommon nature of the clinical illnesses directly attributed to HHV-6, there is currently no recommended HHV-6- specific approach to prevention. However, ganciclovir and valganciclovir, which are primarily intended for the prevention of CMV disease, are also active against HHV-6 and may prevent its reactivation after transplantation. The treatment of established HHV-6 disease is usually with intravenous ganciclovir, cidofovir, or foscarnet, complemented by reduction in the degree of immunosuppression. This article reviews the current advances in the pathogenesis, clinical diagnosis, and therapeutic modalities against HHV6 in the setting of liver transplantation.     

Antral mass due to cytomegalovirus infection requiring gastrectomy in a liver transplant recipient

Abstract: The incidence of cytomegalovirus (CMV) infection after liver transplantation (LT) has decreased in recent years. Advances in immunosuppression and CMV prophylaxis have improved the management of CMV disease. Organ involvement is infrequent and gastrointestinal CMV disease is quite rare. Few cases of an antral mass due to CMV infection have been described; those reported to date have mostly been in patients with acquired immunodeficiency syndrome. We describe a case of a CMV‐seronegative liver transplant patient who received a seropositive liver graft. Owing to gastrointestinal complaints, CMV prophylaxis was stopped one month after LT. The patient developed an antral mass due to CMV infection and an anastomotic biliary stricture. Antigenemia became negative with ganciclovir, but this treatment did not eliminate the mass. Ganciclovir resistance was ruled out as well as other causes of antral mass, especially malignancy. The patient finally required gastrectomy and hepaticojejunostomy. We conclude that CMV disease is less common today but should be included in the diagnosis of gastrointestinal mass after transplantation.     

Impact of cytomegalovirus reactivation just before liver transplantation: A prospective cohort study

BACKGROUNDCytomegalovirus (CMV) is the most common viral pathogen after liver transplantation (LT). Although reactivation of CMV infection is generally described in the context of immunosuppression, it has also been described in critically ill immunocompetent patients including cirrhotic patients.AIMTo determine the incidence of reactivated CMV prior to LT.METHODSThis was a prospective cohort study evaluating adult patients who underwent LT between 2014 and 2016. A plasma sample was obtained from all patients for CMV quantitative real-time PCR testing right before transplantation. Patients were followed for at least 1 year to assess the following outcomes: Incidence of CMV infection, organ rejection and overall mortality. RESULTSA total of 72 patients were enrolled. Four patients died before transplantation, thus 68 patients were followed up for a median of 44 mo (20-50 mo). In 23/72 patients (31.9%) CMV was reactivated before transplantation. Post-transplantation, 16/68 (23.5%) patients had CMV infection and that was significantly associated with the recipient being CMV negative and a CMV-positive donor. Pre-transplant CMV reactivation was not associated with overall mortality (log rank: 0.9).CONCLUSIONThis study shows that CMV infection is common in patients with chronic liver disease just before LT, but the clinical impact of this infection seems to be negligible.     

Cytomegalovirus disease in the highly active antiretroviral therapy era

Cytomegalovirus (CMV) is a major cause of morbidity and mortality in AIDS patients. Epidemiologic studies indicate that until 10 years ago, nearly one half of HIV-infected patients eventually developed CMV end-organ disease, including chorioretinitis, esophagitis, colitis, pneumonia, and central nervous system disease. Since the introduction of highly active antiretroviral therapy (HAART) this incidence has declined dramatically. Nonetheless, patients still present with CMV disease and resistance or intolerance to HAART does develop, which may give rise to a resurgence of CMV syndromes in AIDS patients. Until recently, only intravenous ganciclovir and foscarnet were available for management of CMV infection. With the advent of additional agents, clinicians now face the challenge of optimizing therapy for individual patients. This paper reviews the most common clinical syndromes caused by CMV, the treatment options, as well as an approach to diagnosing and treating antiviral resistance.     

CMV infection of liver transplant recipients: comparison of antigenemia and molecular biology assays

Background  

CMV is a major clinical problem in transplant recipients. Thus, it is important to use sensitive and specific diagnostic techniques to rapidly and accurately detect CMV infection and identify patients at risk of developing CMV disease. In the present study, CMV infection after liver transplantation was monitored retrospectively by two molecular biology assays - a quantitative PCR assay and a qualitative NASBA assay. The results were compared with those obtained by prospective pp65 antigenemia determinations.     

Clinical features and outcomes of cytomegalovirus retinitis after transplantation.

Cytomegalovirus (CMV) infection of the retina is a rarely encountered end-organ disease after transplantation. In order to describe the clinical characteristics and outcomes of CMV retinitis after hematopoietic stem cell and solid organ transplantation, we performed a retrospective review of all cases of CMV retinitis at the Mayo Clinic (Rochester, Minnesota) during 1990-2004. During this 15-year period, CMV retinitis was diagnosed in 14 eyes of 9 patients who had received kidney (n=5), liver (n=2), heart (n=1), and autologous hematopoietic stem cell transplant (n=1). The mean age of the patients was 58 (standard deviation+/-11) years; 6 were male. The median time to diagnosis of CMV retinitis was 9 months (range, 4 months to 13 years) after transplantation. Four (44%) patients had concomitant pneumonitis or hepatitis. Five (55%) patients had bilateral retinitis. Retinal involvement was 10% but 50% in 2 eyes. All patients received induction therapy with intravenous ganciclovir (n=8) or foscarnet (n=1) for a median of 43 days (range, 14-100 days) followed by maintenance therapy with intravenous or oral ganciclovir for a median of 88 days (range, 36-943 days) in 6 (67%) patients. One patient developed bilateral immune recovery uveitis during treatment, and later on progressed to develop rhegmatogenous retinal detachment. During the mean follow-up period of 20 months, visual acuity improved in 4 (28.5%), was stable in 4 (28.5%), and worsened in 6 (43%) eyes. CMV retinitis recurred in 2 patients. In conclusion, CMV retinitis is a rare, progressive, and highly morbid infectious complication of transplantation. The severity of clinical disease at the time of diagnosis may predict poor outcome. Hence, early intervention may be crucial to prevent its progression to irreversible visual loss.     

Intestinal transplantation in The Netherlands: first experience and future perspectives

Intestinal transplantation for intestinal failure is no longer an experimental procedure, but an accepted treatment for patients who fail total parenteral nutrition (TPN) therapy. Early referral for evaluation for small bowel transplantation has to be considered in patients with permanent intestinal failure who have occlusion of more than two major veins, frequent line-related septic episodes, impairment of liver function or an unacceptable quality of life. With the increased experience in post-transplant patient care and newer forms of induction (thymoglobulin, IL-2 receptor antagonists) and maintenance (tacrolimus) therapies the 1-year graft survival has increased to 65% for isolated and to 59% for liver/small bowel transplantation, and is further improving. Rejection, bacterial, fungal and viral (CMV, EBV) infection, post-transplant lymphoproliferative disease (PTLD) and graft versus host disease (GvHD) are the most common complications after intestinal transplantation. Although most of the long-term survivors are TPN-independent and have a good quality of life, the risk of the procedure and long-term adverse effects of immunosuppressive medication limits small bowel, or liver/small bowel transplantation only to patients with severe complications of TPN therapy.     

Preemptive therapy is not adequate for prevention of cytomegalovirus disease in pancreas–kidney transplant recipients

Background. Cytomegalovirus (CMV) remains the most common viral infection after pancreas–kidney transplantation (PKT). Comparative studies about CMV prophylaxis in PKT have not been developed.
Methods. We analyzed CMV disease in a cohort of 84 PKT recipients. All received intravenous ganciclovir during treatment with anti-thymocyte globulin and later one of the following options for pre-transplant CMV-seropositive recipients: (a) no prophylaxis ( n =10 patients), (b) preemptive therapy (PT) ( n =13), or (c) continuous prophylaxis (CP) for 12 weeks ( n =29). Pre-transplant CMV-seronegative recipients received CP ( n =21).
Results. Eleven patients were excluded because of organ explantation in the first 15 days. Incidence of CMV disease in seropositive recipients was 30% under no prophylaxis, 23% under PT, and 6.9% under CP. Incidence of CMV disease under CP was 33.3% in seronegative recipients. Six of 9 episodes of CMV disease under CP occurred after finishing prophylaxis. Under CP, the incidence of CMV disease was significantly higher in seronegative than in seropositive recipients ( P <0.05).
Conclusion. According to the results of our study, for CMV-seropositive PKT recipients, CP is a better strategy than PT. For CMV-seronegative recipients, 3 months of CP is an inadequate strategy.     

Prevention of cytomegalovirus disease in recipients of solid-organ transplants.

The introduction and combination of more-potent immunosuppressive regimens, and the increased transplantation of organs into more severely ill patients, have again placed cytomegalovirus (CMV) disease in the spotlight of posttransplantation complications. Both direct and associated complications related to CMV need to be considered in understanding the pathogenesis of CMV infection after solid-organ transplantation. New diagnostic methods with higher sensitivity for the detection of CMV and the ability to quantify CMV indicate that low levels of CMV replication are present in many patients who don't have clinical symptoms ascribed to CMV infection. How these low levels of CMV replication impact the outcome of the transplanted graft remains unknown. In addition, there needs to be further study regarding whether only patients at high risk for developing CMV disease or, also, those with clinically asymptomatic levels of CMV replication should be the target of effective preventive regimens. This review summarizes our current knowledge of the pathogenesis of CMV infection after solid-organ transplantation, and it outlines different effective preventive regimens and approaches.     

Preemptive use of oral ganciclovir to prevent cytomegalovirus infection in liver transplant patients: a randomized, placebo-controlled trial

The use of postdetection antiviral treatment of cytomegalovirus (CMV) as a strategy to prevent infection and disease in solid-organ transplant patients has not been evaluated by placebo-controlled trials. We carried out such a study in 69 patients who had received liver transplants and had positive results of CMV polymerase chain reaction within 8 weeks after transplantation but did not have concomitant CMV infection or disease. These patients were randomly assigned to receive placebo or oral ganciclovir for 8 weeks. CMV infection developed in 21% and disease developed in 12% of placebo recipients (P =.022), compared with 3% and 0%, respectively, among ganciclovir recipients (P =.003). Similarly, in the placebo arm, 55% and 36% of CMV-negative patients who received organs from CMV-positive donors developed CMV infection or disease, respectively (P =.02), compared with 11% and 0% of such patients in the ganciclovir arm (P <.01). Oral ganciclovir administered on CMV detection by PCR prevents CMV infection or disease after liver transplantation.     

Liver disease after bone marrow transplantation.

Liver dysfunction occurs after bone marrow transplantation but the relative importance of graft versus host disease and other factors, such as infection, radiation, and drugs, has not been clearly established. We have studied liver status before and after bone marrow transplantation in 43 consecutive patients and have related this to survival and factors that are recognised to cause liver injury. Minor abnormalities of liver tests occurred in 21% of patients before grafting but this did not influence survival or the development of liver disease after transplantation. During the first 50 days after grafting, 83% of patients had abnormal liver tests which were more severe in patients who subsequently died. Alanine transaminase was significantly higher in non-survivors and appeared to predict survival early after transplantation. Only non-survivors developed clinical signs of liver disease. Severe liver disease was always associated with graft versus host disease and atypia of the small bile ducts was the most useful histological marker of hepatic involvement with this disease. Two of the patients with hepatic graft versus host disease also has hepatic veno-occlusive disease and three fatalities had opportunistic infection of the liver, although, in the latter, death was not due primarily to liver dysfunction. Previous hepatitis and androgen therapy could not be implicated as important causes of hepatic damage but chemotherapy for acute leukaemia and conditioning regimens for bone marrow transplantation appear to be the most important factors in the development of hepatic veno-occlusive disease.