Graft-versus-host disease (GVHD) is an infrequent complication after liver transplantation (LT), with an incidence of 0.5% to 2%.1-3 Graft-versus-host disease occurs as a result of donor immunocompetent cells recognizing recipient antigens as foreign and mounting an immune response. Grafts containing more immunocompetent donor lymphocytes, such as hematopoietic stem cell, bone marrow, or peripheral blood stem cell transplantations, are associated with a high incidence of GVHD. Among solid organ transplants, intestinal transplantation has the highest incidence of GVHD, followed by LT; with lower rates of GVHD after kidney, heart, or pancreas transplantation.
The mortality rate for GVHD after LT has been reported to be up to 85%.1 In this article, we report a case series and a comprehensive review of the literature on GVHD after LT. The epidemiology, risk factors, clinical features, and treatment outcomes are described; and a diagnostic algorithm is proposed.
MATERIALS AND METHODS
University of Iowa Hospitals and Clinics Case Series
Medical records of all patients diagnosed with GVHD after LT at the University of Iowa Hospitals and Clinics (UIHC) were reviewed. Graft-versus-host disease cases were identified from a prospectively maintained list of complications after LT. Diagnosis of GVHD was established with skin and gastrointestinal biopsies. Histologic grading of skin and gastrointestinal GVHD was also performed (SDC, http://links.lww.com/TP/B327).4,5
Graft-versus-host disease was documented histologically in all patients. Donor chimerism, using a quantitative assay of short tandem DNA repeats (STR) in the cells of the skin, gastrointestinal mucosa, peripheral blood and/or bone marrow, was recorded when available. This study was approved by the University of Iowa Institutional Review Board.
Review of Literature on GVHD After LT
A comprehensive search of the databases of biomedical literature (Medline and Embase) was performed from 1988 (first case report of GVHD after LT) to 2014. The search strategy is described in Appendix 1. All case reports and case series of GVHD after LT in adults were reviewed. Reference lists of published reports were searched to find additional reports. Data on patient demographics, clinical findings, management, and outcomes were extracted. Data were extracted from the United Network for Organ Sharing database, until January 2015, for group comparisons between reported United States cases of GVHD after LT and all US LT patients.
Observations are reported as frequencies, and central tendencies are expressed as mean or median with standard deviation and interquartile range, based on the distribution of data. Categorical variables are reported as number and percent frequency of occurrence. Categorical data were compared using Pearson χ2 or Fisher exact test, where appropriate. All statistical testing was 2-sided and assessed for significance at the 5% level using SAS v9.4 (SAS Institute, Cary, NC).
UIHC Case Series
A total of 762 LT were performed in adults from 1988 to January 31, 2015. Five recipients (0.7%) developed GVHD. A summary of the case series at the University of Iowa has been provided in Table 1.
A 73-year-old diabetic man, with cirrhosis due to nonalcoholic steatohepatitis (NASH), underwent LT in June 2014. He presented 60 days after LT with fever, nausea, vomiting, diarrhea, and maculopapular rash (Figure 1). White blood cell (WBC) count was 1600/mm3; absolute neutrophil count (ANC), 1280/mm3; hemoglobin, 6.8 g/mm3; platelet count, 108 × 103/mm3; and ferritin, 2225 ng/mL. Skin biopsy showed vacuolar interface alteration of the dermal-epidermal junction, overlying lymphocytic infiltration, and scattered apoptotic keratinocytes (GVHD grade 2) (Figure 2). Colonoscopy showed normal colonic mucosa, but mucosal biopsies showed increased crypt epithelial apoptosis (GVHD grade 1) (Figure 3). The STR analysis revealed 21%, 6%, and 3% lymphocyte macrochimerism in the skin, colon, and peripheral blood, respectively. He was started on methylprednisolone 2 mg/kg per day, and his tacrolimus level was kept at 8 to 12 ng/mL. His course was complicated by multiple infections (cytomegalovirus viremia, cryptosporidiosis of the gastrointestinal tract, and lobar pneumonia), all managed medically, while continuing methylprednisolone at 2 mg/kg per day. Rash, gastrointestinal symptoms, and pancytopenia resolved, and peripheral blood macrochimerism decreased to 1%. He was discharged on prednisone 80 mg/d for 2 weeks and 60 mg/d for 2 more weeks, before presenting with fever, vomiting, and pancytopenia (WBC count 1000/mm3). Colonoscopy showed inflamed ulcerated mucosa; biopsies showed abundant apoptotic crypt epithelial cells and crypt dropout (GVHD grade 3). He was again treated with high-dose methylprednisolone, 2 mg/kg, while maintaining the same dose of calcineurin inhibitor (CNI). He developed pneumonia and septic shock and died 220 days after LT.
A 65-year-old diabetic man underwent LT for alcoholic cirrhosis and hepatocellular carcinoma (HCC) in March 2011. He presented 46 days after transplantation with maculopapular skin rash, fatigue, fever, diarrhea, weight loss, and modest leucopenia (WBC count, 2300/mm3; ANC, 1350/mm3). Ferritin was 799 ng/mL. Skin biopsy confirmed GVHD (grade 2). He was treated with methylprednisolone and tacrolimus dose increase. Skin and gastrointestinal symptoms improved, and WBC count rose to 6000/mm3. He was discharged on prednisone taper. Four weeks later, he returned with diarrhea, skin rash, septic arthritis (ankle), bacteremia, and WBC count of 900/mm3. Colonoscopy with biopsies showed extensive crypt dropout and denudation of epithelium (grade 4 GVHD). He had 41% donor lymphocytes in peripheral blood and 31% in the bone marrow. Ferritin was 20 333 ng/mL. Tacrolimus dose was decreased. Clinical features of GVHD worsened. Methylprednisolone was restarted; IVIG and the IL-1 antagonist, Anakinra, were added. He developed vancomycin-resistant enterococcal (VRE) bacteremia with septic shock and died 125 days after LT.
A 60-year-old diabetic man, with cirrhosis and HCC from alcoholic liver disease (ALD) and chronic hepatitis C, underwent LT in November 2011. He presented 117 days after LT with maculopapular skin rash (GVHD grade 2), fever, altered mental status, pancytopenia (WBC, 200/mm3; ANC, 0; hemoglobin, 8.1 g/dL; platelet count, 111 × 103 cells/mm3); and ferritin, 7232 ng/mL. The STR analysis of peripheral blood revealed 78% macrochimerism. Bone marrow biopsy was hypocellular, with 89% macrochimerism. He was treated with an IL-2 receptor blocker (basiliximab), antithymocyte globulin (ATG), methylprednisolone, and IVIG; and tacrolimus was increased to 12 to 16 ng/mL. Because of nonresponse to initial treatment, Anakinra was added, without improvement. He developed VRE bacteremia, septic shock and died 128 days after LT.
A 60-year-old diabetic man, with cirrhosis from ALD and hemochromatosis, underwent LT in 2002. He presented with maculopapular skin rash (GVHD histologic grade 2) and diarrhea (GVHD histologic grade 2) 85 days after LT. Complete blood count was normal. Peak serum ferritin was 733 ng/mL. He was treated with methylprednisolone, IVIG, and topical tacrolimus. Systemic tacrolimus and mycophenolate mofetil were continued at the same dosage. Skin rash and diarrhea resolved. Serum ferritin normalized. He was doing well at follow-up 10 years after LT.
A 65-year-old diabetic woman with primary biliary cholangitis underwent LT in February 1996. Induction immunosuppression regimen included methylprednisolone and tacrolimus. Fourteen days after LT, she developed maculopapular skin rash, altered mental status, pancytopenia (WBC 100/mm3, platelets 17 000/mm3) and septic shock. Skin biopsy was consistent with GVHD. Histologic grading and STR analysis were not performed. She succumbed to septic shock within 5 days of presentation, before she could be started on treatment for GVHD.
A summary of the case series has been provided in Table 1.
Review of Literature on GVHD After LT
A total of 80 articles reported 1 or more case, with a total of 156 cases of GVHD in adult LT recipients. Characteristics of reported cases are summarized in Table 2. Mean age at LT was 55 years, and 67.3% were men. Median time to GVHD onset from LT was 28 days (interquartile range, 21-38 days). The most common clinical features in patients with GVHD were skin rash (92%), followed by cytopenias (78%) and diarrhea (65%). Hepatocellular carcinoma (34.7%) was the most common indication for LT in patients who developed GVHD, followed by ALD (22.9%) and acute or chronic hepatitis B (19.5%). The presenting organ involvement for all patients with GVHD in the world and in the United States is reported in Table 2.
Data on outcome of GVHD management was reported in 138 patients; 73.2% died within 6 months of GVHD onset. There have been no prospective trials of treatment of GVHD after LT. This review found reports of treatment of GVHD after LT in 130 patients. In 8 patients (6.2%), immunosuppression was decreased,6-11 whereas immunosuppression was intensified in 122 patients (93.8%). Six-month mortality was 70.5% in patients who had increased immunosuppression and 62.5% in patients with decreased immunosuppression. This difference was not statistically significant (P = 0.68). The most frequently reported treatment regimen for GVHD after LT was high-dose steroids (ranging from 2 to 20 mg/kg per day). The number of patients treated and mortality rate associated with various treatments regimens are provided in Table 3.
The common causes of death in patients with GVHD after LT were sepsis, multiorgan failure, and gastrointestinal bleeding. In 61 cases (60.4%), sepsis was documented as cause of death. The causative organism was reported in 25 cases (41%); invasive aspergillosis was noted in 9 cases1,9,12,25,34,53,59,62 (36%), disseminated candidiasis in 7 (28%) (3 albicans, 1 kruseii, 1 glabrata and 2 unspecified species),1,9,71,72 enterococci in 7 (28%).1,26,32,60,73 and Enterobacter in 2 (8%).1,74
There were 66 reported cases of GVHD after LT from the US and these were compared to all other LT recipients in the United States, as accessed through the United Network for Organ Sharing (UNOS) database (Table 2). A significant association between age and GVHD was evident, where patients with GVHD were older than 50 years (P < 0.01). Sex was not a risk factor for development of GVHD. Higher GVHD incidence was noted in patients transplanted for HCC (21.6 % vs 13.0%), whereas chronic hepatitis C infection (HCV) was associated with a lower incidence of GVHD after LT, as compared with all other US patients in UNOS database (11.8% vs 29.9%) (Table 2).
There are 37 patients reported in the literature who survived GVHD after LT. The mean age of patients was 56.1 years, 83.3% were men, and mean time from LT to diagnosis of GVHD was 43.3 days (range, 13-80). The etiology of liver disease was ALD in 43% of patients; hepatitis B virus in 27%; NASH in 11%; HCV, PSC, and A1AT in 5% each; with primary biliary cholangitis and acute liver failure in 2% each. Fifty percent of these patients presented with skin involvement only, 21% with bone marrow involvement only, and 18% with both skin and gastrointestinal involvement. The treatment regimens of patients who survived GVHD after LT are provided in Table 4.
This systematic review demonstrates an association between GVHD after LT with recipient older than 50 years. Additional risk factors reported in the literature include donor-recipient age difference greater than 20 years, younger donor age, any HLA class I match, and glucose intolerance.2,76 Based on our results, GVHD may occur more frequently in patients transplanted for HCC and less frequently in patients transplanted for hepatitis C. Immune dysregulation plays a major role in the pathogenesis of HCC. Alterations in innate or adaptive immunity, for example, a decrease in CD4+ T lymphocyte function due to chronic inflammation (alcoholic or NASH), chronic infection (viral hepatitis), or suppression of immunity (cirrhosis), could cause tolerance to tumor antigen and promote the development of HCC.77 Furthermore, HCC itself may cause immune system dysfunction.77 It is possible that the immune dysregulation in the recipient that originally led to the development of HCC, or alterations in the immune system caused by HCC, may predispose to alloreactivity and development of GVHD after LT.13,78 Hepatitis C virus is known to inhibit T cell receptor-mediated signaling required for activation and effector functions of T cells.79 Whether HCV demonstrates the same effect on donor T lymphocytes, thereby decreasing the incidence of GVHD, is unclear.
Our review shows that GVHD usually develops 3 to 5 weeks after LT. Skin rash is erythematous, maculopapular, and can involve any part of the body including palms, soles, and the volar surfaces of extremities and trunk. Skin rashes may be subtle, nonpruritic, and not noticed by the patient. A very careful total-body skin examination in a well-lit room is recommended. Characteristic histologic features are vacuolar alteration at the dermoepidermal junction, apoptosis of keratinocytes in the epidermis, and lymphocyte exocytosis (Figure 2).
Graft-versus-host disease can affect all 3 hematopoietic cell lineages. The alloreactive donor lymphocytes engraft and proliferate in the recipient bone marrow, with subsequent immune-mediated attack on hematopoietic stem cells.
Cytopenia in the first few months after LT is common; infection (herpes virus, cytomegalovirus, Epstein Barr virus, and parvovirus B19) and medications (mycophenolate mofetil, valganciclovir, trimethoprim-sulfamethoxazole) are the usual culprits. In GVHD, the presence of cytopenia may be a poor prognostic indicator, and sepsis associated with leucopenia is a commonly reported cause of death.
Gastrointestinal manifestations are common in GVHD. Diarrhea is a common symptom in solid organ transplant recipients; up to 10% to 13% of patients have diarrhea in the first 4 posttransplant months.80,81 The common etiologies for diarrhea are infection (Clostridium difficile and cytomegalovirus colitis) and medications (mycophenolate mofetil, everolimus, sirolimus, and tacrolimus).82 Endoscopic evidence for GVHD is provided by the presence of erythema, exudates, and superficial ulceration of gastrointestinal mucosa. However, the sensitivity and specificity of endoscopic findings are suboptimal to rule in or rule out GVHD; histopathology is necessary. Rectosigmoid biopsies are most sensitive.83,84 In GVHD, histopathology shows increased crypt epithelial apoptosis, crypt loss, and neutrophilic infiltration. Apoptosis of epithelial cells is induced by activated donor cytotoxic T lymphocytes. It is, however, important to note that epithelial apoptosis can be seen after LT from etiologies other than GVHD, such as cytomegalovirus (CMV) colitis, mycophenolate-induced colitis and nonsteroidal anti-inflammatory drugs. CMV colitis can be diagnosed by immunohistochemical demonstration of CMV viral inclusions. Mycophenolate-induced colitis can be differentiated from GVHD by presence of more than 15 eosinophils per high power field, lack of endocrine cell aggregates in lamina propria, and lack of apoptotic microabscesses.85
Donor lymphocyte microchimerism (<1% donor lymphocyte chimerism) is often seen in liver transplant recipients; it is postulated that microchimerism is important for immune tolerance and graft acceptance by the host.3,86–88 In contrast, patients with GVHD have donor lymphocyte macrochimerism (>1% donor lymphocyte chimerism) in recipient tissues (skin, gastrointestinal mucosa, peripheral blood), ranging from 1% to 80%.3,6,60,62,67,72,88-91 However, donor lymphocyte macrochimerism in peripheral blood alone does not confirm the diagnosis of GVHD.92Macrochimerism in a patient with clinical and histological features suggestive of GVHD (involvement of the skin, bone marrow and/or gastrointestinal tract) should be considered diagnostic of GVHD. Confirmation of macrochimerism should not be required to start treatment for GVHD, because it may take several days for results to be obtained. Monitoring donor lymphocyte macrochimerism in target organs and peripheral blood may be helpful, even after resolution of symptoms, because persistence of macrochimerism may suggest incomplete resolution of GVHD and a high risk of relapse with tapering of immunosuppression.
Ferritin level was checked in 4 of the UIHC GVHD patients and was markedly elevated in all. The mean peak ferritin in patients who died of GVHD in our case series was 9930 ng/mL (range, 2225-20 333), whereas the peak ferritin in the surviving patient was 733 ng/mL. Marked hyperferritinemia in GVHD after LT has not been previously reported. Though serum ferritin is a nonspecific acute phase reactant, an extreme elevation of ferritin level is seen only in a few conditions.93 Cytokines released by activated donor lymphocytes, and the associated inflammatory response, is the likely mechanism behind hyperferritinemia in GVHD.
Treatment and Outcome
Fourteen of the 17 reported treatment regimens for GVHD after LT were associated with mortality rates over 70%, including all regimens that included high-dose intravenous steroids only or an increase in CNI dose (with both tacrolimus and cyclosporine). Only 3 reported treatment regimens for GVHD after LT yielded mortality rates less than 60%. These regimens, used in a small number of patients, included IL-2 antagonists (basiliximab or daclizumab), the CD2 inhibitor alefacept, or TNF-α inhibitors.
The efficacy of IL-2 antagonists in case series of patients with GVHD after hematopoietic stem cell transplantation (HSCT) has shown promise, with survival of 40% to 60%.94,95 Though the survival rate may be better with IL-2 antagonists compared with other reported regimens for GVHD after LT, mortality rate is still substantial.
Starting high-dose steroids on diagnosis of GVHD after LT, with addition of Alefacept and ATG when the patient develops pancytopenia,14,63 was shown to result in the immediate rebound of bone marrow function. Alefacept is a fusion protein that binds to the lymphocyte antigen CD2, inhibits the interaction of CD2 and human leukocyte function antigen-3, thereby preventing the activation of CD4 and CD8 T lymphocytes, whereas ATG eliminates the activated effector T cells. Alefacept also showed potential benefit for treatment of GVHD in bone marrow transplantation recipients.96 Unfortunately, Alefacept, has been discontinued by the manufacturers, without any safety or FDA regulation concerns.97 Sipilizumab is a similar agent that targets the CD2 receptor on T lymphocytes and natural killer cells. A phase I trial of sipilizumab for treatment of GVHD after bone marrow transplantation in children reported a good response, but a higher incidence of posttransplant lymphoproliferative disorder was noted, raising safety concerns.98
Initial studies of patients with steroid-refractory GVHD post-HSCT showed promising results with the use of the TNF α inhibitor, infliximab.99,100 Recent studies, including a phase III study in patients with GVHD after HSCT, showed no benefit of addition of infliximab to methylprednisolone compared with methylprednisolone alone.101 However, higher response rates have been reported with etanercept in patients with GVHD after HSCT.102-106 Etanercept, unlike infliximab, does not lead to antibody-dependent cytotoxicity and induction of apoptosis of TNF-α–positive monocytes, possibly decreasing risk of infection compared to infliximab. The literature on the use of TNF-α inhibitors in GVHD after LT is limited. However, based on the high mortality with the majority of reported regimens, the 75% survival among the 4 patients treated with TNF-α inhibition, and the data on etanercept in HSCT patients with GVHD, etanercept, or other TNF-α antagonists could be useful as a second line agent in patients with GVHD after LT who are steroid-refractory or dependent.
The major drawback of increasing immunosuppression in patients with GVHD after LT is the high risk of death from sepsis. Enterobacter septicemia, invasive aspergillosis, and disseminated Candida infection are common causes of death with GVHD. A study performed on patients with GVHD post-HSCT showed a significant increase in the risk of non-Candida invasive fungal infections with the use of infliximab.107 Thus, vigilance for development of infection and timely use of antibiotics and antifungal agents is very important. Empiric use of antibiotics to cover gram negatives and anaerobic bacteria, especially VRE, and antifungal prophylaxis, appears reasonable. Pneumocystis prophylaxis and CMV is advised during high-level immunosuppression. The role of granulocyte-monocyte colony stimulating factor in GVHD is unclear, but may be given in patients with marked neutropenia.
In patients with gastrointestinal GVHD after HSCT, a stepwise oral “GVHD diet” may be beneficial.108 Severe protein-calorie malnutrition as a result of protein losing enteropathy and malabsorption is treated with 1.5 g/kg per day of protein. In addition, these patients may develop vitamin, micronutrient and essential trace element (including magnesium and zinc) deficiencies. In patients with massive diarrhea, total parenteral nutrition may be needed. When diarrhea is less than 500 mL/d, oral foods are introduced in a stepwise manner.108 This approach may be beneficial in patients with GVHD after LT, though no data are available.
Extracorporeal photopheresis, an apheresis and photodynamic therapy, has shown promising results in the treatment of patients with GVHD after HSCT.109 It is an immunomodulator therapy which involves collection of peripheral blood mononuclear cells, irradiation of these leucocyte cells in vitro by ultraviolet A in the presence of the drug 8-methoxypsoralen, followed by reinfusion of the cells into the patient. The main advantage of this therapy is the absence of generalized immunosuppression, thereby decreasing the risk of developing life-threatening infections. Further trials are needed before establishing extracorporeal photopheresis as a treatment option for GVHD.
Proposed Diagnostic Algorithm and Treatment Recommendations
How then do we diagnose and treat our next patient with GVHD after LT? Based on our interpretation of currently available data, we propose a diagnostic algorithm (Figure 4) for GVHD after LT. Patients who have symptoms involving the most commonly involved organ systems in GVHD, namely, skin, gastrointestinal tract, and bone marrow, should be evaluated for GVHD. Patients with maculopapular skin rash post-LT should undergo skin biopsy, because it is a simple procedure with low morbidity, and the histology can be diagnostic of GVHD. In patients who present with diarrhea or pancytopenia after LT, the most common causes of these symptoms should be ruled out. If symptoms persist, a colonoscopy with mucosal biopsies should be performed to screen for GVHD changes. Strong treatment recommendations cannot be made due to the absence of prospective studies and due to the high mortality rates for the majority of reported treatment regimens. Multidisciplinary involvement, with hematologists, infectious disease specialists, and immunologists, is essential in the management of this complex condition.
The proposed diagnostic algorithm is based on limited evidence. Comparisons of treatment regimen mortality rates are based on small cohort sizes and do not take into consideration other patient- or disease-related factors which may affect mortality rates. With only summary data available from the UNOS database, comparisons with reported US patients with GVHD are limited to univariate tests of association. Clearly, all US cases of GVHD after LT in the US have not been reported, and occurrence of GVHD after LT is not reported in the UNOS database, limiting the interpretation of statistical analysis.
Graft-versus-host disease after LT is infrequent, but is associated with a very high mortality rate. Most patients develop GVHD in 3 to 5 weeks after LT. Graft-versus-host disease may occur more often in LT patients older than 50 years and who have diabetes. When reported US GVHD cases were compared with all LT patients in the UNOS database, HCC appeared to be overrepresented, and HCV was underrepresented. High-dose steroids alone, or combined with increasing CNI dose, are not effective treatment regimens. High-dose steroids combined with IL-2 antagonists or TNF-α inhibitors may be more promising approaches, though experience is limited. Donor macrochimerism and serum ferritin may be helpful for monitoring response to treatment. The participation of multiple institutions in a working group to prospectively study GVHD after LT, along with obligatory reporting of GVHD cases to UNOS, is needed.
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