Volume 12, Issue 12 , Pages 1302-1309, December 2006
Hepatic Injury following Reduced Intensity Unrelated Cord Blood Transplantation for Adult Patients with Hematological Diseases
Article Outline
Abstract
Liver injury is a common complication in allogeneic hematopoietic stem cell transplantation. Its major causes comprise graft-versus-host disease (GVHD), infection, and toxicities of preparative regimens and immunosuppressants; however, we have little information on liver injuries after reduced intensity cord blood transplantation (RICBT). We reviewed medical records of 104 recipients who underwent RICBT between March 2002 and May 2004 at Toranomon Hospital. Preparative regimen and GVHD prophylaxis comprised fludarabine/melphalan/total body irradiation and cyclosporine or tacrolimus. We assessed the etiology of liver injuries based on the clinical presentation, laboratory results, comorbid events, and imaging studies in 85 patients who achieved primary engraftment. The severity of liver dysfunction was assessed according to the National Cancer Institute Common Toxicity Criteria version 2.0. Hyperbilirubinemia was graded according to a report by Hogan et al (Blood. 2004;103:78-84). Moderate to very severe liver injuries were observed in 36 patients. Their causes included cholestatic liver disease (CLD) related to GVHD or sepsis (n = 15), GVHD (n = 7), cholangitis lenta (n = 5), and others (n = 9). Median onsets of CLD, GVHD, and cholangitis lenta were days 37, 40, and 22, respectively. Frequencies of grade 3-4 alanine aminotransferase elevation were comparable across the 3 types of hepatic injuries. Serum γ-glutamil transpeptidase was not elevated in any patients with cholangitis lenta, whereas 27% and 40% of patients with CLD and GVHD, respectively, developed grade 3-4 γ-glutamil transpeptidase elevation. Multivariate analysis identified 2 risk factors for hyperbilirubinemia; grade II-IV acute GVHD (relative risk, 2.23; 95% confidential interval, 1.11-4.47; P = .024) and blood stream infection (relative risk, 3.77; 95% confidential interval, 1.91-7.44; P = .00013). In conclusion, the present study has demonstrated that the hepatic injuries are significant problems after RICBT, and that GVHD and blood stream infection contribute to their pathogenesis.
Key words: Graft-versus-host disease, Cholangitis lenta, Allogeneic stem cell transplantation, Blood stream infection
Introduction
Liver injury is a common and sometimes fatal complication in allogeneic hematopoietic stem cell transplantation (allo-SCT). Its major causes comprise veno-occlusive disease (VOD), graft-versus-host disease (GVHD), infection, and adverse effects of preparative regimens, immunosuppressants, and antibiotics [1]. In the era of myeloablative conditioning, intensive chemoradiotherapy injured hepatic sinusoids, causing VOD with a high incidence of 21%-54% [2, 3, 4, 5, 6]. After the introduction of reduced intensity stem cell transplantation (RIST), the incidence of VOD decreased to 0%-17% [7, 8, 9]. The incidence of GVHD after RIST is comparable to that after conventional allo-SCT [10, 11], whereas patients who undergo RIST, who are usually older and/or have comorbid factors, frequently develop infectious diseases or drug-induced liver injuries [12, 13]. The reported incidence of liver injury after RIST was almost same as that after myeloablative allo-SCT [7].
Cord blood (CB) is an established stem cell source in myeloablative transplantation [14, 15, 16]. The incidence of GVHD after myeloablative CB-transplantation (CBT) is comparable to that of allo-SCT from a matched unrelated donor [14, 15]. Deaths related to GVHD are more common in allo-SCT from an unrelated donor, whereas deaths related to toxicity including regimen-related toxicity and infections are more frequent in CBT [15]. It remains unknown whether the high incidence of infection-related deaths are associated with naive CB cells, disease aggressiveness, or patient conditions. Infectious diseases are frequent and severe after CBT compared with allo-SCT using other stem cell sources [17, 18, 19]. These findings suggest that immune recovery is delayed after CBT [20]. Moreover, owing to the development of universal stem cell source and reduced intensity conditioning regimen [21, 22], increasing numbers of elderly patients are being treated with CBT. Elderly patients can benefit from this curative treatment procedure; however, elderly patients might be easily affected by infectious diseases or other toxicities. As a result, nonrelapse mortality after reduced intensity CBT (RICBT) is high. We have little information on transplant-related toxicity after RICBT [21, 22, 23]. We underwent retrospective study to clarify the incidence and clinical features of liver injuries after RICBT.
Methods
Data Collection
We reviewed medical records of 104 recipients who underwent RICBT between March 2002 and May 2004 at Toranomon Hospital (Tokyo, Japan). Their characteristics are listed in Table 1. Ninety-one of the 104 patients had high-risk disease including acute myeloid leukemia in relapse or advanced (>2) complete remission (CR; n = 31), acute lymphoid leukemia other than first CR (n = 8), chronic myeloid leukemia in blastic phase (n = 1), myelodysplasia other than refractory anemia (n = 8), myeloma in any disease status (n = 4), refractory lymphoma (n = 38, all with lymphoma), and idiopathic myelofibrosis (n = 1).
Table 1. Patients’ Characteristics and Transplantation Procedures
| Patient characteristics | |
 Age (y), median (range) | 57(18-79) |
| Male/female | 61/43 |
| Primary diseases | |
| AML/MDS | 44 |
| Malignant lymphoma | 38 |
| Acute lymphoblastic leukemia | 12 |
| Severe aplastic anemia | 4 |
| Chronic myeloid leukemia | 1 |
| Multiple myeloma | 4 |
| Idiopathic myelofibrosis | 1 |
| Risk of underlying diseases⁎ | |
| High/low | 91/13 |
| Liver status | |
| Positive HBs antigen | 4 |
| Positive HCV antibody | 3 |
| AST/ALT > ULN | 30/24 |
| ALP/GTP > ULN | 77/20 |
| bilirubin >1.2 mg/dL | 32 |
| Transplantation procedures | |
| Conditioning regimen | |
| Flu + Mel + TBI 4 Gy/8 Gy | 97/2 |
| Flu + BU + TBI 4 Gy/8 Gy | 1/4 |
| GVHD prophylaxis | |
| Cyclosporine/tacrolimus | 79/25 |
| Infused nucleated cells × 107/kg, median (range) | 2.8(2.0-4.6) |
| HLA disparity (antigen), 2/1/0 | 88/15/1 |
| Transplantation outcomes† | |
| Documented blood stream infection | 26(31%) |
| CMV disease/antigenemia | 15(18%)/50(59%) |
⁎We divided the risk of transplantation into 2 groups. The low-risk group was characterized as follows: acute myeloid or lymphoid leukemia in first and second remission, chronic myelogeneous leukemia in chronia phase, and myelodysplastic syndrome refractory anemia. The other patients were defined as having high-risk diseases. |
†Percentage was calculated based on 85 patients who achieved primary engraftment. |
Transplantation Procedures and Supportive Care
A CB unit was searched through the Japan Cord Blood Bank Network [24]. CB units that were available for CBT were at least 4/6 serologically HLA-antigen matched, and contained ≥2 × 10E7 nucleated cells/kg of recipient body weight before freezing. All provided CB units were negative for cytomegalovirus-specific immunoglobulin M and G antibodies.
Transplantation procedures are presented in Table 1. All patients received purine analog-based preparative regimens. Granulocyte colony-stimulating factor (G-CSF) was administered from day 1 until neutrophil engraftment. GVHD prophylaxis consisted of tacrolimus 0.03 mg/kg or cyclosporine 3 mg/kg in a continuous infusion starting on day −1. Trough blood levels of these drugs were monitored 2-3 times a week and dosages were modified to maintain target levels of 10-15 ng/mL for tacrolimus and 200-400 ng/mL for cyclosporine [25, 26, 27, 28].
Primary engraftment was defined by an absolute neutrophil count of ≥0.5 × 10E9/L for 3 consecutive days.
The diagnosis of GVHD was made based on clinical judgments and results of skin or gut biopsy. Acute GVHD was graded according to consensus criteria [29]. When patients developed grade II-IV acute GVHD, we initiated 1-2 mg/kg per day of methylprednisolone in addition to tacrolimus or cyclosporine.
Patients were managed in reverse isolation in laminar airflow-equipped rooms. All patients received tosufloxacin 450 mg/d from the start of conditioning until neutrophil engraftment. Fluconazole 200 mg/d or micafungin 150 mg/d and acyclovir 600 mg/d were given from the start of conditioning until cessation of GVHD prophylaxis. They received prophylaxis with trimethoprim-sulfamethoxazole against Pneumocystis jirovecii infection from the start of conditioning until cessation of immunosuppressants or disappearance of chronic GVHD. When patients develop neutropenic fever, tosufloxacin was changed to broad-spectrum antibiotics [30]. Because most patients had been treated severely and received multiple transfusions before transplantation, anticytomegalovirus (CMV) antibodies were not examined before transplantation. All patients were monitored for CMV pp65 antigenemia once a week. When CMV antigenemia exceeded 10/50,000, patients preemptively received foscarnet 30 mg/kg intravenously twice daily.
Assessment of Liver Dysfunction
Before transplantation, patients were evaluated for the presence of liver dysfunction by history, physical examination, and laboratory tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase [ALP], γ-glutamil transpeptidase [GTP], bilirubin, albumin, prothrombin time, and tests for hepatitis B virus [HBV] and hepatitis C virus [HCV]). Patients with symptoms, signs, or laboratory findings of liver dysfunction were evaluated by additional laboratory tests, liver imaging, and consultation to hepatologists as clinically indicated.
Diagnostic Criteria
Severity of liver dysfunction was assessed according to the National Cancer Institute Common Toxicity Criteria version 2.0. Hyperbilirubinemia was graded according to the report by Hogan et al [7]; peak serum levels of total bilirubin 1.2-3.9, 4.0-6.9, 7.0-9.9, and >10.0 mg/dL were classified as mild, moderate, severe, and very severe liver dysfunction, respectively.
Attribution of causes of liver dysfunction were determined by a hepatologist (KR), a hematologist (KE), and a pathologist (SK) based on clinical presentation, laboratory results, comorbid events, liver imaging studies, and histology. When there was disagreement in the diagnosis of liver dysfunction among the 3 researchers, we made a final diagnosis after discussion.
VOD was diagnosed according to criteria of McDonald et al [2]. In allograft recipients with skin or gut GVHD, cholestatic liver abnormalities are usually attributable to liver GVHD [1]. We made a diagnosis of liver GVHD when patients with skin or gut GVHD developed jaundice. Cholangitis lenta was clinically diagnosed when patients with sepsis developed jaundice [1]. Cholangitis lenta frequently occurs in patients with active GVHD, and these 2 factors appear codependent. When patients with active GVHD and sepsis develop jaundice, it is difficult to differentiate between liver GVHD and cholangitis lenta. A diagnosis of “cholestatic liver disease related to GVHD or sepsis (CLD)” was given to these patients [1]. Patients who developed liver dysfunction without evidence of GVHD and/or sepsis were assessed for other causes of liver dysfunction such as drug-induced liver dysfunction, ischemia, or others. A primary cause of each patient’s liver dysfunction was identified, followed by additional causes supported by evidence when liver dysfunction was thought to be multifactorial.
Endpoints and Statistical Analysis
This study investigated the clinical features of liver dysfunction and identified risk factors for hyperbilirubinemia among patients who achieved engraftment after RICBT. The cumulative incidence of the elevation of serum total bilirubin level was evaluated using the Gray method [31], considering death without total bilirubin elevation as a competing risk. Potential confounding factors considered in the analysis were age, sex, disease status, AST levels, ALT levels, ALP levels, GTP levels, total bilirubin levels, HCV antibody, number of HLA mismatches, stem cell dose, GVHD prophylactic agent, CMV antigenemia, grade II-IV acute GVHD, and blood stream infection. Proportional hazard modeling was used to evaluate the influence of these factors on the incidence of total bilirubin elevation by using proportional hazard modeling and treating the development of acute GVHD, positive CMV antigenemia, and bacteremia as time-dependent covariates. Factors associated with at least borderline significance (P < .10) in univariate analyses were subjected to a multivariate analysis using backward stepwise proportional hazard modeling. P values <0.05 were considered statistically significant. Survival was estimated by the Kaplan-Meier method. Median follow-up of surviving patients was 251 days (range, 62-873 days).
Results
Clinical Outcomes after RICBT
Eighty-five (82%) patients achieved primary engraftment at a median of 20 days (range, 9-89 days). The other 19 patients died before engraftment; 17 patients died of sepsis, 1 patient died of probable invasive pulmonary aspergillosis, and the other patient died of progression of primary disease. Seven patients died after day 28; however, they developed sepsis during severe neutropenia soon after transplantation. Of the 85 patients who achieved engraftment, 41 and 27 patients developed grade II-IV and III-IV acute GVHD, respectively. The median onset of grade II-IV acute GVHD was day 28 (range, 11-92). Fifteen of 37 patients (41%) who survived >100 days without disease progression developed chronic GVHD. Estimated 1-year overall survival was 36% (95% confidential interval ([CI], 26%-46%). Causes of deaths were nonrelapse mortality in 56 patients and disease progression in 6 patients. The primary cause was infection in 41 of 56 patients who died without disease progression.
Pathogens of Blood Stream Infections
Causative organisms of bloodstream infections, which is diagnosed when patient had a recognized pathogen cultured from ≥1 blood culture, and the organism cultured from blood was unrelated to any infection at another site, and their outcomes in 26 patients were S epidermidis (n = 6, 3 fatal), P aeruginosa (n = 5, 4 fatal), E faecalis (n = 4, 3 fatal), M tuberculosis (n = 3, 2 fatal), MRSA (n = 2, 1 fatal), S maltophilia (n = 1, 1 fatal), S mitis (n = 1, 1 fatal), gram-positive rod (n = 1, 1 fatal), E faecalis and S epidermidis (n = 1, 0 fatal), A hydrophilia (n = 1, 0 fatal), and S sanguis and E faecalis (n = 1, 0 fatal). Three patients with military tuberculosis received antituberculosis therapy including ethambutol, isoniazid, and rifampicin with or without pyrazinamide [19].
Incidence of Liver Injury
Hyperbilirubinemia was documented in 74 patients (87%; 95% CI, 83%-91%; mild n = 38, moderate n = 11, severe n = 7, and very severe n = 18; Figure 1). Increased AST, ALT, ALP, and GTP levels corresponding to grade 3-4 toxicities were observed in 19, 16, 35, and 13 patients, respectively.
Figure 1.
Cumulative incidences of total bilirubin elevation (>4.0 mg/dL; black line) and death without total bilirubin elevation (gray line).
Clinical Features of Hyperbilirubinemia
Causes of moderate to very severe hyperbilirubinemia included GVHD (n = 7), cholangitis lenta (n = 5), CLD (n = 15), thrombotic thrombocytopenia (n = 2), progression of primary disease (n = 1), omeprazole (n = 1), cyclosporine (n = 1), hemolysis (n = 1), and multifactorial (n = 4; liver congestion due to heart failure and cholangitis lenta, rifampicin and GVHD, cefozopran and GVHD, rifampicin and cholestasis related to GVHD, or sepsis). No patient met diagnostic criteria for VOD.
Clinical features of hyperbilirubinemia according to their etiologies are listed in Table 2. Median onsets of hyperbilirubinemia for GVHD, cholangitis lenta, and CLD were day 40 (range, 22-86 days), day 22 (range, 6-32 days), and day 37 (range, 17-111 days), respectively. Cholangitis lenta developed soon after transplantation compared with GVHD, and higher serum GTP levels were not documented in patients with cholangitis lenta. Patients with GVHD tended to have better prognosis compared with those with chlangitis lenta or CLD.
Table 2. Clinical Features for Three Representative Causes of Liver Dysfunction
| Cumulative Incidence | |||||||
|---|---|---|---|---|---|---|---|
| Median Onset (range) | Mortality Rate | ALT Grade ≥3 | GTP Grade ≥3 | Maximum Bilirubin >7 mg/dL | Day 100 | 1 Year | |
| Cholestatic liver disease related to GVHD or sepsis | 37(17-111) | 93% | 13% | 27% | 67% | 15.4% | 17.9% |
| Cholangitis lenta | 22(6-32) | 80% | 20% | 0% | 80% | 4.7% | 6.0% |
| GVHD | 40(22-86) | 67% | 17% | 40% | 50% | 4.7% | 6.7% |
Histopathologic Finding
Of the 36 patients with moderate to very severe jaundice, 7 had liver histology (Table 3). Bile duct inflammation and cholestasis were observed in 6 and 5 patients, respectively. These findings were not observed in a patient with thrombotic thrombocytopenic purpura (TTP). A patient with rifampicin-induced hepatotoxicity showed intrahepatocyte cholestasis.
Table 3. Pathologic Findings in Patients with Liver Dysfunction after Reduced Intensity Cord Blood Transplantation⁎
| UPN | Age | Sex | Primary Disease | Bacteremia | GVHD | Peak ALT/GTP Grade | Peak Bilirubin (mg/dL) | Autopsy/Biopsy | Clinical Diagnosis of Liver Dysfunction | Bile Duct Inflammation | Venous Endothelial Inflammation | Cholestasis | Other findings |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 186 | 71 | M | AML | Yes | Yes | 1/1 | 20.5 | Autopsy | CLD | + | − | + | |
| 162 | 67 | M | CML | Yes | Yes | 0/3 | 9.0 | Autopsy | Rifampicin and GVHD | + | − | + | Tuberculosis, intrahepatocyte |
| cholestasis | |||||||||||||
| 134 | 72 | F | AML | Yes | Yes | 4/3 | 17.2 | Autopsy | CLD | + | + | + | |
| 155 | 57 | F | AML | No | No | 2/1 | 12.6 | Autopsy | TTP | − | − | − | |
| 144 | 58 | M | SAA | No | Yes | 3/3 | 10.9 | Autopsy | Cefozopran and GVHD | + | − | + | Hemosiderosis |
| 121 | 55 | M | AML | No | Yes | 2/3 | 25.3 | Autopsy | CLD | + | − | + | |
| 258 | 59 | M | AML | Yes | Yes | 1/3 | 5.0 | Biopsy | GVHD | + | − | − |
⁎These patients were seronegative for HBV and HCV, and hepatitis or VOD was not observed in any patients. |
Risk Factor for Development of Hyperbilirubinemia
Results of univariate and multivariate analyses are presented in Table 4. Grade II-IV acute GVHD (relative risk, 2.23; 95% CI, 1.11%-4.47%; P = .024) and blood stream infection (relative risk, 3.77; 95% CI, 1.91%-7.44%; P = .00013) were significant risk factors on multivariate analysis.
Table 4. Risk Factors for Incidence of Hyperbilirubinemia
| Relative Risk | (95% CI) | P | |
|---|---|---|---|
| Univariate analysis | |||
| Pretransplantation factors | |||
| Age | 1.02 | (0.99-1.04) | .20 |
| Sex | 1.56 | (0.80-3.04) | .20 |
| Disease status | 1.52 | (0.59-3.94) | .39 |
| AST elevation | 1.48 | (0.77-2.86) | .24 |
| ALT elevation | 1.90 | (0.97-3.70) | .062 |
| ALP elevation | 0.90 | (0.42-1.91) | .78 |
| GTP elevation | 0.77 | (0.26-2.23) | .63 |
| Total bilirubin elevation | 1.67 | (0.82-3.37) | .16 |
| HCV antibody | 0.94 | (0.13-6.66) | .95 |
| Number of HLA mismatches | 1.35 | (0.49-3.69) | .56 |
| Stem cell dose | 1.25 | (0.70-2.24) | .46 |
| GVHD prophylaxis | 0.49 | (0.20-1.17) | .11 |
| Post-transplantation factors (time-dependent covariates) | |||
| CMV antigenemia | 1.36 | (0.61-3.00) | .45 |
| Grade II-IV acute GVHD | 2.95 | (1.47-5.90) | .0023 |
| Blood stream infection | 4.49 | (2.31-8.73) | 9.4 × 10−6 |
| Multivariate analysis | |||
| Grade II-IV acute GVHD | 2.23 | (1.11-4.47) | .024 |
| Blood stream infectior | 3.77 | (1.91-7.44) | .00013 |
Discussion
Liver injury is a significant complication after RICBT. Moderate to very severe liver injuries were diagnosed in 36 of the 85 patients who underwent RICBT (42%; 95% CI, 37%-47%) in the present study. No study has been reported on liver injuries after RICBT, although approximately 30% of patients who undergo RIST using peripheral blood stem cells develop moderate to very severe liver injuries [7, 32]. The present study suggests that liver injuries are more frequent in RICBT than in RIST using peripheral blood stem cells.
Liver injuries after allo-SCT can be classified into 3 categories; CLD, cholangitis lenta, and GVHD [7]. As presented in Table 2, CLD and GVHD presented similar clinical features, which were characterized by the late onset and elevation of serum GTP. Because CLD has a higher mortality rate than GVHD, it is reasonable to assume that GVHD might underlie the pathogenesis of CLD, and it is frequently complicated with infections in CLD. In contrast, cholangitis lenta developed during neutropenia after RICBT, and serum levels of GTP were not elevated in any of the 5 patients. The pathogenesis of cholangitis lenta might differ from that of GVHD and CLD.
Concerning pathologic examination, all patients with CLD or GVHD showed some evidence of bile duct inflammation. Cholestasis was documented in all but 1 patient with CLD or GVHD. These findings support our hypothesis that GVHD might underlie the pathogenesis of CLD. Interestingly, neither endothelial degradation nor thrombotic lesions were documented in a patient with TTP. These findings were compatible with our previous report that formation of thrombotic lesions is not essential for the pathogenesis of TTP after transplantation [33]. A patient with a clinical diagnosis of rifampicin-induced liver injury showed pathologic evidence of intrahepatocyte cholestasis. These cases have demonstrated that pathologic examination is useful in making a diagnosis of liver injuries after RICBT.
Interestingly, GVHD and blood stream infection were identified as risk factors of hyperbilirubinemia after RICBT. Because GVHD is frequently complicated by infections, it is difficult to distinguish effects of GVHD from those of infections on the development of liver injuries after allo-SCT [7]. It remains unknown whether infections per se cause liver injury after transplantation; however, the present study has demonstrated that the effect of blood stream infection is more significant than that of GVHD in the development of hyperbilirubinemia after RICBT. Although further investigations are warranted to clarify the exact mechanism of hyperbilirubinemia attributable to blood stream infection, we should recognize that jaundice of unknown etiology might be caused by occult blood stream infections in patients after RICBT. Fludarabine is a risk factor for liver dysfunction after nonmyeloablative allo-SCT [7]. We could not investigate this possibility, because all patients received a fludarabine-containing conditioning regimen. Cyclosporine causes hyperbilirubinemia in dose-related manner [34]. The diagnosis of cyclosporine-induced hyperbilirubinemia is always presumptive because it is based on a logistic approach rather than on absolute criteria and specific diagnostic tests [1]. Only 1 patient developed cyclosporine-induced hyperbilirubinemia, so we did not include cyclosporine in the analysis of risk factors for hyperbilirubinemia.
Estimated overall survival of 36% at 1 year is comparable to that of previous reports [35] when considering that most of patients had refractory or advanced diseases. Because infection-related mortality within 100 days is high in CBT compared with unrelated bone marrow transplantation, reduction of infection-related mortality would lead to increased survival rates. Early infection-related mortality among patients after CBT might be attributable to neutropenia, disease status, and physiologic conditions of patients after RICBT [14].
Regimen-related mortality was not documented in the present study. This finding suggests that RICBT is a feasible treatment option for elderly patients with hematologic malignancies. Main causes of nonrelapse mortalities were bacterial infections in this study, and most developed during neutropenia after reduced intensity conditioning: thus, shortening of neutropenia might lead to increased survival. Some researchers have reported the usefulness of CBT using nonmyeloablative conditioning or double-cord transplantation [36, 37, 38]. Further investigation of transplantation procedures is warranted to improve survival of patients after RICBT. Patient selection is also important in RICBT to avoid infection-related mortalities. Because the mortality rate after blood stream infection is high [23], patients who are at high risk for developing blood stream infection should avoid RICBT [24, 35]. A large-scale study is warranted to elucidate the pretransplantation risk factors for developing blood stream infection.
This study provides important information on liver injuries after RICBT; however, there are some limitations to be discussed. First, this was a small retrospective study, and unrecognized bias might have influenced its results. Large-scale prospective studies are required to clarify clinical features of hepatic injuries after RICBT. Second, none of the 5 patients with cholangitis lenta underwent autopsy or biopsy. We have little information on histopathology of cholangitis lenta after RICBT. Third, viral hepatitis is a frequent cause of liver injuries after transplantation, but viral infections other than HBV, HCV, and CMV were not examined in this study. Occult viral infection might have injured the liver in patients after RICBT. Fourth, total parenteral nutrition (TPN) might have caused liver injury. Because some patients were transferred back to their referral hospital in the present study, data regarding the incidence and duration of TPN were not available. Future studies on TPN-induced liver injuries after RICBT are warranted.
In conclusion, the present study has demonstrated that hepatic injury is a significant problem after RICBT, and that 2 factors, GVHD and blood stream infection, contribute to its pathogenesis. Optimal diagnostic and treatment strategies of blood stream infection and proper management of acute GVHD are warranted to decrease hepatic damage after RICBT.
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PII: S1083-8791(06)00518-0
doi:10.1016/j.bbmt.2006.07.013
© 2006 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Volume 12, Issue 12 , Pages 1302-1309, December 2006
