New-Onset Diabetes Mellitus After Living Donor Liver Transplantation: Possible Association With Hepatitis C

New-Onset Diabetes Mellitus After Living Donor Liver Transplantation: Possible Association With Hepatitis C Y. Kishi, Y. Sugawara, S. Tamura, J. Kaneko, Y. Matsui, and M. Makuuchi ABSTRACT Background. The relationship between hepatitis C virus (HCV) infection and new-onset diabetes mellitus (NODM) after liver transplantation is a controversial issue. Methods. A total of 223 adult living donor liver transplantation (LDLT) recipients followed for more than 6 months were analyzed for the prevalence of NODM. The prevalence was compared between 62 HCV-positive and 161 HCV-negative patients. All the HCV-positive patients underwent preemptive antiviral treatment with interferon ␣2b and ribavirin. Results. Preoperative diabetes mellitus was more frequently observed in HCV-positive patients (18% vs 4%, P ⫽ .001). NODM occurred more frequently in HCV-positive patients (41% vs 22%, P ⫽ .003). Multivariate analysis, however, revealed that HCV was not a predictor for NODM. A comparison of 14 HCV-positive patients with persistent NODM and 48 patients without persistent NODM indicated that there was no significant difference in the frequency of the viral response to antiviral therapy nor in HCV-RNA levels. Impaired glucose tolerance did not impact postoperative survival after LDLT. Conclusions. HCV was not associated with the prevalence of NODM after LDLT. NODM did not influence patient survival.

T

HE DEVELOPMENT of postoperative new-onset diabetes mellitus (NODM) after liver transplantation1–13 is common (7% to 38%). The mechanisms underlying impaired glucose tolerance after liver transplantation, however, are poorly understood.2 The high prevalence of NODM has been partly attributed to the diabetogenic effects of the immunosuppressive agents.6 Several recent reports1–3,5,8,9,11 demonstrated a possible association between hepatitis C virus (HCV) infection and NODM. All of the findings, however, are from patients who underwent deceased donor liver transplantation. We conducted the present study to determine the prevalence and predictive factors of diabetes mellitus (DM) after living donor liver transplantation (LDLT). PATIENTS AND METHODS A total of 234 adult patients underwent LDLT in our hospital from January 1996 to January 2005. Ten patients that died within 6 months after LDLT, and one patient who moved abroad were excluded. The remaining 223 patients were the subjects of this study. One hundred nineteen (53%) were men. The mean and standard error of the age was 47 ⫾ 1 years. United Network for Organ Sharing status and Model for End-stage Liver Disease

scores were 2.5 ⫾ 0.05 and 15 ⫾ 0.8, respectively. Sixty-two patients (28%) were HCV-positive. Other etiologies included primary biliary cirrhosis (n ⫽ 47), hepatitis B virus (HBV) - related cirrhosis (n ⫽ 32), fulminant hepatic failure (n ⫽ 26), biliary atresia (n ⫽ 13), cryptogenic cirrhosis (n ⫽ 10), primary sclerosing cholangitis (n ⫽ 8), autoimmune hepatitis (n ⫽ 8), alcoholic cirrhosis (n ⫽ 4), and others (n ⫽ 13). Our criteria for recipient selection included age under 65 years, no past history of cardiovascular or cerebroFrom the Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. Supported by a Grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and Grants-in-aid for Research on HIV/AIDS, a multicenter pilot clinical study to compare the safety and efficacy of a steroid-free immunosuppression protocol with monoclonal antiIL2R antibody in HCV-positive living donor liver transplantation, and Research on Measures for Intractable Diseases from the Ministry of Health, Labor and Welfare of Japan. Address reprint requests to Y. Sugawara, MD, Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Japan. E-mail: [email protected]

© 2006 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710

0041-1345/06/$–see front matter doi:10.1016/j.transproceed.2006.08.112

Transplantation Proceedings, 38, 2989 –2992 (2006)

2989

2990

KISHI, SUGAWARA, TAMURA ET AL Table 1. Profilés of HCV-Positive and -Negative Patients

Age (y) Men/women BMI UNOS MELD Acute rejection (%) Follow up months Preoperative DM (%)

HCV-positive (n ⫽ 62)

HCV-negative (n ⫽ 161)

P value

53 ⫾ 2 47/15 24 ⫾ 0.4 2.5 ⫾ 0.1 16 ⫾ 1.0 26 32 ⫾ 3 18

45 ⫾ 1 72/89 22 ⫾ 0.3 2.5 ⫾ 0.1 14 ⫾ 0.6 36 42 ⫾ 2 4

⬍.0001 ⬍.0001 ⬍.0001 .77 .37 .15 .002 .001

BMI, body mass index; DM, diabetes mellitus; MELD, Model for End-stage Liver Disease; UNOS, United Network for Organ Sharing.

Fig 1. The numbers of patients for each category. Numbers within parentheses are those of HCV-positive patients.

vascular event, and normal cardiac function evaluated by electrocardiogram and ultracardiography. Immunosuppression after LDLT consisted of tacrolimus and methylprednisolone for all patients. The doses of each drug were gradually tapered for 6 months after LDLT. Tacrolimus level was controlled around 16 to 18 ng/mL in the first postoperative week, 14 to 16 ng/mL in the second week, 12 to 14 ng/mL in the third and fourth weeks, 10 to 12 ng/mL until the third postoperative month, 8 to 10 ng/mL until the sixth postoperative month, and 5 to 8 ng/mL thereafter. Methylprednisolone was tapered from 3 mg/kg on the first postoperative day to 0.05 mg/kg on the sixth postoperative months. Actually 2 or 4 mg of methylprednisolone was administered in each patient. Acute cellular rejection confirmed by liver biopsy was treated first by steroid recycle therapy. In HCV-positive patients, preemptive antiviral therapy with interferon ␣2b and rïbavirin were started, as described previously.14 The frequencies of preoperative and postoperative DM were examined and the influence of HCV infection was evaluated. The definition of DM was the necessity of oral drugs or insulin to control fasting blood glucose under 126 mg/dL (7.0 mmol/L) in accordance with the American Diabetes Association.15 Postoperative transient DM was defined as the termination of treatment within 6 months after LDLT, and DM that required treatment for more than 6 months was defined as persistent DM. NODM was defined as DM that occurred after LDLT. The numbers of patients in each category in our series are shown in Fig 1. To evaluate the effect of HCV on DM, the HCV-positive patients were divided into two groups: those with persistent DM and those without. The HCV titer and viral response to the

antiviral therapy were examined. The patients were divided into three groups: no postoperative DM, transient DM, and persistent DM for comparison of survival rate. Data were expressed as mean ⫾ standard error. Statistical comparisons were performed using Wilcoxon signedrank test for quantitative variables and Pearson’s chi square test or Fisher exact test for qualitative variables. Multivariate analysis was performed using a logistic regression test. A P value of less than .05 was considered to be statistically significant.

RESULTS

The patient profile, stratified by HCV infection, is shown in Table 1. HCV-positive patients were characterized by older age, higher proportion of male sex, and higher body mass index (BMI). Eighteen patients had DM preoperatively and the frequency was significantly higher in HCV-positive patients. One of them with HCV was withdrawn from the DM group during the follow-up period after LDLT. The frequency of NODM was significantly higher in HCVpositive patients. Elder age, male sex, and higher BMI were also the significant risk factors for NODM (Table 2). Multivariate analysis, however, indicated that only BMI was a predictor for transient NODM (Table 3). HCV, BMI, sex, and age were not predictors for persistent NODM (Table 4). In the 14 HCV-positive patients being treated for DM for more than 6 months, 8 (57%) patients were positive for HCV-RNA at 6 months after LDLT. In the other 48 HCV-positive patients without DM after 6 months, 29 (60%) patients were positive for HCV-RNA. The HCV-RNA level at this time in patients with or without DM was 294 ⫾ 125 kcopy/mL and 334 ⫾ 67 kcopy/mL, respectively. There was

Table 2. Risk Factors for Postoperative New-Onset Diabetes Mellitus Univariate

Multivariate

Variables

NODM (⫹)

NODM (⫺)

P value

Odds ratio

95% CI

P value

Age (y) Men/women BMI HCV ACR

50 ⫾ 1 47/24 24 ⫾ 0.4 29 (41%) 25 (35%)

46 ⫾ 1 72/80 22 ⫾ 0.3 33 (22%) 49 (32%)

.06 .009 ⬍.0001 .003 .66

0.48 0.60 0.06 0.62

⫺0.04–0.01 ⫺1.16–0.12 ⫺0.25–⫺0.06 ⫺1.17–0.20

.30 .11 .001 .16

CI, confidence interval; BMI, body mass index; ACR, acute cellular rejection; NODM, new-onset diabetes mellitus; HCV, hepatitis C virus.

NEW-ONSET DIABETES MELLITUS

2991

Table 3. Risk Factors for Transient New-Onset Diabetes Mellitus Univariate

Multivariate

Variables

NODM (⫹)

NODM (⫺)

P value

Odds ratio

95% CI

P value

Age (y) Men/women BMI HCV ACR

50 ⫾ 2 37/18 24 ⫾ 0.4 25 (46%) 18 (33%)

46 ⫾ 1 82/86 22 ⫾ 0.3 37 (22%) 56 (33%)

.08 .02 ⬍.0001 .0008 .93

0.53 0.64 0.03 0.50

⫺0.05–0.02 ⫺1.15–0.26 ⫺0.28–⫺0.08 ⫺1.41–0.03

.42 .22 .0004 .06

CI, confidence interval; BMI, body mass index; ACR, acute cellular rejection; NODM, new-onset diabetes mellitus; HCV, hepatitis C virus.

no significant difference in the frequency of the viral response to preemptive antiviral therapy (P ⫽ .83) or in the HCV-RNA level (P ⫽ .83). The cumulative survival rates of patient groups with no postoperative DM, transient DM, and persistent DM are shown in Fig 2. There was no significant difference among the groups. In total 14 patients died. The causes of death were recurrent hepatocellular carcinoma (n ⫽ 4), relapse of original disease (n ⫽ 3) sepsis (n ⫽ 3), thrombotic thrombocytopenic purpura (n ⫽ 2), graft failure due to hepatic vein congestion (n ⫽ 1), and skin cancer (n ⫽ 1). None of the deaths were due to cardiovascular or cerebrovascular events. DISCUSSION

In the present analysis, 41% of the HCV-positive patients experienced NODM. HCV was not an independent predictor for NODM. Tueche10 reported a negative relationship between NODM and HCV and demonstrated that alcoholic cirrhosis, preoperative DM, and male gender were predictive factors of NODM. His results were compatible with ours, but not consistent with previous reports emphasizing the positive relation between NODM and HCV.1,2,3,5,7–9,11 The controversy might be due partly to discrepancies in the diagnostic criteria for NODM.16 The time period between NODM occurrence and transplantation varies among studies from 7 days11 to 1 year,6 or is not mentioned in several articles.3,7,12,13 In our series, all the NODM patients developed DM within 2 weeks after LDLT. Among the 33 patients who continued treatment 6 months after LDLT, six NODM patients (all HCV-negative) and one patient with preoperative DM who was HCV-positive could be withdrawn from treatment after 6 months (11 to 27 months after LDLT).

This result was also inconsistent with previous reports indicating that the mean period from liver transplantation to the onset of NODM was 340 days11 or that the prevalence of NODM at 1 year after liver transplantation was more than that at 3 months after transplantation (20% vs 9%).9 In our study, there was no significant difference in the HCV-RNA titer or in the frequency of the viral response to interferon ␣2b and ribavirin therapy between patients with or without postoperative DM. Baid et al,8 reported that in half of the HCV-positive patients, the onset of postoperative DM occurred after the recurrence of hepatitis C. Furthermore, among these patients, those who responded to antiviral therapy with normalization of liver function demonstrated dramatic improvement of DM. Thus, Baid et al suggested a relation between the viral responses with the improvement of DM in HCV-positive patients. Another report demonstrated an association between increased HCV-RNA and the occurrence of postoperative DM.18 The previous report8 indicated that NODM was a factor for predicting postoperative mortality in HCV patients, which is not consistent with the present results. In summary, the relation between HCV infection and NODM after LDLT was examined. HCV did not influence the prevalence of persistent NODM or increase mortality in our LDLT series.17, 19

Table 4. Risk Factors for Persistent New-Onset Diabetes Mellitus Variables

pNODM (⫹)

pNODM (⫺)

P value

Age (y) Men/women BMI HCV ACR

49 ⫾ 9 10/6 23 ⫾ 0.9 4 (25%) 7 (44%)

47 ⫾ 3 109/98 22 ⫾ 0.2 58 (28%) 67 (32%)

.70 .45 .50 .41 .35

BMI, body mass index; ACR, acute cellular rejection; pNODM, persistent new-onset diabetes mellitus; HCV, hepatitis C virus.

Fig 2. Comparison of cumulative survival rate among patient groups of no postoperative DM (N), transient DM (T), and persistent DM (P).

2992

REFERENCES 1. Parolin MB, Zaina FE, Araújo MV, et al: Prevalence of new-onset diabetes mellitus in Brazilian liver transplant recipients: association with HCV infection. Transplant Proc 36:2776, 2004 2. Aldosary AA, Ramji AS, Ellliott TG, et al: Post-liver transplantation diabetes mellitus: an association with hepatitis C. Liver Transpl 8:356, 2002 3. Mirabella S, Brunati A, Ricchiuti A, et al: New-onset diabetes after liver transplantation. Transplant Proc 37:2636, 2005 4. John PR, Thuluvath PJ: Outcome of patients with new-onset diabetes mellitus after liver transplantation compared with those without diabetes mellitus. Liver Transpl 8:708, 2002 5. Knobler H, Stagnaro-Green A, Wallenstein S, et al: Higher incidence of diabetes in liver transplant recipients with hepatitis C. J Clin Gastroenterol 26:30, 1998 6. Navasa M, Bustamante J, Marroni C, et al: Diabetes mellitus after liver transplantation: prevalence and predictive factors. J Hepatol 25:64, 1996 7. Khalli M, Lim JW, Bass N, et al: New onset diabetes mellitus after liver transplantation: the critical role of hepatitis C infection. Liver Transpl 349:355, 2004 8. Baid S, Cosimi AB, Farrell ML, et al: Posttransplant diabetes mellitus in liver transplant recipients: risk factors, temporal relationship with hepatitis C virus allograft hepatitis, and impact on mortality. Transplantation 72:1066, 2001 9. Bigam DL, Pennington JJ, Carpentier A, et al: Hepatitis C-related cirrhosis: a predictor of diabetes after liver transplantation. Hepatology 32:87, 2000

KISHI, SUGAWARA, TAMURA ET AL 10. Tueche SG: Diabetes mellitus after liver transplant new etiologic clues and cornerstones for understanding. Transplant Proc 35:1466, 2003 11. Soule JL, Olyaei AJ, Boslaugh TA, et al: Hepatitis C infection increases the risk of new-onset diabetes after transplantation in liver allograft recipients. Am J Surg 189:552, 2005 12. Marroni CA, Hoppe L, Diehl JL, et al: Diabetes mellitus and liver transplantation in adults. Transplant Proc 31:3046, 1999 13. Steinmuller TH, Stockmann M, Bechstein WO, et al: Liver transplantation and diabetes mellitus. Exp Clin Endocrinol Diabetes 108:401, 2000 14. Sugawara Y, Makuuchi M, Matsui Y, et al: Preemptive therapy for hepatitis C virus after living donor liver transplantation. Transplantation 78:1308, 2004 15. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 20:1183, 1997 16. Marchetti P: New-onset diabetes after liver transplantation: from pathogenesis to management. Liver Transpl 11:612, 2005 17. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 26(suppl 1):S5, 2003 18. Terrault NA: Treatment of recurrent hepatitis C in liver transplant recipients. Clin Gastroenterol Hepatol 3(suppl 2):S125, 2005 19. Koivisto VA, Pelkonen R, Cantell K: Effect of interferon on glucose tolerance and insulin sensitivity. Diabetes 38:641, 1989