HCV Infection and Post-liver Transplant Diabetes
HCV Infection and Post-liver Transplant Diabetes
During the study period (2003–2012), a total of 17 121 exposed subjects (liver transplant recipients with HCV) and 1450 controls (liver transplant recipients with HBV) with at least one follow-up record were included. The distribution of the successful adult transplants across the study years was nearly uniform, ranging between 1805 and 2019 transplants per year with the exception of 2003 (N = 1742) and 2012 (N = 1469; likely due to delayed submission of follow-up data to UNOS).
Comparison of demographical parameters of hepatitis C patients (exposed subjects) and hepatitis B patients (controls) is shown in Table 1. In comparison to HBV controls, hepatitis C subjects were older, predominantly Caucasian or Hispanic rather than Asian, less likely to have a college degree and less likely to have private rather than publicly sponsored health insurance coverage (all P < 0.05, Table 1). Employment rate and functional status of the subjects were similar between the two groups (P > 0.05). Also, liver transplant recipients with HCV were more likely to be overweight and obese at the time of transplant than HBV controls (Table 2). Despite this, the proportions of those with a pre-transplant clinical diagnosis of diabetes were similar between hepatitis C and hepatitis B cohorts (P > 0.05, Table 2). On the other hand, a history of any malignancy (12.43% vs. 16.18%, P < 0.0001) or primary liver malignancy (10.62% vs. 13.45%, P = 0.0009) was higher in hepatitis B patients as compared to patients with HCV. The rates of other pre-transplant comorbidities were similar between HCV and HBV cohorts. In fact, MELD scores immediately prior to transplant were also similar between the two cohorts (Table 2). Nevertheless, the proportion of patients requiring re-transplantation was higher in HCV: 5.08% vs. 3.52%, P = 0.0086.
Post-liver transplantation, the rates of acute rejection were similar between the two cohorts. We also noted similar post-transplant immunosuppressive regimens, except for HCV subjects being slightly less likely to receive tacrolimus (Table 2).
In the studied cohort that included both HCV subjects and HBV controls, 32.1% of patients had type 2 diabetes during post-transplant follow-up. Of those, 69% had their first onset of DM recorded at the 6 months follow-up, and 82% had it no later than their 1 year follow-up.
Comparing liver transplant recipients in the HCV cohort to the controls, before transplantation, 13.67% of the hepatitis C cohort and 15.10% of the hepatitis B cohort had a history of type II diabetes (P = 0.15). However, in follow-up, 32.47% of patients with hepatitis C and 27.52% of HBV controls recorded at least one onset of diabetes at any time post-transplantation (P < 0.0001) (Table 3). The difference in the rate of post-transplant diabetes was observed starting as early as 6 months post-transplant when 22.47% of hepatitis C patients and 18.94% of hepatitis B patients reported having an onset of DM (P = 0.0043). With longer follow-up, both cumulative and incidental risks of developing post-transplant diabetes were consistently higher in the hepatitis C cohort (Table 3 and Figure 1). In particular, after 5 years post-liver transplantation, the relative risk (RR) of having diabetes was 18% higher among those with hepatitis C than HBV controls (RR = 1.18, 95% CI = 1.08–1.29, P = 0.0002). Furthermore, when the time to developing diabetes was studied, hepatitis C patients were found to have a 1.27 times per year higher chance of developing DM post-transplant when compared to hepatitis B patients (95% CI = 1.15–1.41, P < 0.0001) (Figure 1).
(Enlarge Image)
Figure 1.
Post-transplant diabetes in liver transplant recipients. Zero time point represents pre-transplant history of type II diabetes; N, number at risk.
In multivariate analysis with a Cox proportional hazard regression model (Table 4), after adjustment for important confounders, having hepatitis C was independently associated with the developing post-transplant diabetes: aHR = 1.55 (1.34–1.79), P < 0.0001. Other predictors of DM in post-transplant subjects included age at the time of transplant [aHR = 1.007 (1.003–1.012) per each additional year of age], nonwhite race or ethnicity, and having a history of pre-transplant diabetes [aHR = 2.12 (1.96–2.29)]. After applying multiple test correction, being overweight was not significantly associated with post-transplant DM in the studied cohort (adjusted P = 0.41), while being obese was still associated with an increased risk of developing DM: aHR = 1.12 (1.03–1.21), P < 0.0001. In our analysis, we noted that having primary liver malignancy was associated with lower risk of post-transplant DM [aHR = 0.84 (0.75–0.93)]. We believe this is most likely due to increased mortality in liver transplant patients with viral hepatitis and liver malignancy resulting in a high rate of loss to a competing risk. Finally, as expected, the use of steroids for immunosuppression was also associated with an increased risk of developing post-transplant DM [aHR = 1.47 (1.28–1.68)]. On the other hand, the use of other immunosuppressive medications such as tacrolimus and mycophenolates were not associated with DM post-LT (P > 0.05 after correction for multiple testing) (Table 4).
Calendar year was associated with lower risk of DM [0.926 (0.915–0.938) per year] indicating that, after adjustment for the confounders, the risk of developing post-transplant diabetes still decreases with time, potentially due to improvements in post-transplant management.
Since HCV and HBV populations were found to be ethnically different (2.1% vs. 42.1% of patients were Asians), we also repeated multivariate analysis is Asian and non-Asian cohorts separately. In these two cohorts, independent association of HCV and post-transplant DM was similarly significant: aHR = 1.476 (1.250–1.744) in non-Asians and 1.704 (1.298–2.235) in Asians, respectively (both P < 0.0001).
Since post-transplant DM that occurs in the first year post-transplant is most likely due to intense immunosuppression and could potentially resolve, we also studied long-term post-transplant DM defined. Long-term diabetes was defined as presence of clinical DM that did not resolve after the first year and continue to be reported in the subsequent years of follow-up. Defined this way, long-term DM persisted after the period of highest intensity for post-transplant immunosuppression and when the immunosuppressive regimen was generally stabilized. Patients with DM that resolved after the first year post-transplant were considered as having 'immunosuppression-related DM'.
Although the majority of cases of post-transplant DM resolved within the first year post-transplantation, HCV-infected patients tended to have lower rate of diabetes resolution (post-transplant DM resolution HCV 70.98%, HBV 74.94%, P = 0.0919). Among patients with HCV vs. HBV, the rate of long-term post-transplant DM was 9.40% vs. 7.29%, respectively, for the entire cohort [RR = 1.289 (1.036–1.603), P = 0.0209], and 6.47% vs. 4.75% in patients who did not have DM prior to liver transplantation [RR = 1.363 (1.002–1.854, P = 0.0462].
Results
During the study period (2003–2012), a total of 17 121 exposed subjects (liver transplant recipients with HCV) and 1450 controls (liver transplant recipients with HBV) with at least one follow-up record were included. The distribution of the successful adult transplants across the study years was nearly uniform, ranging between 1805 and 2019 transplants per year with the exception of 2003 (N = 1742) and 2012 (N = 1469; likely due to delayed submission of follow-up data to UNOS).
Comparison of demographical parameters of hepatitis C patients (exposed subjects) and hepatitis B patients (controls) is shown in Table 1. In comparison to HBV controls, hepatitis C subjects were older, predominantly Caucasian or Hispanic rather than Asian, less likely to have a college degree and less likely to have private rather than publicly sponsored health insurance coverage (all P < 0.05, Table 1). Employment rate and functional status of the subjects were similar between the two groups (P > 0.05). Also, liver transplant recipients with HCV were more likely to be overweight and obese at the time of transplant than HBV controls (Table 2). Despite this, the proportions of those with a pre-transplant clinical diagnosis of diabetes were similar between hepatitis C and hepatitis B cohorts (P > 0.05, Table 2). On the other hand, a history of any malignancy (12.43% vs. 16.18%, P < 0.0001) or primary liver malignancy (10.62% vs. 13.45%, P = 0.0009) was higher in hepatitis B patients as compared to patients with HCV. The rates of other pre-transplant comorbidities were similar between HCV and HBV cohorts. In fact, MELD scores immediately prior to transplant were also similar between the two cohorts (Table 2). Nevertheless, the proportion of patients requiring re-transplantation was higher in HCV: 5.08% vs. 3.52%, P = 0.0086.
Post-liver transplantation, the rates of acute rejection were similar between the two cohorts. We also noted similar post-transplant immunosuppressive regimens, except for HCV subjects being slightly less likely to receive tacrolimus (Table 2).
Post-transplant Diabetes
In the studied cohort that included both HCV subjects and HBV controls, 32.1% of patients had type 2 diabetes during post-transplant follow-up. Of those, 69% had their first onset of DM recorded at the 6 months follow-up, and 82% had it no later than their 1 year follow-up.
Comparing liver transplant recipients in the HCV cohort to the controls, before transplantation, 13.67% of the hepatitis C cohort and 15.10% of the hepatitis B cohort had a history of type II diabetes (P = 0.15). However, in follow-up, 32.47% of patients with hepatitis C and 27.52% of HBV controls recorded at least one onset of diabetes at any time post-transplantation (P < 0.0001) (Table 3). The difference in the rate of post-transplant diabetes was observed starting as early as 6 months post-transplant when 22.47% of hepatitis C patients and 18.94% of hepatitis B patients reported having an onset of DM (P = 0.0043). With longer follow-up, both cumulative and incidental risks of developing post-transplant diabetes were consistently higher in the hepatitis C cohort (Table 3 and Figure 1). In particular, after 5 years post-liver transplantation, the relative risk (RR) of having diabetes was 18% higher among those with hepatitis C than HBV controls (RR = 1.18, 95% CI = 1.08–1.29, P = 0.0002). Furthermore, when the time to developing diabetes was studied, hepatitis C patients were found to have a 1.27 times per year higher chance of developing DM post-transplant when compared to hepatitis B patients (95% CI = 1.15–1.41, P < 0.0001) (Figure 1).
(Enlarge Image)
Figure 1.
Post-transplant diabetes in liver transplant recipients. Zero time point represents pre-transplant history of type II diabetes; N, number at risk.
In multivariate analysis with a Cox proportional hazard regression model (Table 4), after adjustment for important confounders, having hepatitis C was independently associated with the developing post-transplant diabetes: aHR = 1.55 (1.34–1.79), P < 0.0001. Other predictors of DM in post-transplant subjects included age at the time of transplant [aHR = 1.007 (1.003–1.012) per each additional year of age], nonwhite race or ethnicity, and having a history of pre-transplant diabetes [aHR = 2.12 (1.96–2.29)]. After applying multiple test correction, being overweight was not significantly associated with post-transplant DM in the studied cohort (adjusted P = 0.41), while being obese was still associated with an increased risk of developing DM: aHR = 1.12 (1.03–1.21), P < 0.0001. In our analysis, we noted that having primary liver malignancy was associated with lower risk of post-transplant DM [aHR = 0.84 (0.75–0.93)]. We believe this is most likely due to increased mortality in liver transplant patients with viral hepatitis and liver malignancy resulting in a high rate of loss to a competing risk. Finally, as expected, the use of steroids for immunosuppression was also associated with an increased risk of developing post-transplant DM [aHR = 1.47 (1.28–1.68)]. On the other hand, the use of other immunosuppressive medications such as tacrolimus and mycophenolates were not associated with DM post-LT (P > 0.05 after correction for multiple testing) (Table 4).
Calendar year was associated with lower risk of DM [0.926 (0.915–0.938) per year] indicating that, after adjustment for the confounders, the risk of developing post-transplant diabetes still decreases with time, potentially due to improvements in post-transplant management.
Since HCV and HBV populations were found to be ethnically different (2.1% vs. 42.1% of patients were Asians), we also repeated multivariate analysis is Asian and non-Asian cohorts separately. In these two cohorts, independent association of HCV and post-transplant DM was similarly significant: aHR = 1.476 (1.250–1.744) in non-Asians and 1.704 (1.298–2.235) in Asians, respectively (both P < 0.0001).
Long-term Diabetes Post-liver Transplantation
Since post-transplant DM that occurs in the first year post-transplant is most likely due to intense immunosuppression and could potentially resolve, we also studied long-term post-transplant DM defined. Long-term diabetes was defined as presence of clinical DM that did not resolve after the first year and continue to be reported in the subsequent years of follow-up. Defined this way, long-term DM persisted after the period of highest intensity for post-transplant immunosuppression and when the immunosuppressive regimen was generally stabilized. Patients with DM that resolved after the first year post-transplant were considered as having 'immunosuppression-related DM'.
Although the majority of cases of post-transplant DM resolved within the first year post-transplantation, HCV-infected patients tended to have lower rate of diabetes resolution (post-transplant DM resolution HCV 70.98%, HBV 74.94%, P = 0.0919). Among patients with HCV vs. HBV, the rate of long-term post-transplant DM was 9.40% vs. 7.29%, respectively, for the entire cohort [RR = 1.289 (1.036–1.603), P = 0.0209], and 6.47% vs. 4.75% in patients who did not have DM prior to liver transplantation [RR = 1.363 (1.002–1.854, P = 0.0462].
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