Fw: NATAP: Diabetes, HCV & Liver Transplantation
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Is there a link between hepatitis C virus and new onset of diabetes mellitus after liver transplantation? EDITORIAL
Liver Transplantation Jan 2007
Paul J. Thuluvath *
Department of Hepatology, The Johns Hopkins University School of Medicine, Baltimore, MD
â?oâ?¦.Liver disease is an additional risk factor for the development of diabetes (DM). A higher prevalence of glucose intolerance is seen in patients with liver disease regardless of the cause of liver disease, and this is perhaps due to reduced hepatic uptake of glucose, insulin resistance, or hyperinsulinemiaâ?¦..the mechanisms remain unclear. The speculated mechanisms include insulin resistance induced by chronic inflammation and possibly mediated by activation of tumor necrosis factor alpha (TNF-a), direct pancreatic beta cell damage, or autoimmunityâ?¦.HCV may have direct involvement in the pathogenesis of insulin resistance. In these models, as in humans, high levels of TNF-a were observed, and the authors suggested that TNF-a might induce insulin resistanceâ?¦..chronic HCV hepatitis [may] unmask DM in susceptible subjects by the interplay of genetics, insulin resistance, hyperinsulinemia, islet cell dysfunction, and liver diseaseâ?¦.As we develop newer immunosuppressive drugs, we now have the ability to improve the control of diabetes by tailoring and manipulating the medications in liver transplant recipients.â?
New-onset diabetes mellitus (NODM) is seen in 10-30% of renal and 9-21% of liver transplant recipients.[1-14] Older age, black race, obesity, hepatitis C virus (HCV) infection, family history of diabetes mellitus (DM), and use of tacrolimus or corticosteroids are important risk factors that predict the development of NODM in transplant recipients.[1-14] There is wide variation (5-15%) in the incidence rates of NODM after liver transplantation in published studies.[4-14] Potential factors that may explain the differences in the incidence rates of NODM may include reporting bias, sample size, definition of NODM, transient nature of DM, immunosuppressive regimens, and confounding factors such as age, race, family history of DM, and body mass index. It is also probable that many of these patients had occult DM that was masked by severe liver disease before transplantation, and alternatively, preexisting DM may disappear after liver transplantation in some patients.
In this issue, Saliba et al. report NODM, defined as fasting blood glucose >126 mg/dL on 2 separate occasions or the use of oral antidiabetic agents or insulin, in 48 (22.7%) of 211 liver transplant recipients who were randomly selected from 10 centers in France. In addition, 12.4% of patients who had normal pretransplantation glucose developed impaired fasting glucose, defined as 2 fasting measurements of blood glucose between 110 and 126 mg/dL. Overall, 35.1% of patients had evidence of either NODM or impaired fasting glucose. It is important to note that only patients who were not overtly diabetic before liver transplantation were selected for this study, but 26 patients (12.3%) had impaired fasting glucose before transplantation. Most patients (81.3%) developed DM within 3 months after transplantation, and an additional 14.6% developed NODM at 3-6 months. In patients with HCV antibody (36 of 211), the incidence of NODM was 41.7 vs. 18.9% without HCV antibody; the difference (46.7 vs. 19.3%) was similar when only those patients receiving tacrolimus therapy (n = 175) were analyzed. Apart from HCV, other independent predictors for the development of DM were pretransplantation impaired fasting glucose and maximum lifetime body mass index >30 kg/m2. The authors conclude that tacrolimus induces a higher incidence of NODM in the HCV-positive compared with HCV-negative patients.
What can we learn from this study? It confirms that a marked number of patients develop NODM after liver transplantation. However, it is important to note that this is a retrospective, cross-sectional study with variable duration (6-24 months) of post-liver transplantation follow-up. Almost all patients developed DM when they were receiving corticosteroids, and most patients (81.3%) were diagnosed within 3 months of transplantation. The mean time to the onset or detection of DM in this study has been less than 2 months - much shorter than previously reported. In a previous study, 24 (27%) of 88 patients were found to have DM at the end of the first postoperative year and were considered as having NODM, but at the second year after liver transplantation, only 8 patients (9%) had evidence of DM, which implies the transient nature of DM in many transplant recipients. This may suggest that many patients in the cohort studied by Saliba et al. may not have diabetes with longer follow-up, especially when corticosteroid therapy is discontinued. However, this does not reduce the importance of their findings if patients were receiving similar doses of corticosteroids. It is unclear whether the actual dose or dose adjusted for body weight is more relevant for the development of corticosteroid-induced DM in transplant recipients. The authors do not provide data on median or mean corticosteroid dose when NODM was diagnosed. Another concern with this study was that the diagnosis of NODM was made on the basis of fasting blood glucose on 2 separate occasions. In a retrospective study from 10 centers, it may not be safe to assume that the blood glucose was drawn in a fasting state even in the most compliant patients.
It appears that 30% of patients with NODM were not receiving insulin or oral antidiabetic agents. This could either mean that physicians were not closely following these blood tests or that they did not believe that many (35.4%) of these patients had DM. Although this study had only 36 patients with HCV antibody, the increased incidence of NODM in patients with HCV is noteworthy and confirms the trends seen in previous studies. This alleged relationship between HCV and DM merits more detailed investigation, but there is no evidence in this study, as claimed by the authors, to suggest that tacrolimus induce higher incidence of NODM in the HCV-positive compared with HCV-negative patients because only 6 of 36 patients who were receiving cyclosporine had HCV antibody. It is probably true that tacrolimus is more diabetogenic than cyclosporine, but only a controlled trial comparing tacrolimus and cyclosporine in patients with and without HCV could address whether tacrolimus is more likely to induce DM in patients with HCV.
How does one explain the possible link between HCV and NODM? The increased incidence of NODM in patients with HCV is not unique to liver transplant recipients with HCV. A meta-analysis suggested renal transplant recipients with HCV are also more likely to develop NODM. Liver disease is an additional risk factor for the development of DM. A higher prevalence of glucose intolerance is seen in patients with liver disease regardless of the cause of liver disease, and this is perhaps due to reduced hepatic uptake of glucose, insulin resistance, or hyperinsulinemia.[17-20] Several studies have reported a higher prevalence of type 2 DM in patients with HCV infection.[21-32] However, there are studies that failed to find an association between HCV and DM. This was not unexpected because DM is a common condition, and the prevalence of DM in patients with liver disease may be influenced by many confounding factors such as age, sex, race, body mass index, or severity of liver disease. Despite the increasing evidence suggesting a possible role of HCV in the pathogenesis of type 2 DM, the mechanisms remain unclear. The speculated mechanisms include insulin resistance induced by chronic inflammation and possibly mediated by activation of tumor necrosis factor alpha (TNF-), direct pancreatic beta cell damage, or autoimmunity.[34-39] Recently, by use of a transgenic mouse model for the HCV core gene, it has been suggested that HCV may have direct involvement in the pathogenesis of insulin resistance. In these models, as in humans, high levels of TNF- were observed, and the authors suggested that TNF- might induce insulin resistance by disturbing tyrosine phosphorylation of insulin receptor substrate 1. It is possible that chronic HCV hepatitis unmasks DM in susceptible subjects by the interplay of genetics, insulin resistance, hyperinsulinemia, islet cell dysfunction, and liver disease.
Finally, what is the effect of NODM on graft and patient survival? Although the short-term survival is excellent in patients who develop NODM, it is associated with marked morbidity. A higher incidence of renal failure and rapid progression of recurrent HCV hepatitis has been reported in patients with NODM in addition to infections and other cardiovascular complications. The duration of DM and control of blood sugar are 2 important factors that predict the development of vascular and renal complications, and to date, to our knowledge, there are no published long-term studies in patients who develop NODM after liver transplantation. It is probable that NODM will effect long-term survival, and therefore it is important to continue to study the impact of NODM and its intervention on long-term graft and patient survival in patients with and without HCV. As we develop newer immunosuppressive drugs, we now have the ability to improve the control of diabetes by tailoring and manipulating the medications in liver transplant recipients.
Risk factors for new-onset diabetes mellitus following liver transplantation and impact of hepatitis c infection : An observational multicenter study
Faouzi Saliba 1 *, Mohamed Lakehal 2, Georges-Philippe Pageaux 3, Bruno Roche 1, Claire Vanlemmens 4, Christophe Duvoux 5, JÃ©rÃ´me Dumortier 6, Ephrem SalamÃ© 7, Yvon Calmus 8, Didier Maugendre 9, Diapason Study Group
1Assistance Publique-HÃ´pitaux de Paris, HÃ´pital Paul Brousse, Centre hÃ©pato-biliaire, Villejuif, France
2HÃ´pital Pontchaillou, Chirurgie digestive et transplantation hÃ©patique, Rennes, France
3HÃ´pital Saint-Eloi, Transplantation hÃ©patique, Montpellier, France
4HÃ´pital Jean Minjoz, HÃ©patologie et transplantation hÃ©patique, BesanÃ§on, France
5Assistance Publique-HÃ´pitaux de Paris, HÃ´pital Henri Mondor, HÃ©patologie et transplantation hÃ©patique, CrÃ©teil, France
6HÃ´pital Edouard Herriot, Transplantation hÃ©patique, Lyon, France
7Centre Hospitals-Universitaire de la CÃ´te de Nacre, Chirurgie digestive et transplantation hÃ©patique, Caen, France
8Assistance Publique-HÃ´pitaux de Paris, HÃ´pital Cochin, Transplantation hÃ©patique, Paris, France
9HÃ´pital Pontchaillou, Endocrinologie DiabÃ©tologie Nutrition, Rennes, France (in memoriam)
New-onset diabetes mellitus (NODM) remains a common complication of liver transplantation (LT). We studied incidence and risk factors in 211 French patients who had undergone a primary LT between 6 and 24 months previously. This is a cross-sectional and retrospective multicenter study. Data were collected on consecutive patients at a single routine post-LT consultation. Demographic details, immunosuppressive regimens, familial and personal histories, hepatitis status, and cardiovascular risk were analyzed to compare those who developed NODM (American Diabetes Association/World Health Organization criteria) with the others. The overall incidence of NODM was 22.7%: 24% in tacrolimus (Tac)-treated patients (n = 175; 82.9%) and 16.7% in cyclosporine-treated patients (n = 36; 17.1%). A total of 81% of the cases were diagnosed within 3 months of LT (M3). Among hepatitis C virus (HCV)-infected (HCV(+)) patients, NODM incidence was 41.7% whereas among those patients negative for this virus (HCV(-)), the incidence was only 18.9% (P = 0.008). In Tac-treated patients, the incidence of NODM in the HCV(+) patients was significantly higher than in the HCV(-) patients (46.7% and 19.3%, respectively, P = 0.0014). Only 1 of 6 (16.7%) of the HCV(+) patients developed NODM on cyclosporine. Other independent pretransplantation risk factors for NODM included impaired fasting glucose (IFG) and a maximum lifetime body-mass index (BMI) over 25 kg/m2. In conclusion, emergence of NODM after LT is related to risk factors that can be detected prior to the graft, like maximum lifetime BMI, IFG, and HCV status. Tac induced a significantly higher incidence of NODM in the HCV(+) compared to the HCV(-) patients. The treatment should therefore be tailored to the patient's risk especially in case of HCV infection.
The development of new-onset diabetes (NODM) after transplantation remains one of the major challenges to reducing premature deaths in recipients of solid organ transplants. The condition is associated with an increase in cardiovascular morbidity and mortality, impaired graft survival and function, more infections, and overall reductions in quality of life and patient survival. NODM is a major predisposing factor for cardiovascular disease and its complications which are second only to tumors as the most common cause of death following liver transplantation (LT). NODM has also been shown to be an independent risk factor for both overall and infection-related mortality in liver transplant recipients.
The exact incidence of NODM remains unclear, largely because studies have used different diagnostic criteria, and posttransplantation blood glucose screening has been patchy. Variations in incidence estimates may also result from differences in follow-up time, whether or not the condition is persistent or transient, and the immunosuppressive regimens prescribed. A recent systematic review of 16 studies of posttransplantation NODM reported a mean incidence of 18.2% in liver transplant recipients on a tacrolimus (Tac)-based regimen compared with 7.7% in patients on a cyclosporine regimen. Other estimates vary between under 10% and over 30%.
No definitive risk factors for NODM have yet been clearly established but characteristics such as advanced age, ethnic origin, family history, obesity, and hepatitis C virus (HCV) infection have all been implicated. Among potentially modifiable factors, immunosuppressive agents have known diabetogenic effects and are a major contributor to the development of NODM. The diabetogenic effects of different immunosuppressive drugs vary greatly, calcineurin inhibitors being less active than steroids. Although both Tac and cyclosporine have been associated with an increased incidence in NODM, several studies have found that the risk is up to 5 times higher with Tac.[10-13] Given the recent emergence of the existence of a clear link between HCV infection and Type II diabetes mellitus (DM) as well as direct evidence as to a link with NODM, choosing a less diabetogenic immunosuppressive regimen may be especially important in HCV-infected (HCV(+)) patients.
The proportion of patients surviving for more than 3 yr following LT is now around 75% and this survival rate could be further improved by reducing the incidence of NODM by careful selection of the most appropriate immunosuppressive therapy as well as by improved diagnosis and management. In kidney transplantation, NODM has been shown to be associated with impaired long-term graft function and reduced survival. One large-scale study reported that the relative risk of graft loss 12 yr after kidney transplantation was 3.72 times higher in patients who had developed NODM than in those with normal glucose metabolism.
We undertook an observational cross-sectional study to describe the incidence, risk factors, diagnosis, and management of NODM using American Diabetes Association/World Health Organization criteria, in a cohort of patients who had undergone LT between 6 and 24 months previously at 10 centers in France.
Impact of Hepatitis C
Among those with positive antibodies against HCV, the incidence of NODM was 41.7%, whereas among those negative for this virus, the incidence was only 18.9% (P = 0.008). Only one of the 6 HCV(+) patients in the CsA-ME group (16.7%) developed NODM compared to 5 of 29 of the HCV(-) patients (17.2%) (P = NS). In the Tac group, the incidence of NODM in the HCV(+) patients was significantly higher than in the HCV(-) patients (46.7% and 19.3%, respectively; P = 0.0014). Within the Tac group, the demographic characteristics of the HCV(+) patients were comparable to those of the HCV(-) patients (except for the mean time since transplantation which was shorter in HCV(+) patients) as were mean fasting preoperative blood glucose levels, maximum lifetime BMI, and corticosteroid dosage (Table 4). In contrast, the mean Tac dosage was higher in the HCV(-) patients (Table 4).
Univariate analysis detected 5 main discrete factors associated with the development of NODM (Table 5), namely positive hepatitis C serology, IFG prior to transplantation, a maximum lifetime BMI of over 25 kg/m2 (but also a maximum lifetime BMI of over 30 compared to 25 and 25-30), the presence of at least 2 cardiovascular risk factors, and, for women, a history of either having given birth to a baby weighing over 4 kg (n = 4) or gestational diabetes (n = 1). A BMI of over 25 kg/m2 at the time of transplantation also emerged as a risk factor with a strong correlation in the univariate analysis but was not kept in the multivariate analysis. Significant correlation emerged with the special composite cardiovascular risk factor based on a combination of at least 2 of the following items at the time of transplantation: male gender, BMI over 25 kg/m2, a family history of diabetes, hypertension, dyslipidemia, age of over 50 yr, or IFG.
Discrete factors that did not correlate with the development of NODM were: male gender, a family history of diabetes, age and gender of the organ donor, hepatitis B status, acute or corticosteroid-resistant rejection, steroid dosage at either M3 or over the whole evaluation period, and certain cardiovascular risk factors taken individually; namely, hypertension, dyslipidemia, and smoking.
Three of these parameters emerged as independent risk factors with strong correlations in a global multivariate analysis (Table 5); namely, evidence of IFG prior to transplantation (odds ratio = 3.8, P = 0.005), positive hepatitis C serology (odds ratio = 2.8, P = 0.01), and a maximum lifetime BMI of over 30 kg/m2 (odds ratio = 2.6, P = 0.003). The composite cardiovascular risk factor did not emerge as an independent risk factor, as well as maximum lifetime BMI of over 25. Other variables that were introduced into the model and rejected were age at the time of transplantation, a family history of diabetes, hepatitis B infection, and the corticosteroid dosage at M3.
The incidence of NODM in our study population was 22.7% (48/211) with 81.3% of cases being diagnosed within 3 months of receiving a primary LT. We also showed that 12.4% of the patients with normal pretransplantation glucose status (23/185) developed de novo IFG. We found a higher incidence of NODM in patients receiving Tac (24% vs. 16.7% in the CsA-ME group) even though the imbalance in numbers of patients taking each agent (82.9% in the Tac group vs. 17.1% in the CsA-ME group) reduced the power of our study to detect a statistically significant difference between the 2 groups (power of the test was only 23%).
Independent risk factors for developing NODM showed by multivariate analysis were HCV infection, IFG prior to transplantation, and a history of clinical obesity (as opposed to normal BMI). Presence of at least 2 cardiovascular risk factors and a history of gestational diabetes or a having given birth to a baby with a birth weight over 4 kg were also identified as risk factors by univariate analysis.
The numbers reported in this study might be underestimated limited by the study design (cross-sectional and retrospective approach). Estimates vary in the literature depending on the diagnostic criteria used for NODM and characteristics such as patient HCV status and immunosuppressive regimens used. Although Heisel et al. reported incidences of 18.2% and 7.7% for Tac-treated and CsA-treated patients in his meta-analysis, the diagnostic criteria used in the included studies were heterogeneous. In the 7 prospective, randomized trials in liver transplant patients included in the review, the average NODM rate was 15.9% for Tac-treated patients and 4.9% for CsA-treated patients. It is not surprising that these rates were lower than the rates in our study since these trials only included patients with insulin-dependent diabetes. In a later study not included in the systematic review, Khalili et al. reported an incidence of de novo diabetes of 37.7% in a cohort of over 900 U.S. patients included in the National Institute of Diabetes and Digestive and Kidney Diseases-Liver Transplant database. Of these, only 9.4% had persistent diabetes and since the presence of de novo diabetes was defined by the use of diabetic medications rather than laboratory measurements, the authors reported that it was probably an underestimate. Baid et al. reported an overall incidence of 38% in their series of 136 liver transplant recipients who did not have diabetes prior to transplantation. In an international, multicenter, randomized study comparing CsA-ME and Tac in de novo LT, NODM at 6 months was significantly more common with Tac: 14% compared to 7% with CsA-ME. In other studies of patients on Tac-based regimens, incidences of between 25% and 40% have also been reported.[18-21]
Methodological differences between studies make it difficult to compare reported incidences of NODM, and recent International Consensus Guidelines have emphasized the importance of using the standardized definitions and diagnostic criteria as endorsed by the World Health Organization and the American Diabetes Association. We used these criteria in our study and also recorded rates of IFG before and after transplantation; these rates have not been reported consistently in other epidemiological reports. We confirmed the presence of abnormal glucose function by a second measurement, so our estimate of NODM is more likely to reflect the incidence of persistent rather than transient NODM. Abnormal glucose regulation prior to transplantation has been implicated as a possible risk factor for NODM and IFG emerged as a strong predictor of the condition in our series, a finding which suggests that pretransplantation glucose screening may be important in helping to predict NODM.
Most of the other risk factors identified in our study have been reported in other studies in the setting of transplantation with the exception, to our knowledge, of maximum lifetime BMI. This parameter proved to be a better indicator than BMI at the time of transplantation, probably because the former better represents a personal tendency to be overweight since many patients are below their usual body weight at the time of transplantation.
We found HCV status to be a strong predictor of NODM, especially when combined with Tac immunosuppressive treatment: almost 1 of 2 (46.7%) of the HCV(+) patients who were taking Tac developed diabetes. This is consistent with the results of other studies in LT; in particular, Baid et al. reported incidences of 64% and 28% in HCV(+) and HCV(-) patients, respectively (P = 0.0001). The association between HCV and NODM has also been established in renal transplant recipients and notably, 1 study in HCV(+) kidney transplant recipients showed that NODM occurred more often in Tac-treated than CsA-ME-treated patients (57.8% vs. 7.7%; P < 0,0001). A large number of papers also mentioned the epidemiologic link between chronic HCV and type II diabetes even in absence of liver cirrhosis.[25-27] One hypothesis with regards to the biological mechanisms (probably multifactorial) is that the virus is directly involved in the development of insulin resistance. In addition to apparently exacerbating the risk of NODM, HCV infection has also been shown to be associated with a significantly lower survival compared with non-HCV(+) liver transplant recipients. In this work, independent risk factors for the worse outcome in HCV patients included increased donor age (P < 0.0001) and the use of Tac (P = 0.009). In other respects, there are growing in vitro and retrospective clinical data suggesting a potential advantage of CsA-ME vs. Tac in HCV(+) patients treated by antiviral bitherapy.[30-32] These convergent findings may lead to reconsider the immunosuppression in HCV(+) patients needing LT.
The age of the recipient did not emerge as a risk factor in our study, a finding consistent with some other reports but not others. NODM, like DM, is probably caused by a complex interaction between environmental and genetic factors. Our study suggests that it may eventually be possible to derive a composite risk factor equation for the development of NODM following liver transplantation with appropriate weighting for each variable, perhaps similar to the risk assessment instruments developed for the primary prevention of cardiovascular disease. A weighted multiple risk factor assessment equation would allow predictions of risk profiles for individual patients to inform posttransplantation management and selection of the least diabetogenic immunosuppressive regimen for patients with high risk of NODM. Given the high incidence of NODM in HCV(+) patients taking Tac, HCV status would be a major parameter; the findings presented here would tend to suggest that additional useful parameters to be included in such a composite might be IFG prior to transplantation and maximum lifetime BMI, together with parameters related to obstetrical history in women. In this study, the incidence of NODM was not significantly different in the small number of patients (16%) who reported a family history of diabetes compared with the majority that did not. Moreover, it may be worth taking stock of recent evidence that some genetic profiles (notably certain polymorphisms in the major histocompatibility complex) may predispose to DM (reviewed in She). More research using a common definition for NODM and consistent diagnostic criteria will be necessary to determine the precise contribution of each of these variables to the risk profile of patients undergoing LT. We found that recognition and management of NODM by physicians and patient education about diabetes is far from comprehensive.
In conclusion, in our study, emergence of NODM after LT is related to risk factors that can be detected prior to the graft: maximum lifetime BMI, IFG, and HCV status. Given the insidious onset of the condition and the potential for saving lives through judicious management tailored to risk profile, it is important to be vigilant in screening for the presence of NODM in recipients of liver transplants. Tac also induced a significantly higher incidence of NODM in the HVC(+) patients compared to the HVC(-) patients. The immunosuppressive treatment should therefore be tailored to the patient's risk, especially in case of HCV infection.
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