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Alterations in carbohydrate metabolism in cirrhotic patients before and after liver transplant
DIAB-6476; No. of Pages 6 diabetes research and clinical practice xxx (2015) xxx–xxx
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Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres
Alterations in carbohydrate metabolism in cirrhotic patients before and after liver transplant Agustı´n Ramos-Prol a,b, David Herva´s-Marı´n c, Beatriz Rodrı´guez-Medina d, ´ ngel Moya-Herraiz d, Vicente Campos-Alborg a, Marina Berenguer d, A Juan Francisco Merino-Torres a,* a
Endocrinology and Nutrition Department, Hospital Universitario y Polite´cnico La Fe, Valencia, Spain Instituto de Investigacio´n Sanitaria La Fe (Health Research Institute La Fe), Valencia, Spain c Biostatistics Unit, Health Research Institute La Fe, Valencia, Spain d Liver Transplantation and Hepatology Unit, Hospital Universitario y Polite´cnico La Fe, Valencia, Spain b
article info
abstract
Article history:
Aim: The main objective of this study is to demonstrate whether carbohydrate metabolism
Received 1 May 2015
alterations identified in patients with advanced cirrhosis show any improvement after liver
Received in revised form
transplant.
6 September 2015
Methods: The study included 86 patients who underwent liver transplant between March
Accepted 1 October 2015
2010 and February 2011. An oral glucose tolerance test was performed before the liver
Available online xxx
transplant, and 6 and 12 months after. Beta cell function and insulin resistance were also calculated, applying formulae that use basal plasma glycaemia and insulin, and plasma
Keywords:
glycaemia and insulin during an oral glucose tolerance test. Risk factors for pre- and post-
Diabetes
transplant diabetes were also studied. The diagnosis of diabetes was based on an OGTT.
Carbohydrate metabolism
Results: The proportion of patients with diabetes before transplant, and at month 6 and 12
Liver cirrhosis
after transplant were 70.9%, 48.8% and 39.2%, respectively. Compared to baseline, at month
Liver transplantation
6 the odds ratio of having diabetes was 0.39 (IC 95% [0.21, 0.73]) and at month 12 it was 0.26 (IC
Insulin resistance
95% [0.14, 0.50]). The composite insulin sensitivity index values at 6 and 12 months were 1.72 units higher (IC 95% [0.84, 2.58]) and 1.58 units higher (IC 95% [0.68, 2.44)] than baseline. A statistically significant association was found between high MELD values and high body mass index, and risk of pre-transplant diabetes ( p = 0.001 and p = 0.033, respectively). Cirrhosis aetiology did not influence the risk of diabetes. Conclusions: In this study, we were able to ascertain that alterations in carbohydrate metabolism typical of advanced cirrhosis improve after liver transplant. This improvement is mainly due to an improvement in insulin resistance. # 2015 Elsevier Ireland Ltd. All rights reserved.
* Corresponding author. Tel.: +34 96 124 5554; fax: +34 96 124 6202. E-mail address: [email protected] (J.F. Merino-Torres). Abbreviations: HbA1c, glycated haemoglobin; OGTT, oral glucose tolerance test; IR-HOMA, homeostatis model assessment for insulin resistance; ISIc, composite insulin sensitivity index; SecrHOMA, homeostatic model assessment for the beta-cella function; FIP, first insulin release phase; SIP, second insulin release phase; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; ADA, American Diabetes Association; MELD, model for end stage liver disease; BMI, body mass index; SD, standard deviation; AUC, area under the curve. http://dx.doi.org/10.1016/j.diabres.2015.10.002 0168-8227/# 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Ramos-Prol A, et al. Alterations in carbohydrate metabolism in cirrhotic patients before and after liver transplant. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.10.002
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1.
Introduction
Glucose intolerance and diabetes are often observed in liver cirrhotic patients [1,2]. The primary alteration that occurs in cirrhotic patients is insulin peripheral resistance with predominance of postprandial hyperglycaemia. However, liver insulin sensitivity tends to remain unchanged, allowing liver glucose production to remain normal and be suppressed responding to insulin in a similar way to patients without cirrhosis [3]. Therefore, the basal glycaemia is not useful in the diagnosis of diabetes in cirrhotic patients. Neither glycated haemoglobin (HbA1c), nor fructosamine, nor 1,5-anhydroglucitol has proven to be useful for diagnosis of diabetes in cirrhotic patients [4–8]. Therefore, the Gold Standard to study alterations in the metabolism of carbohydrates in cirrhotic patients is the oral glucose tolerance test (OGTT). It is unclear whether the metabolism of carbohydrates improves after liver transplant. There are two factors that might influence glucose metabolism after liver transplant: the metabolic effects of the immunosuppressive medication and the persistence of pre-transplant metabolic alterations [9–13]. Several studies have shown a high prevalence of glucose intolerance in transplanted patients [14,15], but often these studies have not tested diabetes prevalence before transplant using the OGTT; hence, these studies are inconclusive as to whether there is an improvement or worsening after transplant. Studies that used the OGTT before and after liver transplant have generally used a low number of participants and the results are inconclusive. However, these studies seem to show that the peripheral insulin sensitivity improves after transplant [9,16,17]. The main objective is to study whether carbohydrate metabolism alterations identified in cirrhotic patients awaiting liver transplant show any improvement after transplant. The prevalence of diabetes before and after transplant was studied using the OGTT. Additional objectives were to determine changes to insulin resistance and insulin secretion, and to study risk factors to have pre- and post-transplant diabetes.
2.
Patients and methods
2.1.
Participants
This was a prospective and unicentric study. The use of the OGTT was recommended to screen for diabetes in patients who are on the hospital’s liver transplantation waiting list. The study included patients who underwent liver transplant between March 2010 and February 2011. Excluded from this study were: patients who had been recipients of other solid organ grafts (5), patients undergoing simultaneous transplant of another organ (3), and patients undergoing transplant due to fulminant liver failure (8). Eleven patients did not give consent and therefore were excluded from the study. In all, 86 patients participated in this study. Patients with known diabetes before liver transplant did not undergo an OGTT. The OGTT was repeated 6 and 12 months after liver transplant. Patients who showed basal glycaemia greater than
126 mg/dl or required anti-diabetic treatment were classified as patients with diabetes and they did not undergo an OGTT. Patients with known pre-transplant diabetes did not undergo OGTT and these patients were treated with steroidfree immunosuppression, according to the protocol used in our hospital. The hospital’s ethics commission approved the study and all patients gave their informed consent for their participation.
2.2.
Procedures
During 72 h prior to the OGTT, all patients were on a normocaloric diet with carbohydrate intake greater than 150 g/day and maintained a normal physical activity. The OGTT was done after an overnight fast for at least 12 h. Venous blood samples for determination of plasma glucose and insulin were taken from participants immediately before and at 30, 60, 90 and 120 min after oral intake of 75 g glucose. Plasma glucose was measured using enzymatic methods. Insulin was measured using immunoassay. The area under the glycaemia curve was calculated by the trapezoidal method. Insulin resistance was estimated using the following formulae: the HOMA index for insulin resistance (IR-HOMA) [18] and the composite insulin sensitivity index (ISIc) [19]. Insulin secretion was estimated using the following formulae: the HOMA index for the beta-cell function (SecrHOMA) [18], first insulin release phase (FIP) [20] and the second insulin release phase (SIP) [20]. IR-HOMA was calculated as follows: IRHOMA = [basal insulin (pmol/L) basal glucose (mmol/L)]/135. ISIc was calculated as follows: vffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi u ISIc ¼ 10000=u½basal glucose ðmg=dlÞ u t basal insulin ðmU=mlÞ ½mean glucose mean insulin during OGTT SecrHOMA was calculated as follows: SecrHOMA = [basal insulin basal(pmol/l) 3.33]/[basal glucose(mmol/l) 3.5]. FIP was calculated as follows: FIP = [1283 + 1.829 Insulin in minute 30 (pmol/l)] [138.7 glucose in minute 30 (mmol/ l) + 3.722 basal insulin]. SIP was calculated as follows: in minute 30 (pmol/ SIP = [287 + 0.4164 Insulin l)] [26.07 glucose in minute 30 (mmol/l) + 0.9226 basal insulin]. Diabetes was diagnosed according to the American Diabetes Association (ADA) criteria: patients with basal plasma glycaemia equal to, or greater than, 126 mg/dl, glycaemia equal to, or greater than, 200 mg/dl 2 h after the OGTT and patients requiring anti-diabetic treatment. Impaired fasting glucose (IFG) was defined as fasting plasma glucose values of 100–125 mg/dl. Impaired glucose tolerance (IGT) was defined as glucose levels of 140–199 mg/dl 2 h after the OGTT. Patients with either IFG or IGT were classified as having pre-diabetes. Diabetes prevalence was compared before, at 6 and at 12 months after transplant. Changes in the area under the glucose curve and changes in insulin resistance and secretion were compared in patients who underwent an OGTT. Pre-transplant risk factors taken into account were: age, gender, body mass index (BMI), model for end stage liver disease (MELD) index [21], hypertension, dyslipidaemia and hepatitis C infection. The following factors were studied as risk factors for the occurrence of diabetes 12 months after
Please cite this article in press as: Ramos-Prol A, et al. Alterations in carbohydrate metabolism in cirrhotic patients before and after liver transplant. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.10.002
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transplant: age, gender, BMI, hypertension, dyslipidaemia, hepatitis C infection, prednisone, tacrolimus and cyclosporine treatment.
2.3.
Statistical analysis
Data were summarized by its mean and standard deviation, mean (SD), in the case of continuous variables and by its relative and absolute frequencies in the case of categorical variables. Statistical analysis was performed with the R software (version 3.0.2) and lme4 (version 1.0-5) R-library. A linear mixed effects model was used to evaluate the relationship between glucose curves and months post-transplantation adding patients as a random factor. Glucose curves were summarized with their area under the curve (AUC). A simpler model was also assessed where the proportion of patients with diabetes was modelled in terms of post-transplantation time (months) using logistic regression. Additionally, the evolution of IR-HOMA, Secr-HOMA, First Phase Insulin Release, Second Phase Insulin Release and ISIc was studied using linear mixed models.
3.
Results
Tables 1 and 2 summarize patients’ clinical characteristics at baseline, and at 6 and 12 months after transplant, respectively. Nineteen patients (21.9%) had diabetes known before liver transplant and 7 (8.1%) were known to have IFG. Sixty-seven patients underwent an OGTT, of which 13 (19.4%) had IGT criteria and 45 (77.2%) met diabetes criteria. Globally, 64 patients (74.4%) had diabetes before transplant and 13 (15.1%) were classified as pre-diabetes (IFG or IGT). At the sixth month, 26 patients (30.2%) had basal glycaemia indicative of diabetes or were undergoing anti-diabetes treatment and 15 (17.4%) had IFG. Sixty patients underwent an OGTT, of which 24 (40%) met IGT criteria and 17 (28.3%) diabetes criteria. Globally, 43 patients (50%) had diabetes at the sixth month after transplant and 24 (27.9%) were classified as pre-diabetes. At the twelfth month, 7 patients had died. Of the remaining patients, 14 (17.7%) had basal glycaemia indicative of diabetes
Table 2 – Clinical data of patients 6 and 12 months after transplant. Time after transplant 6 months 86 N BMI (kg/m2) 26.4 (5.8) 48.8% HTA 26.7% Dyslipidemia 50.0% Diabetes Pre-diabetes 27.9% Current immunosuppressive regimen 39.5% Tacrolimus 52.3% Cyclosporine 69.8% Prednisone 62.8% Mycophenolate 5.8% Monotherapy 50.0% Dual therapy 44.2% Triple therapy
12 months 79 27.0 (6.1) 53.2% 25.3% 40.5% 26.6% 38.4% 51.2% 25.6% 57% 20.9% 65.1% 14.0%
Data are mean (SD) or percentage.
or were undergoing anti-diabetes treatment and 14 (17.7%) had IFG. Sixty-five patients underwent an OGTT, of which 21 (32.3%) met IGT criteria and 18 (27.7%) diabetes criteria. Globally, 32 patients (40.5%) had diabetes at the twelfth month after transplant and 21 (26.6%) were classified as pre-diabetes (Fig. 1). Only one patient without diabetes before liver transplant met diabetes criteria 12 months after transplant. Glucose curves had a mean area of 898.9 (174.8) at baseline. At month 6 the mean area under the glucose curves was 776.2 (171.2) and at month 12 the mean area was 785.1 (144.6). A statistically significant association was found between time (months) after transplantation and the area under the glucose curve ( p < 0.001). Area at 6th month was 120.38 units lower than area at baseline (IC 95% [79.6, 161.3]) and area at 12th month was 116.93 units lower than area at baseline (IC 95% [74.5, 159.2]). There was no statistically significant difference between areas at 6th and at 12th month (Fig. 2). The proportion of patients with diabetes before transplantation was 74.4%. The proportion of patients with diabetes at month 6 and 12 were 50% and 40.5%, respectively. A statistically significant association was also found between months post transplantation and proportion of patients with diabetes ( p < 0.001). Compared to baseline, at month 6 the
Table 1 – Clinical data of patients at baseline. N Gender ratio (m/f) Age (years) BMI (kg/m2) MELD score HCV infection HBV infection HEV infection Hepatocellular carcinoma History of alcoholism Diabetes Pre-diabetes HTA Dyslipidemia Data are means (SD) or percentage.
86 71/15 54.4 (8.2) 25.8 (4.4) 17.6 (5.6) 43.7% 11.6% 2.3% 36% 62.8% 74.4% 15.1% 19.5% 11.5%
Fig. 1 – Percentage of patients with diabetes and prediabetes before liver transplant and at 6 and 12 months after transplant.
Please cite this article in press as: Ramos-Prol A, et al. Alterations in carbohydrate metabolism in cirrhotic patients before and after liver transplant. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.10.002
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Fig. 2 – Mean and 95% C.I. areas under the glycaemia curves for baseline and months 6 and 12 after transplantation.
odds ratio of having diabetes was 0.39 (IC 95% [0.21, 0.73]) and at month 12 it was 0.26 (IC 95% [0.14, 0.50]). We found no association between IR-HOMA and time ( p = 0.56), Secr-HOMA and time ( p = 0.54) and first and second phase insulin release ( p = 0.69 and p = 0.64 respectively), but we found a statistically significant association for ISIc ( p < 0.001). ISIc values at 6th and 12th month were 1.72 units higher (IC 95% [0.84, 2.58]) and 1.58 units higher (IC 95% [0.68, 2.44)] than baseline. A statistically significant association was found between high MELD values and risk of pre-transplant diabetes ( p = 0.001). Likewise, a significant association was found between high BMI and risk of pre-transplant diabetes ( p = 0.033). No association with risk of diabetes was found in the remaining variables studied. It was found that a diabetes history before transplant was a risk factor of post-transplant diabetes ( p = 0.003). It was also found a trend ( p = 0.072) to a greater risk of post-transplant diabetes in patients with dyslipidemia. A statistically significant association was found between the administration of prednisone and a reduction of the risk of diabetes ( p = 0.025).
4.
Discussion
In our study, 89.5% of cirrhotic patients had alterations in carbohydrate metabolism and 74.4% had diabetes before liver transplant. Six months after transplant, the percentage of patients who had alterations in carbohydrate metabolism was 77.9% and the percentage of patients with diabetes was 50%. Twelve months after transplant, the percentage of patients with alterations in carbohydrate metabolism was 67.1%, and the percentage of patients with diabetes was 40.5%. Thus, this study shows that the high percentage of patients with alterations in carbohydrate metabolism before liver transplant decreases significantly after liver transplant. It is known that cirrhotic patients present an increased prevalence of diabetes, although many times this prevalence is not well studied, as only basal glycaemia is used for diagnosis. In cirrhotic patients, there are various alterations that explain the high prevalence of diabetes. For example, there is a decrease in peripheral insulin sensitivity, due to the
reduction of non-oxidative glucose metabolism in skeletal muscle tissue [22–27]. It has been demonstrated that these patients may present a 40–50% decrease in whole body glucose uptake [28,29]. In addition, advanced cirrhotic patients present a reduction of the two first beta-cell secretion phases. Other contributing factors to hyperglycaemia in cirrhotic patients are the prevalence of hepatocellular carcinoma, which favours the release of tumour necrosis factors and insulin-like growth factors that produce resistance to insulin [30–32]. These alterations cause postprandial hyperglycaemia in cirrhotic patients, with normal basal glycaemia. As HbA1c is not useful to diagnose diabetes in this type of patient, the OGTT appears to be the Gold Standard to study carbohydrate alterations in cirrhotic patients. There are few studies that evaluate the prevalence of diabetes in pre- and post-liver transplant patients and results of them have been conflicting. Papers such as those by Merli et al. [16] showed glucose tolerance improvement after transplant. However, other studies, such as Schneiter et al. [17], showed no significant changes. In general, the main limiting factor of these studies is the low number of patients. In our work, we had a sample of 86 patients with liver cirrhosis in which we studied carbohydrate metabolism before and after transplant, using basal glycaemia and the OGTT as methods to diagnose diabetes. We proved an improvement in the alterations in carbohydrate metabolism in two ways. First, the area under the glucose curve in an OGTT carried out at 6 and 12 months after liver transplant is significantly smaller than in an OGTT carried out before transplant. Second, the total ratio of patients with diabetes falls significantly at 6 and 12 months after transplant. This study also included evolution of beta function and insulin resistance, applying formulae that use basal plasma glycaemia and insulin or during an OGTT. Insulin sensitivity studied by ISIc showed an improvement in relation to basal of 1.72 units at 6 months and of 1.58 units at 12 months. IR-HOMA results do not vary after transplant. This may be explained because IR-HOMA only uses the calculation of basal glycaemia and insulin, whilst ISIc uses glycaemia and insulin calculated during OGTT. It is known that postprandial glycaemia is altered in cirrhotic patients but not basal glycaemia [3]; thus, it makes sense that after transplant there are no changes in results from formulae using basal glycaemia only. Results from formulae that study beta function (SecrHOMA, FIP and SIP) had no significant variation after transplant. Analysis of diabetes risk factors before liver transplant shows that BMI and the severity of descompensation of liver cirrhosis according to the MELD score, are the key risk factors. The relationship between HCV and diabetes is controversial. Several epidemiological studies have associated hepatitis C infection with diabetes risk [33,34], suggesting that activation of TNF-a may be the cause of the increase in diabetes risk [35]. The problem is that few of these studies are population-based or have applied standard criteria for the diagnosis of diabetes. A case-cohort study suggested that HCV infection increased the risk of diabetes but did not include enough cases to draw a definitive conclusion [36]. A Taiwanese community-based cohort study found a strong association of HCV infection with diabetes risk (HR 1.7; 95% CI: 1.3–2.1) [37]. However, in an
Please cite this article in press as: Ramos-Prol A, et al. Alterations in carbohydrate metabolism in cirrhotic patients before and after liver transplant. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.10.002
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Italian population-based cohort study, HCV infection was unrelated to incident diabetes [38], and a recent study by Ruhl et al. [39] including data from 15,128 participants from the US National Health and Nutrition Examination Survey, did not show a significant association between hepatitis C and diabetes risk. The limitations of the latter study were that was retrospective and the proportion of patients with HCV infection was small (1.7%). In our study with advanced cirrhotic patients, it was also not demonstrated that hepatitis C was associated with diabetes risk, but sample size is small compared to other studies that analyse this topic. Therefore, the results are not conclusive. There are two factors after liver transplant that may influence glucose metabolism: persistence of pre-transplant alterations and the effects of immunosuppressive medication (it has also been proposed that alterations in regulation response caused by denervation of the graft may influence glucose metabolism, but this factor was ruled out in a study by Perseghin et al. [40]). None of the studied immunosuppressants has shown to be a major diabetes risk in patients with liver graft. However, a contradiction is that prednisone appears as a diabetes protector factor; however, this result is due to a bias, because according to our hospital’s protocol, patients undergoing diabetes treatment before liver transplant are prescribed immunosuppressors without corticoids, and pre-transplant diabetes is a risk factor for the occurrence of post-transplant diabetes. Other immunosuppressive medications associated with diabetes risk are tacrolimus and cyclosporine. Some studies have reported that diabetes risk is greater with the use of tacrolimus [13,41], but others have shown no difference when comparing both drugs [9,42,43]. No statistically significant differences in carbohydrate metabolism were found in this study between patients treated with tacrolimus and cyclosporine. In conclusion, in this study we were able to confirm that there is a large percentage of diabetes in patients with advanced cirrhosis, that may go unnoticed unless tested by an OGTT; and that alterations in carbohydrate metabolism improve after liver transplant, with a significant reduction in the percentage of diabetes. This improvement is mainly due to an improvement in insulin resistance, as shown by the calculation of insulin resistance parameters using ISIc. This study has also confirmed that diabetes risk factors in cirrhotic patients are BMI and the degree of cirrhosis as calculated by MELD. Last, according to results from this study, we conclude that immunosuppressive medication does not influence the risk of developing diabetes after liver transplant.
Authors’ contributions Agustı´n Ramos-Prol: Principal author, patient visits, testing, data collection; David Herva´s-Marı´n: bioestatistical analysis; Beatriz Rodrı´guez-Medina: help in search for patients, application of liver transplant protocols; Vicente Campos-Alborg: help in data collection; Marina Berenguer: help in coordination, help in search for patients, application of liver transplant ´ ngel Moya-Herraiz: help in search for patients, protocols; A application of surgery and liver transplant protocols; Juan
5
Francisco Merino-Torres: help in coordination, help in analysis and discussion, and help in data collection.
Financial support None.
Conflict of interest The authors declare that there are no potential conflicts of interest relevant to this article.
Acknowledgments Agustı´n Ramos-Prol and Juan Francisco Merino-Torres are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. English writing was performed with the help of the service ‘‘OnLine EnglishTM Superior English Editing’’.
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Please cite this article in press as: Ramos-Prol A, et al. Alterations in carbohydrate metabolism in cirrhotic patients before and after liver transplant. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.10.002
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Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres
Alterations in carbohydrate metabolism in cirrhotic patients before and after liver transplant Agustı´n Ramos-Prol a,b, David Herva´s-Marı´n c, Beatriz Rodrı´guez-Medina d, ´ ngel Moya-Herraiz d, Vicente Campos-Alborg a, Marina Berenguer d, A Juan Francisco Merino-Torres a,* a
Endocrinology and Nutrition Department, Hospital Universitario y Polite´cnico La Fe, Valencia, Spain Instituto de Investigacio´n Sanitaria La Fe (Health Research Institute La Fe), Valencia, Spain c Biostatistics Unit, Health Research Institute La Fe, Valencia, Spain d Liver Transplantation and Hepatology Unit, Hospital Universitario y Polite´cnico La Fe, Valencia, Spain b
article info
abstract
Article history:
Aim: The main objective of this study is to demonstrate whether carbohydrate metabolism
Received 1 May 2015
alterations identified in patients with advanced cirrhosis show any improvement after liver
Received in revised form
transplant.
6 September 2015
Methods: The study included 86 patients who underwent liver transplant between March
Accepted 1 October 2015
2010 and February 2011. An oral glucose tolerance test was performed before the liver
Available online xxx
transplant, and 6 and 12 months after. Beta cell function and insulin resistance were also calculated, applying formulae that use basal plasma glycaemia and insulin, and plasma
Keywords:
glycaemia and insulin during an oral glucose tolerance test. Risk factors for pre- and post-
Diabetes
transplant diabetes were also studied. The diagnosis of diabetes was based on an OGTT.
Carbohydrate metabolism
Results: The proportion of patients with diabetes before transplant, and at month 6 and 12
Liver cirrhosis
after transplant were 70.9%, 48.8% and 39.2%, respectively. Compared to baseline, at month
Liver transplantation
6 the odds ratio of having diabetes was 0.39 (IC 95% [0.21, 0.73]) and at month 12 it was 0.26 (IC
Insulin resistance
95% [0.14, 0.50]). The composite insulin sensitivity index values at 6 and 12 months were 1.72 units higher (IC 95% [0.84, 2.58]) and 1.58 units higher (IC 95% [0.68, 2.44)] than baseline. A statistically significant association was found between high MELD values and high body mass index, and risk of pre-transplant diabetes ( p = 0.001 and p = 0.033, respectively). Cirrhosis aetiology did not influence the risk of diabetes. Conclusions: In this study, we were able to ascertain that alterations in carbohydrate metabolism typical of advanced cirrhosis improve after liver transplant. This improvement is mainly due to an improvement in insulin resistance. # 2015 Elsevier Ireland Ltd. All rights reserved.
* Corresponding author. Tel.: +34 96 124 5554; fax: +34 96 124 6202. E-mail address: [email protected] (J.F. Merino-Torres). Abbreviations: HbA1c, glycated haemoglobin; OGTT, oral glucose tolerance test; IR-HOMA, homeostatis model assessment for insulin resistance; ISIc, composite insulin sensitivity index; SecrHOMA, homeostatic model assessment for the beta-cella function; FIP, first insulin release phase; SIP, second insulin release phase; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; ADA, American Diabetes Association; MELD, model for end stage liver disease; BMI, body mass index; SD, standard deviation; AUC, area under the curve. http://dx.doi.org/10.1016/j.diabres.2015.10.002 0168-8227/# 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Ramos-Prol A, et al. Alterations in carbohydrate metabolism in cirrhotic patients before and after liver transplant. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.10.002
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1.
Introduction
Glucose intolerance and diabetes are often observed in liver cirrhotic patients [1,2]. The primary alteration that occurs in cirrhotic patients is insulin peripheral resistance with predominance of postprandial hyperglycaemia. However, liver insulin sensitivity tends to remain unchanged, allowing liver glucose production to remain normal and be suppressed responding to insulin in a similar way to patients without cirrhosis [3]. Therefore, the basal glycaemia is not useful in the diagnosis of diabetes in cirrhotic patients. Neither glycated haemoglobin (HbA1c), nor fructosamine, nor 1,5-anhydroglucitol has proven to be useful for diagnosis of diabetes in cirrhotic patients [4–8]. Therefore, the Gold Standard to study alterations in the metabolism of carbohydrates in cirrhotic patients is the oral glucose tolerance test (OGTT). It is unclear whether the metabolism of carbohydrates improves after liver transplant. There are two factors that might influence glucose metabolism after liver transplant: the metabolic effects of the immunosuppressive medication and the persistence of pre-transplant metabolic alterations [9–13]. Several studies have shown a high prevalence of glucose intolerance in transplanted patients [14,15], but often these studies have not tested diabetes prevalence before transplant using the OGTT; hence, these studies are inconclusive as to whether there is an improvement or worsening after transplant. Studies that used the OGTT before and after liver transplant have generally used a low number of participants and the results are inconclusive. However, these studies seem to show that the peripheral insulin sensitivity improves after transplant [9,16,17]. The main objective is to study whether carbohydrate metabolism alterations identified in cirrhotic patients awaiting liver transplant show any improvement after transplant. The prevalence of diabetes before and after transplant was studied using the OGTT. Additional objectives were to determine changes to insulin resistance and insulin secretion, and to study risk factors to have pre- and post-transplant diabetes.
2.
Patients and methods
2.1.
Participants
This was a prospective and unicentric study. The use of the OGTT was recommended to screen for diabetes in patients who are on the hospital’s liver transplantation waiting list. The study included patients who underwent liver transplant between March 2010 and February 2011. Excluded from this study were: patients who had been recipients of other solid organ grafts (5), patients undergoing simultaneous transplant of another organ (3), and patients undergoing transplant due to fulminant liver failure (8). Eleven patients did not give consent and therefore were excluded from the study. In all, 86 patients participated in this study. Patients with known diabetes before liver transplant did not undergo an OGTT. The OGTT was repeated 6 and 12 months after liver transplant. Patients who showed basal glycaemia greater than
126 mg/dl or required anti-diabetic treatment were classified as patients with diabetes and they did not undergo an OGTT. Patients with known pre-transplant diabetes did not undergo OGTT and these patients were treated with steroidfree immunosuppression, according to the protocol used in our hospital. The hospital’s ethics commission approved the study and all patients gave their informed consent for their participation.
2.2.
Procedures
During 72 h prior to the OGTT, all patients were on a normocaloric diet with carbohydrate intake greater than 150 g/day and maintained a normal physical activity. The OGTT was done after an overnight fast for at least 12 h. Venous blood samples for determination of plasma glucose and insulin were taken from participants immediately before and at 30, 60, 90 and 120 min after oral intake of 75 g glucose. Plasma glucose was measured using enzymatic methods. Insulin was measured using immunoassay. The area under the glycaemia curve was calculated by the trapezoidal method. Insulin resistance was estimated using the following formulae: the HOMA index for insulin resistance (IR-HOMA) [18] and the composite insulin sensitivity index (ISIc) [19]. Insulin secretion was estimated using the following formulae: the HOMA index for the beta-cell function (SecrHOMA) [18], first insulin release phase (FIP) [20] and the second insulin release phase (SIP) [20]. IR-HOMA was calculated as follows: IRHOMA = [basal insulin (pmol/L) basal glucose (mmol/L)]/135. ISIc was calculated as follows: vffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi u ISIc ¼ 10000=u½basal glucose ðmg=dlÞ u t basal insulin ðmU=mlÞ ½mean glucose mean insulin during OGTT SecrHOMA was calculated as follows: SecrHOMA = [basal insulin basal(pmol/l) 3.33]/[basal glucose(mmol/l) 3.5]. FIP was calculated as follows: FIP = [1283 + 1.829 Insulin in minute 30 (pmol/l)] [138.7 glucose in minute 30 (mmol/ l) + 3.722 basal insulin]. SIP was calculated as follows: in minute 30 (pmol/ SIP = [287 + 0.4164 Insulin l)] [26.07 glucose in minute 30 (mmol/l) + 0.9226 basal insulin]. Diabetes was diagnosed according to the American Diabetes Association (ADA) criteria: patients with basal plasma glycaemia equal to, or greater than, 126 mg/dl, glycaemia equal to, or greater than, 200 mg/dl 2 h after the OGTT and patients requiring anti-diabetic treatment. Impaired fasting glucose (IFG) was defined as fasting plasma glucose values of 100–125 mg/dl. Impaired glucose tolerance (IGT) was defined as glucose levels of 140–199 mg/dl 2 h after the OGTT. Patients with either IFG or IGT were classified as having pre-diabetes. Diabetes prevalence was compared before, at 6 and at 12 months after transplant. Changes in the area under the glucose curve and changes in insulin resistance and secretion were compared in patients who underwent an OGTT. Pre-transplant risk factors taken into account were: age, gender, body mass index (BMI), model for end stage liver disease (MELD) index [21], hypertension, dyslipidaemia and hepatitis C infection. The following factors were studied as risk factors for the occurrence of diabetes 12 months after
Please cite this article in press as: Ramos-Prol A, et al. Alterations in carbohydrate metabolism in cirrhotic patients before and after liver transplant. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.10.002
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transplant: age, gender, BMI, hypertension, dyslipidaemia, hepatitis C infection, prednisone, tacrolimus and cyclosporine treatment.
2.3.
Statistical analysis
Data were summarized by its mean and standard deviation, mean (SD), in the case of continuous variables and by its relative and absolute frequencies in the case of categorical variables. Statistical analysis was performed with the R software (version 3.0.2) and lme4 (version 1.0-5) R-library. A linear mixed effects model was used to evaluate the relationship between glucose curves and months post-transplantation adding patients as a random factor. Glucose curves were summarized with their area under the curve (AUC). A simpler model was also assessed where the proportion of patients with diabetes was modelled in terms of post-transplantation time (months) using logistic regression. Additionally, the evolution of IR-HOMA, Secr-HOMA, First Phase Insulin Release, Second Phase Insulin Release and ISIc was studied using linear mixed models.
3.
Results
Tables 1 and 2 summarize patients’ clinical characteristics at baseline, and at 6 and 12 months after transplant, respectively. Nineteen patients (21.9%) had diabetes known before liver transplant and 7 (8.1%) were known to have IFG. Sixty-seven patients underwent an OGTT, of which 13 (19.4%) had IGT criteria and 45 (77.2%) met diabetes criteria. Globally, 64 patients (74.4%) had diabetes before transplant and 13 (15.1%) were classified as pre-diabetes (IFG or IGT). At the sixth month, 26 patients (30.2%) had basal glycaemia indicative of diabetes or were undergoing anti-diabetes treatment and 15 (17.4%) had IFG. Sixty patients underwent an OGTT, of which 24 (40%) met IGT criteria and 17 (28.3%) diabetes criteria. Globally, 43 patients (50%) had diabetes at the sixth month after transplant and 24 (27.9%) were classified as pre-diabetes. At the twelfth month, 7 patients had died. Of the remaining patients, 14 (17.7%) had basal glycaemia indicative of diabetes
Table 2 – Clinical data of patients 6 and 12 months after transplant. Time after transplant 6 months 86 N BMI (kg/m2) 26.4 (5.8) 48.8% HTA 26.7% Dyslipidemia 50.0% Diabetes Pre-diabetes 27.9% Current immunosuppressive regimen 39.5% Tacrolimus 52.3% Cyclosporine 69.8% Prednisone 62.8% Mycophenolate 5.8% Monotherapy 50.0% Dual therapy 44.2% Triple therapy
12 months 79 27.0 (6.1) 53.2% 25.3% 40.5% 26.6% 38.4% 51.2% 25.6% 57% 20.9% 65.1% 14.0%
Data are mean (SD) or percentage.
or were undergoing anti-diabetes treatment and 14 (17.7%) had IFG. Sixty-five patients underwent an OGTT, of which 21 (32.3%) met IGT criteria and 18 (27.7%) diabetes criteria. Globally, 32 patients (40.5%) had diabetes at the twelfth month after transplant and 21 (26.6%) were classified as pre-diabetes (Fig. 1). Only one patient without diabetes before liver transplant met diabetes criteria 12 months after transplant. Glucose curves had a mean area of 898.9 (174.8) at baseline. At month 6 the mean area under the glucose curves was 776.2 (171.2) and at month 12 the mean area was 785.1 (144.6). A statistically significant association was found between time (months) after transplantation and the area under the glucose curve ( p < 0.001). Area at 6th month was 120.38 units lower than area at baseline (IC 95% [79.6, 161.3]) and area at 12th month was 116.93 units lower than area at baseline (IC 95% [74.5, 159.2]). There was no statistically significant difference between areas at 6th and at 12th month (Fig. 2). The proportion of patients with diabetes before transplantation was 74.4%. The proportion of patients with diabetes at month 6 and 12 were 50% and 40.5%, respectively. A statistically significant association was also found between months post transplantation and proportion of patients with diabetes ( p < 0.001). Compared to baseline, at month 6 the
Table 1 – Clinical data of patients at baseline. N Gender ratio (m/f) Age (years) BMI (kg/m2) MELD score HCV infection HBV infection HEV infection Hepatocellular carcinoma History of alcoholism Diabetes Pre-diabetes HTA Dyslipidemia Data are means (SD) or percentage.
86 71/15 54.4 (8.2) 25.8 (4.4) 17.6 (5.6) 43.7% 11.6% 2.3% 36% 62.8% 74.4% 15.1% 19.5% 11.5%
Fig. 1 – Percentage of patients with diabetes and prediabetes before liver transplant and at 6 and 12 months after transplant.
Please cite this article in press as: Ramos-Prol A, et al. Alterations in carbohydrate metabolism in cirrhotic patients before and after liver transplant. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.10.002
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Fig. 2 – Mean and 95% C.I. areas under the glycaemia curves for baseline and months 6 and 12 after transplantation.
odds ratio of having diabetes was 0.39 (IC 95% [0.21, 0.73]) and at month 12 it was 0.26 (IC 95% [0.14, 0.50]). We found no association between IR-HOMA and time ( p = 0.56), Secr-HOMA and time ( p = 0.54) and first and second phase insulin release ( p = 0.69 and p = 0.64 respectively), but we found a statistically significant association for ISIc ( p < 0.001). ISIc values at 6th and 12th month were 1.72 units higher (IC 95% [0.84, 2.58]) and 1.58 units higher (IC 95% [0.68, 2.44)] than baseline. A statistically significant association was found between high MELD values and risk of pre-transplant diabetes ( p = 0.001). Likewise, a significant association was found between high BMI and risk of pre-transplant diabetes ( p = 0.033). No association with risk of diabetes was found in the remaining variables studied. It was found that a diabetes history before transplant was a risk factor of post-transplant diabetes ( p = 0.003). It was also found a trend ( p = 0.072) to a greater risk of post-transplant diabetes in patients with dyslipidemia. A statistically significant association was found between the administration of prednisone and a reduction of the risk of diabetes ( p = 0.025).
4.
Discussion
In our study, 89.5% of cirrhotic patients had alterations in carbohydrate metabolism and 74.4% had diabetes before liver transplant. Six months after transplant, the percentage of patients who had alterations in carbohydrate metabolism was 77.9% and the percentage of patients with diabetes was 50%. Twelve months after transplant, the percentage of patients with alterations in carbohydrate metabolism was 67.1%, and the percentage of patients with diabetes was 40.5%. Thus, this study shows that the high percentage of patients with alterations in carbohydrate metabolism before liver transplant decreases significantly after liver transplant. It is known that cirrhotic patients present an increased prevalence of diabetes, although many times this prevalence is not well studied, as only basal glycaemia is used for diagnosis. In cirrhotic patients, there are various alterations that explain the high prevalence of diabetes. For example, there is a decrease in peripheral insulin sensitivity, due to the
reduction of non-oxidative glucose metabolism in skeletal muscle tissue [22–27]. It has been demonstrated that these patients may present a 40–50% decrease in whole body glucose uptake [28,29]. In addition, advanced cirrhotic patients present a reduction of the two first beta-cell secretion phases. Other contributing factors to hyperglycaemia in cirrhotic patients are the prevalence of hepatocellular carcinoma, which favours the release of tumour necrosis factors and insulin-like growth factors that produce resistance to insulin [30–32]. These alterations cause postprandial hyperglycaemia in cirrhotic patients, with normal basal glycaemia. As HbA1c is not useful to diagnose diabetes in this type of patient, the OGTT appears to be the Gold Standard to study carbohydrate alterations in cirrhotic patients. There are few studies that evaluate the prevalence of diabetes in pre- and post-liver transplant patients and results of them have been conflicting. Papers such as those by Merli et al. [16] showed glucose tolerance improvement after transplant. However, other studies, such as Schneiter et al. [17], showed no significant changes. In general, the main limiting factor of these studies is the low number of patients. In our work, we had a sample of 86 patients with liver cirrhosis in which we studied carbohydrate metabolism before and after transplant, using basal glycaemia and the OGTT as methods to diagnose diabetes. We proved an improvement in the alterations in carbohydrate metabolism in two ways. First, the area under the glucose curve in an OGTT carried out at 6 and 12 months after liver transplant is significantly smaller than in an OGTT carried out before transplant. Second, the total ratio of patients with diabetes falls significantly at 6 and 12 months after transplant. This study also included evolution of beta function and insulin resistance, applying formulae that use basal plasma glycaemia and insulin or during an OGTT. Insulin sensitivity studied by ISIc showed an improvement in relation to basal of 1.72 units at 6 months and of 1.58 units at 12 months. IR-HOMA results do not vary after transplant. This may be explained because IR-HOMA only uses the calculation of basal glycaemia and insulin, whilst ISIc uses glycaemia and insulin calculated during OGTT. It is known that postprandial glycaemia is altered in cirrhotic patients but not basal glycaemia [3]; thus, it makes sense that after transplant there are no changes in results from formulae using basal glycaemia only. Results from formulae that study beta function (SecrHOMA, FIP and SIP) had no significant variation after transplant. Analysis of diabetes risk factors before liver transplant shows that BMI and the severity of descompensation of liver cirrhosis according to the MELD score, are the key risk factors. The relationship between HCV and diabetes is controversial. Several epidemiological studies have associated hepatitis C infection with diabetes risk [33,34], suggesting that activation of TNF-a may be the cause of the increase in diabetes risk [35]. The problem is that few of these studies are population-based or have applied standard criteria for the diagnosis of diabetes. A case-cohort study suggested that HCV infection increased the risk of diabetes but did not include enough cases to draw a definitive conclusion [36]. A Taiwanese community-based cohort study found a strong association of HCV infection with diabetes risk (HR 1.7; 95% CI: 1.3–2.1) [37]. However, in an
Please cite this article in press as: Ramos-Prol A, et al. Alterations in carbohydrate metabolism in cirrhotic patients before and after liver transplant. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.10.002
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Italian population-based cohort study, HCV infection was unrelated to incident diabetes [38], and a recent study by Ruhl et al. [39] including data from 15,128 participants from the US National Health and Nutrition Examination Survey, did not show a significant association between hepatitis C and diabetes risk. The limitations of the latter study were that was retrospective and the proportion of patients with HCV infection was small (1.7%). In our study with advanced cirrhotic patients, it was also not demonstrated that hepatitis C was associated with diabetes risk, but sample size is small compared to other studies that analyse this topic. Therefore, the results are not conclusive. There are two factors after liver transplant that may influence glucose metabolism: persistence of pre-transplant alterations and the effects of immunosuppressive medication (it has also been proposed that alterations in regulation response caused by denervation of the graft may influence glucose metabolism, but this factor was ruled out in a study by Perseghin et al. [40]). None of the studied immunosuppressants has shown to be a major diabetes risk in patients with liver graft. However, a contradiction is that prednisone appears as a diabetes protector factor; however, this result is due to a bias, because according to our hospital’s protocol, patients undergoing diabetes treatment before liver transplant are prescribed immunosuppressors without corticoids, and pre-transplant diabetes is a risk factor for the occurrence of post-transplant diabetes. Other immunosuppressive medications associated with diabetes risk are tacrolimus and cyclosporine. Some studies have reported that diabetes risk is greater with the use of tacrolimus [13,41], but others have shown no difference when comparing both drugs [9,42,43]. No statistically significant differences in carbohydrate metabolism were found in this study between patients treated with tacrolimus and cyclosporine. In conclusion, in this study we were able to confirm that there is a large percentage of diabetes in patients with advanced cirrhosis, that may go unnoticed unless tested by an OGTT; and that alterations in carbohydrate metabolism improve after liver transplant, with a significant reduction in the percentage of diabetes. This improvement is mainly due to an improvement in insulin resistance, as shown by the calculation of insulin resistance parameters using ISIc. This study has also confirmed that diabetes risk factors in cirrhotic patients are BMI and the degree of cirrhosis as calculated by MELD. Last, according to results from this study, we conclude that immunosuppressive medication does not influence the risk of developing diabetes after liver transplant.
Authors’ contributions Agustı´n Ramos-Prol: Principal author, patient visits, testing, data collection; David Herva´s-Marı´n: bioestatistical analysis; Beatriz Rodrı´guez-Medina: help in search for patients, application of liver transplant protocols; Vicente Campos-Alborg: help in data collection; Marina Berenguer: help in coordination, help in search for patients, application of liver transplant ´ ngel Moya-Herraiz: help in search for patients, protocols; A application of surgery and liver transplant protocols; Juan
5
Francisco Merino-Torres: help in coordination, help in analysis and discussion, and help in data collection.
Financial support None.
Conflict of interest The authors declare that there are no potential conflicts of interest relevant to this article.
Acknowledgments Agustı´n Ramos-Prol and Juan Francisco Merino-Torres are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. English writing was performed with the help of the service ‘‘OnLine EnglishTM Superior English Editing’’.
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