Abnormal serum alanine transaminase levels in adult patients with type 1 diabetes

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1 Abnormal serum alanine transaminase levels in adult patients with type 1 diabetes Gautam Das 1 MD, MRCP (Diabetes and Endocrinology), FRCP, FACE (USA), Consultant in Endocrinology John Geen 2,3 MSc, PhD, FRCPath, Professor of Clinical Science and Consultant in Clinical Biochemistry Rebekah Johnson 1 MRCP, Core Medical Trainee Hussam Abusahmin 1 MSc, MRCP (Diabetes and Endocrinology), Consultant in Endocrinology 1 Department of Endocrinology, Prince Charles Hospital, Cwm Taf University Health Board, Merthyr Tydfil, UK 2 Department of Clinical Biochemistry, Prince Charles Hospital, Cwm Taf University Health Board, Merthyr Tydfil, UK 3 Faculty of Life Sciences and Education, University of South Wales, Pontypridd, UK Correspondence to: Gautam Das, Consultant in Endocrinology, Prince Charles Hospital, Cwm Taf University Health Board, Merthyr Tydfil CF47 9DT, UK; gautam.das@ wales.nhs.uk Abstract Obesity in type 1 diabetes increases the risk of insulin resistance, metabolic syndrome (MetS) and greater susceptibility to fatty liver disease. We evaluated the prevalence of elevated alanine transaminase (ALT) and its likely predictors in patients with type 1 diabetes and also investigated its relationship with MetS. We undertook a retrospective analysis of 215 patients above 18 years of age with type 1 diabetes who attended our diabetes clinics from October 2014 to December Patients anthropometric, clinical, biochemical and radiological data were obtained from the hospital portal. Patients were stratified according to the presence of normal or elevated ALT and as per presence or absence of MetS. In all, 20.5% of patients had raised ALT levels. They had higher systolic and diastolic blood pressure (SBP and DBP; p-value for both: <0.0001), higher insulin requirement (p<0.007), lower HDL levels (p=0.01) and higher urine albumin excretion (UACR; p=0.004) in comparison to patients with normal ALT. In the raised ALT group, 56.8% had MetS in comparison to 16.4% in the normal ALT group as per WHO criteria. Overall, 57 patients had an ultrasound scan and only 10 patients had fatty liver (seven in the raised ALT group) radiologically. Linear regression showed correlation of ALT with female gender, SBP, DBP, insulin dose, HDL and UACR. In the raised ALT group, the predictors of ALT were gender, BMI and UACR. In conclusion, raised ALT is not uncommon in type 1 diabetes. These patients may often have underlying insulin resistance and higher risk of MetS and therefore should be assessed promptly to establish abnormalities which may be amenable to interventions. Copyright 2018 John Wiley & Sons. Practical Diabetes 2018; 35(5): Key words type 1 diabetes; obesity; alanine transaminase; metabolic syndrome Received: 26 April 2018 Accepted in revised form: 3 July 2018 Introduction Chronic mild elevation of liver aminotransferases are frequently encountered in patients with type 2 diabetes. Such abnormalities are usually attributed to obesity, insulin resistance, inflammation, hepatocyte injury and metabolic syndrome (MetS). 1 The most common cause of elevated liver function test in these patients is non-alcoholic fatty liver disease (NAFLD) which represents a spectrum of histological findings from hepatic steatosis without inflammation to fat accumulation with a necro inflammatory component with or without fibrosis. 2 Although type 1 diabetes is characterised by selective autoimmune destruction of the pancreatic islet beta cells, in a significant subgroup of patients there is marked interplay between autoimmunity and insulin resistance. 3 There is increasing contemporary evidence that the prevalence of obesity has risen substantially in the type 1 diabetes population. 4 Much of this weight gain is attributed to cultural, societal and lifestyle changes; however, some may be also related to the use of more intense insulin regimens and route of administration of exogenous insulin. 5 Individuals with type 2 diabetes have insulin resistance at the level of adipose, hepatic and skeletal muscle tissue, 6 but mechanisms of insulin resistance in type 1 diabetes remain less well defined and are likely due to a combination of obesity and supraphysiological levels of exogenous subcutaneous insulin which causes marked peripheral hyperinsulinaemia and hepatic hypoinsulinaemia compared to normal physiology. 3 With the ever increasing rise in the obesity epidemic, up to 30% of patients with type 1 diabetes are found to be overweight or obese during follow up in tertiary hospitals. 7,8 These patients will have the risk of all the complications associated with MetS 9 and thus will have a PRACTICAL DIABETES VOL. 35 NO. 5 COPYRIGHT 2018 JOHN WILEY & SONS 165

2 higher susceptibility to NAFLD and abnormal liver function tests (LFTs). Alanine transaminase (ALT) is widely accepted as a marker of liver disease and hepatocellular injury, and is also a good predictor of mortality from liver disease. 10 ALT has been used as a marker for NAFLD in epidemiological studies 11 and some authors have reported elevated levels of the enzyme in up to 10 35% of patients with type 1 diabetes in the past. 12,13 Diabetes is a major risk factor for chronic liver disease, 14 and it also increases the risk of primary liver cancers 14,15 and death from liver cirrhosis. 16 Several studies have examined liver functions in patients with type 2 diabetes 17,18 and NAFLD is a well-documented comorbidity in these patients, 17,19 but the corresponding data about associations of abnormal LFTs in type 1 diabetes are sparse and limited although such a biochemical abnormality is commonly encountered in clinical practice. Annual assessment of liver function is recommended in clinical practice guidelines for diabetes, 20 but the clinical relevance of measuring liver enzymes in type 1 diabetes routinely as a part of annual screening is unclear. Therefore, in this study we attempted to evaluate the prevalence of abnormal LFTs (measured as ALT) in adults with type 1 diabetes and also investigated the underlying aetiologies and independent risk factors that may be associated with such findings. Methods Patients This is a retrospective cross-sectional analysis of patients with type 1 diabetes who attended the diabetes clinic at our hospital for an annual review from October 2014 to December All individuals with type 1 diabetes over the age of 18 years, in whom insulin therapy was clearly documented, were considered for analysis. Type 1 diabetes was defined as per the American Diabetes Association position statement. 21 Patients were included if they had type 1 diabetes and have had LFTs measured at least once in the past 12 months from the date of data extraction. Initially, 289 patients were identified but we excluded patients with chronic liver disease (alcoholic and nonalcoholic: n=9); coeliac disease (n=23); on common medications that are known to cause abnormal LFTs (NSAIDs, cortico steroids, statins, anti-epileptics, methotrexate, amiodarone: n=24); and those who had missing anthropometric or biochemical data (n=18). We finally included 215 patients for whom anthropometric data were collected from their clinical notes recorded during their last visit, and biochemical and radiological data were collected from the hospital clinical portal reporting system. Biochemical measurements and radiology Laboratory variables were obtained from the hospital portal and included: glycated haemoglobin (HbA1c), creatinine, lipid profile (total cholesterol [TC], triglycerides [TGA], HDL and LDL), liver function tests (measured as ALT) all of which were determined on a blood sample that was taken on the day of the patients visit. An early morning spot urine sample was used to measure urine albumin creatinine ratio (UACR) as containers are sent routinely to patients prior to their visit. HbA1c concentrations were determined by ion-exchange HPLC (G8, Tosoh, Amsterdam, Netherlands). Serum TC, TGA, HDL, creatinine and ALT were all determined on a Roche Cobas Modular P unit or 702 by different enzymatic techniques. LDL was calculated employing the Friedewald equation. Estimated glomerular filtration rate (egfr) was calculated by IDMS aligned MDRD equation: {175 x (([Creat] Ser ) x Age ) x (0.742 if female)}. Raised ALT was defined as >33U/L in females and >41U/L in males as per laboratory reference range. Urine albumin and creatinine was determined on a Cobas Integra 400 instrument (Roche, Burgess Hill, UK). The albumin:creatinine ratio (UACR) was then calculated (mg/ mmol). Radiological data were obtained for patients who had an ultrasound of abdomen/liver for any cause during the inclusion period. Patients were stratified according to the presence or absence of MetS which was defined as per World Health Organisation (WHO) criteria; 22 that is, they all had diabetes, together with two or more of the other components: raised arterial blood pressure 160/90mmHg, raised plasma TGA 1.7mmol/L and/or HDL of <0.9mmol/L in men and <1.0mmol/L in women, central obesity measured as BMI >30kg/m 2 and microalbuminuria (UACR >2.5mg/mmol in males and >3.5mg/mmol in females). Statistical analysis Analysis was performed in the whole group and in subgroups who were stratified according to normal or elevated levels of ALT and as per presence or absence of MetS. All data were expressed as mean ± SD (standard deviation). UACR was log transformed as it was not uniformly distributed. Comparison between groups was performed using Student s t-test or Mann-Whitney test depending on their distribution. Multiple regression analysis was used to determine the risk factors for abnormal ALT levels. A p-value of <0.05 was considered to be statistically significant. All analyses were performed using SPSS version 16.0 (SPSS Inc, Chicago, IL, USA). Project approval The study was registered and approved by the Research and Development Department of Cwm Taf University Health Board. Results Table 1 shows the baseline anthropometric, clinical and laboratory parameters of the total group. Our patients were young with no significant difference in gender distribution. Moreover, they had long duration of diabetes (17.9±12.3 years), were overweight (BMI 28.3±5.0kg/m 2 ) and had sub-optimal glycaemic control (HbA1c 78.0±21.7mmol/mol) and were also on large doses of insulin (55.5±26.1 units per day). A total of 44 patients (20.5%) had ALT above the range of normality as per the local laboratory reference range (Table 2). Patients who had raised ALT were predominantly females (59.1%). Their systolic and diastolic BP were higher by 12mmHg 166 PRACTICAL DIABETES VOL. 35 NO. 5 COPYRIGHT 2018 JOHN WILEY & SONS

3 Variables Values Variables Normal ALT (n=171) Raised ALT (n=44) P-value** Sex (male/female) 105/110 Age (years) 37.5±15.4 Duration of diabetes (years) 17.9±12.3 Weight (kg) 77.1±15.0 BMI (kg/m 2 ) 28.3±5.0 Systolic BP (mmhg) 129.8±15.5 Diastolic BP (mmhg) 76.2±11.5 Total insulin dose (units/day) 55.5±26.1 HbA1c (mmol/mol) 78.0±21.7 Creatinine (µmol/l) 77.1±22.8 egfr (ml/min/1.73m 2 ) 82.4±14.8 Total cholesterol (mmol/l) 4.7±1.1 Triglycerides (mmol/l) 1.7±1.8 HDL (mmol/l) 1.5±0.6 LDL (mmol/l) 2.7±1.0 Alanine transaminase (U/L) 29.4±26.8 Urine ACR (mg/mmol)* 1.2 (2.1) Urine ACR (log transformed) 0.2±0.5 *All data expressed as mean ± standard deviation except urine ACR which is expressed as median (interquartile range). Table 1. Baseline characteristics of the total group (n=215) and 8mmHg, respectively (both p<0.0001). In addition, these patients were requiring higher doses of insulin (p=0.007), had lower levels of HDL (p=0.01) and also had higher rates of microalbuminuria (p=0.004) in comparison to patients who had normal ALT levels. Table 3 shows the difference among groups with normal or raised ALT levels who had MetS in comparison to patients who did not. In patients with normal ALT, 16.4% (28/171) had MetS as per WHO criteria. Apart from the significant statistical differences in parameters used to define MetS, patients in this group with MetS were older (p<0.001), had longer duration of diabetes (p=0.03) and were receiving large doses of insulin (67.0 units per day; p<0.001). In addition, they also had higher levels of TC Sex (male/female) 86/85 18/26 Age (years) 37.6± ± Duration of diabetes (years) 17.6± ± Weight (kg) 76.8± ± BMI (kg/m 2 ) 28.3± ± Systolic BP (mmhg) 127.4± ±15.3 < Diastolic BP (mmhg) 74.4± ±10.7 < Total insulin dose (units/day) 53.3± ± HbA1c (mmol/mol) 78.3± ± Creatinine (µmol/l) 80.0± ± egfr (ml/min/1.73m 2 ) 82.7± ± Total cholesterol (mmol/l) 4.7± ± Triglycerides (mmol/l) 1.6± ± HDL (mmol/l) 1.5± ± LDL (mmol/l) 2.6± ± Alanine transaminase (U/L) 17.5± ±26.3 < Urine ACR (mg/mmol)* 1.2 (1.7) 1.9 (2.8) Urine ACR (log transformed) 0.1± ± *All data expressed as mean ± standard deviation except urine ACR which is expressed as median (interquartile range). **Bold type indicates statistical significance (p<0.05). Table 2. Comparison of anthropometric, clinical and biochemical characteristics in patients with normal and raised ALT (p<0.001), LDL (p=0.03) and creatinine (p=0.03), and lower levels of egfr (p<0.001). In comparison, the prevalence of MetS in the group with raised ALT was much higher (56.8% [25/44]). Patients in this group predictably had statistically significant higher levels of weight, BMI, SBP and DBP but they were also found to have a more compromised renal function (creatinine p=0.03 and egfr p=0.06) in comparison to patients without MetS: fairly similar to the group with normal ALT. In the whole group, linear regression analysis showed that ALT correlated with female gender, systolic and diastolic blood pressure, cumulative insulin dose, HDL and UACR levels (Table 4). Subgroup analysis in patients who had abnormal ALT levels showed that the most likely predictors for an increase in ALT were female gender (r=21.52; p=0.04), BMI (r=4.06; p=0.03), and UACR (r=0.52; p=0.002). A total of 57/215 (26.5%) patients had an ultrasound scan (USS) of the abdomen or liver for different clinical reasons during the inclusion period. Among individuals who had a normal ALT, 30 patients had a USS and only three (10%) patients were found to have fatty liver but none had MetS. In comparison, of those patients who had raised ALT and had a USS (n=27) only seven (25.9%) had fatty liver but all of them had MetS. Discussion Elevated liver enzymes in patients with type 1 diabetes are relatively common but may be under-recognised and under-reported as the major focus in recent years has been PRACTICAL DIABETES VOL. 35 NO. 5 COPYRIGHT 2018 JOHN WILEY & SONS 167

4 Variables Normal ALT Raised ALT on identification and exploration of abnormal LFTs and NAFLD in patients with type 2 diabetes. The prevalence of raised ALT in our patients was 20.5% which is similar to a study conducted from a multicentre German/Austrian database 23 but is different from other previous studies who reported a prevalence of %. 12,24 The difference in prevalence may be due to the size of study population, ethnicity and heterogeneity of patients in other studies in comparison to ours, but the principal determinant may have been the cut-off that has been used to define elevated ALT. Leeds et al. 13 showed that prevalence of raised ALT in type 1 diabetes changes with rise in cut-offs (34.5% at cut-off >30IU/L, 4.3% at cut-off >50IU/L and 1.9% at cut-off >63IU/L). These MetS + (n=28) MetS - (n=143) P-value** MetS + (n=25) MetS - (n=19) P-value** Sex (male/female) 17/11 71/72 11/14 7/12 Age (years) 46.2± ±14.2 < ± ± Duration of diabetes (years) 21.4± ± ± ± Weight (kg) 87.8± ±13.1 < ± ±9.4 <0.001 BMI (kg/m 2 ) 32.4± ±4.5 < ± ±3.1 <0.001 Systolic BP (mmhg) 135.4± ±13.6 < ± ± Diastolic BP (mmhg) 76.1± ± ± ± Total insulin dose (units/day) 67.0± ±21.3 < ± ± HbA1c (mmol/mol) 77.2± ± ± ± Creatinine (µmol/l) 93.2± ± ± ± egfr (ml/min/1.73m 2 ) 74.1± ±12.1 < ± ± Total cholesterol (mmol/l) 5.3± ±0.9 < ± ± Triglycerides (mmol/l) 3.6± ±0.8 < ± ± HDL (mmol/l) 1.5± ± ± ± LDL (mmol/l) 2.9± ± ± ± Alanine transaminase (U/L) 19.2± ± ± ± Urine ACR (mg/mmol)* 2.8 (3.7) 1.0 (1.3) < (6.2) 1.9 (1.7) 0.29 Urine ACR (log transformed) 0.46± ±0.39 < ± ± *All data expressed as mean ± standard deviation except urine ACR which is expressed as median (interquartile range). **Bold type indicates statistical significance (p<0.05). Table 3. Comparison of anthropometric, clinical and laboratory parameters between groups with or without metabolic syndrome ( MetS + and MetS -, respectively), stratified by normal or raised ALT levels findings have implications as currently there is no clear consensus as to where to set the cut-off thresholds for elevated liver enzymes in type 1 diabetes. Therefore, the proportion of individuals who would need further evaluation with ultrasound and liver biopsies depends on the diagnostic threshold that has been applied to define raised levels. However, these patients had poor glycaemic control, hypertension, dyslipidaemia and raised urine albumin excretion, which are often considered to be surrogate markers of insulin resistance. In addition, they also required higher doses of insulin to achieve a normoglycaemic profile which may itself cause weight gain thereby leading to peripheral hyperinsulin aemia and insulin resistance. 3 The association between type 2 diabetes and NAFLD is well recognised and this has been consistently linked to insulin resistance and hyperinsulinaemia. 25 A previous study has shown that an elevated ALT in type 1 diabetes may be also associated with NAFLD related risk factors and those patients with persistently raised ALT also had higher BMI compared to age and sex matched controls. 13 This echoes findings in our group where patients with raised ALT levels had a strong association with BMI which may reflect that they have a variable degree of insulin resistance predisposing them to develop MetS. With the ever increasing burden of obesity in type 1 diabetes, some authors 5,26 have referred to these patients as having double diabetes 168 PRACTICAL DIABETES VOL. 35 NO. 5 COPYRIGHT 2018 JOHN WILEY & SONS

5 Variables Coefficients P-value* Sex Age (years) Duration of diabetes Weight BMI Systolic BP < Diastolic BP Total insulin dose HbA1c Creatinine egfr Total cholesterol Triglycerides HDL LDL Urine ACR *Bold type indicates statistical significance (p<0.05). Table 4. Regression analysis using ALT as a dependent variable in the total group because they have all the risk of complications associated with MetS and thus a higher susceptibility to develop NAFLD. In our cohort, the prevalence of MetS was much higher in patients with raised ALT (56.8% vs 16.4%) in comparison to patients who had normal ALT levels. These patients also had hypertension, dyslipidaemia, impaired renal function and microalbuminuria which predispose them to a greater risk of atherosclerosis, endothelial dysfunction and vascular disease. As MetS is a known risk factor for NAFLD, aminotransferase levels should be evaluated, especially ALT as it correlates to liver fat content. 27,28 In our cohort with raised ALT, all the patients who were identified to have fatty liver on USS had MetS. Therefore, it is important that these patients with MetS and Key points Abnormal ALT levels in type 1 diabetes are relatively common but under-recognised, under-reported and often not investigated With the rise in the prevalence of obesity in type 1 diabetes, patients have a higher risk of insulin resistance, metabolic syndrome and greater susceptibility for developing nonalcoholic fatty liver disease (NAFLD) As ALT is a reliable predictor for NAFLD, all patients with type 1 diabetes and abnormal ALT levels should be promptly referred for imaging and further investigations for early diagnosis and appropriate interventions with abnormal ALT in type 1 diabetes should be referred for abdominal imaging although definitive diagnosis of NAFLD depends on liver biopsy. Application of liver biopsy to all patients with NAFLD would be impractical; hence, there has been a greater shift in using a non-invasive screening test. USS is simple, easily available and detects fatty liver with good sensitivity but does not differentiate between simple steatosis from steatohepatitis. 29 In contrast, fibroscan (transient elastography) measures liver stiffness 30 and is a more rapid, accurate and reliable predictor of NAFLD and its progression to fibrosis, and it explores a greater volume of liver parenchyma in comparison to biopsy. 29 Clinical biochemistry services are also using other non-invasive markers such as AST:ALT ratio 31 and Fib-4 scores 32 to help identify at-risk patients at a stage where lifestyle changes could be effective in minimising progressive hepatic disease. The diagnosis of NAFLD in these asymptomatic individuals with type 1 diabetes mellitus would be of significant importance as NAFLD increases the risk of cardiovascular disease and contributes to hepatic insulin resistance, 28,33 preventing optimal glycaemic targets being achieved. Our study has limitations. First, we used a single estimation of ALT to define abnormality. Such single measurement can over- or underestimate disease burden. Second, although patients with established chronic liver disease irrespective of their aetiologies were excluded from the study, high alcohol consumption can be a confounder leading up to transient elevation in ALT levels and this aspect was not investigated in our cohort of patients. Third, different classifications of MetS are available, but we chose the WHO classification as per data that were available to us to define the condition for individual patients (waist:hip ratio was not available); we therefore acknowledge that the outcome may be different if other available criteria are used to define MetS in these patients. Finally, we used cut-offs to define raised ALT as per the reference range recommended by our local laboratory. We accept that if the cut-offs were determined as per range of normality recommended by the American College of Gastroenterology (ALT 25U/L for women and 33U/L for men), the prevalence of raised ALT would have been different. Conclusion An elevated ALT is now being identified with increasing frequency in patients with type 1 diabetes. This may be a reflection of underlying insulin resistance and MetS. ALT appears to be associated with NAFLD related risk factors; hence, these patients need to be assessed and investigated promptly so that appropriate interventions can be undertaken to lower the risk of diseases associated with NAFLD. Declaration of interests There are no conflicts of interest declared. References 1. Harris EH. Elevated liver functions tests in type 2 diabetes. Clin Diabetes 2005;23: Alba LM, Lindor K. Non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2003;17: Nokoff NJ. The interplay of autoimmunity and insulin resistance in type 1 diabetes. Discov Med 2012; 13: PRACTICAL DIABETES VOL. 35 NO. 5 COPYRIGHT 2018 JOHN WILEY & SONS 169

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