|Year : 2020 | Volume
| Issue : 3 | Page : 806-812
Does nonalcoholic fatty liver disease predict kidney injury in type 2 diabetic patients?
Hassan Abdelhady1, Yassin S Yassin1, Khaled M Elzorkany1, Yasser M. A. Shahein2
1 Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Gastroenterology and Hepatology, Damanhour Fever Hospital, Beheira, Egypt
|Date of Submission||24-Aug-2019|
|Date of Decision||02-Oct-2019|
|Date of Acceptance||07-Oct-2019|
|Date of Web Publication||30-Sep-2020|
Yasser M. A. Shahein
Source of Support: None, Conflict of Interest: None
To explore the association between the presence of nonalcoholic fatty liver disease (NAFLD) and chronic kidney disease in type 2 diabetic patients.
NAFLD is the most common cause of chronic liver disease worldwide. The histologic spectrum of NAFLD ranges from simple steatosis to nonalcoholic steatohepatitis, liver fibrosis, and cirrhosis.
Patients and methods
A prospective randomized comparative study was conducted during March 2018 to February 2019 on 40 type 2 diabetic patients, who were classified into two groups: group I included 20 patients with type 2 diabetes with fatty liver, and they were classified by ultrasound into patients with mild, moderate, and severe fatty liver, and group II consisted of 20 patients with type 2 diabetes without fatty liver. Full history was taken, and routine examination, physical examination, and special investigations were done.
The mean albumin/creatinine ratio in group I was higher than in group II (77.24 ± 89.98 and 10.94 ± 2.76, respectively), and the difference was statistically significant (t = 3.294, P = 0.004). Estimated glomerular filtration rate was lower in group I than in group II, and the difference was statistically insignificant. Estimated glomerular filtration rate mean value was higher in patients with mild degree of fatty liver, and the differences were statistically insignificant. Albumin/creatinine ratio, serum creatinine, and serum uric acid were higher in patients with severe fatty liver, and the differences were statistically significant (t = 3.542, P = 0.024; t = 3.132, P = 0.037; and t = 7.647, P = 0.000, respectively).
Kidney injury in diabetic patients with NAFLD was higher than in diabetic patients without fatty liver and was obvious in those with severe degree of fatty liver. NAFLD is associated with an increased frequency of chronic kidney disease in type 2 diabetic patients.
Keywords: kidney injury, liver disease, nonalcoholic fatty, type 2 diabetes
|How to cite this article:|
Abdelhady H, Yassin YS, Elzorkany KM, Shahein YM. Does nonalcoholic fatty liver disease predict kidney injury in type 2 diabetic patients?. Menoufia Med J 2020;33:806-12
|How to cite this URL:|
Abdelhady H, Yassin YS, Elzorkany KM, Shahein YM. Does nonalcoholic fatty liver disease predict kidney injury in type 2 diabetic patients?. Menoufia Med J [serial online] 2020 [cited 2020 Oct 20];33:806-12. Available from: http://www.mmj.eg.net/text.asp?2020/33/3/806/296655
| Introduction|| |
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide . It is defined as the accumulation of fat (>5%) in liver cells in the absence of excessive alcohol intake or other causes of liver disease. including autoimmune, drug-induced, or viral hepatitis. The histologic spectrum of NAFLD ranges from simple steatosis to nonalcoholic steatohepatitis, liver fibrosis, and cirrhosis . This disease reportedly affects up to 30% of the general population in Western countries, especially in patients with metabolic syndrome, obesity, and type II diabetes. Given the high prevalence of this disease, it had been associated with hepatocellular carcinoma. In addition, nonalcoholic steatohepatitis as the primary indication for liver transplantation has increased from 1.2 to 9.7% in the past decade. NAFLD is considered to be an independent risk factor for cardiovascular disease, and there is accumulating evidence to support a causative role in the development of chronic kidney disease (CKD) . In addition to NAFLD, CKD represents a significant health burden in the Western adult population, and it affects more than 25% of individuals older than 65 years . CKD was defined as decreased estimated glomerular filtration rate (eGFR) and/or the presence of significant proteinuria (>500 mg) . In the United States, more than 400 000 people currently receive some form of renal replacement therapy, and this number was expected to reach 22 million by 2030 . However, less than half of patients with CKD develop end-stage renal disease owing to the high risk of mortality associated with cardiovascular events . Furthermore, the incidence of simultaneous liver–kidney transplantation continues to increase exponentially over the past 5 years. An analysis of the United Network Organ Sharing database during the years 2002–2011 revealed that 35% of patients transplanted for NAFLD-related cirrhosis progressed to stage 3b-4 CKD within 2 years after liver transplantation in comparison with 10% of patients transplanted for other etiologies . Despite these findings, CKD often goes unrecognized, and in the Third National Health and Nutrition Survey (NHANES III), among all individuals with moderately decreased GFR (<60 ml/min; stage 3), the awareness is ∼8%. The similarity in traditional risk factors for CKD, including hypertension, obesity, dyslipidemia, and insulin resistance, makes it difficult to determine a causational relationship with NAFLD adjusting for 'hepatorenal' and 'cardiorenal' features . The aim of this study was to explore the association between the presence of NAFLD and CKD in type 2 diabetic patients.
| Patients and Methods|| |
A prospective randomized comparative study was conducted on 40 patients with type 2 diabetes; they were diagnosed by both clinical, laboratory, and radiological criteria. Patients were enrolled from the Internal Medicine Department of Damanhour Fever Hospital, Beheira, during the period extending from March 2018 to February 2019. The study was approved by the local medical ethical committee.
The study patients were classified into two groups: group I (type 2 diabetic patients with fatty liver) included 20 patients (seven males and 13 females) having type 2 diabetes with fatty liver disease, and group II (type 2 diabetic patients without fatty liver) included 20 patients (eight males and 12 females) having type 2 diabetes without fatty liver disease.
This study was conducted in accordance with the ethical guidelines of 1975 Declaration of Helsinki. The study was approved by the local authority of Damanhour Fever Hospital, and an informed consent was taken from all included patients.
Selection criteria for the patients
The patients included in this study were selected according to inclusion and exclusion criteria. Inclusion criteria included adult patients with type 2 diabetes mellitus without history or clinical evidence of other causes of fatty liver. Exclusion criteria were alcohol (ethanol) consumption (>140 g/w in males and >70 g/w in females); specific diseases that could result in fatty liver such as drug-induced liver diseases (e.g., valproate, amiodarone, and methotrexate); primary biliary cirrhosis; autoimmune hepatitis; viral hepatitis (HBV and HCV infections); and specific renal diseases other than diabetic nephropathy.
All cases were subjected to the following: complete history, where patients were subjected to predesigned sheet for full medical history, with stress on age, sex, smoking, history of hypertension, history of ischemic heart disease, physical inactivity, and duration of diabetes mellitus, and clinical examination, comprising general, which included anthropometric measurements such as weight, height, and calculation of BMI (kg/m 2), as well as waist circumference (cm), and local, which included CVS, abdominal and chest. Blood pressure was measured twice using a standard mercury manometer after the participants had been rested for at least 5 min. Investigations included complete urine examination with estimation of urine albumin/creatinine ratio (ACR) by Beckman microalbumin test kit on Synchron CX9 autoanalyzer (250 S. Kraemer Blvd. Brea, California, USA) , blood glucose levels using Sysmex KX-21 automatized hematology analyzer (Sysmex Corporation, 1-2-2 Osaki, Shinagawa-ku, Tokyo, Japan), HbA1c% measured based on a specific chemical reaction to the glycated N-terminal valine of the β-chain , and plasma lipid profile (total cholesterol, triglycerides, low-density lipoprotein, and high-density lipoprotein) using the open system autoanalyzer Synchron CX5 (Beckman). Complete blood count was done using Sysmex KX-21 automatized hematology analyzer (Sysmex Corporation) . C-reactive protein titer was assessed by latex agglutination test . Kidney function tests (serum creatinine, blood urea, serum uric acid, and eGFR by MDRD equation) were done using the open system autoanalyzer Synchron CX5 (Beckman). Liver function tests, including liver transaminases (aspartate transaminase and alanine transaminase), gamma-glutamyltransferase, serum albumin, serum bilirubin (total and direct), prothrombin, and international normalized ratio, were done using a biochromatic (405–510 nm) rate technique. Radiological examination included abdominal ultrasound, which was done to predict the fatty liver. Patients had been divided into three grades according to the degree of increased echogenicity, visualization of right hemidiaphragm and intrahepatic vessels, and through transmission of sound beam . Patients were classified into three grade as follows: grade 1 (mild), a slight diffuse increase in the fine echoes in the hepatic parenchyma and normal visualization of intrahepatic vessel borders and diaphragm; grade 2 (moderate), a moderately diffuse increase in fine echoes in the hepatic parenchyma and slightly impaired visualization of intrahepatic vessel borders and diaphragm; and grade 3 (severe), a severe increase in fine echoes in hepatic parenchyma and poor or no visualization of intrahepatic vessel borders, diaphragm, and posterior portion of the right lobe .
Data were collected, coded, revised, and entered to the statistical package for the social science (IBM SPSS), version 20. The data were presented as number and percentages for the qualitative data, and mean, SD, and ranges for quantitative data.
| Results|| |
Results showed that there were no significant differences between studied groups regarding age, sex, and blood pressure. In contrast, BMI mean value was higher in group I diabetics with fatty liver (33.41 ± 5.51), showing that most patients were obese, versus the mean BMI among group II diabetics without fatty liver (27.01 ± 1.75), which indicated that most patients were overweight, and the difference was statistically significant (P = 0.000). Regarding waist circumference (cm), the mean value was higher in group I than in group II (111.95 ± 9.83 and 96.3 ± 5.79, respectively), and the difference was statistically significant (P = 0.000) [Table 1]. Regarding liver function tests, the mean values of total and direct serum bilirubin, alanine transaminase, and serum albumin were found to be nearly equal in both groups, and the difference was statistically insignificant. On the contrary, the mean values of aspartate transaminase and gamma-glutamyltransferase were found to be higher in group I diabetic patients with fatty liver, and the differences were statistically significant (P = 0.022 and P = 0.000, respectively). Kidney function tests showed that the mean values of blood urea, serum uric acid, and ACR were higher in group I patients with fatty liver more than the other group, and the differences were statistically significant (P = 0.02, 0.000, and 0.004, respectively). On the contrary, serum creatinine mean value was higher in group I, but the difference was statistically insignificant (P = 0.067) [Table 2]. In comparison of group I patients according to fatty liver degree by ultrasound, serum cholesterol and triglycerides were found to be higher in patients with severe degree of fatty liver than in those with mild and moderate degree of fatty liver, and the differences were statistically significant (t = 3.257, P = 0.033 and t = 10.47, P = 0.000, respectively) [Table 3]. In relation to kidney function tests of group I patients according to degree of fatty liver by ultrasound, the mean values of urea were near to each other, and the differences were statistically insignificant. Regarding serum creatinine and serum uric acid, the highest mean values belonged to patients with severe fatty liver, and the differences were statistically significant (t = 3.132, P = 0.037 and t = 7.647, P = 0.000, respectively). Urine ACR shows that the mean value was higher in patients with severe degree of fatty liver more than those with mild and moderate degree of fatty liver, and the difference was statistically significant (t = 3.542, P = 0.024). The comparison of group I patients according to degree of fatty liver by ultrasound and homeostatic model assessment of insulin resistance (HOMA-IR) shows that the highest mean value of HOMA-IR belonged to severe fatty liver (8.65 ± 4.71), and the difference was statistically insignificant [Table 4].
|Table 1: Demographic and clinical characteristics of the studied patient groups|
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|Table 2: Comparison between group I and group II regarding liver and kidney function tests|
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|Table 4: Liver and kidney function tests among diabetics with fatty liver|
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| Discussion|| |
CKD represents a significant health burden in the Western adult population, and it affects more than 25% of individuals older than 65 years. CKD is defined as decreased eGFR and/or the presence of significant proteinuria (>500 mg) . In the present study, we investigated the association between the presence of NAFLD and albuminuria (early marker of kidney injury) in type 2 diabetic patients, that is, does presence of NAFLD necessitate assessment of renal function in type 2 diabetic patients? We found that mean ACR in group I was higher than in group II, (77.24 ± 89.98 and 10.94 ± 2.76, respectively), and the difference was statistically significant. The mean value of blood urea among group I was higher than the mean value among group II, and the difference was statistically significant. On the contrary, regarding serum creatinine, the difference was statistically insignificant. The mean value of serum uric acid among group I was higher than the mean value among group II, and the difference was statistically significant (t = 4.572, P = 0.000). On the contrary, eGFR value in group I was lower than the mean value in group II, and the difference was statistically insignificant (t = −0.616, P = 0.544). On comparison of group I patients according to degree of fatty liver by ultrasound and urine ACR, we found that the difference was statistically significant among the different degrees of fatty liver (t = 3.542, P = 0.024), with the highest mean value among patients with severe fatty liver. On the contrary, regarding serum creatinine and serum uric acid mean values, the difference was statistically significant. Kasapoglu et al.  in their study revealed increased microalbuminuria prevalence among patients with NAFLD; this retrospective study was carried out on 479 nonobese (BMI <30) and nondiabetic cases. All patients underwent liver ultrasonography scanning to determine the presence and stage of fatty liver disease. The patients were grouped according to the ultrasound findings as follows: 182 (37.9%) cases without any fat accumulation in liver were regarded as control group, and among the remaining cases, 124 (25.8%) had mild, 93 (19.4%) had moderate, and 80 (16.7%) had severe fatty liver disease. There was no statistically significant difference between groups regarding age, sex, liver function tests, renal function tests, or GFR. However, urinary protein/creatinine ratio was statistically significantly higher in severe NAFLD group than the other groups. In moderate and severe NAFLD groups, microalbuminuria was statistically significantly more common compared with the control and mild NAFLD groups. Regarding the results of multiple logistic regression analysis, presence of fatty liver disease increased the risk of microalbuminuria by 1.87 times, independent of increased BMI and increased HOMA-IR values. Jenks et al.  in their study on 933 patients with type 2 diabetes who were analyzed for 4 years of follow-up reported that the presence of NAFLD was not associated with decline in renal function. Interestingly, in a study of Ryu et al.  on 10 337 healthy Korean men who were followed for ∼3.5 years, mildly elevated serum gamma-glutamyltransaminase concentrations, as surrogate markers of NAFLD, were associated with an increased risk for CKD. El-Azeem et al.  reported that the frequency of cardiovascular accident and renal impairment was significantly higher in patients with NAFLD. They determined that in 3 years of follow-up, the microalbuminuria prevalence was 32.8% among patients with NAFLD, and it was statistically significantly higher compared with the 18.4% prevalence of control cases. They also reported that mean eGFR was significantly lower in patients with NAFLD, and they determined that NAFLD was a good predictor of cardiovascular and renal diseases. Hwang et al.  reported that the association of microalbuminuria and fatty liver disease has also been studied in different populations. Microalbuminuria has been determined to be significantly more frequent in patients with NAFLD among type 2 diabetics and in patients who had an abnormal oral glucose tolerance test. They reported that patients with NAFLD had higher prevalence rates of microalbuminuria. The microalbuminuria rates of patients with NAFLD were reported to be as 19% in prediabetics and as 32.6% in diabetics. Kim et al.  investigated the microalbuminuria prevalence in a sample of 2489 nondiabetic, nonhypertensive men and reported that the NAFLD group had a significantly higher prevalence of microalbuminuria compared with the non-NAFLD group. They reported the microalbuminuria prevalence of 6.3% in NAFLD group. Yılmaz et al.  evaluated the relationships between microalbuminuria and liver histology in a hospital-based sample of 87 adults with biopsy-proven NAFLD. They defined that 14 patients had microalbuminuria and those cases had a significantly higher homeostasis model assessment of insulin resistance values as well as the mean fibrosis scores compared with the cases without microalbuminuria. There are some limitations of this study. First of all, the diagnosis and staging of fatty liver disease was based on the findings of ultrasound instead of biopsy. Second, GFR was calculated with the MDRD equation instead of a direct measurement, as this estimation facilitates the recognition, evaluation, and management of chronic renal disease.
| Conclusion|| |
NAFLD is strongly associated with an increased frequency of CKD in the studied type 2 diabetic patients. So, screening of diabetic patients with ultrasonography for NAFLD detection and grading is necessary. Moreover, there should be scheduled investigations for diabetic patients with fatty liver with stress on assessment of kidney function. Furthermore, early workup should be done if CKD is detected.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Maurice J, Manousou P. Non-alcoholic fatty liver disease. Clin Med (Lond) 2018; 18
Dulai PS, Singh S, Patel J, Soni M, Prokop LJ, Younossi Z, et al
. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis. Hepatology 2017; 65
Nasr P, Ignatova S, Kechagias S, Ekstedt M. Natural history of nonalcoholic fatty liver disease: a prospective follow-up study with serial biopsies. Hepatol Commun 2018; 2
Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, et al
. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2018; 15
Targher G, Chonchol MB, Byrne CD. CKD and non-alcoholic fatty liver disease. Am J Kidney Dis 2014; 64
Chopra S, Lai M. Management of nonalcoholic fatty liver disease in adults. In: Post TW, Waltham MA, ed. wolters kluwer; 2019. 20–25.
Athyros V, Tziomalos K, Katsiki N, Doumas M, Karagiannis A, Mikhailidis DP. Cardiovascular risk across the histological spectrum and the clinical manifestations of non- alcoholic fatty liver disease; an update. World J Gastroenterol 2015; 21
Singal AK, Salameh H, Kuo YF, Wiesner RH. Evolving frequency and outcomes of simultaneous liver kidney transplants based on liver disease etiology. Transplantation 2014; 98
Tommasi S, Besaratinia A. DNA hydroxymethylation at the interface of the environment and nonalcoholic fatty liver disease. Int J Environ Res Public Health 2019; 16
Sacks KB. How did Jews become white folks? Race 1994; 1
Jaisson S, Leroy N, Meurice J, Guillard E, Gillery P. First evaluation of Capillarys 2 Flex Piercing (Sebia) as a new analyzer for HbA1c assay by capillary electrophoresis. Clin Chem Lab Med 2012; 50
Tatsumi N, Okuda K, Tsuda I. A new direction in automated laboratory testing in Japan: five years of experience with total laboratory automation system management. Clin Chim Acta 1999; 290
Singer JM, Plotz CM, Pader E, Elster SK. The latex-fixation test: III. agglutination test for C-reactive protein and comparison with the capillary precipitin method. Am J Clin Pathol 1957; 28
Carol A, Vishan L, Ronald LG. Sonographic characteristics of fatty Infiltration. Ultrasound atlas of disease process. Appleton Lange Netw Conn 1993; 1
Pavkov ME, Nelson RG. Estimating GFR in the elderly-new approaches to an old problem. Kidney Int Rep 2019; 4
Kasapoglu B, Turkay C, Yalcın KS, Boga S, Bozkurt A. Increased microalbuminuria prevalence among patients with nonalcoholic fatty liver disease. Ren Fail 2016; 38
Jenks SJ, Conway BR, Hor TJ. Hepatic steatosis and nonalcoholic fatty liver disease are not associated with decline in renal function in people with type 2 diabetes. Diabet Med 2014; 31
Ryu S, Chang Y, Kim DI. Gammaglutamyl transferase as a predictor of chronic kidney disease in non-hypertensive and nondiabetic Korean men. Clin Chem 2017; 53
El-Azeem HA, Khalek El- SA, El-Akabawy H. Association between nonalcoholic fatty liver disease and the incidence of cardiovascular and renal events. J Saudi Heart Assoc 2013; 25
Hwang ST, Cho YK, Yun JW, Park JH, Kim HJ, Park DI, et al
. Impact of non-alcoholic fatty liver disease on microalbuminuria in patients with prediabetes and diabetes. Intern Med J 2010; 40
Kim BJ, Kim BS, Kang JH. The association between serum ferritin level, microalbuminuria and non-alcoholic fatty liver disease in non-diabetic, non-hypertensive men. Clin Exp Hypertens 2015; 36
Yilmaz Y, Alahdab YO, Yonal OF. Microalbuminuria in nondiabet patients with nonalcoholic fatty liver disease: association with liver fibrosis. Metab Clin Exp 2010; 59
[Table 1], [Table 2], [Table 3], [Table 4]