Back to Journals » International Journal of General Medicine » Volume 16

Factors Associated with Liver Fibrosis in Chinese Patients with Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease

Authors Luo Y , Wang C , Zhang T, He X , Hao J , Shen A, Zhao H, Chen S, Ren L

Received 2 November 2022

Accepted for publication 8 January 2023

Published 24 January 2023 Volume 2023:16 Pages 293—302

DOI https://doi.org/10.2147/IJGM.S395948

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Scott Fraser



Yu Luo,1 Cuiyu Wang,1,2 Tian Zhang,1,3 Xiaoyu He,1,4 Jianan Hao,1,4 Andong Shen,3,5 Hang Zhao,1 Shuchun Chen,1 Luping Ren1

1Endocrinology Department, Hebei General Hospital, Shijiazhuang, People’s Republic of China; 2Graduate School, Hebei North University, Zhangjiakou, People’s Republic of China; 3Graduate School, North China University of Science and Technology, Tangshan, People’s Republic of China; 4Graduate School, Hebei Medical University, Shijiazhuang, People’s Republic of China; 5Gastroenterology Department, Hebei General Hospital, Shijiazhuang, People’s Republic of China

Correspondence: Luping Ren, Email [email protected]

Purpose: Non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are frequently co-occurring diseases. Liver fibrosis (LF), with increasing incidence, has a prognostic value for NAFLD mortality. Our study aimed to investigate the relevant factors for FL in T2DM individuals with NAFLD.
Patients and Methods: A total of 565 T2DM patients with NAFLD from Hebei General Hospital participated in the study. Patients underwent an abdominal ultrasound, a questionnaire and laboratory tests. The fibrosis-4 index (FIB-4) was used to evaluate LF, with FIB ≥ 1.3 indicating LF and FIB ≥ 2.67 indicating F3-4 fibrosis.
Results: Compared with NLF group, LF group had higher levels of systolic blood pressure (SBP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutamyl transpeptidase (GGT). The glomerular filtration rate (GFR), low-density lipoprotein cholesterol (LDL), glycated hemoglobin (HbA1c), and platelets (PLT) in LF patients were lower than those without LF. Patients with LF were older than those without LF. ALT, AST, and GGT in patients with severe LF were higher than those with mild LF, while platelet was lower. Age, SBP, duration of diabetes, ALT, AST, and GGT were positively correlated with FIB-4, while eGFR, TC, LDL, and HbA1c were negatively correlated with FIB-4. Logistic regression showed that age, SBP, ALT, GGT, LDL, and PLT were independently associated with LF.
Conclusion: For T2DM patients combined with NAFLD, older age, higher SBP, higher ALT, higher GGT, lower LDL, and lower PLT were relevant factors for LF.

Keywords: type 2 diabetes mellitus, non-alcoholic fatty liver disease, fibrosis-4 index, liver fibrosis

Introduction

Type 2 diabetes mellitus (T2DM) is a common chronic disease, with an estimated global prevalence of between 6% and 9%.1 Its pathogenesis involves insulin resistance (IR) and relatively insufficient insulin secretion, with hyperglycemia as its feature. Some epidemiological studies have reported a high comorbidity rate between T2DM and non-alcoholic fatty liver disease (NAFLD). NAFLD is regarded as a manifestation of metabolic syndrome (MS) in the liver. With a prevalence of about 25%, it has been the primary cause of chronic liver disease.2,3 It refers to a group of diseases that range from simple steatohepatitis to non-alcoholic steatohepatitis (NASH). In some cases, it can further progress to liver fibrosis (LF), cirrhosis, and hepatocellular carcinoma. In addition, NAFLD is associated with an increased risk of extra-hepatic cancers, including colorectal and breast cancers.3

LF serves as a crucial mortality predictor for those with NAFLD. The all-cause and liver-related mortality in NAFLD patients increases dramatically with the severity of fibrosis.4 According to a meta-analysis of 49,419 participants, the prevalence of NAFLD in T2DM patients was approximately 55.5%, and the proportion of severe LF was as high as 17.7%.5 LF is associated with diabetic nephropathy, diabetic peripheral neuropathy, cardiovascular disease, and osteoporosis.6–9 Early LF could still be reversed with early intervention.10 Therefore, it is meaningful to screen LF in T2DM patients with NAFLD so that early intervention can be provided.

Some studies have looked into the causes of LF in those who have both T2DM and NAFLD. Most studies diagnosed LF by transient elastography (TE) and FibroScan. Obesity, which is manifested as a higher body mass index (BMI) and waist circumference, has proven to be one of the outstanding risk factors for LF.11–13 Higher levels of liver enzymes are independently associated with LF.14–16 Other risk factors include age,17,18 dyslipidemia,19 hypertension20 and race.11,21 To date, there are few studies to explore the relevant factors of LF in Chinese diabetes patients combined with NAFLD.

TE, FibroScan, and serological diagnostic panels are recommended noninvasive methods for screening LF. The fibrosis-4 index (FIB-4), AST-to-platelet (PLT) ratio index (APRI) and NAFLD fibrosis score (NFS) are common serological diagnostic panels. Serological diagnostic panels are cheaper and more suitable for primary screening LF in community hospitals than TE and FibroScan. FIB-4 was proposed by Sterling and initially used to assess LF in patients with viral hepatitis.22 A meta-analysis that compared different noninvasive methods of diagnosing LF showed that FIB-4 had a negative predictive value of 95% and a positive predictive value of 70% for LF with a 1.30 cut-off.23 In addition, FIB ≥2.67 was found to identify F3-4 fibrosis.24 This study is the first to use FIB-4 to assess LF in Chinese patients with T2DM combined with NAFLD and to explore its associated factors.

Patients and Methods

Participants

All participants were selected from individuals with T2DM and NAFLD, who were hospitalized in the Department of Endocrinology, Hebei General Hospital from January 2019 to January 2020. Inclusion criteria were as follows: (1) T2DM was diagnosed by the diagnostic criteria for diabetes issued by the World Health Organization in 1999 or according to the self-reported history of T2DM; (2) Abdominal ultrasound indicated fatty liver; (3) Participants were at least 18 years old and at most 80 years old; (4) No history of alcohol consumption or alcohol consumption <70 gram every week for women and <140 gram every week for men. Exclusion criteria were as follows: (1) autoimmune hepatitis, drug-related liver injury, viral hepatitis, hepatomegaly, and other liver diseases; (2) type 1 diabetes, specific types of diabetes, gestational diabetes mellitus, and T2DM with acute complications; (3) malignant tumors and hematological diseases or recent received chemotherapy or immunotherapy; (4) taking drugs that may cause fatty liver; (5) pregnant or lactating women; (6) others: hypothyroidism, acute cardiovascular and cerebrovascular diseases, mental diseases and severe renal dysfunction, defined as glomerular filtration rate (GFR) <30 mL/min. The study eventually included 565 participants. Our study conformed to the Declaration of Helsinki and was approved by the Hebei General Hospital Ethics Committee. All subjects signed written informed consent. We promised that all patients’ information was confidential.

Methods

Basic information such as age, gender, duration of diabetes and history of underlying diseases and current medicine were collected through a questionnaire survey. Height and weight were measured while wearing light clothing and without shoes. Systolic/diastolic blood pressure (SBP/DBP) was measured after the patient rested quietly for at least 10 minutes. All patients had venous blood samples drawn after fasting for at least 8 hours to perform laboratory examinations, including total protein (TP), albumin (ALB), globulin (GLB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), blood urea nitrogen (BUN), serum creatinine (Scr), serum uric acid (SUA), glomerular filtration rate (GFR), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), fasting plasma glucose (FPG), fasting insulin (FINS), glycosylated hemoglobin (HbAlc), hemoglobin (HGB), and platelet (PLT). In addition, all subjects underwent abdominal ultrasonography operated by experienced technicians on an empty stomach.

SBP ≥140 mmHg and/or DBP ≥90 mmHg was defined as hypertension, as well as a history of antihypertensive medication use. Hyperlipidemia was defined as total cholesterol ≥5.7 mmol/L and/or triglycerides ≥1.7 mmol/L and a history of lipid-lowering drug use. Body mass index (BMI) was calculated by dividing weight (kg) by height (m) squared. A BMI of 25 kg/m2 or more was considered obese. Homeostasis assessment of insulin resistance (HOMA-IR) was equal to the product of FPG and FINS divided by 22.5. . . .

The data was analyzed by SPSS 26.0. The Kolmogorov–Smirnov test was used to determine whether continuous variables had a normal distribution. The Normally distributed variables were expressed as mean ± standard deviation, and the ANOVA test was used to compare group differences. The non-normal distributed variables were expressed as quartile, and differences between groups were compared using Nonparametric test. The enumeration data was expressed in the form of percentile and the Chi-square test was applied to test differences between groups. Spearman correlation analysis and binary logistic regression analysis were carried out to determine the relevant factors for LF. And P < 0.05 was deemed statistically significant.

Results

A total of 565 participants were included in the study (median age: 57 years and BMI: 27.31 kg/m2), and 334 (59.12%) of them were male. The number of patients in the NLF group (FIB-4 <1.3) was 336 while 229 patients were in the LF group (FIB-4 ≥1.3). Of the patients with LF, 44 had F3-4 fibrosis (FIB-4 ≥2.67).

Clinical Characters of T2DM Patients with and without LF

There was no significant difference between the two groups in terms of gender, DBP, BMI, duration of diabetes, TP, ALB, GLB, ALP, FBG, BUN, Scr, UA, TC, TG, HDL, HGB, and HOMA-IR according to the data in Table 1. Patients with LF had lower GFR, LDL, HbAlc, and PLT than those without LF. Meanwhile, the age was older, and the levels of SBP, ALT, AST, GGT were higher in patients with LF compared to those without LF. Compared to the NLF group, the other two LF scores, APRI and NFS in the LF group were higher. Figure 1 showed that no difference was found in the prevalence of obesity and hyperlipidemia between the LF and NLF groups, while the proportion of hypertensive patients was higher in the LF group than that in the NLF group.

Table 1 Comparison of Clinical Parameters Between Patients with and without Liver Fibrosis

Figure 1 Comparison of prevalence of hypertension, hyperlipidemia, and obesity between NLF group and LF group. (A) Comparison of prevalence of hypertension, between NLF group and LF group; (B) Comparison of prevalence of hyperlipidemia between NLF group and LF group; (C) Comparison of prevalence of obesity between NLF group and LF group. **P < 0.01.

Comparison of Clinical Parameters in Patients with Different Degrees of LF

Patients were further divided into F1-2 (1.3≤ FIB <2.67) and F3-4 (FIB-4 ≥2.67) fibrosis groups. As shown in Table 2, ALT, AST, and GGT in patients with F3-4 fibrosis were higher than those with F1-2 fibrosis, while platelet was lower. There were no group differences in terms of other clinical parameters.

Table 2 Comparison of Clinical Parameters in Patients with Different Degrees of Liver Fibrosis

Spearman Correlation Analysis of the FIB-4 and Other Factors

Table 3 showed that FIB-4 was positively correlated with age, SBP, duration of diabetes, ALT, AST, GGT, APRI, and NFS, while negatively correlated with GFR, TC, LDL, and HbA1c. DBP, BMI, TP, GLB, ALP, BUN, Scr, UA, TG, HDL, FPG, HOMA-IR, and HGB were not correlated with FIB-4.

Table 3 Correlation Between FIB-4 and Other Indicators

Logistic Regression Analysis of LF in T2DM Patients Combined with NAFLD

LF was used as the dependent variable, with age, SBP, ALT, AST, GGT, GFR, LDL, PLT, and HbAlc as the independent variables. Age, SBP, ALT, GGT, LDL, and PLT were all independently associated with LF in T2DM patients with NAFLD according to the binary logistic regression analysis. However, this association was not found between LF and AST, GFR, and HbA1c. The results were shown in Table 4.

Table 4 Logistic Regression Analysis of Liver Fibrosis in Type 2 Diabetes Mellitus Patients Combined with Non-Alcoholic Fatty Liver Disease

Discussion

To our knowledge, FIB-4 is the first to be used as the diagnostic indicator for LF in Chinese T2DM patients with NAFLD to investigate the relevant factors. FIB-4 was found to be positively correlated with age, SBP, duration of diabetes, ALT, AST, GGT, APRI, and NFS, while negatively correlated with GFR, TC, LDL, and HbA1c. After adjustment for confounding factors, logistic regression showed that age, SBP, ALT, GGT, LDL, and PLT were independently correlated with LF.

In our study, the LF group showed higher ALT, AST and GGT than the NLF group. Further analysis showed that ALT, AST and GGT were positively correlated with FIB-4. However, after adjusting for confounding factors, only ALT and GGT were associated with LF. Previous studies have found that subjects with LF had higher ALT, AST and GGT levels compared with those without LF.25–28 Liver enzymes reflect liver function and hepatocellular injury and have been suggested to predict NAFLD.29 AST is mainly found in mitochondria and elevated AST is often associated with severe hepatocellular injury.14 Our study found that AST was not an independent predictor of FL, perhaps because our patients had less severe liver lesions.

Our findings demonstrated that age was a risk factor for LF. Individuals aged ≥50 years were 4.315 times more likely to develop LF than patients aged <50 years. It agrees with the findings of several studies.30,31 The prevalence of NAFLD is high in the elderly.32 It may be related to the fact that elderly patients are prone to hypertension, obesity and dyslipidemia, which are all risk factors for NAFLD. On the other hand, liver function deteriorates with ageing and chronic liver disease is more likely to worsen in older patients.20,33

We found that SBP but not DBP was correlated with LF after correction for confounding factors. Hypertension and NAFLD are both considered to be manifestations of MS, showing a potential mutual causality.34–37 Hypertension is often accompanied by RAS activation, and studies have shown that Angiotensin II (Ang II) is associated with LF. Ang II can activate hepatic stellate cells (HSCs) and cause LF.38 Meanwhile, Ang II can aggravate IR though activating insulin signaling pathways.39 Yuan et al40 found that mice with hypertension showed more severe LF than those without hypertension, and that cytokine activation and inflammation played an important role. RAS activation, IR, and inflammation are important pathophysiological mechanisms underlying the co-morbidity of hypertension and NAFLD.41,42

In our study, lower levels of LDL in the LF group were observed compared to the NLF group. Meanwhile, LDL was negatively associated with LF. There are some studies supporting our results. Jaafar et al43 found that LDL in patients with T2DM combined with NAFLD was lower compared to the patients with NAFLD alone. Another study assessing LF with FIB-4 also showed a negative correlation between LDL and LF.44 Low LDL levels may reflect decreased liver function. As liver function worsens, so does the hepatic ability to synthesize LDL. In addition, genetic mutations may be involved. PNPLA-3 is a genetic variant closely related to NAFLD, and people carrying the PNPLA3rs738409 GG allele show lower TC and LDL.45 The exact mechanism is unclear.

As the results illustrated, the LF group showed lower HbAlc and FBG levels compared with the NLF group. As we know, the liver is the hub of glucose metabolism. In some liver diseases, including LF, cirrhosis, and liver cancer, blood glucose levels decrease as the ability of the liver to store glycogen and gluconeogenesis decreases.46 This is also associated with large fluctuations in blood glucose, mainly manifested as decreased FBG and increased postprandial blood glucose.47 Some patients with NAFLD already have subclinical hypersplenism at the time of initial diagnosis.48 Our study also showed the FL group had lower levels of PLT and HGB than the NFL group, although PLT and HGB in both groups were in the normal range. Due to shortened erythrocyte lifespan as a result of hypersplenism, they have lower HbAlc levels.49 However, some studies have found that HbA1c is positively correlated with NAFLD, regardless of whether diabetes is present.50–53 A study showed that each 1% increase in HbA1c increased the probability of LF progress by 15%.54 Subclinical hypersplenism was not excluded in our study population, so HBA1C did not truly reflect blood glucose. Continuous glucose monitoring system and time in range may be more suitable for blood glucose monitoring in patients with T2DM complicated with chronic liver disease.

Moreover, our results showed that HOMA-IR in both LF and NLF groups was ≥3, indicating IR existed in both groups, although HOMA-IR was not statistically different between groups. Our study revealed that IR may not be connected to the development of LF. Mikolasevic et al26 found that HOMA-IR was independently associated with hepatic steatosis, but not with moderate and advanced LF in T2DM patients with NAFLD. Mantovani et al55 conducted a cross-sectional study on T2DM patients who were not treated with insulin. The diagnosis of NAFLD is based on abdominal color ultrasound and liver hardness measurement. Their results showed that HOMA-IR was not independently associated with LF. However, some studies found that IR was closely related to LF in NAFLD patients whether or not diabetes is present.56–58 The reasons for this discrepancy are not fully elucidated, but race and experimental methods may be underlying factors.

Our research had some limitations. Firstly, as a cross-sectional study, it cannot provide evidence for further exploration of the causal relationship between relevant factors and LF. Secondly, FIB-4 was used to diagnose LF and grade the lesion degree, which may be different from the actual clinical situation. Third, this was a single-center study, and it was not possible to generalize the findings to the other population.

Conclusion

In conclusion, LF is independently associated with age, SBP, ALT, GGT, LDL, and PLT in patients with T2DM and NAFLD. For T2DM patients with NAFLD, intensive comprehensive care of blood glucose, blood pressure, and blood lipid is required. When conditions are suitable, further liver biopsy is advised to identify the severity of NAFLD.

Funding

This study was not funded in any form.

Disclosure

The authors report no conflicts of interest in this work.

References

1. Lindekilde N, Scheuer SH, Rutters F, et al. Prevalence of type 2 diabetes in psychiatric disorders: an umbrella review with meta-analysis of 245 observational studies from 32 systematic reviews. Diabetologia. 2022;65(3):440–456. doi:10.1007/s00125-021-05609-x

2. Marjot T, Moolla A, Cobbold JF, Hodson L, Tomlinson JW. Nonalcoholic fatty liver disease in adults: current concepts in etiology, outcomes, and management. Endocr Rev. 2020;41(1). doi:10.1210/endrev/bnz009

3. Kim GA, Lee HC, Choe J, et al. Association between non-alcoholic fatty liver disease and cancer incidence rate. J Hepatol. 2017. doi:10.1016/j.jhep.2017.09.012

4. Dulai PS, Singh S, Patel J, et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis. Hepatology. 2017;65(5):1557–1565. doi:10.1002/hep.29085

5. Younossi ZM, Golabi P, de Avila L, et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis. J Hepatol. 2019;71(4):793–801. doi:10.1016/j.jhep.2019.06.021

6. Chun HS, Lee JS, Lee HW, et al. Association between the severity of liver fibrosis and cardiovascular outcomes in patients with type 2 diabetes. J Gastroenterol Hepatol. 2021;36(6):1703–1713. doi:10.1111/jgh.15387

7. Saito H, Tanabe H, Kudo A, et al. High FIB4 index is an independent risk factor of diabetic kidney disease in type 2 diabetes. Sci Rep. 2021;11(1):11753. doi:10.1038/s41598-021-88285-6

8. Kim K, Oh TJ, Cho HC, et al. Liver fibrosis indices are related to diabetic peripheral neuropathy in individuals with type 2 diabetes. Sci Rep. 2021;11(1):24372. doi:10.1038/s41598-021-03870-z

9. Zhu X, Yan H, Chang X, et al. Association between non-alcoholic fatty liver disease-associated hepatic fibrosis and bone mineral density in postmenopausal women with type 2 diabetes or impaired glucose regulation. BMJ Open Diabetes Res Care. 2020;8(1):e000999. doi:10.1136/bmjdrc-2019-000999

10. Tacke F, Weiskirchen R. Non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH)-related liver fibrosis: mechanisms, treatment and prevention. Ann Transl Med. 2021;9(8):729. doi:10.21037/atm-20-4354

11. Ciardullo S, Monti T, Perseghin G. High prevalence of advanced liver fibrosis assessed by transient elastography among U.S. adults with type 2 diabetes. Diabetes Care. 2021;44(2):519–525. doi:10.2337/dc20-1778

12. Yao VJH, Sun M, Rahman AA, et al. Comparative analysis of metabolic risk factors for progression of non-alcoholic fatty liver disease. Clin Exp Hepatol. 2021;7(2):241–247. doi:10.5114/ceh.2021.107567

13. Younossi ZM, Pham H, Felix S, et al. Identification of high-risk patients with nonalcoholic fatty liver disease using noninvasive tests from primary care and endocrinology real-world practices. Clin Transl Gastroenterol. 2021;12(4):e00340. doi:10.14309/ctg.0000000000000340

14. Mansour A, Mohajeri-Tehrani MR, Samadi M, et al. Risk factors for non-alcoholic fatty liver disease-associated hepatic fibrosis in type 2 diabetes patients. Acta Diabetol. 2019;56(11):1199–1207. doi:10.1007/s00592-019-01374-x

15. Sporea I, Mare R, Popescu A, et al. Screening for liver fibrosis and steatosis in a large cohort of patients with type 2 diabetes using vibration controlled transient elastography and controlled attenuation parameter in a single-center real-life experience. J Clin Med. 2020;9(4):1032. doi:10.3390/jcm9041032

16. Tuong TTK, Tran DK, Phu PQT, et al. Non-alcoholic fatty liver disease in patients with type 2 diabetes: evaluation of hepatic fibrosis and steatosis using fibroscan. Diagnostics. 2020;10(3). doi:10.3390/diagnostics10030159

17. Zhao H, Song X, Li Z, Wang X. Risk factors associated with nonalcohol fatty liver disease and fibrosis among patients with type 2 diabetes mellitus. Medicine. 2018;97(37):e12356. doi:10.1097/MD.0000000000012356

18. Dai CY, Fang TJ, Hung WW, Tsai HJ, Tsai YC. The determinants of liver fibrosis in patients with nonalcoholic fatty liver disease and type 2 diabetes mellitus. Biomedicines. 2022;10(7):1487. doi:10.3390/biomedicines10071487

19. Mendez-Sanchez N, Cerda-Reyes E, Higuera-de-la-Tijera F, et al. Dyslipidemia as a risk factor for liver fibrosis progression in a multicentric population with non-alcoholic steatohepatitis. F1000Res. 2020;9:56. doi:10.12688/f1000research.21918.1

20. Chen K, Sng WK, Quah JH, et al. Clinical spectrum of non-alcoholic fatty liver disease in patients with diabetes mellitus. PLoS One. 2020;15(8):e0236977. doi:10.1371/journal.pone.0236977

21. Browning MG, Khoraki J, DeAntonio JH, et al. Protective effect of black relative to white race against non-alcoholic fatty liver disease in patients with severe obesity, independent of type 2 diabetes. Int J Obes. 2018;42(4):926–929. doi:10.1038/ijo.2017.309

22. Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43(6):1317–1325. doi:10.1002/hep.21178

23. Sun W, Cui H, Li N, et al. Comparison of FIB-4 index, NAFLD fibrosis score and BARD score for prediction of advanced fibrosis in adult patients with non-alcoholic fatty liver disease: a meta-analysis study. Hepatol Res. 2016;46(9):862–870. doi:10.1111/hepr.12647

24. Tatoli R, Tirelli S, Lampignano L, et al. Liver fibrosis and hearing loss in an older mediterranean population: results from the salus in apulia study. J Clin Med. 2022;11(23):7213. doi:10.3390/jcm11237213

25. Sandhu S, Orsi C, Francis GL, et al. Shear wave elastography reveals a high prevalence of liver fibrosis in overweight or obese Hispanic youth. J Ultrason. 2020;20(82):e162–e168. doi:10.15557/JoU.2020.0027

26. Mikolasevic I, Domislovic V, Turk Wensveen T, et al. Screening for nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus using transient elastography - a prospective, cross sectional study. Eur J Intern Med. 2020;82:68–75. doi:10.1016/j.ejim.2020.08.005

27. Kuchay MS, Choudhary NS, Mishra SK, et al. Prevalence of clinically relevant liver fibrosis due to nonalcoholic fatty liver disease in Indian individuals with type 2 diabetes. JGH Open. 2021;5(8):915–922. doi:10.1002/jgh3.12606

28. Alam MS, Kamrul-Hasan ABM, Kalam ST, et al. Liver stiffness measurement by using transient elastography in Bangladeshi patients with type 2 diabetes mellitus and ultrasonography-diagnosed nonalcoholic fatty liver disease. Diabetes Metab Syndr Obes. 2021;14:3089–3096. doi:10.2147/DMSO.S317876

29. Bril F, McPhaul MJ, Caulfield MP, et al. Performance of plasma biomarkers and diagnostic panels for nonalcoholic steatohepatitis and advanced fibrosis in patients with type 2 diabetes. Diabetes Care. 2020;43(2):290–297. doi:10.2337/dc19-1071

30. Pitisuttithum P, Chan WK, Piyachaturawat P, et al. Predictors of advanced fibrosis in elderly patients with biopsy-confirmed nonalcoholic fatty liver disease: the GOASIA study. BMC Gastroenterol. 2020;20(1):88. doi:10.1186/s12876-020-01240-z

31. Naguib M, Abou Elfotouh M, Wifi MN. Elevated serum cyclophilin D level is associated with nonalcoholic fatty liver disease and higher fibrosis scores in patients with diabetes mellitus. Int J Gen Med. 2021;14:4665–4675. doi:10.2147/IJGM.S322986

32. Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73–84. doi:10.1002/hep.28431

33. Hirose S, Matsumoto K, Tatemichi M, et al. Nineteen-year prognosis in Japanese patients with biopsy-proven nonalcoholic fatty liver disease: lean versus overweight patients. PLoS One. 2020;15(11):e0241770. doi:10.1371/journal.pone.0241770

34. Petta S, Di Marco V, Pipitone RM, et al. Prevalence and severity of nonalcoholic fatty liver disease by transient elastography: genetic and metabolic risk factors in a general population. Liver Int. 2018;38(11):2060–2068. doi:10.1111/liv.13743

35. Han J, Wang Y, Yuan Z, et al. Nonalcoholic fatty liver disease represents a greater metabolic burden in patients with atherosclerosis: a cross-sectional study. Medicine. 2019;98(11):e14896. doi:10.1097/MD.0000000000014896

36. Zhao YC, Zhao GJ, Chen Z, et al. Nonalcoholic fatty liver disease: an emerging driver of hypertension. Hypertension. 2020;75(2):275–284. doi:10.1161/HYPERTENSIONAHA.119.13419

37. Lorbeer R, Bayerl C, Auweter S, et al. Association between MRI-derived hepatic fat fraction and blood pressure in participants without history of cardiovascular disease. J Hypertens. 2017;35(4):737–744. doi:10.1097/HJH.0000000000001245

38. Granzow M, Schierwagen R, Klein S, et al. Angiotensin-II type 1 receptor-mediated Janus kinase 2 activation induces liver fibrosis. Hepatology. 2014;60(1):334–348. doi:10.1002/hep.27117

39. Godoy-Lugo JA, Thorwald MA, Hui DY, et al. Chronic angiotensin receptor activation promotes hepatic triacylglycerol accumulation during an acute glucose challenge in obese-insulin-resistant OLETF rats. Endocrine. 2022;75(1):92–107. doi:10.1007/s12020-021-02834-7

40. Yuan Y, Naito H, Kitamori K, et al. The antihypertensive agent hydralazine reduced extracellular matrix synthesis and liver fibrosis in nonalcoholic steatohepatitis exacerbated by hypertension. PLoS One. 2020;15(12):e0243846. doi:10.1371/journal.pone.0243846

41. Cotter TG, Rinella M. Nonalcoholic fatty liver disease 2020: the state of the disease. Gastroenterology. 2020;158(7):1851–1864. doi:10.1053/j.gastro.2020.01.052

42. Marquez-Exposito L, Tejedor-Santamaria L, Valentijn FA, et al. Oxidative stress and cellular senescence are involved in the aging kidney. Antioxidants. 2022;11(2). doi:10.3390/antiox11020301

43. Jaafar RF, Hajj Ali AM, Zaghal AM, et al. Fibroscan and low-density lipoprotein as determinants of severe liver fibrosis in diabetic patients with nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol. 2019;31(12):1540–1544. doi:10.1097/MEG.0000000000001461

44. Fujihara Y, Hamanoue N, Yano H, et al. High sex hormone-binding globulin concentration is a risk factor for high fibrosis-4 index in middle-aged Japanese men. Endocr J. 2019;66(7):637–645. doi:10.1507/endocrj.EJ18-0505

45. Ruschenbaum S, Schwarzkopf K, Friedrich-Rust M, et al. Patatin-like phospholipase domain containing 3 variants differentially impact metabolic traits in individuals at high risk for cardiovascular events. Hepatol Commun. 2018;2(7):798–806. doi:10.1002/hep4.1183

46. Ogawa Y, Nakahara T, Ono M, et al. Underestimation of impaired glucose tolerance and usefulness of a continuous glucose monitoring system in chronic liver disease. J Gastroenterol Hepatol. 2021;36:2275–2284. doi:10.1111/jgh.15487

47. Honda F, Hiramatsu A, Hyogo H, et al. Evaluation of glycemic variability in chronic liver disease patients with type 2 diabetes mellitus using continuous glucose monitoring. PLoS One. 2018;13(4):e0195028. doi:10.1371/journal.pone.0195028

48. Mendes FD, Suzuki A, Sanderson SO, Lindor KD, Angulo P. Prevalence and indicators of portal hypertension in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2012;10(9):1028–1033 e1022. doi:10.1016/j.cgh.2012.05.008

49. Inoue K, Goto A, Kishimoto M, et al. Possible discrepancy of HbA1c values and its assessment among patients with chronic renal failure, hemodialysis and other diseases. Clin Exp Nephrol. 2015;19(6):1179–1183. doi:10.1007/s10157-015-1110-6

50. Yoo JH, Kang M, Kim G, et al. Mean and visit-to-visit variability of glycated hemoglobin, and the risk of non-alcoholic fatty liver disease. J Diabetes Investig. 2021;12(7):1252–1262. doi:10.1111/jdi.13455

51. Tanaka K, Takahashi H, Hyogo H, et al. Epidemiological survey of hemoglobin A1c and liver fibrosis in a general population with non-alcoholic fatty liver disease. Hepatol Res. 2019;49(3):296–303. doi:10.1111/hepr.13282

52. Kamalraj N, Sathishkumar M, Arunvignesh M, et al. Retrospective analysis (2009–2017) of factors associated with progression and regression of non-alcoholic fatty liver disease (Hepatic steatosis) in patients with type 2 diabetes seen at a tertiary diabetes centre in Southern India. Diabetes Metab Syndr. 2021;15(5):102261. doi:10.1016/j.dsx.2021.102261

53. Fernando JN, Alba RL, Alba W. Factors associated with the severity of findings on hepatic transient elastography among persons with type 2 diabetes and fatty liver. J ASEAN Fed Endocr Soc. 2019;34(2):134–143. doi:10.15605/jafes.034.02.03

54. Alexopoulos AS, Crowley MJ, Wang Y, et al. Glycemic control predicts severity of hepatocyte ballooning and hepatic fibrosis in nonalcoholic fatty liver disease. Hepatology. 2021;74(3):1220–1233. doi:10.1002/hep.31806

55. Mantovani A, Zusi C, Csermely A, et al. Association between lower plasma adiponectin levels and higher liver stiffness in type 2 diabetic individuals with nonalcoholic fatty liver disease: an observational cross-sectional study. Hormones. 2022;21:477–486. doi:10.1007/s42000-022-00387-6

56. Koo DJ, Lee MY, Jung I, et al. Changes in insulin resistance index and the risk of liver fibrosis in patients with nonalcoholic fatty liver disease without diabetes: Kangbuk Samsung health study. Endocrinol Metab. 2021;36(5):1016–1028. doi:10.3803/EnM.2021.1110

57. Koo DJ, Lee MY, Jung I, et al. Baseline homeostasis model assessment of insulin resistance associated with fibrosis progression in patients with nonalcoholic fatty liver disease without diabetes: a cohort study. PLoS One. 2021;16(8):e0255535. doi:10.1371/journal.pone.0255535

58. Aller R, Siguenza R, Pina M, et al. Insulin resistance is related with liver fibrosis in type 2 diabetic patients with non-alcoholic fatty liver disease proven biopsy and Mediterranean diet pattern as a protective factor. Endocrine. 2020;68(3):557–563. doi:10.1007/s12020-020-02268-7

Creative Commons License © 2023 The Author(s). This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.