Abstract
Introduction
Nonalcoholic fatty liver disease (NAFLD) is becoming an important public health concern globally. It is associated with cardiovascular disease, type 2 diabetes, and cancers. In the United States, it is the third leading cause of cirrhosis and second most common indication for liver transplant (first in women). Global prevalence of NAFLD is about 25% with a significant recent increase in emerging economies, and in the Middle East the presence of NAFLD may be as high as 70% in patients with type 2 diabetes. Unfortunately, a significant number of patients with NAFLD go on to develop non‐alcoholic steatohepatitis (NASH) which is much more common in patients with type 2 diabetes. About 20% of the United States population have NAFLD without associated diabetes. However, 33%–66% of patients with type 2 diabetes have NAFLD. Other risk factors associated with NAFLD include obesity, age, gender, dyslipidemia, metabolic syndrome, and polycystic ovarian syndrome.
There are many ways to image NAFLD and NASH, including abdominal ultrasound, CT scan, and magnetic resonance imaging (MRI) or MR spectroscopy. More recently, elastography performed with ultrasound or MR has gained traction in diagnosing different stages of NAFLD and NASH. In this article, we plan to review some of the challenges in increasing global prevalence and early diagnostic methods to evaluate NAFLD.
Key Articles Reviewed for the Article
Shen X, Cai J, Gao J, Vaidya A, Liu X, Li W, Chen S, Zhou Y, Li Y, Zhang Y, Zhao J, Hu FB, Wu S, Gao X
Rivera‐Andrade A, Kroker‐Lobos MF, Lazo M, Freedman ND, Smith JW, Torres O, McGlynn KA, Groopman JD, Guallar E, Ramirez‐Zea M
Pang Y, Kartsonaki C, Turnbull I, Guo Y, Clarke R, Chen Y, Bragg F, Yang L, Bian Z, Millwood IY, Hao J, Han X, Zang Y, Chen J, Li L, Holmes MV, Chen Z
Alsabaani AA, Mahfouz AA, Awadalla NJ, Musa MJ, Al Humayed SM
Herath HMM, Kodikara I, Weerarathna TP, Liyanage G
Atsawarungruangkit A, Chenbhanich J, Dickstein G
Oki Y, Ono M, Hyogo H, Ochi T, Munekage K, Nozaki Y, Hirose A, Masuda K, Mizuta H, Okamoto N, Saibara T1
Kumar A, Shalimar, Walia GK, Gupta V, Sachdeva MP
Canfora EE, Meex RCR, Venema K, Blaak EE
Wijarnpreecha K, Thongprayoon C, Boonpheng B, Panjawatanan P, Sharma K, Ungprasert P, Pungpapong S, Cheungpasitporn W
Zhang M, Li L, Chen J, Li B, Zhan Y, Zhang C
Weinstein AA, de Avila L, Paik J, Golabi P, Escheik C, Gerber L, Younossi ZM
Leoni S, Tovoli F, Napoli L, Serio I, Ferri S, Bolondi L
Bajaj HS, Brown RE, Bhullar L, Sohi N, Kalra S, Aronson R
Bruinstroop E, Dalan R, Cao Y, Bee YM, Chandran K, Cho LW, Soh SB, Teo EK, Toh SA, Leow MKS, Sinha RA, Sadananthan SA, Michael N, Stapleton HM, Leung C, Angus PW, Patel SK, Burrell LM, Lim SC, Sum CF, Velan SS, Yen PM
Eriksson JW, Lundkvist P, Jansson PA, Johansson L, Kvarnström M, Moris L, Miliotis T, Forsberg GB, Risérus U, Lind L, Oscarsson J
Kuchay MS, Krishan S, Mishra SK, Farooqui KJ, Singh MK, Wasir JS, Bansal B, Kaur P, Jevalikar G, Gill HK, Choudhary NS, Mithal A
Tian F, Zheng Z, Zhang D, He S, Shen J
Zhou J, Massey S, Story D, Li L
Nonalcoholic fatty liver disease and risk of diabetes: a prospective study in China
Shen X1, Cai J2,3, Gao J4, Vaidya A,5 Liu X6, Li W6, Chen S4, Zhou Y7, Li Y8, Zhang Y9, Zhao J10, Hu FB11, Wu S4, Gao X8
1Department of Nutrition, Xinhua Hospital, School of Public Health, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; 2Department of Nephrology, Peking Union Medical College Hospital, and Chinese Academy of Medical Sciences, Beijing, China; 3Clinical Epidemiology Unit, Peking Union Medical College Hospital, and Chinese Academy of Medical Sciences, Beijing, China; 4Department of Cardiology, Kailuan Hospital Affiliated to Hebei United University, Tangshan, China; 5Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital & Harvard Medical School, Boston, MA; 6Department of Ultrasound, Kailuan Hospital Affiliated to Hebei United University, Tangshan, China; 7Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China; 8Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA; 9Department of Gastroenterology, Kailuan Hospital Affiliated to Hebei United University, Tangshan, China; 10Department of Anesthesiology, Kailuan Hospital Affiliated to Hebei United University, Tangshan, China; 11Department of Nutrition, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
Objective
This large cohort study investigated whether the risk of developing diabetes is related to the severity of liver steatosis.
Methods
A prospective study was carried out to examine the association between diabetes and steatotis in 41,650 Chinese adults with negative hepatitis‐B surface antigen. Only patients who did not consume alcohol and did not have diabetes or liver cirrhosis at baseline were included. Cox proportional models were used to estimate the risk of diabetes after a mean of 3.6 years of follow‐up. NAFLD was evaluated using hepatic ultrasonography. Elevated alanine transaminase (ALT) was defined as ALT concentration >19 in females and >30 U/L in males, a fasting blood glucose (BG) level of 7.0 mmol/L or treatment with hypoglycemic medication was defined as diabetes.
Results
A significant association was found between liver steatosis severity and higher risks of developing diabetes (adjusted hazard ratio [HR] for severe vs without NAFLD=2.66 [95% confidence interval 2.17–3.25], P‐trend <0.001) and impaired fasting BG (5.6–6.9 mmol/L, adjusted HR=1.36 [95% CI 1.16–1.59], P‐trend <0.001)—and also a faster increase rate for fasting BG concentrations (P‐trend <0.001)—during 3.6 years of follow‐up. after adjusting for NAFLD and other covariates, higher ALT levels were also associated with incident diabetes (HR=1.12 [95% CI 1.02–1.22]).
Conclusion
A dose–response relationship was seen between severity of liver steatosis and increased diabetes risk. The study also found ALT may predict incident diabetes independently of NAFLD.
High prevalence of non‐alcoholic fatty liver disease and metabolic risk factors in Guatemala: a population‐based study
Rivera‐Andrade A1, Kroker‐Lobos MF1, Lazo M2,3, Freedman ND4, Smith JW5, Torres O6, McGlynn KA4, Groopman JD5, Guallar E3, Ramirez‐Zea M1
1INCAP Research Center for the Prevention of Chronic Diseases, Institute of Nutrition of Central America and Panama, Guatemala City, Guatemala; 2Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD; 3Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD; 4Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD; 5Department of Environmental Health and Engineering, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD; 6Laboratorio de Diagnóstico Molecular, Guatemala City, Guatemala
Background
No data are currently available on the rate of nonalcoholic fatty liver disease (NAFLD) at the general population level in South American countries, including Guatemala. This study assesses the prevalence and distribution of NAFLD along with its associated risk factors in a population‐based sample of Guatemalan adults.
Methods
A cross‐sectional study was conducted in 411 urban and rural Guatemalan adults ≥40 years of age. Metabolic outcomes included obesity, central obesity, hypercholesterolemia, diabetes, and metabolic syndrome (MetS). Liver disease outcomes included elevated liver enzymes, elevated fatty liver index (FLI), and elevated fibrosis‐4 (FIB‐4) score.
Results
The overall rates of obesity, central obesity, diabetes, and MetS in the populations were 30.9, 74.3, 21.6, and 64.2%, respectively. For women versus men, the fully adjusted prevalence ratios (95% CI) were 2.83 (1.86–4.30), 1.72 (1.46–2.02), 1.18 (1.03–1.34), and 1.87 (1.53–2.29), respectively. The frequency of elevated liver enzymes (ALT or AST), elevated FLI, and elevated FIB‐4 scores among the subjects overall were 38.4, 60.1, and 4.1%, respectively, and the fully adjusted prevalence ratios (95% CI) for elevated ALT or aspartate transaminase (AST) liver enzymes and elevated FLI score comparing women to men were 2.99 (1.84–4.86) and 1.47 (1.18–1.84) respectively.
Conclusions
This general population study revealed very high prevalence of metabolic abnormalities and liver outcomes in this general population of adults in Guatemala. The rate was particularly high among women; this could explain the atypical 1:1 male to female ratio of liver cancer in Guatemala.
Diabetes, plasma glucose, and incidence of fatty liver, cirrhosis, and liver cancer: a prospective study of 0.5 million people
Pang Y1, Kartsonaki C1,2, Turnbull I1, Guo Y3, Clarke R1, Chen Y1,2, Bragg F1, Yang L1,2, Bian Z3, Millwood IY1,2, Hao J4, Han X5, Zang Y6, Chen J7, Li L3,8, Holmes MV1,2,9, Chen Z1,2
1Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK; 2Medical Research Council Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK; 3Chinese Academy of Medical Sciences, Beijing, China; 4Qingdao Cancer Hospital, Qingdao, China; 5Yongqinglu Community Health Service Center, Qingdao, China; 6Qingdao Center for Disease Prevention and Control, Qingdao, China; 7National Center for Food Safety Risk Assessment, Beijing, China; 8School of Public Health, Peking University; 9National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospital, Oxford, UK
Background
The prevalence of diabetes is increasing rapidly in China, but there is a limited amount of data regarding its effects on chronic liver diseases and liver cancer. Findings from the large prospective China Kadoorie Biobank study are reported.
Methods
Associations of diabetes and random plasma glucose (RPG) with chronic liver diseases and liver cancer, along with possible interaction by hepatitis B virus infection, in Chinese adults without diabetes were examined. From 2004 through 2008, the prospective China Kadoorie Biobank recruited 512,891 adults (210,222 men; 302,669 women) aged 30–79 years in 5 urban and 5 rural locations in China. Ten years of follow‐up recorded 2,568 liver cancer; 2,082 cirrhosis; 1,298 hospitalized NAFLD; and 244 hospitalized alcoholic liver disease (ALD) cases among 503,993 participants who had no baseline prior history of cancer or chronic liver diseases. HRs were estimated using Cox regression for each disease by diabetes status (previously diagnosed or screen detected) and by RPG levels among those with no previously diagnosed diabetes. Overall, 5.8% of participants had diabetes at baseline.
Results
Compared with those without diabetes, individuals with diabetes had adjusted HRs of 1.49 (95% CI 1.30–1.70) for liver cancer, 1.81 (1.57–2.09) for cirrhosis, 1.76 (1.47–2.16) for NAFLD, and 2.24 (1.42–3.54) for ALD. Although the excess risks decreased with longer duration of diabetes, the levels were still elevated. Among those without previously diagnosed diabetes, RPG was positively associated with liver diseases, with adjusted HRs per 1 mmol/L higher RPG of 1.04 (1.03–1.06) for liver cancer, 1.07 (1.05–1.09) for cirrhosis, 1.07 (1.05–1.10) for NAFLD, and 1.10 (1.05–1.15) for ALD. Hepatitis B virus infection status did not affect these associations.
Conclusion
In Chinese adults, diabetes and higher BG levels among those with no known diabetes are associated with elevated risks of liver cancer and major chronic liver diseases.
Non‐alcoholic fatty liver disease among type‐2 diabetes mellitus patients in Abha City, South Western Saudi Arabia
Alsabaani AA1, Mahfouz AA1,2, Awadalla NJ1,3, Musa MJ4, Al Humayed SM5
1Department of Family and Community Medicine, College of Medicine, King Khalid University, Abha, Saudi Arabia; 2Department of Epidemiology, High Institute of Public Health, Alexandria University, Alexandria, Egypt; 3Department of Community Medicine, College of Medicine Mansoura University, Mansoura, Egypt; 4Department of Radiology, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia; 5Department of Internal Medicine, College of Medicine, King Khalid University, Abha, Saudi Arabia
Objective
The objectives of this study was to determine the prevalence and the most important associated factors for nonalcoholic fatty liver disease (NAFLD) among patients with T2DM in Abha City, Southwestern Saudi Arabia.
Methods
A cross‐sectional study was conducted, in 245 adult T2DM patients recruited from all primary healthcare diabetes clinics in Abha City. Criteria for participation were age of 18 years and above and diagnosis of T2DM; patients were excluded if they presented with coexisting liver disease as were those who consume alcohol or take steatogenic drugs. A detailed medical history was conducted and laboratory investigations were done. Abdominal ultrasound was used to diagnose NAFLD.
Results
The overall prevalence of NAFLD was 72.8% (95% CI 66.6%–78.1%). Multivariable regression analysis for personal and clinical factors associated with NAFLD showed that among the study sample, only body mass index (BMI) was found to be significant factor: the risk of NAFLD was significantly higher among overweight T2DM patients (adjusted odds ratio, aOR=6.112 [95% CI 1.529–4.432]) and obese patients (aOR=10.455 [2.645–41.326]). Among biochemical factors, high ALT (>12 IU/L) resulted in higher risk than normal ATL (aOR=2.335[1.096–5.062]). Additionally, moderately diet‐compliant patients had twice the risk (aOR=2.413 [1.003–5.805]) and poorly diet‐compliant patients had six times the risk (aOR=6.562 [2.056–20.967]) of NAFLD compared with adequately compliant patients. On the other hand, high HDL (high density cholesterol) (in mg/dL) was a protective factor for NAFLD (aOR=0.044 [0.005–0.365]).
Conclusions
NAFLD is commonly associated with T2DM. Elevated BMI, lower HDL, and poor dietary control are significant factors associated with NAFLD risk among T2DM patients. Health education to improve dietary control and avoid excessive weight gain and testing for NAFLD among diabetic patients, especially those with abnormal BMI and HDL, are recommended for early detection and to ensure optimal levels of HDL.
Prevalence and associations of non‐alcoholic fatty liver disease (NAFLD) in Sri Lankan patients with type 2 diabetes: a single center study
Herath HMM1, Kodikara I2, Weerarathna TP1, Liyanage G3
1Department of Medicine, Faculty of Medicine, Galle, Sri Lanka; 2Department of Anatomy, Faculty of Medicine, Galle, Sri Lanka; 3Department of Pharmacology, Faculty of Medicne, Galle, Sri Lanka
Background
Among Asians, NAFLD is one of the most common causes of chronic liver disease, particularly in patients with T2DM. Despite this there is very little information regarding prevalence and associations of NAFLD in the Sri Lankan population. The primary aim of this study was to investigate the prevalence and factors associated with NAFLD in a cohort of diabetic patients in Sri Lanka.
Methods
Participants were recruited by convenience sampling method from patients receiving follow‐up services at a diabetes center in Southern Sri Lanka. A total of 233 patients with T2DM were included in the study. A detailed medical history was collected from each participants, and each underwent a physical examination, laboratory tests, and abdominal ultrasonography (USS). Diagnosis of NAFLD was made according to established criteria using USS.
Results
The overall prevalence of NAFLD based on USS was 62.6%, with no significant gender difference. Compared with USS, elevated AST and ALT levels, based on the third National Health and Nutrition Examination Survey (NHANES III) criteria, occurred only in 42% (98/234) of participants. The patients with NAFLD (56.7±8.9) were significantly younger and had higher BMI and waist circumference, and elevated AST and ALT, compared with those without NAFLD. The use of pioglitazone, higher BMI, and waist circumference were independently and significantly associated with NAFLD based on binary logistic regression analysis.
Conclusions
NAFLD is common in Sri Lankan patients with T2DM, and central and global obesity are significant associations. Use of pioglitazone appeared to offer protection against the development of NAFLD. These findings highlight the need for weight management as a preventive measure for NAFLD in T2DM patients.
C‐peptide as a key risk factor for non‐alcoholic fatty liver disease in the United States population
Atsawarungruangkit A, Chenbhanich J, Dickstein G
Department of Medicine, MetroWest Medical Center, Framingham, MA
Objective
C‐peptide has been associated with many risk factors for NAFLD, including cardiovascular diseases and metabolic syndrome, but there is limited evidence of the association between NAFLD and C‐peptide at the multivariate level. The primary objective for this study was to determine whether fasting C‐peptide is an independent predictor for NAFLD in United States population.
Methods
Participants were selected from the NHANES III (1988–1994) data set. A total of 18,825 NAFLD subjects aged 20 years or older without any other liver diseases met the inclusion criteria. Exclusion criteria included ungradable or missing ultrasound results for hepatic steatosis, excessive alcohol consumption (>2 drinks per day for males and >1 drink per day for females); hepatitis B or hepatitis C infection; fasting period outside of 8–24 h; and incomplete or missing data on physical examination and laboratory testing. C‐peptide and 27 other factors associated with NAFLD (e.g., age, gender, BMI, waist circumference, race/ethnicity, liver chemistries, and other diabetes tests) were analyzed using both univariate and multivariate logistic regression with a P‐value 0.05.
Results
Of the 18,825 patients who met the inclusion criteria, 3,235 passed the exclusion criteria. Twenty‐three factors were associated with NAFLD by univariate analysis. Nine factors, ranked by the highest change in pseudo R 2, were found to be significant predictors of NAFLD in multivariate analysis: waist circumference, fasting C‐peptide, natural log of alanine aminotransferase (ALT), total protein, Mexican American ethnicity, natural log of glycated hemoglobin (HbA1c), triglyceride level, being non‐Hispanic white, and ferritin level.
Conclusion
The most significant NAFLD risk factor in both univariate and multivariate levels is waist circumference. Fasting C‐peptide and ALT round out the three most important predictors of NAFLD in the NHANES U.S. population data set. Further study is required to validate the clinical utility of fasting C‐peptide in diagnosis or monitoring insulin resistance in NAFLD patients.
Comment
These six abstracts highlight the increased prevalence of NAFLD among individuals from China, Guatemala, Saudi Arabia, Sri Lanka, and the United States. It is important to note that the risk of NAFLD among patients with T2D can be as high as 73% in the southwestern part of Saudi Arabia (Abha City). The studies also highlight different biomarkers that might predict early NAFLD, for example elevations in ALT. Subjects with higher blood glucose levels, especially those with known T2D, were associated with high risk for liver cancer and other chronic liver diseases. There have been attempts to characterize other biomarkers that might predict NAFLD. The study by Atsawarungruangkit et al. highlighted other markers, like elevations in fasting C‐peptide levels, in addition to elevated ALT, triglyceride levels, and BMI and their utility as early indicators of NAFLD. The study by Rivera‐Andrade et al. from Guatemala highlighted gender differences that have been observed, where metabolic and liver abnormalities were high amongst women and thus might explain the unusual observation of a 1:1 male:female ratio of liver cancer in Central America.
Evaluation of postprandial hypoglycemia in patients with nonalcoholic fattyliver disease by oral glucose tolerance testing and continuous glucose monitoring
Oki Y1, Ono M1, Hyogo H2, Ochi T1, Munekage K1, Nozaki Y1, Hirose A1, Masuda K1, Mizuta H1, Okamoto N1, Saibara T1
1Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi; 2Department of Gastroenterology and Hepatology, JA Hiroshima General Hospital, Hiroshima, Japan
Objective
Nonalcoholic fatty liver disease (NAFLD) is often associated with insulin resistance and glucose intolerance, and the number of patients with NAFLD has increased worldwide. T2DM is considered to be an independent risk factor for the development of NAFLD. Hypoglycemia can be one important predictive factor for the progression of hepatic fibrosis in patients with NAFLD, and postprandial hypoglycemia frequently occurs in NAFLD patients; however, the details regarding the causes and background on hypoglycemia are not well understood. This study investigated characteristics of hypoglycemia in T2DM patients with NAFLD by comparing the results of continuous glucose monitoring (CGM) and the 75‐g oral glucose tolerance test (75gOGTT).
Patients and Methods
A total of 502 patients (197 female and 305 male patients) with biopsy‐proven NAFLD were included in the study. All subjects underwent the 75gOGTT and laboratory blood tests, and CGM was carried out in 20 patients. These results and statistical analyses were used to investigate the characteristics and causes of postprandial hypoglycemia.
Results
Among subjects with normal glucose, the percentage of patients in the Hypo subgroup (plasma glucose [PG] at 180 minutes <fasting PG [FPG]) was significantly higher than that among those with diabetes mellitus and impaired glucose tolerance or impaired fasting glucose. FPG and HbA1c were lower, and area under the curve of total insulin secretion within 120 minutes (<120 minutes) was higher in Hypo than Hyper in overall patients. Although FPG and PG at 30 minutes were higher in Hypo than Hyper, HOMA‐IR and the insulinogenic index were not different in normal glucose tolerance and impaired glucose tolerance or impaired fasting glucose. Results of multivariate logistic regression analysis showed low HbA1c, low fasting immunoreactive insulin, and high area under the curve of total insulin secretion (<120 minutes) to be independent factors associated with hypoglycemia. CGM revealed postprandial hypoglycemia until lunch in 70% of NAFLD patients. Our analysis did not identify any remarkable association between the 75 g OGTT and CGM in terms of hypoglycemia.
Conclusion
Postprandial hypoglycemia was identified in many NAFLD patients detected by 75gOGTT and CGM. The results of this study clarified that postprandial hypoglycemia is related to low HbA1c, an early elevation of PG, low fasting and relatively low early insulin secretion, and delayed hyperinsulinemia. 75gOGTT and/or CGM should be performed in NAFLD patients because they provide important, useful data for the evaluation and understanding of postprandial hyperglycemia and hypoglycemia in these individuals.
Genetics of nonalcoholic fatty liver disease in Asian populations
Kumar A1, Shalimar2, Walia GK3, Gupta V1, Sachdeva MP1
1Department of Anthropology, University of Delhi, New Delhi, India; 2Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India; 3Public Health Foundation of India, Gurugram, India
Background
Nonalcoholic fatty liver disease (NAFLD) is defined by the accumulation of fat in the liver confirmed by liver biopsy, in the absence of any history of chronic/excessive alcohol consumption. It comprises a wide spectrum of diseases that range from simple steatosis to nonalcoholic steatohepatitis. NAFLD is strongly associated with obesity, insulin resistance/tT2DM, and metabolic syndrome. Environmental and genetic factors interact with NAFLD manifestation and determine its progression, making it a complex condition.
Methods
This review endeavors to convey current facts and information on genetic variants of NAFLD in Asian populations. Studies published through September 30, 2018, were included. The literature search was limited to Asia populations and carried out using PubMed, Medline, and Google Scholar database. Candidate gene, validation, and genome‐wide association studies were used in this review.
Results
A total of 41 studies met the inclusion criteria. Twelve candidate gene studies focused entirely on the PNPLA3 gene and 17 studies looking at other important candidate genes (e.g., NCANCILP2, PPARG, AGTR1, FABP1, APOC3) reported significant connection with NAFLD. Eight validation studies identified associations of variants on PNPLA3, LYPLAL1, TM6SF2, ADIPOR2, STAT3, GCKR, SAMM50, etc. with NAFLD. At the time of this review, four genome‐wide association studies have been conducted in Asian populations that reported PNPLA3, SAMM50, PARVB, and GATAD2A genes that were significantly associated with NAFLD.
Conclusion
In this literature review PNPLA3, APOC3, PPARG, NCAN, and GCKR genes emerged as the important biological markers associated with NAFLD in Asian populations.
Gut microbial metabolites in obesity, NAFLD and T2DM
Canfora EE, Meex RCR, Venema K, Blaak EE
Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre, Maastricht, Netherlands
Background
An increasing body of evidence indicated that the gut microbiome is involved in the etiology of obesity and obesity‐related complications, including NAFLD, insulin resistance, and T2DM. This review focuses on the role microbial carbohydrate and protein fermentation products in relation to obesity and obesity‐associated insulin resistance, T2DM, and NAFLD, and discusses the mechanisms involved.
Methods
Gut microbiota have the ability to ferment indigestible carbohydrates such as dietary fiber to yield vital metabolites such as short‐chain fatty acids and succinate. A large number of animal studies and a handful of human studies suggest that these metabolites play a beneficial role in the prevention and treatment of obesity and its comorbidities. In the more distal colonic region the major energy source, fermentable fiber, is limited, so the microbiota primarily ferments peptides and proteins.
Results
The microbial metabolites created as a result of proteolytic fermentation by the distal colonic microbiota (such as ammonia, phenols, and branched‐chain fatty acids) are thought to be detrimental for host gut integrity and metabolic health. For this reason, a switch from proteolytic to saccharolytic fermentation could be beneficial for the prevention and/or treatment of metabolic diseases.
Conclusion
Consuming a mixture of dietary fiber to increase carbohydrate fermentation in distal colonic microbiota, and thereby inhibiting protein fermentation, might provide a pathway by obesity, T2DM, and NAFLD could be reduced.
Comment
A small study by Oki et al. evaluated postprandial hypoglycemia in patients with NAFLD. The evaluation of postprandial hypoglycemia was done by a 75gOGTT, and a subgroup of patients also wore a CGM. Many patients with NAFLD were documented to have postprandial hypoglycemia on OGTT and CGM data analysis. This might act as a biomarker for early diagnosis of NAFLD.
A review by Kumar et al. highlighted genetic factors associated with NAFLD. Specifically, PNPLA3, APOC3, PPARG, NCAN, and GCKR genes have been associated with the condition.
There are multiple articles examining gut microbiota and its association with NAFLD and T2D. The review by Canfora et al. focuses on the role of products derived from microbial carbohydrate and protein fermentation as they relate to obesity, T2D, and NAFLD.
Nonalcoholic fatty liver disease and albuminuria: a systematic review and meta‐analysis
Wijarnpreecha K1, Thongprayoon C1, Boonpheng B2, Panjawatanan P4, Sharma K1, Ungprasert P5, Pungpapong S3, Cheungpasitporn W6
1Department of Internal Medicine, Bassett Medical Center, Cooperstown, NY; 2Department of Internal Medicine, East Tennessee State University, Johnson City, TN; 3Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Mayo Clinic, Jacksonville, FL; 4Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; 4Clinical Epidemiology Unit, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; 6Department of Medicine, Division of Nephrology, University of Mississippi Medical Center, Jackson, MS
Background
Many previous epidemiologic studies have shown the relationship between NAFLD and albuminuria, although the results have been inconsistent. A meta‐analysis of this literature was completed to summarize all available data and estimate the risk of albuminuria in patients with NAFLD.
Methods
The Medline and Embase databases were searched for studies published through January 2018 to identify those with data comparing the risk of albuminuria among patients with NAFLD versus those without NAFLD. Using DerSimonian and Laird's random-effect, generic inverse variance methods, effect estimates from the results of each such study were extracted and combined.
Results
Nineteen studies (17 cross‐sectional studies, 2 cohort studies) with a total of 24,804 subjects were eligible according to our criteria and were included in this meta‐analysis. The risk of albuminuria was significantly higher for patients with NAFLD versus those without (pooled OR 1.67 [95% CI 1.32–2.11]). Risk of albuminuria was significantly increased in patients with NAFLD without diabetes (pooled OR 2.25 [1.65–3.06]). However, no significant association between albuminuria and NAFLD was found among diabetic patients (pooled OR 1.28 [0.94–1.75]).
Conclusion
This meta‐analysis spotlights the significantly increased risk of albuminuria among patients with NAFLD. In light of these findings, it is clear that physicians should focus more attention on early detection and treatment of individuals with microalbuminuria, especially in patients with NAFLD.
Presence of diabetic retinopathy is lower in type 2 diabetic patients with non‐alcoholic fatty liver disease
Zhang M1,2, Li L1, Chen J1, Li B1, Zhan Y1, Zhang C1
1Department of Gastroenterology, Beijing Tongren Hospital, Capital Medical University, Beijing, China; 2Department of Gastroenterology, Xian XD Group Hospital, Xi'an, Shaanxi Province, China
Objective
NAFLD is common in patients with T2DM, occurring in as many as 75% of these individuals. Current data suggest that NAFLD can increase the risk of T2DM complications, especially vascular complications, which can include coronary artery disease and cerebrovascular disease as well as retinopathy. The present study investigated whether NAFLD (as diagnosed by ultrasonography) is associated with an increased risk of diabetic retinopathy (DR) in a clinical cohort of Chinese patients with T2DM.
Methods
An initial group of 800 inpatients with T2DM at the Department of Endocrinology, Beijing Tongren Hospital met inclusion criteria and were recruited into the cohort study between December 2014 and December 2016. All patients were screened based on medical history, physical examinations, and laboratory measurements. After initial screening and exclusion criteria, a total of 411 patients were enrolled in the study and divided into NAFLD and control groups. NAFLD was diagnosed via ultrasound. Fundus photography was used to diagnose retinopathy.
Results
The prevalence of NAFLD and DR in T2DM patients was 60.8% and 40.9%, respectively. The presence of DR was associated with diabetes duration, systolic blood pressure, HbA1c, and proteinuria (all P<0.001) using univariate and multivariate regression analyses. The prevalence of DR was lower in patients with NAFLD than in those without NAFLD (37.2% vs 46.6%, P=0.065), and significantly lower in patients with moderate and severe NAFLD (30.2% vs 46.6%, P=0.012; 14.3% vs 46.6%, P=0.024). The presence of DR in NAFLD patients was associated with diabetes duration (P=0.032) in Chi‐squared analysis. NAFLD and DR were highly prevalent in T2DM patients.
Conclusions
Diabetes duration, systolic blood pressure, HbA1c, and proteinuria were risk factors for DR in T2DM patients. The presence of DR was lower in T2DM patients with NAFLD, which was mainly due to their shorter diabetes duration.
Cognitive performance in individuals with non‐alcoholic fatty liver disease and/or type 2 diabetes mellitus
Weinstein AA1,2, de Avila L1, Paik J1, Golabi P1, Escheik C1, Gerber L2,3, Younossi ZM1,3
1Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA; Center for the Study of Chronic Illness and Disability, George Mason University, Fairfax, VA; 2Center for the Study of Chronic Illness and Disability, George Mason University, Fairfax, VA; 3Center for Liver Disease, Department of Medicine, Inova Fairfax Hospital, Falls Church, VA
Background
Patients with NAFLD have some of the same common pathophysiological features as individuals with T2DM. Although the association between T2DM and cognitive decline is well established, there is no corollary data regarding individuals with NAFLD and without T2DM or whether a combination of these two disorders is correlated with additive deficits in cognitive performance. Here, measures of cognitive performance are compared in four groups of patients: those with NAFLD, those with T2DM, those with both, and those with neither.
Methods
NHANES data from 2011–2014 were used to identify 1,102 individuals who had completed cognitive assessments.
Results
Patients were tested on a task combining processing speed, sustained attention, and working memory. After controlling for demographics, metabolic components, and comorbidities, patients with both NAFLD and T2DM scored significantly lower than patients with neither (Beta=−3.44 [95% CI −6.75 to −0.12]). Verbal fluency scores were significantly lower for individuals with T2DM/without NAFLD than for those with neither (Beta=−1.47 [ −2.7 to −0.23]).
Conclusions
The results of this study suggest that individuals with T2DM and individuals with both NAFLD and T2DM exhibit lower cognitive performance when carrying out certain tasks. These findings support an approach focusing on preventive strategies to optimize management of T2DM in patients with NAFLD.
Comment
The three preceding abstracts highlight the relationship between NAFLD, microvascular complications, and cognitive performance in patients with T2D. In the meta‐analysis by Wijarnpreecha et al., it is interesting to note that microalbuminuria was significantly increased in patients with NAFLD. Clinicians may need to consider monitoring for early kidney disease in patients with NAFLD. Few studies have reviewed the relationship with estimated glomerular filtration rate (eGFR). Another microvascular complication, diabetic retinopathy, was observed with lower frequency in patients with NAFLD associated with T2D. The mechanistic differences contributing to microvascular complications need to be further evaluated. Finally, Weinstein et al. report cognitive performance differences in individuals with T2D associated with NAFLD and thus recommend preventative strategies to optimize type 2 diabetes management.
Current guidelines for the management of non‐alcoholic fatty liver disease: A systematic review with comparative analysis
Leoni S, Tovoli F, Napoli L, Serio I, Ferri S, Bolondi L
Department of Medical and Surgical Sciences, Division of Internal Medicine, University of Bologna, Bologna, Italy
Background
The prevalence of NAFLD is increasing at an alarming rate in both adults and children/adolescents, and this epidemic is reshaping the field of hepatology worldwide. The widespread spread of metabolic risk factors such as obesity, insulin resistance, T2DM, and dyslipidemia has led to a worldwide increase in NAFLD. At the same time that effective anti‐viral agents have become more widely available, NAFLD is quickly becoming the most common cause of chronic liver disease in Western countries, and a similar trend is expected in Eastern countries in the coming years. This epidemic and its consequences have prompted experts from all over the word in identifying effective strategies for the diagnosis, management, and treatment of NAFLD. Experts around the globe, from Europe, America, and Asia‐Pacific regions, have proposed guidelines for identifying effective strategies in the diagnosis, management, and treatment of NAFLD based on the most recent knowledge and data about NAFLD. These guidelines are consistent in the key elements regarding the management of NAFLD, but still contain significant differences about some critical points.
Methods
An English‐language review of current literature was conducted to identify the most recent scientific guidelines on NAFLD in an effort to find and critically analyze the primary differences.
Results
Guidelines were identified from five different scientific societies with globally recognized reputations and who are representative of clinical practices in different geographical regions. Differences between the guidelines were noted in these categories: how NAFLD is defined, opportunities for NAFLD screening in high‐risk patients, proposed noninvasive test for NAFLD diagnosis, the identification of NAFLD patients with advanced fibrosis in the follow‐up protocols, and lastly, treatment strategy (particularly proposed pharmacological management).
Conclusion
Identified differences are been discussed in light of the possible progression of the NAFLD worldwide in the next years.
SGLT2 inhibitors and incretin agents: associations with alanine aminotransferase activity in type 2 diabetes
Bajaj HS1,2, Brown RE3, Bhullar L1, Sohi N4, Kalra S4, Aronson R3
1LMC Diabetes and Endocrinology Brampton, Brampton, Ontario, Canada; 2Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Ontario, Canada; 3LMC Diabetes and Endocrinology Toronto, Toronto, Ontario, Canada; 4Royal College of Surgeons, Dublin, Ireland
Objective
The incidence of NAFLD associated with T2D is rapidly increasing. Currently, the only class of diabetes drugs with proven beneficial liver effects are thiazolidinediones. New classes of glucose‐lowering medications have been developed, but their effects on markers of NAFLD associated with T2D have been inconsistent in their magnitude and independence. This large retrospective study investigates changes in alanine aminotransferase (ALT) levels among subjects beginning treatment with newer classes of T2D medications in comparison to a reference control group.
Methods
Participants were drawn from a large Canadian diabetes register. Individuals who had canagliflozin, dapagliflozin, liraglutide, sitagliptin, or no further treatment added to their diabetes treatments were included in the study. The association between HbA1c and weight change on ALT was determined using stepwise multiple regression. Propensity score weighting was used to balance baseline characteristics between treatment groups.
Results
A total of 3,667 subjects met the criteria and were included in the study. ALT levels (mean follow‐up 4.8 months) were lower after treatment with the SGLT2 inhibitors canagliflozin (4.3 U/L, P<0.01) and dapagliflozin (−3.5 U/L, P<0.01) versus the incretin agents liraglutide (−2.1 U/L, P<0.01) and sitagliptin (−1.8 U/L, P<0.01), each of which were greater than the control group. Only the SGLT2 inhibitor treatment groups maintained a significant reduction in ALT levels compared with the control group following multivariable adjustment and propensity score weighting. Greater ALT reductions were seen with higher baseline ALT for both the SGLT2 inhibitor treatment groups.
Conclusion
SGLT2 inhibitors canagliflozin and dapagliflozin resulted in a weight‐ and A1c‐independent reduction of ALT levels compared with incretin agents A similar association between SGLT2 inhibitors and ALT change persisted in a propensity score–weighted analysis that balanced baseline characteristics between treatment groups. In addition, with SGLT2 inhibitors, a significant dose response was observed for ALT reduction at higher baseline ALT levels. Further studies should be undertaken to evaluate the differential effects of these drug classes on NAFLD and insulin/glucagon levels as a potential mechanism explaining these differences.
Low‐dose levothyroxine reduces intrahepatic lipid content in patients with type 2 diabetes mellitus and NAFLD
Bruinstroop E1,2, Dalan R3,4, Cao Y5, Bee YM6, Chandran K7, Cho LW8, Soh SB8, Teo EK9, Toh SA10, Leow MKS1,3,11, Sinha RA1, Sadananthan SA11, Michael N11, Stapleton HM12, Leung C13,14,15, Angus PW13,14, Patel SK13, Burrell LM13,15, Lim SC16,17, Sum CF16,18, Velan SS11,19, Yen PM1
1Cardiovascular and Metabolic Disorders Program, Duke–NUS Graduate Medical School, Singapore; 2Department of Endocrinology and Metabolism, Amsterdam, Netherlands; 3Department of Endocrinology, Tan Tock Seng Hospital, Singapore; 4NTU‐Lee Kong Chian School of Medicine, Singapore; 5Singapore Clinical Research Institute, Singapore; 6Department of Endocrinology, Singapore General Hospital, Singapore; 7Department of Medicine, Ng Teng Fong General Hospital, Singapore; 8Department of Endocrinology, Changi General Hospital, Singapore; 9Department of Gastroenterology, Changi General Hospital, Singapore; 10Department of Endocrinology, National University Health System, Singapore; 11Singapore Institute for Clinical Sciences, A*STAR, Singapore; 12Duke University, Nicholas School of the Environment, Durham, NC; 13Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Melbourne, Victoria, Australia; 14Department of Gastroenterology, Austin Health, Heidelberg, Victoria, Australia; 15Department of General Medicine, Austin Health, Heidelberg, Victoria, Australia; 16Department of Endocrinology, Khoo Teck Puat Hospital, Singapore; 17Saw Swee Hock School of Public Health, National University Health System, Singapore; 18Diabetes Centre, Admiralty Medical Centre, Singapore; 19Singapore Bioimaging Consortium, Singapore
Background
NAFLD occurs at a high rate in patients with T2DM and is tied to significant morbidity and mortality. TH has been shown to increase beta‐oxidation of fatty acids and decrease IHLC in rodents with NAFLD. This study examined the possibility of low intrahepatic TH concentration in NAFLD and investigated the effect of TH treatment in humans.
Methods
This phase 2b single‐arm intervention study was carried out in six hospitals in Singapore. Intrahepatic TH concentrations were first measured in a rat model with induced NAFLD. These results provided further rationale for investigating whether short‐term, low‐dose levothyroxine therapy decreased IHLC as measured by posttreatment proton magnetic resonance spectroscopy in patients with T2DM and NAFLD. Participants in the study were Asian male euthyroid patients with T2DM and steatosis measured by ultrasonography. For the intervention, levothyroxine was titrated to achieve a level of thyroid‐stimulating hormone at 0.34–1.70 mIU/L prior to a 16‐week maintenance phase.
Results
Twenty male patients were included in the per‐protocol analysis (mean±SD: age, 47.8±7.8 years; BMI, 30.9±4.4 kg/m2; baseline IHLC, 13%±4%). After treatment, IHLC was decreased 12% (± 26% SEM) relative to baseline (absolute change −2% [95% CI −3 to 0]; P=0.046). Small decreases were observed in BMI (P=0.044), visceral adipose tissue volume (P=0.047), and subcutaneous adipose tissue volume (P=0.045). No significant changes in glucose regulation or lipid profile occurred.
Conclusion
This study demonstrated the efficacy and safety of low‐dose TH therapy for NAFLD in men. TH or TH analogs may be beneficial for this condition.
Effects of dapagliflozin and n‐3 carboxylic acids on non‐alcoholic fatty liver disease in people with type 2 diabetes: a double‐blind randomised placebo‐controlled study
Eriksson JW1, Lundkvist P1, Jansson PA2, Johansson L3, Kvarnström M4, Moris L5, Miliotis T4, Forsberg GB4, Risérus U6, Lind L1, Oscarsson J4
1Department of Medical Sciences, Uppsala University, Uppsala University Hospital, Uppsala, Sweden; 2Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden; 3Antaros Medical AB, Gothenburg, Sweden; 4AstraZeneca Gothenburg, Gothenburg, Sweden; 5Karolinska Trial Alliance, Karolinska University Hospital, Stockholm, Sweden; 6Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden
Objective
The EFFECT‐II trial was a 12‐week study investigating the effects of dapagliflozin and omega‐3 carboxylic acids (OM‐3CA), individually or combined, on liver fat content in adult patients with T2D and NAFLD.
Methods
This randomized placebo‐controlled double‐blind parallel‐group study was conducted in 84 adults 40–75 years of age with type 2 diabetes and NAFLD at five clinical research centers at university hospitals in Sweden. A centralized randomization system was used to assign participants 1:1:1:1 to four treatment groups, each of which received oral doses of one of the following: 10 mg dapagliflozin (n=21), 4 g OM‐3CA (n=20), a combination of both (n=22), or placebo (n=21). All participants, investigators, and staff involved with the study were blinded to the treatments. The primary endpoint was liver fat content as quantified by MRI (proton density fat fraction [PDFF]). Total liver volume and markers of glucose and lipid metabolism, hepatocyte injury, and oxidative stress were also assessed at baseline and at completion of the trial (12 weeks of treatment).
Results
Participants had a mean age of 65.5±5.9 years, BMI 31.2±3.5 kg/m2, and liver PDFF 18±9.3%. All active treatments significantly reduced liver PDFF from baseline. The relative change in OM‐3CA was −15%, while the change for dapagliflozin, was −13%; and for OM‐3CA + dapagliflozin, −21%. Only the combination treatment reduced liver PDFF (P=0.046) and total liver fat volume (relative change, −24%, P=0.037) in comparison with placebo. The active treatment groups exhibited an interaction between the PNPLA3 I148M polymorphism and change in liver PDFF. Dapagliflozin monotherapy, but not the combination with OM‐3CA, reduced the levels of hepatocyte injury biomarkers, including alanine aminotransferase, aspartate aminotransferase, gamma‐glutamyl transferase (gamma‐GT), cytokeratin (CK) 18‐M30 and CK 18‐M65, and plasma fibroblast growth factor 21 (FGF21). Changes in gamma‐GT correlated with changes in liver PDFF (rho=0.53, P=0.02). Improved glucose control was observed with dapagliflozin alone and in combination with OM‐3CA, as was a reduction in body weight and abdominal fat volumes. None of the treatments affected fatty acid oxidative stress biomarkers. There were no new or unexpected adverse events compared with previous studies using these treatments.
Conclusions
Treatment with dapagliflozin combined with OM‐3CA produced a significant reduction in liver fat content. Dapagliflozin monotherapy reduced all measured hepatocyte injury biomarkers as well as FGF21, inferring a disease‐modifying effect in NAFLD.
Effect of empagliflozin on liver fat in patients with type 2 diabetes and nonalcoholic fatty liver disease: a randomized controlled trial (E‐LIFT Trial)
Kuchay MS1, Krishan S2, Mishra SK3, Farooqui KJ3, Singh MK4, Wasir JS3, Bansal B3, Kaur P3, Jevalikar G3, Gill HK3, Choudhary NS5, Mithal A3
1Division of Endocrinology and Diabetes, Medanta‐The Medicity Hospital, Gurugram, Haryana, India; 2Department of Radiology, Medanta‐The Medicity Hospital, Gurugram, Haryana, India; 3Division of Endocrinology and Diabetes, Medanta‐The Medicity Hospital, Gurugram, Haryana, India; 4Department of Clinical Research and Studies, Medanta‐The Medicity Hospital, Gurugram, Haryana, India; 5Institute of Digestive and Hepatobiliary Sciences, Medanta‐The Medicity Hospital, Gurugram, Haryana, India
This manuscript is also discussed in the article on New Medications for the Treatment of Diabetes, page S‐149.
Objective
SGLT‐2 inhibitors have been shown to reduce liver fat in rodent models; however, there is very little data regarding the effect of SGLT‐2 inhibitors on liver fat in humans. This study employed MRI‐derived proton density fat fraction (MRI‐PDFF) images to investigate the effect of the SGLT‐2 inhibitor empagliflozin on liver fat in patients with T2D and NAFLD.
Methods
A 20‐week, investigator‐initiated, prospective, open‐label, randomized clinical study was conducted in 50 patients with type 2 diabetes and NAFLD. Participants were randomly assigned to either the empagliflozin group, which entailed standard treatment for type 2 diabetes plus empagliflozin 10 mg daily, or the control group, who received standard treatment without empagliflozin. Change in liver fat (primary outcome) was measured by MRI‐PDFF. Secondary outcomes included change in ALT, AST, and gamma‐glutamyl transferase levels.
Results
Twenty‐two patients completed the empagliflozin arm of the study (3 developed complications related to the study medication), and 20 patients completed the control arm (3 were lost to follow‐up and 2 with work schedule conflicts). The empagliflozin group showed a significant reduction in liver fat versus the control group (mean MRI‐PDFF difference vs control −4.0%; P<0.0001). Compared with baseline, the end‐of‐treatment MRI‐PDFF showed a significant difference for the empagliflozin group (from 16.2% to 11.3%; P<0.0001), while the control group showed a nonsignificant change (from 16.4% to 15.5%; P=0.057). The two groups showed a significant difference for change in serum ALT level (P=0.005) and nonsignificant differences for AST (P=0.212) and GGT (P=0.057) levels.
Conclusions
The results of this trial showed that when empagliflozin is included in the standard treatment for type 2 diabetes, liver fat is reduced and ALT levels improve in patients with type 2 diabetes and NAFLD.
Efficacy of liraglutide in treating type 2 diabetes mellitus complicated with non‐alcoholic fatty liver disease
Tian F1, Zheng Z2, Zhang D2, He S2, Shen J3
1Department of Endocrinology and Metabolism, Shenzhen Guangming New District People's Hospital, Shenzhen, China; 2Department of Internal Medicine, Shenzhen Yantian District People's Hospital, Shenzhen, China; 3Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
Background
Type 2 diabetes mellitus is a common health issue worldwide, with NAFLD co‐occurring in a majority of patients, and T2DM complicated with NAFLD is difficult to treat. Many advancements have been made in treating T2DM in recent years, but the best treatment for T2DM complicated with NAFLD remains elusive.
Methods
The present study investigated the efficacy of liraglutide (Lira) in the treatment of T2DM complicated with NAFLD. A total of 127 patients suffering from T2DM complicated with NAFLD were included and randomly assigned to one of two groups, defined by treatment. The Lira group (n=52) were treated with liraglutide injection, 0.6–1.2 mg/day, for 12 weeks; the Metformin (Met) (n=75) group received oral metformin, 1,000–1,500 mg/day, for 12 weeks.
Results
In all, 127 patients (Lira n=52; Met n=75) completed the 12‐week treatment. During the treatment phase, the levels for fasting plasma glucose (FPG), 2‐hour plasma glucose (2hPG), glycated hemoglobin (HbA1c), aspartate aminotransferase (AST)/alanine aminotransferase (ALT), and adiponectin (APN) decreased in both the Lira and Met groups, and values for Delta2hPG, DeltaAST/ALT, and DeltaAPN in the Lira group were significantly lower than those in the Met group. Total cholesterol, triglycerides, low‐ and high‐density lipoproteins, ALT, AST, weight, BMI, waist to hip ratio (WHR), and C‐reactive protein levels increased significantly in both groups, while levels of DeltaAST, DeltaALT, Deltaweight, DeltaBMI, DeltaWHR, and DeltaCRP (C‐reactive protein) in the Lira group were significantly higher than those in the Met group.
Conclusion
Both liraglutide and metformin could improve the abnormal glucose and lipid metabolism, in addition to the inflammation found in patients with combined T2DM and NAFLD. However, treatment efficacy analysis showed that liraglutide was superior to metformin in its ability to significantly decrease ALT levels. Furthermore, liraglutide was more effective than metformin at lessening the severity of T2DM complicated with NAFLD and produced its effects by alleviating liver inflammation and improving liver function.
Metformin: an old drug with new applications
Zhou J1, Massey S2, Story D3, Li L2
1College of Medicine, Central Michigan University, Mount Pleasant, MI; 2Physician Assistant Program, College of Health Professions, Central Michigan University, Mount Pleasant, MI; 3Program in Neuroscience, Central Michigan University, Mount Pleasant, MI
Background
Metformin is a biguanide drug that has been used as a safe, cost‐effective glucose‐lowering treatment for T2DM for over 60 years.
Methods
A review of current studies and results was conducted to present the currently available data on the effects of metformin on NAFLD, inflammation, and cardiovascular and pancreatic β‐cell dysfunction. The United Kingdom Prospective Diabetic Study has shown metformin to improve outcomes and decrease mortality rates in diabetes patients, and other recent studies suggest that metformin has additional promise in treating cancer, obesity, NAFLD, polycystic ovary syndrome, and metabolic syndrome. Metformin has also been shown to alleviate weight gain associated with antipsychotic medication.
Results
Recently, metformin has been extensively studied, and evidence reported suggesting that metformin decreases the accumulation of hepatocyte triglyceride in NAFLD and prevents liver tumorigenesis. Interestingly, studies have also shown metformin reduces visceral fat, suppresses white‐adipose‐tissue extracellular matrix remodeling, and inhibits obesity‐induced inflammation. Clinical evidence regarding the use of metformin to treat NAFLD, cancer, or metabolic syndrome or to prevent hepatocellular carcinoma in NAFLD patients is lacking.
Conclusion
There are many putative applications of metformin across a wide array of diseases; however, numerous mechanisms are still unclear. More clinical evidence is required before the therapeutic application of metformin can be widened to include treatment of diseases outside of diabetes.
Comment
Many therapeutic agents have been evaluated for treating early stages of NAFLD, especially when it is associated with type 2 diabetes. The abstracts listed in this section show the importance of metformin, GLP analogues, SGLT2 inhibitors, and levothyroxine (alone or in combinations) in reducing NAFLD. Most of these drugs help by facilitating weight loss. Many investigators have emphasized that lifestyle modifications play an important role in weight loss and NAFLD.
The two drugs that have consistently been shown to improve insulin resistance in patients with NAFLD include thiazoladinediones and vitamin E. Many new drugs, such as dual GLP‐1 and GIP agonist tirzepatide, have shown promise in early phase 2 studies. Most of the effect was associated with weight loss, improving glucose control in type 2 diabetes, and associated reduction of liver fat.
Conclusion
Unfortunately, NAFLD with NASH is increasing in prevalence globally and is becoming the leading cause of end‐stage liver failure. Newer imaging methods are becoming more popular in screening and managing patients with NAFLD/NASH. A significant number of patients with NASH will go on to develop cirrhosis, which may result in hepatocellular carcinoma. Thus, early detection and management of NAFLD is critical. Percutaneous liver biopsy is no longer considered the gold standard for diagnosing NAFLD/NASH because of the small sample size, sampling error, and complications related to the invasive nature of the procedure. Newer imaging technologies like MR elastography and other associated biochemical markers are noninvasive and reasonably accurate in diagnosing NAFLD.
Studies have shown that in people with extremely high BMI, bariatric surgery helps not only with type 2 diabetes but also in advanced stages of NASH, with a significant reversal of liver function test. Many type 2 diabetes medications like GLP analogs and SGLT2 inhibitors, alone or in combination, have been shown to significantly reduce the liver fat and further progression of NAFLD and NASH. Many attempts are being made to look at other targets like anti‐CD3 and dual GLP‐GIP agonists are being evaluated for treatment of early stages of NAFLD.
Footnotes
Author Disclosure Statement
No competing financial interests exist.