|Year : 2015 | Volume
| Issue : 1 | Page : 45-52
Nonalcoholic fatty liver disease and risk of diabetes and cardiovascular disease: What is important for primary care physicians?
Mohamed H Ahmed1, Nazik Elmalaika OS Husain2, Ahmed O Almobarak3
1 Department of Medicine, Milton Keynes Hospital NHS Foundation Trust, Eaglestone, Milton Keynes, Buckinghamshire, United Kingdom
2 Department of Pathology, Faculty of Medicine and Health Sciences, Omdurman Islamic University, Khartoum, Sudan
3 Department of Pathology, Faculty of Medicine, University of Medical Sciences and Technology, Khartoum, Sudan
|Date of Web Publication||27-Feb-2015|
Mohamed H Ahmed
Department of Medicine, Milton Keynes Hospital NHS Foundation Trust, Eaglestone, Milton Keynes, Buckinghamshire
Source of Support: None, Conflict of Interest: None
Nonalcoholic fatty liver disease (NAFLD) is emerging as the most common chronic liver condition in Western World and across the globe. NAFLD prevalence is estimated to be around one-third of the total population. There are no published data that project the future prevalence of NAFLD, but with an increase in epidemic of diabetes and obesity, it is possible to suggest an increase in a number of individuals with NAFLD. NAFLD is associated with insulin resistance and occurs with an increase in cluster of features of metabolic syndrome and type 2 diabetes. Therefore, it is important to exclude the possibility of diabetes in those individuals with evidence of fatty liver. The global diabetes epidemic continues to grow, and it is estimated that the number of people with diabetes will double by year 2030. NAFLD is also a risk factor for an increase in cardiovascular incidence independent of age, sex, low-density lipoprotein-cholesterol, smoking, and cluster of metabolic syndromes. It is expected that NAFLD will be an important challenge for health providers in the near future. Taking all these factors into consideration, we believe that increasing awareness of metabolic and cardiovascular impact of NAFLD among general practitioners and health authorities may decrease the serious consequences of late diagnosis of NAFLD. Importantly, the collaboration between medical specialties is vital in decreasing the impact of the epidemic of NAFLD. The focus of this review is in the role of primary care physician in diagnosis, treatment and prevention of NAFLD and patients education.
Keywords: Cardiovascular disease, insulin resistance, nonalcoholic fatty liver disease, primary care physician, type 2 diabetes mellitus
|How to cite this article:|
Ahmed MH, Husain NO, Almobarak AO. Nonalcoholic fatty liver disease and risk of diabetes and cardiovascular disease: What is important for primary care physicians?. J Family Med Prim Care 2015;4:45-52
|How to cite this URL:|
Ahmed MH, Husain NO, Almobarak AO. Nonalcoholic fatty liver disease and risk of diabetes and cardiovascular disease: What is important for primary care physicians?. J Family Med Prim Care [serial online] 2015 [cited 2020 May 30];4:45-52. Available from: http://www.jfmpc.com/text.asp?2015/4/1/45/152252
| Introduction|| |
Nonalcoholic fatty liver disease (NAFLD) is a common liver disease across the globe and become an increasingly important health issue. NAFLD is a condition given to the spectrum of liver disorders associated with hepatic steatosis that is not due to significant alcohol intake and other secondary causes of liver diseases.  The histological spectrum of NAFLD ranges from steatosis to steatosis with evidence of hepatocellular inflammation and damage [nonalcoholic steatohepatitis (NASH) [Figure 1].  NAFLD is emerging as a common cause of liver disease, and most of the individuals thought to have cryptogenic cirrhosis are now believed to have cirrhosis due to NASH.  There is an invariable association between NAFLD and insulin resistance and its estimated that more than 90% of NAFLD patients have insulin resistance or feature of metabolic syndrome.  Importantly, in the view of the increase in the prevalence of diabetes, it is projected that NAFLD will be the leading cause of liver cirrhosis in the near future. 
|Figure 1: Conditions associated with nonalcoholic fatty liver disease (NAFLD) and factors that lead to nonalcoholic steatohepatits|
Click here to view
| Epidemiology and Natural History|| |
The prevalence of NAFLD in USA was found to be around 34% and 90% of these cases of NAFLD were attributed to nonalcoholic causes.  In addition, the prevalence in an ethnically diverse community in USA was estimated to be around 33.6%.  While in Europe, the prevalence of NAFLD was ~ 25% and 35% was associated with most features of the metabolic syndrome.  In Japan and China, the prevalence of NAFLD is estimated to be around 25%. ,,, The prevalence of NAFLD in the far East and Asian population has been estimated to vary between 5% and 40%.  The increase in the epidemics of obesity and diabetes in the Middle-East may have a significant impact in the increase in the prevalence of the epidemic of NAFLD in that region. In a study by El-Hassan et al. in 1992, the prevalence of NAFLD was ~ 10%  and increased to 33.3% in 2012.
The prevalence of NAFLD in Africa is similar to Asia. For instance Almobarak et al showed that the prevalence of NAFLD in sudan is around 20%.  The synergistic effect of alcohol and obesity may worsen the NAFLD phenotype and may lead to an increase in risk of cirrhosis. , NAFLD per se is associated with high mortality.  NAFLD is also associated with worsening lipid profile in individuals with metabolic syndrome especially, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), and high plasma triglyceride. 
Hyperglycemia is also significant risk factor for the development of NAFLD. For instance, the prevalence of NAFLD in the Japanese population rises with increasing degrees of hyperglycemia, being around 27% in people with normal fasting glucose levels, increasing to 43% among those with impaired fasting glycemia, and 62% among newly diagnosed diabetes.  Importantly, features of metabolic syndrome such as waist circumference, triglyceride level, and insulin resistance were independently associated with NAFLD in the normal-weight group.  Alarmingly, obese children are also at risk of developing NAFLD and this risk increases with features of the metabolic syndrome. NAFLD in children is also associated with risk of liver cirrhosis and transplantation and overall increase in mortality. ,,
There is growing the body of evidence from the natural history of NAFLD, which suggests that NAFLD has a benign course without excess mortality. , However, a recent large study by Adams et al., concluded that the overall death rate is higher than expected in individuals with NAFLD, and this increase in mortality was associated with age, impaired fasting glucose/diabetes and cirrhosis.  Furthermore, the natural history of NASH is associated with the possibility of progression to cirrhosis, fibrosis, and in small number of patients hepatocellulars carcinoma , and once cirrhosis develops in patients with NAFLD, the prognosis is poor. ,,,,
| Nonalcoholic Fatty Liver Disease, Metabolic Syndrome, and Diabetes|| |
Nonalcoholic fatty liver disease is associated with insulin resistance and is regarded as hepatic component of the metabolic syndrome. , This due to the fact that most of the features of metabolic syndrome are commonly present in subjects with NAFLD, with 67-71% being obese, 12-37% having impaired fasting glycemia, 57-68% having disturbed lipid profiles, and 36-70% being hypertensive.  Metabolic syndrome can be diagnosed in the presence of three of the five criteria-including high waist circumference, high triglycerides, LDL, HDL-C levels, high blood pressure, and high fasting-glucose levels. Waist circumference is just one of five criteria that physicians can use when diagnosing the metabolic syndrome (Population- and country-specific definitions).  Insulin resistance is an important shared unique feature between metabolic syndrome, NAFLD and type 2 diabetes. Importantly, the increase in the features of the metabolic syndrome is associated with a parallel increase in the degree of insulin resistance. ,, Therefore, it is not surprising that NAFLD can be a manifestation of type 2 diabetes mellitus (T2DM) and present in up to 30% of patients with type 2 diabetes or impaired glucose tolerance , [Figure 1]. Several studies have showed a high prevalence of NAFLD among type 2 diabetes individuals. For instance, the prevalence of NAFLD among type 2 diabetes individuals in Brazil, Malaysia, and China were estimated to be 42%, 49.6%, and 61%, respectively. ,, In UK, the estimated prevalence of NAFLD among type 2 diabetes people was found to be around 42.6%, while in Italy, the prevalence of NAFLD among type 2 diabetes was ~ 70%.  Furthermore, a recent small study in diabetic Saudi individuals has suggested the prevalence of NAFLD is ~ 55%. 
Brinks et al. showed that the number of people with type 2 diabetes (age from 55 to 74 years old) in Germany will increase from 2.4 to 3.9 million by year 2030.  Honeycutt et al. showed that the projected number of people with diagnosed diabetes in USA will increase from 12 million to 39 million in 2050 (form 4.4% to 9.7%).  Boyle et al. showed that annual diagnosed diabetes incidence (new cases) will increase from about 8 cases/1,000 in 2008 to about 15 in 2050. The authors suggested that in case of low incidence and relatively high diabetes mortality, total diabetes prevalence (diagnosed and undiagnosed cases) is projected to increase from 14% in 2010 to 21% of the US adult population by 2050. Furthermore, it is projected that the prevalence of diabetes will increase to 33% by 2050 if diabetes mortality remained low and no decreased in incidence of diabetes is reported. Their projection is that the middle-ground scenario projects a prevalence of 25% to 28% by 2050.  Importantly, in 10 countries, it is estimated that the number of people with diabetes will increase from 366 million people to 552 million people by 2030.  The impact of the epidemic of diabetes not only in increasing the prevalence of NAFLD but also in how primary care resources will be able to cope is not yet established.
| Nonalcoholic Fatty Liver Disease and Obesity and Dyslipidemia|| |
Obesity and dyslipidemia are important risk factors for NAFLD. In a population-based studies in Japan and Korea, showed that obesity, dyslipidemia, and hypertension were independent risk factors for NAFLD. , Interestingly, visceral fat accumulation and insulin resistance were found to correlate with the severity of NAFLD in obese and nonobese individuals.  Therefore, it is not surprising that 50% of individuals with dyslipidemia have NAFLD.  Obesity is regarded as inflammatory condition and inflammation are crucial part of the pathogenesis of NAFLD. ,, Interestingly, around 70-100% of NASH patients are obese. In addition, steatosis is a common observation in obesity and may be associated with inflammatory signs of the nonspecific hepatitis. ,, In one large study of 528 patients with an average BMI of 42 kg/m 2 , 74% of liver biopsies showed fatty deposition  and in another study, 12% of autopsies in cirrhotic patients obesity was the only recognized risk factor.  Therefore, it is important in obese individuals with long-standing obesity to exclude diabetes and fatty liver/cirrhosis.
| Nonalcoholic Fatty Liver Disease and Cardiovascular Disease|| |
Recent data suggest that NAFLD may be linked to increased cardiovascular disease (CVD) risk in both nondiabetic and type 2 diabetes. Interestingly, studies have reported associations between increased liver enzymes (particularly serum g-GGT levels), as surrogate markers of NAFLD, with the occurrence of CVD events in both nondiabetic subjects and people with type 2 diabetes. The following table is summary of studies linking NAFLD and CVD [Table 1],,,,,,,,,,.
A full understanding of the pathogenesis of NAFLD is not yet established and involves complex factors that alter different metabolic events [Figure 2]. Insulin resistance is one of the unique features of the pathogenesis of NAFLD and reported in the majority of individuals with obesity and visceral obesity. Insulin resistance leads to an increase in supply of free fatty acids to the liver. ,,,, Furthermore, insulin resistance is associated with impaired suppression of lipolysis by insulin leading to increased nonesterified fatty acid delivery to the liver. There is also reduced glucose uptake in the fed state by adipose tissue and skeletal muscle resulting in hyperglycemia and diversion of glucose to the hepatic de novo pathway. In addition, fatty food may also precipitate NASH. Excessive consumption of glucose or sucrose is also shown to promote NAFLD due increase de novo lipogenesis. ,,,,
|Figure 2: Schematic figure showing possible pathways involved in the pathogenesis of nonalcoholic fatty liver disease|
Click here to view
There is a strong link between insulin resistance and excessive deposition of triglyceride in the hepatocytes, which is the unique features for diagnosis of NAFLD. ,, Different factors lead to more accumulation of fat in the liver. For instance, increased dietary fat, decreased mitochondrial β oxidation, and decreased clearance of very low-density lipoprotein (VLDL). Other important factors are increased fatty acid delivery from adipose tissue, increased synthesis of fatty acid via the de novo pathway. 
At cellular level, different factors are thought to induce different impacts. For instance, inflammation and oxidative stress are associated different metabolic changes that lead to insulin resistance and excess hepatic fat accumulation through increased triglyceride synthesis in the liver. Furthermore, because mitochondrial fat oxidation and export of VLDL particles are not able to match triglyceride synthesis, this will lead to further deposition of fat in the liver and worsening of insulin resistance. Inflammation is the link between obesity and insulin resistance and may have an important role in the pathogenesis of hepatic and systemic insulin resistance and CVD. , Adiponectin has been shown to decrease de novo fatty acid synthesis and enhance fat oxidation and improved insulin sensitivity.  Low levels of adiponectin are associated with NAFLD independent of the components of the metabolic syndrome, and low adiponectin is associated with CVD. ,,
| Primary Care Physician and Nonalcoholic Fatty Liver Disease-What to Do?|| |
It is good practice to exclude NAFLD in obese individuals and those with features of metabolic syndrome [summary of features of metabolic syndrome and patients at risk of developing NAFLD are shown in [Figure 2] and [Figure 3]. The role of primary care physician is to diagnose and treat NAFLD and promote weight loss through lifestyle changes.
|Figure 3: Possible algorithm for management of nonalcoholic fatty liver disease in primary health care|
Click here to view
There are no biochemical markers for NAFLD. A combination of laboratory tests, imaging, and histology can provide a diagnosis. Laboratory test results may show mild to moderate increase in liver enzymes e.g. of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) , [Figure 3]. Ultrasound commonly used in the diagnosis of NAFLD. Ultrasound has a sensitivity of 90% and specificity of 80%, for diagnosing hepatic steatosis but ultrasound cannot detect hepatic inflammation or mild fibrosis. Confusion between a diagnosis of NAFLD or malignancy arising from a computed tomography scan may be resolved using magnetic resonance imaging , [Figure 3]. Liver biopsy is requested by liver specialist in patients with persistent increased liver enzymes despite attempts to reverse known risk factors or those with possible risk of developing fibrosis. This is especially important in patients with clinical conditions associated with insulin resistance such as T2DM, hyperlipidemia, and obesity. ,,
Currently, there is no definitive treatment for NAFLD. The aim of management should be to reverse the progression of NAFLD and to prevent liver-related illness and death.
Both weight loss and exercise improve insulin sensitivity. The current evidence suggests that gradual weight loss should be advocated in all patients with NAFLD as the majority of subjects are overweight. Importantly, a reasonable target is the loss of 10% of body weight over 6 months [Figure 3]. 
Therapeutic agents shown potential benefit in treating nonalcoholic fatty liver disease
Antiobesity medication like orlistat showed significant improvement in histology, ultrasound and reduced ALT. Anidiabetic medication has role in NAFLD treatment. For instance, metformin can be useful in treating insulin resistance but is contraindicated in advanced liver failure. Thiazolidinediones, pioglitazone decreased ALT, hepatic fat content, glucose and free fatty acid concentration, and associated with both improvements in insulin sensitivity and liver histology. Statins, all statins, are safe in NAFLD, there is a theoretical benefit from using statins not metabolized by the liver, i.e. Rosuvastatin, fluvastatin, and pravastatin. Rarely, statins cause irreversible liver damage. Some statins (pravastatin, rosuvastatin, and pravastatin) showed decrease in ALT, GGT, and AST, while pravastatin and atrovastatin showed histological improvement. Long-term administration of satins (10-16 years) showed a significant reduction in steatosis. Increase in ALT > 3 times upper reference range may warrant need to stop statin treatment. 
| Conclusion|| |
NAFLD is emerging as a common liver disease and is associated with obesity and insulin resistance. Insulin resistance is associated with increased intrahepatic production of free fatty acids from glucose not taken up by peripheral adipocytes and myocytes. Therefore, it is important to exclude diabetes in individuals with abnormal liver enzymes and features of the metabolic syndrome. NAFLD had an insidious course of action and associated with high prevalence of obesity and diabetes. It is possible to postulate, in view of expected high prevalence of undiagnosed NAFLD, an increase in prevalence of liver cirrhosis. In addition, large proportions of patients are regularly reviewed by primary care physicians will also receive liver function test. In the view of absence of sensitive and specific biochemical markers that will allow easy and rapid mass screening of NAFLD, we recommend that using current criteria for diagnosis and management of NAFLD may assist in early diagnosis of both diabetes and liver fibrosis and direct patient to receive appropriate treatment from diabetologists, gastroenterologists, hepatologist, and bariatric surgeons. Ultimately, this may assist in early diagnosis of NAFLD and associated metabolic disturbances and in part in decreasing the epidemic of type 2 diabetes.
| References|| |
Angulo P, Keach JC, Batts KP, Lindor KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999;30:1356-62.
Loria P, Adinolfi LE, Bellentani S, Bugianesi E, Grieco A, Fargion S, et al
. Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee. Dig Liver Dis 2010;42:272-82.
Ahmed MH. Biochemical markers: The road map for the diagnosis of nonalcoholic fatty liver disease. Am J Clin Pathol 2007;127:20-2.
Marchesini G, Brizi M, Morselli-Labate AM, Bianchi G, Bugianesi E, McCullough AJ, et al
. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med 1999;107:450-5.
Ahmed MH, Byrne CD. Non-Alcoholic Fatty Liver Disease in the Metabolic Syndrome. UK: Wiley-Blackwell; 2011. p. 245-77.
Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, et al
. Prevalence of hepatic steatosis in an urban population in the United States: Impact of ethnicity. Hepatology 2004;40:1387-95.
Szczepaniak LS, Nurenberg P, Leonard D, Browning JD, Reingold JS, Grundy S, et al
. Magnetic resonance spectroscopy to measure hepatic triglyceride content: Prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 2005;288:E462-8.
Bellentani S, Saccoccio G, Masutti F, Crocè LS, Brandi G, Sasso F, et al
. Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med 2000;132:112-7.
Kojima S, Watanabe N, Numata M, Ogawa T, Matsuzaki S. Increase in the prevalence of fatty liver in Japan over the past 12 years: Analysis of clinical background. J Gastroenterol 2003;38:954-61.
Fan JG, Zhu J, Li XJ, Chen L, Lu YS, Li L, et al
. Fatty liver and the metabolic syndrome among Shanghai adults. J Gastroenterol Hepatol 2005;20:1825-32.
Fan JG, Zhu J, Li XJ, Chen L, Li L, Dai F, et al
. Prevalence of and risk factors for fatty liver in a general population of Shanghai, China. J Hepatol 2005;43:508-14.
Kang WM, Zhang JS, Wang MS, Gu YC, Yu JC. Prevalence of metabolic syndrome and its associations with other metabolic disorders and cardiovascular changes in health examination population in Beijing. Chin Med Sci J 2009;24:227-30.
Amarapurkar DN, Hashimoto E, Lesmana LA, Sollano JD, Chen PJ, Goh KL, et al
. How common is non-alcoholic fatty liver disease in the Asia-Pacific region and are there local differences? J Gastroenterol Hepatol 2007;22:788-93.
El-Hassan AY, Ibrahim EM, al-Mulhim FA, Nabhan AA, Chammas MY. Fatty infiltration of the liver: Analysis of prevalence, radiological and clinical features and influence on patient management. Br J Radiol 1992;65:774-8.
Onyekwere CA, Ogbera AO, Balogun BO. Non-alcoholic fatty liver disease and the metabolic syndrome in an urban hospital serving an African community. Ann Hepatol 2011;10:119-24.
Liu B, Balkwill A, Reeves G, Beral V, Million Women Study Collaborators. Body mass index and risk of liver cirrhosis in middle aged UK women: Prospective study. BMJ 2010;340:c912.
Hart CL, Morrison DS, Batty GD, Mitchell RJ, Davey Smith G. Effect of body mass index and alcohol consumption on liver disease: Analysis of data from two prospective cohort studies. BMJ 2010;340:c1240.
Adams LA, Harmsen S, St Sauver JL, Charatcharoenwitthaya P, Enders FB, Therneau T, et al
. Nonalcoholic fatty liver disease increases risk of death among patients with diabetes: A community-based cohort study. Am J Gastroenterol 2010;105:1567-73.
Chiang PH, Chang TY, Chen JD. Synergistic effect of fatty liver and smoking on metabolic syndrome. World J Gastroenterol 2009;15:5334-9.
Jimba S, Nakagami T, Takahashi M, Wakamatsu T, Hirota Y, Iwamoto Y, et al
. Prevalence of non-alcoholic fatty liver disease and its association with impaired glucose metabolism in Japanese adults. Diabet Med 2005;22:1141-5.
Kim HJ, Kim HJ, Lee KE, Kim DJ, Kim SK, Ahn CW, et al
. Metabolic significance of nonalcoholic fatty liver disease in nonobese, nondiabetic adults. Arch Intern Med 2004;164:2169-75.
Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C. Prevalence of fatty liver in children and adolescents. Pediatrics 2006;118:1388-93.
Radetti G, Kleon W, Stuefer J, Pittschieler K. Non-alcoholic fatty liver disease in obese children evaluated by magnetic resonance imaging. Acta Paediatr 2006;95:833-7.
Feldstein AE, Charatcharoenwitthaya P, Treeprasertsuk S, Benson JT, Enders FB, Angulo P. The natural history of non-alcoholic fatty liver disease in children: A follow-up study for up to 20 years. Gut 2009;58:1538-44.
Dam-Larsen S, Franzmann M, Andersen IB, Christoffersen P, Jensen LB, Sørensen TI, et al
. Long term prognosis of fatty liver: Risk of chronic liver disease and death. Gut 2004;53:750-5.
Bedogni G, Miglioli L, Masutti F, Tiribelli C, Marchesini G, Bellentani S. Prevalence of and risk factors for nonalcoholic fatty liver disease: The Dionysos nutrition and liver study. Hepatology 2005;42:44-52.
Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, et al
. The natural history of nonalcoholic fatty liver disease: A population-based cohort study. Gastroenterology 2005;129:113-21.
Fassio E, Alvarez E, Domínguez N, Landeira G, Longo C. Natural history of nonalcoholic steatohepatitis: A longitudinal study of repeat liver biopsies. Hepatology 2004;40:820-6.
Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: A spectrum of clinical and pathological severity. Gastroenterology 1999;116:1413-9.
Ratziu V, Bonyhay L, Di Martino V, Charlotte F, Cavallaro L, Sayegh-Tainturier MH, et al
. Survival, liver failure, and hepatocellular carcinoma in obesity-related cryptogenic cirrhosis. Hepatology 2002;35:1485-93.
Hui JM, Kench JG, Chitturi S, Sud A, Farrell GC, Byth K, et al
. Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C. Hepatology 2003;38:420-7.
Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002;346:1221-31.
Chitturi S, Abeygunasekera S, Farrell GC, Holmes-Walker J, Hui JM, Fung C, et al
. NASH and insulin resistance: Insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology 2002;35:373-9.
Pagano G, Pacini G, Musso G, Gambino R, Mecca F, Depetris N, et al
. Nonalcoholic steatohepatitis, insulin resistance, and metabolic syndrome: Further evidence for an etiologic association. Hepatology 2002;35:367-72.
Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al
. Harmonizing the metabolic syndrome: A joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009;120:1640-5.
Church TS, Kuk JL, Ross R, Priest EL, Biltoft E, Blair SN. Association of cardiorespiratory fitness, body mass index, and waist circumference to nonalcoholic fatty liver disease. Gastroenterology 2006;130:2023-30.
Rocha R, Cotrim HP, Carvalho FM, Siqueira AC, Braga H, Freitas LA. Body mass index and waist circumference in non-alcoholic fatty liver disease. J Hum Nutr Diet 2005;18:365-70.
Dam-Larsen S, Becker U, Franzmann MB, Larsen K, Christoffersen P, Bendtsen F. Final results of a long-term, clinical follow-up in fatty liver patients. Scand J Gastroenterol 2009;44:1236-43.
Chan WK, Tan AT, Vethakkan SR, Tah PC, Vijayananthan A, Goh KL. Non-alcoholic fatty liver disease in diabetics - Prevalence and predictive factors in a multiracial hospital clinic population in Malaysia. J Gastroenterol Hepatol 2013;28:1375-83.
Lv WS, Sun RX, Gao YY, Wen JP, Pan RF, Li L, et al
. Nonalcoholic fatty liver disease and microvascular complications in type 2 diabetes. World J Gastroenterol 2013;19:3134-42.
Ferreira VS, Pernambuco RB, Lopes EP, Morais CN, Rodrigues MC, Arruda MJ, et al
. Frequency and risk factors associated with non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus. Arq Bras Endocrinol Metabol 2010;54:362-8.
Williamson RM, Price JF, Glancy S, Perry E, Nee LD, Hayes PC, et al
. Prevalence of and risk factors for hepatic steatosis and nonalcoholic Fatty liver disease in people with type 2 diabetes: The edinburgh type 2 diabetes study. Diabetes Care 2011;34:1139-44.
Akbar DH, Kawther AH. Nonalcoholic fatty liver disease in Saudi type 2 diabetic subjects attending a medical outpatient clinic: Prevalence and general characteristics. Diabetes Care 2003;26:3351-2.
Brinks R, Tamayo T, Kowall B, Rathmann W. Prevalence of type 2 diabetes in Germany in 2040: Estimates from an epidemiological model. Eur J Epidemiol 2012;27:791-7.
Honeycutt AA, Boyle JP, Broglio KR, Thompson TJ, Hoerger TJ, Geiss LS, et al
. A dynamic Markov model for forecasting diabetes prevalence in the United States through 2050. Health Care Manag Sci 2003;6:155-64.
Boyle JP, Thompson TJ, Gregg EW, Barker LE, Williamson DF. Projection of the year 2050 burden of diabetes in the US adult population: Dynamic modeling of incidence, mortality, and prediabetes prevalence. Popul Health Metr 2010;8:29.
Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: Global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract 2011;94:311-21.
Tsuneto A, Hida A, Sera N, Imaizumi M, Ichimaru S, Nakashima E, et al
. Fatty liver incidence and predictive variables. Hypertens Res 2010;33:638-43.
Lee JY, Kim KM, Lee SG, Yu E, Lim YS, Lee HC, et al
. Prevalence and risk factors of non-alcoholic fatty liver disease in potential living liver donors in Korea: A review of 589 consecutive liver biopsies in a single center. J Hepatol 2007;47:239-44.
Eguchi Y, Eguchi T, Mizuta T, Ide Y, Yasutake T, Iwakiri R, et al
. Visceral fat accumulation and insulin resistance are important factors in nonalcoholic fatty liver disease. J Gastroenterol 2006;41:462-9.
Assy N, Kaita K, Mymin D, Levy C, Rosser B, Minuk G. Fatty infiltration of liver in hyperlipidemic patients. Dig Dis Sci 2000;45:1929-34.
Trayhurn P, Beattie JH. Physiological role of adipose tissue: White adipose tissue as an endocrine and secretory organ. Proc Nutr Soc 2001;60:329-39.
Tripathy D, Mohanty P, Dhindsa S, Syed T, Ghanim H, Aljada A, et al
. Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects. Diabetes 2003;52:2882-7.
Hotamisligil GS, Spiegelman BM. Tumor necrosis factor alpha: A key component of the obesity-diabetes link. Diabetes 1994;43:1271-8.
Luyckx FH, Desaive C, Thiry A, Dewé W, Scheen AJ, Gielen JE, et al
. Liver abnormalities in severely obese subjects: Effect of drastic weight loss after gastroplasty. Int J Obes Relat Metab Disord 1998;22:222-6.
Luyckx FH, Scheen AJ, Desaive C, Dewe W, Gielen JE, Lefebvre PJ. Effects of gastroplasty on body weight and related biological abnormalities in morbid obesity. Diabetes Metab 1998;24:355-61.
Luyckx FH, Lefebvre PJ, Scheen AJ. Non-alcoholic steatohepatitis: Association with obesity and insulin resistance, and influence of weight loss. Diabetes Metab 2000;26:98-106.
Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: An autopsy study with analysis of risk factors. Hepatology 1990;12:1106-10.
Jousilahti P, Rastenyte D, Tuomilehto J. Serum gamma-glutamyl transferase, self-reported alcohol drinking, and the risk of stroke. Stroke 2000;31:1851-5.
Wannamethee G, Ebrahim S, Shaper AG. Gamma-glutamyltransferase: Determinants and association with mortality from ischemic heart disease and all causes. Am J Epidemiol 1995;142:699-708.
Targher G, Bertolini L, Poli F, Rodella S, Scala L, Tessari R, et al
. Nonalcoholic fatty liver disease and risk of future cardiovascular events among type 2 diabetic patients. Diabetes 2005;54:3541-6.
Ioannou GN, Weiss NS, Boyko EJ, Mozaffarian D, Lee SP. Elevated serum alanine aminotransferase activity and calculated risk of coronary heart disease in the United States. Hepatology 2006;43:1145-51.
Monami M, Bardini G, Lamanna C, Pala L, Cresci B, Francesconi P, et al
. Liver enzymes and risk of diabetes and cardiovascular disease: Results of the Firenze Bagno a Ripoli (FIBAR) study. Metabolism 2008;57:387-92.
Fracanzani AL, Burdick L, Raselli S, Pedotti P, Grigore L, Santorelli G, et al
. Carotid artery intima-media thickness in nonalcoholic fatty liver disease. Am J Med 2008;121:72-8.
Targher G, Bertolini L, Padovani R, Rodella S, Zoppini G, Zenari L, et al
. Relations between carotid artery wall thickness and liver histology in subjects with nonalcoholic fatty liver disease. Diabetes Care 2006;29:1325-30.
Volzke H, Robinson DM, Kleine V, Deutscher R, Hoffmann W, Ludemann J, et al
. Hepatic steatosis is associated with an increased risk of carotid atherosclerosis. World J Gastroenterol 2005;11:1848-53.
Targher G, Bertolini L, Padovani R, Poli F, Scala L, Zenari L, et al
. Non-alcoholic fatty liver disease is associated with carotid artery wall thickness in diet-controlled type 2 diabetic patients. J Endocrinol Invest 2006;29:55-60.
Targher G, Zoppini G, Lippi G, Guidi GC, Muggeo M. Effect of serum gamma-glutamyltransferase and obesity on the risk of dyslipidemia and poor glycemic control in type 2 diabetic patients: Cross-sectional findings from the Verona Diabetes Study. Clin Chem 2007;53:1867-9.
Targher G, Bertolini L, Padovani R, Rodella S, Tessari R, Zenari L, et al
. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care 2007;30:1212-8.
Lewis GF, Carpentier A, Adeli K, Giacca A. Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev 2002;23:201-29.
Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 2005;115:1343-51.
Nguyen-Duy TB, Nichaman MZ, Church TS, Blair SN, Ross R. Visceral fat and liver fat are independent predictors of metabolic risk factors in men. Am J Physiol Endocrinol Metab 2003;284:E1065-71.
Kelley DE, McKolanis TM, Hegazi RA, Kuller LH, Kalhan SC. Fatty liver in type 2 diabetes mellitus: Relation to regional adiposity, fatty acids, and insulin resistance. Am J Physiol Endocrinol Metab 2003;285:E906-16.
Utzschneider KM, Kahn SE. Review: The role of insulin resistance in nonalcoholic fatty liver disease. J Clin Endocrinol Metab 2006;91:4753-61.
Hudgins LC, Hellerstein M, Seidman C, Neese R, Diakun J, Hirsch J. Human fatty acid synthesis is stimulated by a eucaloric low fat, high carbohydrate diet. J Clin Invest 1996;97:2081-91.
Timlin MT, Parks EJ. Temporal pattern of de novo lipogenesis in the postprandial state in healthy men. Am J Clin Nutr 2005;81:35-42.
Musso G, Gambino R, De Michieli F, Cassader M, Rizzetto M, Durazzo M, et al. Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatology 2003;37:909-16.
McDevitt RM, Bott SJ, Harding M, Coward WA, Bluck LJ, Prentice AM. De novo lipogenesis during controlled overfeeding with sucrose or glucose in lean and obese women. Am J Clin Nutr 2001;74:737-46.
Faeh D, Minehira K, Schwarz JM, Periasamy R, Park S, Tappy L. Effect of fructose overfeeding and fish oil administration on hepatic de novo lipogenesis and insulin sensitivity in healthy men. Diabetes 2005;54:1907-13.
Abdelmalek MF, Diehl AM. Nonalcoholic fatty liver disease as a complication of insulin resistance. Med Clin North Am 2007;91:1125-49, ix.
Charlton M. Nonalcoholic fatty liver disease: A review of current understanding and future impact. Clin Gastroenterol Hepatol 2004;2:1048-58.
Adams LA, Lindor KD. Nonalcoholic fatty liver disease. Ann Epidemiol 2007;17:863-9.
Postic C, Girard J. Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: Lessons from genetically engineered mice. J Clin Invest 2008;118:829-38.
Samuel VT, Liu ZX, Qu X, Elder BD, Bilz S, Befroy D, et al
. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem 2004;279:32345-53.
Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, et al
. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med 2005;11:183-90.
Musso G, Gambino R, De Michieli F, Durazzo M, Pagano G, Cassader M. Adiponectin gene polymorphisms modulate acute adiponectin response to dietary fat: Possible pathogenetic role in NASH. Hepatology 2008;47:1167-77.
Pagano C, Soardo G, Esposito W, Fallo F, Basan L, Donnini D, et al
. Plasma adiponectin is decreased in nonalcoholic fatty liver disease. Eur J Endocrinol 2005;152:113-8.
Targher G, Bertolini L, Scala L, Poli F, Zenari L, Falezza G. Decreased plasma adiponectin concentrations are closely associated with nonalcoholic hepatic steatosis in obese individuals. Clin Endocrinol (Oxf) 2004;61:700-3.
Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB, Rimm EB. Plasma adiponectin levels and risk of myocardial infarction in men. JAMA 2004;291:1730-7.
Ong JP, Younossi ZM. Approach to the diagnosis and treatment of nonalcoholic fatty liver disease. Clin Liver Dis 2005;9:617-34, vi.
[Figure 1], [Figure 2], [Figure 3]
|This article has been cited by|
||Model-based cost-effectiveness analysis of atorvastatin drugs for prevention of cardiovascular diseases in Iran
| ||Alireza Jabbari,Abdosaleh Jafari,Marziye Hadian,Mohammad Ghasemi |
| ||International Journal of Preventive Medicine. 2020; 11(1): 57 |
|[Pubmed] | [DOI]|
||To Protect Fatty Livers from Ischemia Reperfusion Injury: Role of Ischemic Postconditioning
| ||Julia Schewe,Marie-Christine Makeschin,Andrej Khandoga,Jiang Zhang,Doris Mayr,Simon Rothenfußer,Max Schnurr,Alexander L. Gerbes,Christian J. Steib |
| ||Digestive Diseases and Sciences. 2020; |
|[Pubmed] | [DOI]|
||Environmental Risk Factors for Liver Cancer and Nonalcoholic Fatty Liver Disease
| ||Trang VoPham |
| ||Current Epidemiology Reports. 2019; 6(1): 50 |
|[Pubmed] | [DOI]|
||Free fatty acid-induced histone acetyltransferase activity accelerates lipid accumulation in HepG2 cells
| ||Sangwon Chung,Jin-Taek Hwang,Jae Ho Park,Hyo-Kyoung Choi |
| ||Nutrition Research and Practice. 2019; 13(3): 196 |
|[Pubmed] | [DOI]|
||Non-alcoholic fatty liver disease (NAFLD): survey of awareness and understanding among professionals in secondary care
| ||Bronwen Williams,Nurun Tania,Lynsey Corless |
| ||Gastrointestinal Nursing. 2019; 17(Sup6): S22 |
|[Pubmed] | [DOI]|
||Therapeutic effect of treatment with metformin and/or 4-hydroxychalcone in male Wistar rats with nonalcoholic fatty liver disease
| ||Selene de Jesús Acosta-Cota,Elsa Maribel Aguilar-Medina,Rosalío Ramos-Payán,José Guadalupe Rendón Maldonado,José Geovanni Romero-Quintana,Julio Montes-Avila,Juan I. Sarmiento-Sánchez,Carolina Gabriela Plazas-Guerrero,Marcela J. Vergara-Jiménez,Araceli Sánchez-López,David Centurión,Ulises Osuna-Martínez |
| ||European Journal of Pharmacology. 2019; 863: 172699 |
|[Pubmed] | [DOI]|
||Histopathological and biochemical changes in the development of nonalcoholic fatty liver disease induced by high-sucrose diet at different times
| ||Selene de Jesús Acosta-Cota,Elsa Maribel Aguilar-Medina,Rosalio Ramos-Payán,Ana Karen Ruiz-Quiñónez,José Geovanni Romero-Quintana,Julio Montes-Avila,José Guadalupe Rendón-Maldonado,Araceli Sánchez-López,David Centurión,Ulises Osuna-Martínez |
| ||Canadian Journal of Physiology and Pharmacology. 2018; : 1 |
|[Pubmed] | [DOI]|
||Dietary supplementation of vitamin D prevents the development of western diet-induced metabolic, hepatic and cardiovascular abnormalities in rats
| ||Giovanna Mazzone,Carmine Morisco,Vincenzo Lembo,Giuseppe D’Argenio,Maria D’Armiento,Antonella Rossi,Carmine Del Giudice,Bruno Trimarco,Nicola Caporaso,Filomena Morisco |
| ||United European Gastroenterology Journal. 2018; 6(7): 1056 |
|[Pubmed] | [DOI]|
||Effect of Helicobacter pylori on insulin resistance in nonobese, nondiabetic, and normolipidemic Egyptian patients
| ||Ahmed S. Allam,Somia Bawady,Ahmed S. Abdel-Moaty,Sarah El-Nakeep |
| ||Egyptian Liver Journal. 2018; 8(1): 23 |
|[Pubmed] | [DOI]|
||Metabolic clinic for individuals with HIV/AIDS
| ||Mohamed H. Ahmed,Clare Woodward,Dushyant Mital |
| ||Cardiovascular Endocrinology. 2017; 6(3): 109 |
|[Pubmed] | [DOI]|
||DNA methylation alters transcriptional rates of differentially expressed genes and contributes to pathophysiology in mice fed a high fat diet
| ||Pili Zhang,Tianjiao Chu,N. Dedousis,Benjamin S. Mantell,Ian Sipula,Lucy Li,Kimberly D. Bunce,Patricia A. Shaw,Liora S. Katz,Jun Zhu,Carmen Argmann,Robert M. OæDoherty,David G. Peters,Donald K. Scott |
| ||Molecular Metabolism. 2017; |
|[Pubmed] | [DOI]|
||Preclinical models of non-alcoholic fatty liver disease
| ||Prasanna K. Santhekadur,Divya P. Kumar,Arun J. Sanyal |
| ||Journal of Hepatology. 2017; |
|[Pubmed] | [DOI]|
||Fatty acid-binding protein 5 function in hepatocellular carcinoma through induction of epithelial-mesenchymal transition
| ||Takanori Ohata,Hideki Yokoo,Toshiya Kamiyama,Moto Fukai,Takeshi Aiyama,Yutaka Hatanaka,Kanako Hatanaka,Kenji Wakayama,Tatsuya Orimo,Tatsuhiko Kakisaka,Nozomi Kobayashi,Yoshihiro Matsuno,Akinobu Taketomi |
| ||Cancer Medicine. 2017; |
|[Pubmed] | [DOI]|
||Esteatosis hepática: diagnóstico y seguimiento
| ||Llorenç Caballería Rovira,Irfan Majeed,Alba Martínez Escudé,Ingrid Arteaga Pillasagua,Pere Torán Monserrat |
| ||FMC - Formación Médica Continuada en Atención Primaria. 2017; 24(7): 378 |
|[Pubmed] | [DOI]|
||Benefits and Harms of Sodium-Glucose Co-Transporter 2 Inhibitors in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis
| ||Heidi Storgaard,Lise L. Gluud,Cathy Bennett,Magnus F. Grøndahl,Mikkel B. Christensen,Filip K. Knop,Tina Vilsbøll,Noel Christopher Barengo |
| ||PLOS ONE. 2016; 11(11): e0166125 |
|[Pubmed] | [DOI]|
||Haplotype analysis of the HFE gene among populations of Northern Eurasia, in patients with metabolic disorders or stomach cancer, and in long-lived people
| ||S. V. Mikhailova,V. N. Babenko,D. E. Ivanoshchuk,M. A. Gubina,V. N. Maksimov,I. G. Solovjova,M. I. Voevoda |
| ||BMC Genetics. 2016; 17(1) |
|[Pubmed] | [DOI]|
||Hígado graso no alcohólico. Papel de los médicos de atención primaria
| ||Juan Caballeria,Llorenç Caballeria |
| ||Medicina Clínica. 2015; 145(3): 112 |
|[Pubmed] | [DOI]|
||Non-alcoholic fatty liver disease. Role of primary care physicians
| ||Juan Caballeria,Llorenç Caballeria |
| ||Medicina Clínica (English Edition). 2015; 145(3): 112 |
|[Pubmed] | [DOI]|
||Nuciferine downregulates Per-Arnt-Sim kinase expression during its alleviation of lipogenesis and inflammation on oleic acid-induced hepatic steatosis in HepG2 cells
| ||Dan-Dan Zhang,Ji-Gang Zhang,Xin Wu,Ying Liu,Sheng-Ying Gu,Guan-Hua Zhu,Yu-Zhu Wang,Gao-Lin Liu,Xiao-Yu Li |
| ||Frontiers in Pharmacology. 2015; 6 |
|[Pubmed] | [DOI]|
||Polyphenol-Rich Fraction of Ecklonia cava Improves Nonalcoholic Fatty Liver Disease in High Fat Diet-Fed Mice
| ||Eun-Young Park,Hojung Choi,Ji-Young Yoon,In-Young Lee,Youngwan Seo,Hong-Seop Moon,Jong-Hee Hwang,Hee-Sook Jun |
| ||Marine Drugs. 2015; 13(11): 6866 |
|[Pubmed] | [DOI]|