Nonalcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus: The Hidden Epidemic

doi:10.1097/MAJ.0b013e3182018598

The American Journal of the Medical Sciences

Volume 341, Issue 6, June 2011, Pages 485-492

https://doi.org/10.1097/MAJ.0b013e3182018598 Get rights and content

Abstract

Nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized cause of liver disease worldwide. With obesity being a universally important risk factor, NAFLD is now receiving greater attention as a public health issue, and the burden of NAFLD is expected to increase in years to come. The prevalence of NAFLD among subjects with diabetes and with severe obesity is on the rise around the world, including in Saudi Arabia. Efforts in developing new strategies for its prevention, diagnosis and management are needed to alter the course of this disease. The purpose of this review is to enhance awareness about the close interrelationship between NAFLD and type 2 diabetes mellitus and recent diagnostic and treatment advances in the field.

Section snippets

PATHOGENESIS OF NAFLD/NASH

Cellular processes that have been well studied with respect to the pathogenesis of NAFLD include IR, oxidative stress and hepatic stellate cell.¹² NAFLD is associated with whole body, adipose tissue and hepatic IR, which cause hypertriglyceridemia and high free fatty acids (FFAs); both are associated with increased visceral adiposity.¹³ The mechanism by which increased visceral adiposity leads to IR is unclear, although previous studies have shown that circulating hormones secreted from adipose

IR, NAFLD AND DIABETES MELLITUS

IR is known to play a key role in the pathophysiology of NAFLD.17., 18. In addition, studies suggest that a higher degree of IR (>2) is associated with a higher likelihood of the development of steatohepatitis in patients with steatosis.¹⁹ Patients with NASH have higher homeostasis model assessment (HOMA) scores, serum insulin levels and C-peptide levels compared with controls.¹⁷ HOMA-IR is calculated as insulin (mU/L) × [glucose (mg/dL) × 0.055]/22.5.²⁰ It is well established that patients

DIAGNOSIS OF NAFLD/NASH

Clinicians need to consider that NAFLD/NASH is the most likely cause of liver test abnormalities in the presence of metabolic risk factors and when other causes of liver disease have been excluded. NAFLD/NASH is usually suspected because of abnormal liver biochemical tests in an apparently healthy person with no symptoms. However, fatigue or vague discomfort over the liver with hepatomegaly is common. The presence of a shrunken liver or more rarely a palpable spleen, ascites, jaundice or

TREATMENT OF NAFLD

NAFLD is largely a manifestation of obesity and metabolic syndrome and is characterized by excess calorie intake and lack of optimal health-related fitness or physical activity.⁴⁸ The current view of NAFLD as a serious condition with the potential for considerable morbidity and mortality has stimulated the search for strategies ranging from lifestyle changes to a variety of pharmacological interventions.

LONG-TERM OUTCOME OF NAFLD AND T2DM

The long-term prognosis of NAFLD in T2DM has been poorly described in published literature. The liver-related mortality is significantly higher in patients with NASH than with simple steatosis. A recent population-based study⁶⁸ reports an 80% increase in mortality in 256 patients with elevated liver enzymes who underwent liver biopsy and had a mean follow up of 21 years. At the time of the initial biopsy, 8% of those with NAFLD had cirrhosis, and 43% had NASH. However, the overall survival was

CONCLUSIONS

NAFLD has become a significant and challenging epidemic worldwide. NAFLD is no longer considered a benign condition in patients with T2DM. The possibility of fatty liver disease should be entertained as a part of the routine evaluation of patients with T2DM, in the same way that we search for microvascular complications and cardiovascular disease. Liver biopsy remains the current gold standard for the diagnosis of NASH and for assessment of the extent of fibrosis. Many advances have been made

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Cited by (19)

Use of noninvasive scores for advanced liver fibrosis can guide the need for hepatic biopsy during bariatric procedures
2021, Surgery for Obesity and Related Diseases
Patients with obesity are at increased risk for nonalcoholic fatty liver disease (NAFLD). The effectiveness of noninvasive screening tests for ruling out advanced fibrosis (stage 3–4) is unknown.
To determine the prevalence of advanced fibrosis in patients undergoing routine liver biopsy during bariatric surgery and assess the effectiveness of existing noninvasive risk calculators.
Academic medical center in the United States.
Routine liver biopsies were obtained during first-time bariatric surgery (January 2001–December 2017). Patient demographic characteristics, co-morbidities, and preoperative laboratory values were compiled. Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) were compared between 3 noninvasive risk calculators for advanced fibrosis: the fibrosis-4 index, NAFLD fibrosis score, and aminotransferase-to-platelet ratio index (APRI).
Among 2465 patients, the prevalence of advanced fibrosis (stage 3–4) was 3.4%. The mean age was 45.5 years, and the mean body mass index was 46.8. The sensitivity of noninvasive risk calculators ranged from 85% (NAFLD fibrosis score) to 24% (APRI). The NAFLD fibrosis score performed best in screening out advanced fibrosis, with an NPV of 99%. The PPV ranged from 9% to 65%. In this study cohort, the use of the NALFD fibrosis score correctly ruled out advanced fibrosis in 893 (36%) patients, with 13 false negatives.
The prevalence of advanced fibrosis in individuals undergoing routine first-time bariatric procedures is 3.4%. Use of the NALFD fibrosis score can rule out advanced fibrosis in one-third of this population, and guide surgical decision-making.
Risk factors and prevalence of liver disease in review of 2557 routine liver biopsies performed during bariatric surgery
2019, Surgery for Obesity and Related Diseases
Citation Excerpt :
Stage 2 to 4 fibrosis was found in 7.8%. Our work confirms an association between NAFLD and diabetes and builds on prior studies by showing an association with preoperative laboratory abnormalities, most notably elevated transaminases, an AST to ALT ratio >.8, and reduced HDL [9,16]. As with prior studies in patients undergoing bariatric operations (but unlike the general population), we did not see a significant association with age or BMI in multivariable analysis [8].
Obesity is a known risk factor for nonalcoholic fatty liver disease (NAFLD). However, among individuals undergoing bariatric surgery, the prevalence and risk factors for NAFLD, as well as distinct phenotypes of steatosis, nonalcoholic steatohepatitis (NASH), and fibrosis remain incompletely understood.
To determine the prevalence and risk factors for steatosis, NASH, and fibrosis in individuals undergoing routine bariatric surgery.
Academic medical center in the United States.
Liver wedge biopsies were performed at the time of surgery between 2001 and 2017. Pathology reports were reviewed, and individuals were grouped by NAFLD phenotype. Covariates including demographic characteristics, co-morbidities, and preoperative laboratory values were compared between groups using Student’s t test, Pearson’s χ², and logistic regression.
Liver biopsies were obtained in 97.7% of first-time bariatric procedures, representing 2557 patients. Mean age was 45.6 years, mean body mass index was 46.7, and most were non-Hispanic white (76.1%) and female (71.6%). On histologic review 61.2% had steatosis and 30.9% NASH. Fibrosis was identified in 29.3% of individuals, and 7.8% had stage ≥2 fibrosis. On logistic regression, elevated aspartate aminotransferase (odds ratio [OR] 1.87; P < .001) and elevated alanine aminotransferase (OR 1.62; P < .001) were independently associated with fibrosis. Elevated hemoglobin A1C of 5.7% to 6.5% (OR 1.29; P < .01) and >6.5% (OR 3.23; P < .001) were also associated with fibrosis. A similar trend was seen for NASH.
NASH and/or fibrosis is present in nearly one third of patients undergoing routine bariatric surgery. Risk factors include diabetes, elevated liver enzymes, and diabetes. Risk assessment and aggressive screening should be considered in patients undergoing bariatric surgery.
Nonalcoholic fatty liver disease in patients with different baseline glucose status undergoing bariatric surgery: analysis of intraoperative liver biopsies and literature review
2018, Surgery for Obesity and Related Diseases
Citation Excerpt :
Other authors have reported a high incidence of liver damage in obese patients with NAFLD, which is now considered the hepatic manifestation of the metabolic syndrome [16,25]. According to Ismail [26], patients with diabetes and NAFLD showed a 2.4 times greater risk of mortality compared with diabetics without NAFLD. He suggests that diabetic patients should be routinely evaluated for NAFLD, much like microvascular complications and cardiovascular disease.
Bariatric surgery has been investigated as a treatment option for obese patients with nonalcoholic fatty liver disease (NAFLD). Because patients with NAFLD and type 2 diabetes show accelerated progression from liver disease to cirrhosis, it has been suggested that surgery could be indicated for patients with lower degrees of obesity and type 2 diabetes.
To analyze the degree of tissue damage in liver biopsies obtained from patients undergoing bariatric surgery, correlating histopathologic findings with their baseline glucose status.
General hospital in the public health system.
Intraoperative liver biopsies were obtained from 521 obese patients undergoing bariatric surgery. Patients were divided into 3 study groups according to their preoperative glucose levels: 167 (32.05%) type 2 diabetic, 132 (25.33%) prediabetic, and 222 (42.61%) normoglycemic patients. Tissue samples were classified in accordance with Brunt and Clinical Research Network Nonalcoholic Steatohepatis criteria.
Prevalence of NAFLD was 95%. Higher rates of hepatic fibrosis were observed in diabetic patients (56.4%) compared with prediabetic (29.2%), and normoglycemic patients (28.6%) (P<.001). Nonalcoholic steatohepatitis was diagnosed in 59.4% of the diabetics, in 49.2% of the prediabetics, and in 36% of the normoglycemic obese (P<.001). Only 1.5% of the diabetics had no histologic hepatic alterations.
NAFLD is markedly more severe in diabetic patients. Our data suggest that intraoperative liver biopsy should be considered for diabetic patients undergoing bariatric surgery. Early bariatric surgery should be investigated as a means to prevent progression of NAFLD.
Bisphenol A alters gut microbiome: Comparative metagenomics analysis
2016, Environmental Pollution
Citation Excerpt :
Current evidence shows that alteration of the gut microbiota plays an important role in animal physiology and pathophysiology (Festi et al., 2014; Ojeda et al., 2015). The incidence of metabolic diseases (i.e., obesity, diabetes, and fatty liver) has become highly prevalent globally (Chiang et al., 2011; Ismail, 2011). Although genetic and nutritional factors have been found to be associated with the development of diseases like type 2 diabetes (T2D) and obesity (Casals-Casas and Desvergne, 2011; Rinaudo and Wang, 2011), emerging evidence has included two additional contributing factors: (i) gut microbial communities and (ii) environmental “obesogens” (Alonso-Magdalena et al., 2011) such as bisphenol A (BPA).
Mounting evidence has shown that an alteration of the gut microbiota is associated with diet, and plays an important role in animal health and metabolic diseases. However, little is known about the influence of environmental contaminants on the gut microbial community. Bisphenol A (BPA), which is widely used for manufacturing plastic products, has recently been classified as an environmental obesogen. Although many studies have demonstrated the metabolic-disrupting effects of BPA on liver and pancreatic functions, the possible effects of this synthetic compound on the metabolic diversity of the intestinal microbiota is unknown. Using 16S rRNA gene sequencing analysis on caecum samples of CD-1 mice, the present study aimed to test the hypothesis that dietary BPA intake may influence the gut microbiota composition and functions, an important attributing factor to development of the metabolic syndrome. A high-fat diet (HFD) and high-sucrose diet (HSD) were included as the positive controls for comparing the changes in the intestinal microbial profiles. Our results demonstrated a significant reduction of species diversity in the gut microbiota of BPA-fed mice. Alpha and beta diversity analyses showed that dietary BPA intake led to a similar gut microbial community structure as that induced by HFD and HSD in mice. In addition, comparative analysis of the microbial communities revealed that both BPA and a HFD favored the growth of Proteobacteria, a microbial marker of dysbiosis. Consistently, growth induction of the family Helicobacteraceae and reduction of the Firmicutes and Clostridia populations were observed in the mice fed BPA or a HFD. Collectively, our study highlighted that the effects of dietary BPA intake on the shift of microbial community structure were similar to those of a HFD and HSD, and revealed microbial markers for the development of diseases associated with an unstable microbiota.
Lipid and liver abnormalities in haemoglobin A1c-defined prediabetes and type 2 diabetes
2014, Nutrition, Metabolism and Cardiovascular Diseases
Citation Excerpt :
Moreover, non-alcoholic fatty liver disease (NAFLD) has been shown to be markedly increased in type 2 diabetes [6] – and to a lower extent in prediabetes [7] – diagnosed from plasma glucose measurements. NAFLD is promoted by overweight [6], dyslipidaemia [8], and diabetes [9], and is considered the hepatic expression of the metabolic dysfunctions induced by insulin resistance. The overall mortality in patients with NAFLD is significantly higher than the background population [10].
We aimed to investigate lipid abnormalities and liver steatosis in patients with HbA1c-defined prediabetes and type 2 diabetes compared to individuals with HbA1c-defined normoglycaemia.
Ninety-one subjects with prediabetes according to HbA1c, i.e. from 5.7 to 6.4% (39–46 mmol/mol), 50 newly diagnosed patients with HbA1c-defined type 2 diabetes (HbA1c ≥6.5% [≥48 mmol/mol]), and 67 controls with HbA1c lower than 5.7% (<39 mmol/mol), were studied. Fasting blood samples for lipid profiles, fatty liver index (FLI), bioimpedance analysis, ultrasound scan of the liver, and BARD (body mass index, aspartate aminotransferase/alanine aminotransferase ratio, diabetes) score for evaluation of liver fibrosis, were performed in all subjects. In comparison to controls, subjects with prediabetes were characterised by: lower apolipoprotein AI and HDL cholesterol levels, higher blood pressure, triglycerides levels and apolipoprotein B/apolipoprotein AI ratio, higher FLI, increased prevalence of and more severe hepatic steatosis, similar BARD score, and higher total body fat mass. In comparison to subjects with diabetes, subjects with prediabetes exhibited: similar blood pressure and apolipoprotein B/apolipoprotein AI ratio, similar FLI, reduced prevalence of and less severe hepatic steatosis, lower BARD score, increased percent fat and lower total body muscle mass. In comparison to controls, subjects with diabetes showed: lower apolipoprotein AI and HDL cholesterol levels, higher blood pressure and triglycerides levels, higher FLI, increased prevalence of and more severe hepatic steatosis, higher BARD score, and higher total body muscle mass. Moreover, HbA1c was correlated with BMI, HOMA-IR, triglycerides, HDL cholesterol, AST, and ALT.
Subjects with HbA1c-defined prediabetes and type 2 diabetes, respectively, are characterised by abnormalities in lipid profile and liver steatosis, thus exhibiting a severe risk profile for cardiovascular and liver diseases.
Health-related quality of life and its determinants among South Indian type 2 diabetes patients with and without non-alcoholic fatty liver disease
2023, Egyptian Liver Journal

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Review ArticleNonalcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus: The Hidden Epidemic

Abstract

Section snippets

PATHOGENESIS OF NAFLD/NASH

IR, NAFLD AND DIABETES MELLITUS

DIAGNOSIS OF NAFLD/NASH

TREATMENT OF NAFLD

LONG-TERM OUTCOME OF NAFLD AND T2DM

CONCLUSIONS

Gastroenterology

Gastroenterology

Hepatology

Clin Gastroenterol Hepatol

Hepatology

Gastroenterology

Mod Pathol

Gastroenterology

Hepatology

Am J Gastroenterol

Hepatology

J Hepatol

Clin Gastroenterol Hepatol

Clin Liver Dis

Gastroenterology

Surgery

Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease

Mayo Clin Proc

GI epidemiology: nonalcoholic fatty liver disease

Aliment Pharmacol Ther

Review: nonalcoholic steatohepatitis

J Gastroenterol Hepatol

What are the risk factors and settings for non-alcoholic fatty liver disease in Asia–Pacific?

J Gastroenterol Hepatol

Fatty infiltration of the liver: analysis of prevalence, radiological and clinical features and influence on patient management

Br J Radiol

Pattern of chronic liver disease in the eastern province of Saudi Arabia. A hospital-based clinicopathological study

Trop Geogr Med

Nonalcoholic fatty liver: from steatosis to cirrhosis

Hepatology

Non-alcoholic fatty liver disease, the metabolic syndrome and the risk of cardiovascular disease: the plot thickens

Diabet Med

Abdominal obesity is associated with increased risk of acute coronary events in men

Eur Heart J

Distribution of adipose tissue and risk of cardiovascular disease and death: a 12 year follow up of participants in the population study of women in Gothenburg, Sweden

Br Med J (Clin Res Ed)

The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years

Hepatology

Mechanisms of Disease: hepatic steatosis in type 2 diabetes–pathogenesis and clinical relevance

Nat Clin Pract Endocrinol Metab

Pathogenesis and management issues for non-alcoholic fatty liver disease

World J Gastroenterol

A fresh look at NASH pathogenesis. Part 1: the metabolic movers

J Gastroenterol Hepatol

Pathophysiology of non-alcoholic steatohepatitis

J Clin Gastroenterol

Identification of individuals with insulin resistance using routine clinical measurements

Diabetes

Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man

Diabetologia

Prevalence and predictors of asymptomatic liver disease in patients undergoing gastric bypass surgery

Arch Surg

Review Article
Nonalcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus: The Hidden Epidemic