Grace L. Su, MD

Nonalcoholic fatty liver disease (NALFD) is now the most common chronic liver disease in the developed world and affects about 25% to 30% of adults in the US and 30% of veterans who receive care in the VHA system (Figure 1). 

Comprised of a spectrum of disease severity, NAFLD ranges from simple steatosis to nonalcoholic steatohepatitis ([NASH] steatosis with hepatocyte inflammation, necrosis, and fibrosis). Patients with NALFD have significantly increased mortality because of both hepatic (such as cirrhosis and hepatocellular carcinoma [HCC]) and extrahepatic complications (such as metabolic syndrome [MetS], cardiovascular disease [CVD], and malignancy). In this article, we will focus on the extrahepatic manifestations of NAFLD and its impact on diagnosis and management.

Related: 

NAFLD is significantly associated with the presence of MetS, so much so that it has been considered the hepatic manifestation of MetS. NAFLD also is strongly associated with type 2 diabetes mellitus (T2DM), CVD, chronic kidney disease (CKD), and obstructive sleep apnea (OSA) (Figure 2). 

Although these associations may result from shared risk factors, strong evidence suggests that for some of the factors at least, there is bidirectional influence on the natural history of the other comorbid conditions (Table). 

This means that the management of NAFLD can help improve the management of comorbidities and vice versa. This is important, as the primary cause of mortality in patients with NAFLD, particularly in those without advanced fibrosis or cirrhosis, is related to CVD and extrahepatic malignancy and not from liver disease.

Obesity/Visceral Adiposity

Obesity (body mass index [BMI] > 30) prevalence in the US has almost doubled over the past 30 years and continues to climb.¹ Obesity affects 41% of veterans in the Veterans Health Administration and is the most common risk factor for NAFLD.² NAFLD is 4 times more prevalent in obese patients, thus, it is not surprising that 80% to 90% of patients evaluated in bariatric centers have NAFLD, reported in 2 large series.^3,4 Increased BMI and waist circumference predict the presence of NASH and advanced fibrosis.⁵

While obesity is a hallmark for NAFLD, particularly in the US, it is important to note that up to 20% of Americans with normal BMI have NAFLD, based on findings of steatosis on ultrasound.⁶ These patients with lean NAFLD are often underdiagnosed. In addition to the patient’s BMI, it is important to recognize that in NAFLD, the distribution and type of fat deposition is more important than just BMI. Visceral fat refers to fat accumulation within the abdominal cavity and is key to the pathogenesis of NAFLD. Visceral fat, compared with subcutaneous fat, is metabolically active and can deliver an overabundance of free fatty acids to the liver as well as secrete proinflammatory mediators in the setting of insulin resistance. Visceral fat stores can predict increased hepatic fat content, inflammation, and fibrosis.⁵ Thus, it is important to recognize that those patients with relatively more visceral fat are more prone to NAFLD. The best clinical indicator of visceral adiposity is abdominal obesity, indicated by waist circumference > 40 inches in men and > 35 inches in women.

 

Metabolic Syndrome

Hepatic fat deposition can be associated with or precede MetS. MetS is defined as having at least 3 of the following characteristics: abdominal obesity, elevated triglycerides (TGs) (≥ 150 mg/dL), reduced high-density lipoprotein cholesterol (< 40 mg/dL in men or < 50 mg/dL in women), elevated blood pressure (BP) (systolic BP ≥ 130 mm Hg or diastolic BP ≥ 85 mm Hg), or elevated fasting glucose (≥ 110 mg/dL). Population studies have found that 50% of patients with MetS have NAFLD, and liver fat content is strongly correlated with the number of MetS features present in an individual.^5,7 In addition to this association, NAFLD also promotes the development of MetS. Increased energy intake relative to energy expenditure will facilitate ectopic fat accumulation in the liver, which then increases hepatic gluconeogenesis and drives the pathogenesis of insulin resistance.⁸ Therefore, the presence of NAFLD is both a marker and a promotor of insulin resistance and its complications.

Related: 

Type 2 Diabetes Mellitus

At 70% to 75%, the prevalence of NAFLD in patients with T2DM is more than twice as high as that in the general US adult population. Conversely, about 23% of patients with NAFLD also have T2DM.⁹

Influence of NAFLD on T2DM

Patients with ultrasound-based evidence of NAFLD are 2 to 5 times more likely to develop T2DM after adjusting for lifestyle and metabolic risk factors in multiple epidemiologic studies.^10,11 The severity of hepaticfat content measured by ultrasound also is associated with an increasing risk of T2DM incidence over the next 5 years (normal,7%; mild, 9.8%; moderate-severe, 17.8%; P < .001).¹² In another study, 58% of patientswith biopsy-proven NAFLD developed T2DM after a mean follow-up of 13.7 years.¹³ Those who were found to have NASH had a 3-fold higher risk of developing T2DM than did those with simple steatosis. This finding was confirmed in another study where T2DM incidence was 2 times higher in patients predicted to have advanced fibrosis compared with those who did not.¹⁴

Because liver steatosis interferes with insulin-induced glycogen production and suppression of gluconeogenesis, hepatic fat content predicts the insulin dose required for adequate glucose control in patients with diabetes mellitus (DM) and NAFLD.¹⁵ Higher levels of insulin are required in patients with DM and NAFLD compared with those without NAFLD.⁵ 

Furthermore, patients with DM and NAFLD have increased complications, including both retinopathy and CKD.⁵ It is thus not surprising that a population-based study of more than 330 patients with T2DM found that the presence of NAFLD was associated with a 2-fold increase in all-cause mortality over a mean follow-up period of 11 years.¹⁶

Additionally, a 10-year cohort study found that resolution of ultrasound-based NAFLD in patients without baseline T2DM, was associated with a reduced T2DM incidence (multivariate odds ratio [OR] 0.27, 95% CI, 0.12-0.61) after controlling for factors such as age, BMI, and impaired fasting glucose.^11,17

Given this close relationship between T2DM and NAFLD, both the American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of Liver Diseases (EASL) guidelines recommend that patients found to have NAFLD should be screened for the presence of impaired fasting glucose/T2DM by testing hemoglobin A_1c or fasting glucose levels.^18,19 Recognizing the role that NAFLD can play in patients with DM also is important, as improving hepatic steatosis may also improve DM.

 

Influence of DM on NAFLD

Patients with T2DM and NAFLD are at increased risk of progressive liver disease and have increased rates of NASH, cirrhosis, and HCC. In a paired-biopsy study, the development of T2DM was the strongest predictor of progression of NASH and hepatic fibrosis.²⁰ This fibrosis progression can easily go undetected, as NASH can be present even with normal aminotransferases. This increased risk of fibrosis progression in the setting of comorbid T2DM is clinically important, as it is the severity of fibrosis that predicts all-cause and liver-related mortality in patients with NAFLD/NASH.^21,22 In fact, the prevalence of biopsy-proven NASH in overweight/obese patients with DM with normal liver aminotransferases (defined as aspartate aminotransferase and alanine aminotransferase < 40 U/L) was found to be 58%.²³ Because chronic liver disease, including NAFLD, is underrecognized in the “healthy population” used to establish normal aminotransferase levels, more recent AASLD and ACG guidelines now define normal aminotransferase levels as < 35 U/L for males and < 25 U/L for females.²⁴ These stricter cutoffs are based on populations with normal BMI and negative testing for chronic liver diseases.²⁴ The lower cutoffs may improve recognition of progressive liver disease in NAFLD and NASH patients.

Medications used in the treatment of T2DM, such as metformin, pioglitazone, and liraglutide, have been studied in patients with biopsy-proven NASH. The initial data showing histologic improvement in NAFLD patients taking metformin was more likely related to the associated weight loss in the treatment group. In a study by Loomba and colleagues the improvement in the NAFLD activity score was only seen in patients who lost ≥ 5% of their total body weight.²⁵ Pioglitazone is a PPAR-γ agonist that helps regulate glucose and lipid metabolism as well as inflammation. Pioglitazone helps adipose tissue, hepatocytes, and muscle cells restore insulin sensitivity. A recent trial in 100 patients with prediabetes or T2DM as well as NASH showed that 36 weeks of pioglitazone treatment was associated with significant improvements in steatosis, inflammation, and most important, in stage of fibrosis compared with that of placebo.²⁶

Related: 

Glucagon-like peptide-1 (GLP-1) receptor agonists, such as liraglutide, have effects on lipid and glucose metabolism as well. They can lower glucose levels by increasing insulin secretion, reducing glucagon concentration, suppressing appetite (resulting in weight loss), and increasing sensitivity to insulin in hepatocytes and adipocytes. Liraglutide has been studied in patients with NASH both with and without DM, and results of the largest study to date show that it is associated with significant improvement in hepatic inflammation compared with that of placebo.²⁷ Additional phase 3 clinical trials are currently underway.

Current AASLD guidelines do not recommend routine screening for NAFLD, even among high-risk patients, such as patients with DM.¹⁸ This is due to the widespread prevalence of NAFLD, the unclear utility of diagnostic tests, and limited efficacy of available treatment. Lifestyle modification to achieve weight loss remains the backbone of management, and rates of successful adherence are low.²⁸ Contrary to this, EASL guidelines state that NAFLD screening with ultrasound even in patients with normal liver enzymes should be performed in high-risk patients with T2DM.¹⁹

Once detected, T2DM should be diligently treated in patients with NAFLD, and pioglitazone may be considered in patients with biopsy-proven NASH per AASLD guidelines.¹⁸ Pioglitazone has been studied in patients with biopsy-proven NASH both with and without DM and has been associated with significant resolution of NASH, as well as improvement in histologic changes of NASH and improvement in fibrosis.^29,30 Because of potential medication AEs, including a mean weight gain of 2.5 kg to 4.7 kg in trials of 12- to 36-months’ duration, as well as potential bone loss in women, discussions about the risks and benefits of treatment should occur prior to treatment initiation.¹⁸ Additionally, pioglitazone is not safe in the setting of left ventricular heart failure. Future studies may point to the utility of other DM medications, such as GLP-receptor agonists.

 

Cardiovascular Disease

Given the association between features of MetS and NAFLD, it is not surprising that the primary cause of death in patients with NAFLD is related to CVD.^21,22,31 However, it is increasingly recognized that NAFLD predicts CVD independently of the traditional risk factors associated with MetS. The increase in cardiovascular risk in the setting of NAFLD can be partly explained by the increased hepatic de novo lipogenesis that is associated with increased production of highly atherogenic small dense low-density lipoproteins (sd-LDL) independent of BMI and presence of insulin resistance.³² Additionally, increased intracellular free fatty acids can activate proinflammatory cytokine production by hepatocytes in addition to the increase in systemic inflammatory mediators and oxidative stress associated with NASH.

A recent meta-analysis of 27 studies confirmed the association between NAFLD and many subclinical features of CVD, including increases in coronary-artery calcium score, carotid artery intimal media thickness, and arterial wall stiffness, as well as impaired flow-mediated vasodilation after controlling for classic CVD risk factors.³³ The risk of subclinical carotid and coronary atherosclerosis progression was higher in NAFLD patients with evidence of advanced fibrosis using noninvasive measures. Additionally, NAFLD was associated with increased severity of coronary artery disease in > 600 patients undergoing cardiac angiograms.³⁴ Conversely, the regression of NAFLD on ultrasound was associated with a decreased risk of carotid atherosclerosis progression.³⁵

Multiple epidemiologic studies have found an increased incidence of clinically overt CVD in patients with NAFLD after controlling for confounders. The largest updated meta-analysis, which included more than 34,000 patients with 2,600 CVD outcomes over a median of 6.9 years found that the presence of NAFLD (based on imaging or biopsy) was associated with an odds ratio (OR) of 1.64 (95% CI, 1.26-2.13) for fatal and nonfatal incident CVD.³⁶ In the same meta-analysis, patients with NASH, with or without fibrosis, were at an even higher risk, with an OR of 2.58 (95% CI, 1.78-3.75).

Initial studies of statin medications for the treatment of NASH using surrogate endpoints like improvement in aminotransferases or imaging, suggested a potential liver-related benefit. However, there was no histologic improvement in the single study comparing 12 months of simvastatin therapy with placebo in patients with NASH.³⁷ Although it is unclear whether statin use will directly improve NAFLD, there is no evidence to suggest that statin use should be avoided in patients with elevated CVD risk.³⁸ Treatment with atorvastatin has been shown to be associated with a greater reduction in cardiovascular events in patients with NAFLD compared with that of patients without NAFLD.³⁹

The strong association between CVD and NAFLD has important clinical implications that may influence the decision to initiate treatment for primary prevention, including lipid-lowering, antihypertensive, or antiplatelet therapies. The clinical algorithms currently used to help risk stratify patients and determine appropriate preventative strategies, the Framingham risk equation or the systemic coronary risk evaluation, do not incorporate NAFLD as a potential risk factor for CVD. Additional studies are needed to determine whether adding NAFLD to the assessment will improve the predictive accuracy of future CVD events. Nevertheless, European clinical guidelines recommend performing a CVD risk assessment for patients with NAFLD.¹⁹

 

Chronic Kidney Disease

The prevalence of CKD, defined as estimated glomerular filtration rate (GFR) < 60 mL/min/1.72 m², abnormal albuminuria, or proteinuria, is significantly increased in patients with NAFLD. Several epidemiologic studies have shown the prevalence of CKD in NAFLD patients ranges from 20% to 55% compared with 5% to 30% among patients without NAFLD.⁴⁰ Overall, patients with NAFLD have a 2-fold increased risk of prevalent (OR 2.12; 95% CI, 1.69-2.66) or incident (hazard ratio 1.79; 95% CI, 1.65-1.95) CKD, even after adjusting for T2DM, visceral fat, and insulin resistance.⁴⁰ There is an additional 2-fold increase in CKD risk in patients with NASH and advanced fibrosis compared with those with NASH and mild/no fibrosis. Additionally, advancing NASH fibrosis stage is independently associated with worsening stage of CKD.⁴¹

Data regarding the exact mechanism of kidney pathology in the setting of NAFLD is lacking. The accelerated atherogenesis in NAFLD likely contributes to renal damage. Another potential mechanism to explain the association between NASH and CKD involves the increased activation of the angiotensin-aldosterone system (RAAS) seen in NASH, which leads to increased hepatic fibrogenesis as well as kidney damage.⁴²

Similar to the previously listed comorbidities, there is evidence that improvement in NAFLD can lead to improvements in renal disease. A prospective study of NASH patients undergoing 52 weeks of lifestyle modification found that the patients who had improvements in histologic NASH endpoints also had improvement in renal function.⁴³

There are currently no specific recommendations on screening for CKD in professionalguidelines, but many experts propose monitoring for CKD yearly with serum creatinine and urinalysis and referring to nephrology if needed. Given the association between NASH and activation of the RAAS pathway that is associated with worsening hepatic fibrosis, RAAS-inhibitors should be a first-line agent in the treatment of hypertension in patients with NAFLD.

Obstructive Sleep Apnea

OSA is characterized by repeated pharyngeal collapse during sleep, which leads to chronic intermittent hypoxia and is associated with increased metabolic and cardiovascular morbidity and mortality. The cycle of intermittent hypoxia and reoxygenation in OSA results in inflammation and oxidative stress. Multiple studies have supported a link between NAFLD and OSA.

Hepatic fat content on ultrasound was increased in patients with OSA independent of BMI. There also has been evidence of a positive association between the severity of chronic intermittent hypoxia and increased hepatic fibrosis based on liver elastography.⁴⁴ A meta-analysis using histologic NAFLD diagnosis showed that the presence of OSA was associated with a higher risk of fibrosis compared with that of patients with NAFLD without OSA (OR 2.6; 95% CI, 1.3-5.2).⁴⁵

Based on animal models, hypoxia can drive fat accumulation and inflammation in the liver via multiple different pathways. Hypoxia can increase fasting glucose and systemic TG levels and induce hepatic lipogenesis by altering gene expression.⁴⁵ Hypoxia also can increase oxidative stress and reduce β-oxidation, which leads to the production of lipotoxic lipids. These hypoxia-induced changes are typically more pronounced in subjects with obesity compared with that in subjects without obesity. Despite multiple adverse metabolic effects of OSA-induced hypoxia in the setting of NAFLD, preliminary, short-term studies have failed to find an association with OSA treatment with continuous positive airway pressure and improvement in NAFLD.⁴⁵ Perhaps larger, long-term prospective trials will clarify this question.

 

Malignancy

Extrahepatic malignancy (colon, esophagus, stomach, pancreas, kidney, and breast) is the second most common cause of death in patients with NAFLD.^21,22 The primary association between NAFLD and malignancy is found in the colon. Most large population-based studies have been performed in East Asia and have found that NAFLD is associated with a 1.5 to 1.7-fold increased risk for colonic adenomas and a 1.9 to 3.1-fold increased risk of colorectal cancer.^46-49 Using magnetic resonance spectroscopy and liver biopsy to diagnose NAFLD and NASH, respectively, Wong and colleagues found that NASH, but not simple steatosis, is associated with a higher risk of advanced colorectalneoplasia (OR 5.34; 95% CI, 1.9-14.8), after adjusting for age, gender, BMI, family history, smoking, and T2DM.⁵⁰

Data showing a definitive causative role of NAFLD in the development of colorectal cancer are lacking, but the presence of increased insulin levels has many potential effects on carcinogenesis in general, including stimulation of cell proliferation and apoptosis. Currently, there are no recommended changes to the standard colorectal cancer screening recommendations specifically for patients with NAFLD.

Conclusion

NAFLD is a multisystem disease that is associated with increased liver-related and all-cause mortality. Data on the close association between NAFLD and several extrahepatic complications, including MetS, T2DM, CVD, CKD, and malignancy are well established. There also is growing evidence of a bidirectional relationship between some of these diagnoses, whereas NAFLD is not only a consequence, but also a cause of MetS, T2DM, and CKD independent of other typical risk factors.

Given the multiple comorbidities associated with NAFLD and its potential to influence the severity of these diagnoses, management of these complex patients requires diligence and a multidisciplinary approach. In order to engage in early recognition and intervention to prevent potential morbidity and mortality, regular screening and surveillance for the development of NAFLD in patients with metabolic risk factors can be considered, and careful screening for metabolic complications in patients with established NAFLD is important.

Nonalcoholic fatty liver disease (NALFD) is now the most common chronic liver disease in the developed world and affects about 25% to 30% of adults in the US and 30% of veterans who receive care in the VHA system (Figure 1). 

Comprised of a spectrum of disease severity, NAFLD ranges from simple steatosis to nonalcoholic steatohepatitis ([NASH] steatosis with hepatocyte inflammation, necrosis, and fibrosis). Patients with NALFD have significantly increased mortality because of both hepatic (such as cirrhosis and hepatocellular carcinoma [HCC]) and extrahepatic complications (such as metabolic syndrome [MetS], cardiovascular disease [CVD], and malignancy). In this article, we will focus on the extrahepatic manifestations of NAFLD and its impact on diagnosis and management.

Related: 

NAFLD is significantly associated with the presence of MetS, so much so that it has been considered the hepatic manifestation of MetS. NAFLD also is strongly associated with type 2 diabetes mellitus (T2DM), CVD, chronic kidney disease (CKD), and obstructive sleep apnea (OSA) (Figure 2). 

Although these associations may result from shared risk factors, strong evidence suggests that for some of the factors at least, there is bidirectional influence on the natural history of the other comorbid conditions (Table). 

This means that the management of NAFLD can help improve the management of comorbidities and vice versa. This is important, as the primary cause of mortality in patients with NAFLD, particularly in those without advanced fibrosis or cirrhosis, is related to CVD and extrahepatic malignancy and not from liver disease.

Obesity/Visceral Adiposity

Obesity (body mass index [BMI] > 30) prevalence in the US has almost doubled over the past 30 years and continues to climb.¹ Obesity affects 41% of veterans in the Veterans Health Administration and is the most common risk factor for NAFLD.² NAFLD is 4 times more prevalent in obese patients, thus, it is not surprising that 80% to 90% of patients evaluated in bariatric centers have NAFLD, reported in 2 large series.^3,4 Increased BMI and waist circumference predict the presence of NASH and advanced fibrosis.⁵

While obesity is a hallmark for NAFLD, particularly in the US, it is important to note that up to 20% of Americans with normal BMI have NAFLD, based on findings of steatosis on ultrasound.⁶ These patients with lean NAFLD are often underdiagnosed. In addition to the patient’s BMI, it is important to recognize that in NAFLD, the distribution and type of fat deposition is more important than just BMI. Visceral fat refers to fat accumulation within the abdominal cavity and is key to the pathogenesis of NAFLD. Visceral fat, compared with subcutaneous fat, is metabolically active and can deliver an overabundance of free fatty acids to the liver as well as secrete proinflammatory mediators in the setting of insulin resistance. Visceral fat stores can predict increased hepatic fat content, inflammation, and fibrosis.⁵ Thus, it is important to recognize that those patients with relatively more visceral fat are more prone to NAFLD. The best clinical indicator of visceral adiposity is abdominal obesity, indicated by waist circumference > 40 inches in men and > 35 inches in women.

 

Metabolic Syndrome

Hepatic fat deposition can be associated with or precede MetS. MetS is defined as having at least 3 of the following characteristics: abdominal obesity, elevated triglycerides (TGs) (≥ 150 mg/dL), reduced high-density lipoprotein cholesterol (< 40 mg/dL in men or < 50 mg/dL in women), elevated blood pressure (BP) (systolic BP ≥ 130 mm Hg or diastolic BP ≥ 85 mm Hg), or elevated fasting glucose (≥ 110 mg/dL). Population studies have found that 50% of patients with MetS have NAFLD, and liver fat content is strongly correlated with the number of MetS features present in an individual.^5,7 In addition to this association, NAFLD also promotes the development of MetS. Increased energy intake relative to energy expenditure will facilitate ectopic fat accumulation in the liver, which then increases hepatic gluconeogenesis and drives the pathogenesis of insulin resistance.⁸ Therefore, the presence of NAFLD is both a marker and a promotor of insulin resistance and its complications.

Related: 

Type 2 Diabetes Mellitus

At 70% to 75%, the prevalence of NAFLD in patients with T2DM is more than twice as high as that in the general US adult population. Conversely, about 23% of patients with NAFLD also have T2DM.⁹

Influence of NAFLD on T2DM

Patients with ultrasound-based evidence of NAFLD are 2 to 5 times more likely to develop T2DM after adjusting for lifestyle and metabolic risk factors in multiple epidemiologic studies.^10,11 The severity of hepaticfat content measured by ultrasound also is associated with an increasing risk of T2DM incidence over the next 5 years (normal,7%; mild, 9.8%; moderate-severe, 17.8%; P < .001).¹² In another study, 58% of patientswith biopsy-proven NAFLD developed T2DM after a mean follow-up of 13.7 years.¹³ Those who were found to have NASH had a 3-fold higher risk of developing T2DM than did those with simple steatosis. This finding was confirmed in another study where T2DM incidence was 2 times higher in patients predicted to have advanced fibrosis compared with those who did not.¹⁴

Because liver steatosis interferes with insulin-induced glycogen production and suppression of gluconeogenesis, hepatic fat content predicts the insulin dose required for adequate glucose control in patients with diabetes mellitus (DM) and NAFLD.¹⁵ Higher levels of insulin are required in patients with DM and NAFLD compared with those without NAFLD.⁵ 

Furthermore, patients with DM and NAFLD have increased complications, including both retinopathy and CKD.⁵ It is thus not surprising that a population-based study of more than 330 patients with T2DM found that the presence of NAFLD was associated with a 2-fold increase in all-cause mortality over a mean follow-up period of 11 years.¹⁶

Additionally, a 10-year cohort study found that resolution of ultrasound-based NAFLD in patients without baseline T2DM, was associated with a reduced T2DM incidence (multivariate odds ratio [OR] 0.27, 95% CI, 0.12-0.61) after controlling for factors such as age, BMI, and impaired fasting glucose.^11,17

Given this close relationship between T2DM and NAFLD, both the American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of Liver Diseases (EASL) guidelines recommend that patients found to have NAFLD should be screened for the presence of impaired fasting glucose/T2DM by testing hemoglobin A_1c or fasting glucose levels.^18,19 Recognizing the role that NAFLD can play in patients with DM also is important, as improving hepatic steatosis may also improve DM.

 

Influence of DM on NAFLD

Patients with T2DM and NAFLD are at increased risk of progressive liver disease and have increased rates of NASH, cirrhosis, and HCC. In a paired-biopsy study, the development of T2DM was the strongest predictor of progression of NASH and hepatic fibrosis.²⁰ This fibrosis progression can easily go undetected, as NASH can be present even with normal aminotransferases. This increased risk of fibrosis progression in the setting of comorbid T2DM is clinically important, as it is the severity of fibrosis that predicts all-cause and liver-related mortality in patients with NAFLD/NASH.^21,22 In fact, the prevalence of biopsy-proven NASH in overweight/obese patients with DM with normal liver aminotransferases (defined as aspartate aminotransferase and alanine aminotransferase < 40 U/L) was found to be 58%.²³ Because chronic liver disease, including NAFLD, is underrecognized in the “healthy population” used to establish normal aminotransferase levels, more recent AASLD and ACG guidelines now define normal aminotransferase levels as < 35 U/L for males and < 25 U/L for females.²⁴ These stricter cutoffs are based on populations with normal BMI and negative testing for chronic liver diseases.²⁴ The lower cutoffs may improve recognition of progressive liver disease in NAFLD and NASH patients.

Medications used in the treatment of T2DM, such as metformin, pioglitazone, and liraglutide, have been studied in patients with biopsy-proven NASH. The initial data showing histologic improvement in NAFLD patients taking metformin was more likely related to the associated weight loss in the treatment group. In a study by Loomba and colleagues the improvement in the NAFLD activity score was only seen in patients who lost ≥ 5% of their total body weight.²⁵ Pioglitazone is a PPAR-γ agonist that helps regulate glucose and lipid metabolism as well as inflammation. Pioglitazone helps adipose tissue, hepatocytes, and muscle cells restore insulin sensitivity. A recent trial in 100 patients with prediabetes or T2DM as well as NASH showed that 36 weeks of pioglitazone treatment was associated with significant improvements in steatosis, inflammation, and most important, in stage of fibrosis compared with that of placebo.²⁶

Related: 

Glucagon-like peptide-1 (GLP-1) receptor agonists, such as liraglutide, have effects on lipid and glucose metabolism as well. They can lower glucose levels by increasing insulin secretion, reducing glucagon concentration, suppressing appetite (resulting in weight loss), and increasing sensitivity to insulin in hepatocytes and adipocytes. Liraglutide has been studied in patients with NASH both with and without DM, and results of the largest study to date show that it is associated with significant improvement in hepatic inflammation compared with that of placebo.²⁷ Additional phase 3 clinical trials are currently underway.

Current AASLD guidelines do not recommend routine screening for NAFLD, even among high-risk patients, such as patients with DM.¹⁸ This is due to the widespread prevalence of NAFLD, the unclear utility of diagnostic tests, and limited efficacy of available treatment. Lifestyle modification to achieve weight loss remains the backbone of management, and rates of successful adherence are low.²⁸ Contrary to this, EASL guidelines state that NAFLD screening with ultrasound even in patients with normal liver enzymes should be performed in high-risk patients with T2DM.¹⁹

Once detected, T2DM should be diligently treated in patients with NAFLD, and pioglitazone may be considered in patients with biopsy-proven NASH per AASLD guidelines.¹⁸ Pioglitazone has been studied in patients with biopsy-proven NASH both with and without DM and has been associated with significant resolution of NASH, as well as improvement in histologic changes of NASH and improvement in fibrosis.^29,30 Because of potential medication AEs, including a mean weight gain of 2.5 kg to 4.7 kg in trials of 12- to 36-months’ duration, as well as potential bone loss in women, discussions about the risks and benefits of treatment should occur prior to treatment initiation.¹⁸ Additionally, pioglitazone is not safe in the setting of left ventricular heart failure. Future studies may point to the utility of other DM medications, such as GLP-receptor agonists.

 

Cardiovascular Disease

Given the association between features of MetS and NAFLD, it is not surprising that the primary cause of death in patients with NAFLD is related to CVD.^21,22,31 However, it is increasingly recognized that NAFLD predicts CVD independently of the traditional risk factors associated with MetS. The increase in cardiovascular risk in the setting of NAFLD can be partly explained by the increased hepatic de novo lipogenesis that is associated with increased production of highly atherogenic small dense low-density lipoproteins (sd-LDL) independent of BMI and presence of insulin resistance.³² Additionally, increased intracellular free fatty acids can activate proinflammatory cytokine production by hepatocytes in addition to the increase in systemic inflammatory mediators and oxidative stress associated with NASH.

A recent meta-analysis of 27 studies confirmed the association between NAFLD and many subclinical features of CVD, including increases in coronary-artery calcium score, carotid artery intimal media thickness, and arterial wall stiffness, as well as impaired flow-mediated vasodilation after controlling for classic CVD risk factors.³³ The risk of subclinical carotid and coronary atherosclerosis progression was higher in NAFLD patients with evidence of advanced fibrosis using noninvasive measures. Additionally, NAFLD was associated with increased severity of coronary artery disease in > 600 patients undergoing cardiac angiograms.³⁴ Conversely, the regression of NAFLD on ultrasound was associated with a decreased risk of carotid atherosclerosis progression.³⁵

Multiple epidemiologic studies have found an increased incidence of clinically overt CVD in patients with NAFLD after controlling for confounders. The largest updated meta-analysis, which included more than 34,000 patients with 2,600 CVD outcomes over a median of 6.9 years found that the presence of NAFLD (based on imaging or biopsy) was associated with an odds ratio (OR) of 1.64 (95% CI, 1.26-2.13) for fatal and nonfatal incident CVD.³⁶ In the same meta-analysis, patients with NASH, with or without fibrosis, were at an even higher risk, with an OR of 2.58 (95% CI, 1.78-3.75).

Initial studies of statin medications for the treatment of NASH using surrogate endpoints like improvement in aminotransferases or imaging, suggested a potential liver-related benefit. However, there was no histologic improvement in the single study comparing 12 months of simvastatin therapy with placebo in patients with NASH.³⁷ Although it is unclear whether statin use will directly improve NAFLD, there is no evidence to suggest that statin use should be avoided in patients with elevated CVD risk.³⁸ Treatment with atorvastatin has been shown to be associated with a greater reduction in cardiovascular events in patients with NAFLD compared with that of patients without NAFLD.³⁹

The strong association between CVD and NAFLD has important clinical implications that may influence the decision to initiate treatment for primary prevention, including lipid-lowering, antihypertensive, or antiplatelet therapies. The clinical algorithms currently used to help risk stratify patients and determine appropriate preventative strategies, the Framingham risk equation or the systemic coronary risk evaluation, do not incorporate NAFLD as a potential risk factor for CVD. Additional studies are needed to determine whether adding NAFLD to the assessment will improve the predictive accuracy of future CVD events. Nevertheless, European clinical guidelines recommend performing a CVD risk assessment for patients with NAFLD.¹⁹

 

Chronic Kidney Disease

The prevalence of CKD, defined as estimated glomerular filtration rate (GFR) < 60 mL/min/1.72 m², abnormal albuminuria, or proteinuria, is significantly increased in patients with NAFLD. Several epidemiologic studies have shown the prevalence of CKD in NAFLD patients ranges from 20% to 55% compared with 5% to 30% among patients without NAFLD.⁴⁰ Overall, patients with NAFLD have a 2-fold increased risk of prevalent (OR 2.12; 95% CI, 1.69-2.66) or incident (hazard ratio 1.79; 95% CI, 1.65-1.95) CKD, even after adjusting for T2DM, visceral fat, and insulin resistance.⁴⁰ There is an additional 2-fold increase in CKD risk in patients with NASH and advanced fibrosis compared with those with NASH and mild/no fibrosis. Additionally, advancing NASH fibrosis stage is independently associated with worsening stage of CKD.⁴¹

Data regarding the exact mechanism of kidney pathology in the setting of NAFLD is lacking. The accelerated atherogenesis in NAFLD likely contributes to renal damage. Another potential mechanism to explain the association between NASH and CKD involves the increased activation of the angiotensin-aldosterone system (RAAS) seen in NASH, which leads to increased hepatic fibrogenesis as well as kidney damage.⁴²

Similar to the previously listed comorbidities, there is evidence that improvement in NAFLD can lead to improvements in renal disease. A prospective study of NASH patients undergoing 52 weeks of lifestyle modification found that the patients who had improvements in histologic NASH endpoints also had improvement in renal function.⁴³

There are currently no specific recommendations on screening for CKD in professionalguidelines, but many experts propose monitoring for CKD yearly with serum creatinine and urinalysis and referring to nephrology if needed. Given the association between NASH and activation of the RAAS pathway that is associated with worsening hepatic fibrosis, RAAS-inhibitors should be a first-line agent in the treatment of hypertension in patients with NAFLD.

Obstructive Sleep Apnea

OSA is characterized by repeated pharyngeal collapse during sleep, which leads to chronic intermittent hypoxia and is associated with increased metabolic and cardiovascular morbidity and mortality. The cycle of intermittent hypoxia and reoxygenation in OSA results in inflammation and oxidative stress. Multiple studies have supported a link between NAFLD and OSA.

Hepatic fat content on ultrasound was increased in patients with OSA independent of BMI. There also has been evidence of a positive association between the severity of chronic intermittent hypoxia and increased hepatic fibrosis based on liver elastography.⁴⁴ A meta-analysis using histologic NAFLD diagnosis showed that the presence of OSA was associated with a higher risk of fibrosis compared with that of patients with NAFLD without OSA (OR 2.6; 95% CI, 1.3-5.2).⁴⁵

Based on animal models, hypoxia can drive fat accumulation and inflammation in the liver via multiple different pathways. Hypoxia can increase fasting glucose and systemic TG levels and induce hepatic lipogenesis by altering gene expression.⁴⁵ Hypoxia also can increase oxidative stress and reduce β-oxidation, which leads to the production of lipotoxic lipids. These hypoxia-induced changes are typically more pronounced in subjects with obesity compared with that in subjects without obesity. Despite multiple adverse metabolic effects of OSA-induced hypoxia in the setting of NAFLD, preliminary, short-term studies have failed to find an association with OSA treatment with continuous positive airway pressure and improvement in NAFLD.⁴⁵ Perhaps larger, long-term prospective trials will clarify this question.

 

Malignancy

Extrahepatic malignancy (colon, esophagus, stomach, pancreas, kidney, and breast) is the second most common cause of death in patients with NAFLD.^21,22 The primary association between NAFLD and malignancy is found in the colon. Most large population-based studies have been performed in East Asia and have found that NAFLD is associated with a 1.5 to 1.7-fold increased risk for colonic adenomas and a 1.9 to 3.1-fold increased risk of colorectal cancer.^46-49 Using magnetic resonance spectroscopy and liver biopsy to diagnose NAFLD and NASH, respectively, Wong and colleagues found that NASH, but not simple steatosis, is associated with a higher risk of advanced colorectalneoplasia (OR 5.34; 95% CI, 1.9-14.8), after adjusting for age, gender, BMI, family history, smoking, and T2DM.⁵⁰

Data showing a definitive causative role of NAFLD in the development of colorectal cancer are lacking, but the presence of increased insulin levels has many potential effects on carcinogenesis in general, including stimulation of cell proliferation and apoptosis. Currently, there are no recommended changes to the standard colorectal cancer screening recommendations specifically for patients with NAFLD.

Conclusion

NAFLD is a multisystem disease that is associated with increased liver-related and all-cause mortality. Data on the close association between NAFLD and several extrahepatic complications, including MetS, T2DM, CVD, CKD, and malignancy are well established. There also is growing evidence of a bidirectional relationship between some of these diagnoses, whereas NAFLD is not only a consequence, but also a cause of MetS, T2DM, and CKD independent of other typical risk factors.

Given the multiple comorbidities associated with NAFLD and its potential to influence the severity of these diagnoses, management of these complex patients requires diligence and a multidisciplinary approach. In order to engage in early recognition and intervention to prevent potential morbidity and mortality, regular screening and surveillance for the development of NAFLD in patients with metabolic risk factors can be considered, and careful screening for metabolic complications in patients with established NAFLD is important.

Nonalcoholic fatty liver disease (NALFD) is now the most common chronic liver disease in the developed world and affects about 25% to 30% of adults in the US and 30% of veterans who receive care in the VHA system (Figure 1). 

Comprised of a spectrum of disease severity, NAFLD ranges from simple steatosis to nonalcoholic steatohepatitis ([NASH] steatosis with hepatocyte inflammation, necrosis, and fibrosis). Patients with NALFD have significantly increased mortality because of both hepatic (such as cirrhosis and hepatocellular carcinoma [HCC]) and extrahepatic complications (such as metabolic syndrome [MetS], cardiovascular disease [CVD], and malignancy). In this article, we will focus on the extrahepatic manifestations of NAFLD and its impact on diagnosis and management.

Related: 

NAFLD is significantly associated with the presence of MetS, so much so that it has been considered the hepatic manifestation of MetS. NAFLD also is strongly associated with type 2 diabetes mellitus (T2DM), CVD, chronic kidney disease (CKD), and obstructive sleep apnea (OSA) (Figure 2). 

Although these associations may result from shared risk factors, strong evidence suggests that for some of the factors at least, there is bidirectional influence on the natural history of the other comorbid conditions (Table). 

This means that the management of NAFLD can help improve the management of comorbidities and vice versa. This is important, as the primary cause of mortality in patients with NAFLD, particularly in those without advanced fibrosis or cirrhosis, is related to CVD and extrahepatic malignancy and not from liver disease.

Obesity/Visceral Adiposity

Obesity (body mass index [BMI] > 30) prevalence in the US has almost doubled over the past 30 years and continues to climb.¹ Obesity affects 41% of veterans in the Veterans Health Administration and is the most common risk factor for NAFLD.² NAFLD is 4 times more prevalent in obese patients, thus, it is not surprising that 80% to 90% of patients evaluated in bariatric centers have NAFLD, reported in 2 large series.^3,4 Increased BMI and waist circumference predict the presence of NASH and advanced fibrosis.⁵

While obesity is a hallmark for NAFLD, particularly in the US, it is important to note that up to 20% of Americans with normal BMI have NAFLD, based on findings of steatosis on ultrasound.⁶ These patients with lean NAFLD are often underdiagnosed. In addition to the patient’s BMI, it is important to recognize that in NAFLD, the distribution and type of fat deposition is more important than just BMI. Visceral fat refers to fat accumulation within the abdominal cavity and is key to the pathogenesis of NAFLD. Visceral fat, compared with subcutaneous fat, is metabolically active and can deliver an overabundance of free fatty acids to the liver as well as secrete proinflammatory mediators in the setting of insulin resistance. Visceral fat stores can predict increased hepatic fat content, inflammation, and fibrosis.⁵ Thus, it is important to recognize that those patients with relatively more visceral fat are more prone to NAFLD. The best clinical indicator of visceral adiposity is abdominal obesity, indicated by waist circumference > 40 inches in men and > 35 inches in women.

 

Metabolic Syndrome

Hepatic fat deposition can be associated with or precede MetS. MetS is defined as having at least 3 of the following characteristics: abdominal obesity, elevated triglycerides (TGs) (≥ 150 mg/dL), reduced high-density lipoprotein cholesterol (< 40 mg/dL in men or < 50 mg/dL in women), elevated blood pressure (BP) (systolic BP ≥ 130 mm Hg or diastolic BP ≥ 85 mm Hg), or elevated fasting glucose (≥ 110 mg/dL). Population studies have found that 50% of patients with MetS have NAFLD, and liver fat content is strongly correlated with the number of MetS features present in an individual.^5,7 In addition to this association, NAFLD also promotes the development of MetS. Increased energy intake relative to energy expenditure will facilitate ectopic fat accumulation in the liver, which then increases hepatic gluconeogenesis and drives the pathogenesis of insulin resistance.⁸ Therefore, the presence of NAFLD is both a marker and a promotor of insulin resistance and its complications.

Related: 

Type 2 Diabetes Mellitus

At 70% to 75%, the prevalence of NAFLD in patients with T2DM is more than twice as high as that in the general US adult population. Conversely, about 23% of patients with NAFLD also have T2DM.⁹

Influence of NAFLD on T2DM

Patients with ultrasound-based evidence of NAFLD are 2 to 5 times more likely to develop T2DM after adjusting for lifestyle and metabolic risk factors in multiple epidemiologic studies.^10,11 The severity of hepaticfat content measured by ultrasound also is associated with an increasing risk of T2DM incidence over the next 5 years (normal,7%; mild, 9.8%; moderate-severe, 17.8%; P < .001).¹² In another study, 58% of patientswith biopsy-proven NAFLD developed T2DM after a mean follow-up of 13.7 years.¹³ Those who were found to have NASH had a 3-fold higher risk of developing T2DM than did those with simple steatosis. This finding was confirmed in another study where T2DM incidence was 2 times higher in patients predicted to have advanced fibrosis compared with those who did not.¹⁴

Because liver steatosis interferes with insulin-induced glycogen production and suppression of gluconeogenesis, hepatic fat content predicts the insulin dose required for adequate glucose control in patients with diabetes mellitus (DM) and NAFLD.¹⁵ Higher levels of insulin are required in patients with DM and NAFLD compared with those without NAFLD.⁵ 

Furthermore, patients with DM and NAFLD have increased complications, including both retinopathy and CKD.⁵ It is thus not surprising that a population-based study of more than 330 patients with T2DM found that the presence of NAFLD was associated with a 2-fold increase in all-cause mortality over a mean follow-up period of 11 years.¹⁶

Additionally, a 10-year cohort study found that resolution of ultrasound-based NAFLD in patients without baseline T2DM, was associated with a reduced T2DM incidence (multivariate odds ratio [OR] 0.27, 95% CI, 0.12-0.61) after controlling for factors such as age, BMI, and impaired fasting glucose.^11,17

Given this close relationship between T2DM and NAFLD, both the American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of Liver Diseases (EASL) guidelines recommend that patients found to have NAFLD should be screened for the presence of impaired fasting glucose/T2DM by testing hemoglobin A_1c or fasting glucose levels.^18,19 Recognizing the role that NAFLD can play in patients with DM also is important, as improving hepatic steatosis may also improve DM.

 

Influence of DM on NAFLD

Patients with T2DM and NAFLD are at increased risk of progressive liver disease and have increased rates of NASH, cirrhosis, and HCC. In a paired-biopsy study, the development of T2DM was the strongest predictor of progression of NASH and hepatic fibrosis.²⁰ This fibrosis progression can easily go undetected, as NASH can be present even with normal aminotransferases. This increased risk of fibrosis progression in the setting of comorbid T2DM is clinically important, as it is the severity of fibrosis that predicts all-cause and liver-related mortality in patients with NAFLD/NASH.^21,22 In fact, the prevalence of biopsy-proven NASH in overweight/obese patients with DM with normal liver aminotransferases (defined as aspartate aminotransferase and alanine aminotransferase < 40 U/L) was found to be 58%.²³ Because chronic liver disease, including NAFLD, is underrecognized in the “healthy population” used to establish normal aminotransferase levels, more recent AASLD and ACG guidelines now define normal aminotransferase levels as < 35 U/L for males and < 25 U/L for females.²⁴ These stricter cutoffs are based on populations with normal BMI and negative testing for chronic liver diseases.²⁴ The lower cutoffs may improve recognition of progressive liver disease in NAFLD and NASH patients.

Medications used in the treatment of T2DM, such as metformin, pioglitazone, and liraglutide, have been studied in patients with biopsy-proven NASH. The initial data showing histologic improvement in NAFLD patients taking metformin was more likely related to the associated weight loss in the treatment group. In a study by Loomba and colleagues the improvement in the NAFLD activity score was only seen in patients who lost ≥ 5% of their total body weight.²⁵ Pioglitazone is a PPAR-γ agonist that helps regulate glucose and lipid metabolism as well as inflammation. Pioglitazone helps adipose tissue, hepatocytes, and muscle cells restore insulin sensitivity. A recent trial in 100 patients with prediabetes or T2DM as well as NASH showed that 36 weeks of pioglitazone treatment was associated with significant improvements in steatosis, inflammation, and most important, in stage of fibrosis compared with that of placebo.²⁶

Related: 

Glucagon-like peptide-1 (GLP-1) receptor agonists, such as liraglutide, have effects on lipid and glucose metabolism as well. They can lower glucose levels by increasing insulin secretion, reducing glucagon concentration, suppressing appetite (resulting in weight loss), and increasing sensitivity to insulin in hepatocytes and adipocytes. Liraglutide has been studied in patients with NASH both with and without DM, and results of the largest study to date show that it is associated with significant improvement in hepatic inflammation compared with that of placebo.²⁷ Additional phase 3 clinical trials are currently underway.

Current AASLD guidelines do not recommend routine screening for NAFLD, even among high-risk patients, such as patients with DM.¹⁸ This is due to the widespread prevalence of NAFLD, the unclear utility of diagnostic tests, and limited efficacy of available treatment. Lifestyle modification to achieve weight loss remains the backbone of management, and rates of successful adherence are low.²⁸ Contrary to this, EASL guidelines state that NAFLD screening with ultrasound even in patients with normal liver enzymes should be performed in high-risk patients with T2DM.¹⁹

Once detected, T2DM should be diligently treated in patients with NAFLD, and pioglitazone may be considered in patients with biopsy-proven NASH per AASLD guidelines.¹⁸ Pioglitazone has been studied in patients with biopsy-proven NASH both with and without DM and has been associated with significant resolution of NASH, as well as improvement in histologic changes of NASH and improvement in fibrosis.^29,30 Because of potential medication AEs, including a mean weight gain of 2.5 kg to 4.7 kg in trials of 12- to 36-months’ duration, as well as potential bone loss in women, discussions about the risks and benefits of treatment should occur prior to treatment initiation.¹⁸ Additionally, pioglitazone is not safe in the setting of left ventricular heart failure. Future studies may point to the utility of other DM medications, such as GLP-receptor agonists.

 

Cardiovascular Disease

Given the association between features of MetS and NAFLD, it is not surprising that the primary cause of death in patients with NAFLD is related to CVD.^21,22,31 However, it is increasingly recognized that NAFLD predicts CVD independently of the traditional risk factors associated with MetS. The increase in cardiovascular risk in the setting of NAFLD can be partly explained by the increased hepatic de novo lipogenesis that is associated with increased production of highly atherogenic small dense low-density lipoproteins (sd-LDL) independent of BMI and presence of insulin resistance.³² Additionally, increased intracellular free fatty acids can activate proinflammatory cytokine production by hepatocytes in addition to the increase in systemic inflammatory mediators and oxidative stress associated with NASH.

A recent meta-analysis of 27 studies confirmed the association between NAFLD and many subclinical features of CVD, including increases in coronary-artery calcium score, carotid artery intimal media thickness, and arterial wall stiffness, as well as impaired flow-mediated vasodilation after controlling for classic CVD risk factors.³³ The risk of subclinical carotid and coronary atherosclerosis progression was higher in NAFLD patients with evidence of advanced fibrosis using noninvasive measures. Additionally, NAFLD was associated with increased severity of coronary artery disease in > 600 patients undergoing cardiac angiograms.³⁴ Conversely, the regression of NAFLD on ultrasound was associated with a decreased risk of carotid atherosclerosis progression.³⁵

Multiple epidemiologic studies have found an increased incidence of clinically overt CVD in patients with NAFLD after controlling for confounders. The largest updated meta-analysis, which included more than 34,000 patients with 2,600 CVD outcomes over a median of 6.9 years found that the presence of NAFLD (based on imaging or biopsy) was associated with an odds ratio (OR) of 1.64 (95% CI, 1.26-2.13) for fatal and nonfatal incident CVD.³⁶ In the same meta-analysis, patients with NASH, with or without fibrosis, were at an even higher risk, with an OR of 2.58 (95% CI, 1.78-3.75).

Initial studies of statin medications for the treatment of NASH using surrogate endpoints like improvement in aminotransferases or imaging, suggested a potential liver-related benefit. However, there was no histologic improvement in the single study comparing 12 months of simvastatin therapy with placebo in patients with NASH.³⁷ Although it is unclear whether statin use will directly improve NAFLD, there is no evidence to suggest that statin use should be avoided in patients with elevated CVD risk.³⁸ Treatment with atorvastatin has been shown to be associated with a greater reduction in cardiovascular events in patients with NAFLD compared with that of patients without NAFLD.³⁹

The strong association between CVD and NAFLD has important clinical implications that may influence the decision to initiate treatment for primary prevention, including lipid-lowering, antihypertensive, or antiplatelet therapies. The clinical algorithms currently used to help risk stratify patients and determine appropriate preventative strategies, the Framingham risk equation or the systemic coronary risk evaluation, do not incorporate NAFLD as a potential risk factor for CVD. Additional studies are needed to determine whether adding NAFLD to the assessment will improve the predictive accuracy of future CVD events. Nevertheless, European clinical guidelines recommend performing a CVD risk assessment for patients with NAFLD.¹⁹

 

Chronic Kidney Disease

The prevalence of CKD, defined as estimated glomerular filtration rate (GFR) < 60 mL/min/1.72 m², abnormal albuminuria, or proteinuria, is significantly increased in patients with NAFLD. Several epidemiologic studies have shown the prevalence of CKD in NAFLD patients ranges from 20% to 55% compared with 5% to 30% among patients without NAFLD.⁴⁰ Overall, patients with NAFLD have a 2-fold increased risk of prevalent (OR 2.12; 95% CI, 1.69-2.66) or incident (hazard ratio 1.79; 95% CI, 1.65-1.95) CKD, even after adjusting for T2DM, visceral fat, and insulin resistance.⁴⁰ There is an additional 2-fold increase in CKD risk in patients with NASH and advanced fibrosis compared with those with NASH and mild/no fibrosis. Additionally, advancing NASH fibrosis stage is independently associated with worsening stage of CKD.⁴¹

Data regarding the exact mechanism of kidney pathology in the setting of NAFLD is lacking. The accelerated atherogenesis in NAFLD likely contributes to renal damage. Another potential mechanism to explain the association between NASH and CKD involves the increased activation of the angiotensin-aldosterone system (RAAS) seen in NASH, which leads to increased hepatic fibrogenesis as well as kidney damage.⁴²

Similar to the previously listed comorbidities, there is evidence that improvement in NAFLD can lead to improvements in renal disease. A prospective study of NASH patients undergoing 52 weeks of lifestyle modification found that the patients who had improvements in histologic NASH endpoints also had improvement in renal function.⁴³

There are currently no specific recommendations on screening for CKD in professionalguidelines, but many experts propose monitoring for CKD yearly with serum creatinine and urinalysis and referring to nephrology if needed. Given the association between NASH and activation of the RAAS pathway that is associated with worsening hepatic fibrosis, RAAS-inhibitors should be a first-line agent in the treatment of hypertension in patients with NAFLD.

Obstructive Sleep Apnea

OSA is characterized by repeated pharyngeal collapse during sleep, which leads to chronic intermittent hypoxia and is associated with increased metabolic and cardiovascular morbidity and mortality. The cycle of intermittent hypoxia and reoxygenation in OSA results in inflammation and oxidative stress. Multiple studies have supported a link between NAFLD and OSA.

Hepatic fat content on ultrasound was increased in patients with OSA independent of BMI. There also has been evidence of a positive association between the severity of chronic intermittent hypoxia and increased hepatic fibrosis based on liver elastography.⁴⁴ A meta-analysis using histologic NAFLD diagnosis showed that the presence of OSA was associated with a higher risk of fibrosis compared with that of patients with NAFLD without OSA (OR 2.6; 95% CI, 1.3-5.2).⁴⁵

Based on animal models, hypoxia can drive fat accumulation and inflammation in the liver via multiple different pathways. Hypoxia can increase fasting glucose and systemic TG levels and induce hepatic lipogenesis by altering gene expression.⁴⁵ Hypoxia also can increase oxidative stress and reduce β-oxidation, which leads to the production of lipotoxic lipids. These hypoxia-induced changes are typically more pronounced in subjects with obesity compared with that in subjects without obesity. Despite multiple adverse metabolic effects of OSA-induced hypoxia in the setting of NAFLD, preliminary, short-term studies have failed to find an association with OSA treatment with continuous positive airway pressure and improvement in NAFLD.⁴⁵ Perhaps larger, long-term prospective trials will clarify this question.

 

Malignancy

Extrahepatic malignancy (colon, esophagus, stomach, pancreas, kidney, and breast) is the second most common cause of death in patients with NAFLD.^21,22 The primary association between NAFLD and malignancy is found in the colon. Most large population-based studies have been performed in East Asia and have found that NAFLD is associated with a 1.5 to 1.7-fold increased risk for colonic adenomas and a 1.9 to 3.1-fold increased risk of colorectal cancer.^46-49 Using magnetic resonance spectroscopy and liver biopsy to diagnose NAFLD and NASH, respectively, Wong and colleagues found that NASH, but not simple steatosis, is associated with a higher risk of advanced colorectalneoplasia (OR 5.34; 95% CI, 1.9-14.8), after adjusting for age, gender, BMI, family history, smoking, and T2DM.⁵⁰

Data showing a definitive causative role of NAFLD in the development of colorectal cancer are lacking, but the presence of increased insulin levels has many potential effects on carcinogenesis in general, including stimulation of cell proliferation and apoptosis. Currently, there are no recommended changes to the standard colorectal cancer screening recommendations specifically for patients with NAFLD.

Conclusion

NAFLD is a multisystem disease that is associated with increased liver-related and all-cause mortality. Data on the close association between NAFLD and several extrahepatic complications, including MetS, T2DM, CVD, CKD, and malignancy are well established. There also is growing evidence of a bidirectional relationship between some of these diagnoses, whereas NAFLD is not only a consequence, but also a cause of MetS, T2DM, and CKD independent of other typical risk factors.

Given the multiple comorbidities associated with NAFLD and its potential to influence the severity of these diagnoses, management of these complex patients requires diligence and a multidisciplinary approach. In order to engage in early recognition and intervention to prevent potential morbidity and mortality, regular screening and surveillance for the development of NAFLD in patients with metabolic risk factors can be considered, and careful screening for metabolic complications in patients with established NAFLD is important.

Nonalcoholic fatty liver disease (NAFLD) is a silent epidemic affecting nearly 1 in 3 Americans and is increasing within the Veterans Health Administration (VHA).^1,2 NAFLD independently increases the risk of type 2 diabetes mellitus (T2DM), cardiovascular disease, chronic kidney disease, cirrhosis, liver cancer, and death and impairs health-related quality of life (QOL).³ NAFLD primarily affects those with metabolic risk factors (prediabetes, T2DM, and metabolic syndrome) or obesity (Figure 1).^4,5 

In the US, 1 in 3 adults have prediabetes and 1 in 10 have T2DM (increasing to 1 in 4 aged ≥ 65 years).⁶ Among veterans, obesity affects 31% within 6 years postdeployment and 41% overall who receive VHA care.^7,8 Other patient characteristics associated with higher rates of NAFLD include Hispanic ethnicity and older age.^9-11

Among those with NAFLD, most have nonalcoholic fatty liver (NAFL), or simple steatosis, affecting > 5% of liver cells (Figure 2).¹² 

However, 25% to 30% exhibit nonalcoholic steatohepatitis (NASH), with steatosis, inflammation, hepatocyte injury, and often alanine aminotransferase (ALT) elevations.¹³About 4% of patients progress to cirrhosis and/or hepatocellular carcinoma (HCC) on 7- to 15-year follow-up (with 9% cirrhosis or end-stage liver disease rates in 1 recent study with up to 23-year follow-up).^1,14

In most patients (80%), NAFLD progresses slowly over decades. The progression is related to continuing insulin resistance.^15,16 Greater disease progression is seen in patients with T2DM or concomitant chronic liver disease (such as hepatitis C).^10,11,16 Patients with NAFLD who develop advanced fibrosis or cirrhosis experience increased rates of overall mortality, liver-related events, and liver transplantation.^1,9,17,18 Within the VHA, NAFLD is the third most common cause of cirrhosis and HCC, occurring at an average age of 66 and 70 years, respectively.¹⁹Less commonly, HCC also can occur in NAFLD without cirrhosis.²⁰

Although no pharmaceuticals are yet approved to treat NAFLD, even modest weight loss is beneficial. For example, weight loss > 4% improves fatty liver, ≥ 7% improves liver inflammation, and ≥ 10% decreases liver fibrosis (or scarring).^21-23 In patients with a prior lack of success with weight loss, weight loss medications may be beneficial for short-term use.²⁴ When comparing the effects of diet, exercise, obesity pharmacotherapy, and combinations for these approaches, intensive lifestyle modification with exercise had the greatest, most enduring benefit.²⁵ Additionally, bariatric (weight loss) surgery has significantly improved health and liver-related outcomes for patients with NASH.²⁶

In at-risk veterans, NAFLD has myriad negative effects on health and QOL. To improve its early identification and management in the VHA, we summarize strategies that all providers can use to screen and treat patients for this condition.

Screening for Advanced Fibrosis

Advanced fibrosis in NAFLD is diagnosed by analyzing adequately sized liver biopsies.^27,28 However, noninvasive approaches to quantify advanced fibrosis by imaging or use of a simple fibrosis prediction score also are available. Imaging modalities include measuring liver stiffness, using transient elastography (FibroScan, Waltham, MA) or magnetic resonance elastography.^1,29-31 Fibrosis prediction scores use common clinical and laboratory data to predict the presence or absence of advanced fibrosis (Table 1).²⁹ 

Of these, the fibrosis-4 (FIB-4) index requires only ALT, aspartate aminotransferase (AST), platelet count, and age to calculate the score and performs similarly to the NAFLD fibrosis score.^32-35 FIB-4 and the NAFLD fibrosis score are validated in ethnically diverse populations, recommended in evidence-based guidelines, and can be calculated using online calculators (eg, FIB-4).^11,16,33 The easily summed BARD score also detects NAFLD advanced fibrosis yet incorrectly identified advanced fibrosis in many patients without liver biopsy evidence of advanced fibrosis in a recent VHA study.^36,37 With increasing VHA rates of NAFLD, these scores are a simple way to identify patients with probable advanced fibrosis who may benefit from hepatology or gastroenterology consultation.²

 

Does This Patient Have NAFLD?

To identify NAFLD, patients with metabolic syndrome and modest or no alcohol use are first assessed for liver injury with ALT, AST, and complete blood count (Figure 3; Case 1).¹⁶ 

Among patients presenting with incidental liver enzyme elevations to primary care, NAFLD was the most common cause.³⁸

Next, common underlying liver diseases that cause liver injury should be excluded by hepatitis B and C virus serology.^11,16 Other underlying liver diseases are uncommon and should be assessed only if clinically indicated. 

After excluding secondary causes of fatty liver (eg, drugs causing steatosis, parenteral nutrition, severe malnutrition, etc), NAFLD is likely, particularly in those displaying fatty liver or steatosis on liver imaging (Table 2).^11,16

Evaluation of fasting glucose or hemoglobin A_1c (HbA_1c)can identify undiagnosed T2DM. NAFL, or simple steatosis, is independently associated with an increased risk of T2DM, cardiovascular and kidney disease, yet not overall mortality.¹⁶ Over 10 to 20 years, few patients (4%) with simple steatosis progress to cirrhosis.³⁹In contrast, NAFLD advanced fibrosis significantly increases overall and liver-related mortality and can be assessed with high probability by calculating the patient’s FIB-4, even in those with normal liver enzymes.^11,16 Patients with highly probable advanced fibrosis merit evaluation by hepatology or gastroenterology (Figure 3).

In NAFLD, simple steatosis can resolve, and NASH can significantly improve with 7% to 10% weight loss.^16,23,40 Patients with simple steatosis on imaging and normal liver enzymes should be monitored with periodic liver enzymes and fibrosis prediction scores (eg, FIB-4) and encouraged to pursue intensive lifestyle intervention.^16,33 Without weight loss and exercise interventions metabolic syndrome, T2DM, and NAFLD may progress.

Patients with combined liver steatosis and liver enzyme elevations may exhibit NASH and warrant an evaluation by a hepatologist or gastroenterologist for consideration of additional testing or liver biopsy.¹⁶While ALT elevations often have been used as a marker of NASH, ALT can be normal in NASH and in advanced fibrosis.^41,42 A liver biopsy is required to establish the diagnosis of NASH, which progresses to cirrhosis in 15% to 20% over a 10- to 20-year follow-up period (Case 2).³⁹ Fibrosis prediction scores also can evaluate the probability of advanced fibrosis in these patients.

Encouraging Patients to Pursue Intensive Lifestyle InterventionS

Most veterans wish to collaborate in their care (Table 3, Figure 4) yet experience many barriers, such as low health literacy, high rates of comorbidities, and ongoing drug/alcohol misuse.^43,44 

  To motivate patients to action to prevent the progression of NAFLD, patients must understand how it affects the development of T2DM, cardiovascular disease, and liver disease and the value of the intervention.  To enhance disease understanding, the VHA provides a simple 2-page patient information sheet about NAFLD and its treatment.⁴⁵ A 2-page pictorial patient education handout on NAFLD and its treatment is available as well (eAppendix)

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In addition to patient education, motivational interviewing significantly improves weight loss, resulting in a 3.3 lb (1.5 kg) increased weight loss in the intervention group vs the control group in weight loss studies.⁴⁶By being supportive, empathic, and clearly sharing the rationale for change, motivational interviewing is a collaborative conversation to guide patients to strengthen their motivation and commitment to change.⁴⁷ It helps patients examine and address their ambivalence—most recognize they should exercise and lose weight, but it can be difficult.

To start the conversation, the health care provider can explain that NAFLD increases the risk of T2DM, heart disease, and liver injury or scarring and can be effectively treated (or improved) with modest weight loss and regular exercise (ie, 14 lb weight loss if 200 lb, or 21 lb weight loss if 300 lb). Exercise can start with a 5-minute walk and build to 30 minutes daily). Then, the provider can ask the following 4 questions:

 

1. Why would you want to lose weight and exercise?
2. How might you go about it in order to succeed?
3. What are the 3 best reasons for you to do it?
4. How important is it for you to make this change, and why? The provider can also ask the patient to quantify on a scale of 1 to 10: (a) How likely is it that they will make each required change? (b) How hard will each change be for them?
5. The provider then summarizes the patient’s reasons for wanting change, how he/she can effect change, what their best reasons are, and how to successfully change. The provider then asks a final question:
6. So what do you think you will do?

Most patients report feeling engaged, empowered, open, and understood with motivational interviewing. People are “persuaded by what they hear themselves say,” increasing motivation to change.⁴⁷

This personalized action plan facilitates successful health behavior change.⁴⁸ Action plans should integrate daily routines. For example, by placing the scale near the toothbrush, daily weighing is encouraged. Daily weighing is associated with significantly greater weight loss and less weight regain.⁴⁹ In a 6-month, randomized controlled weight loss trial in men and women, daily weighing (using a scale that automatically transmitted weight data), with weekly e-mails and tailored feedback yielded an overall 9% weight loss and increased use of exercise and diet behaviors associated with weight loss in comparison with those who weighed themselves less than weekly.⁵⁰ This simple daily measure seems to reinforce a patient’s action plan.

Adherence to an action plan significantly improves with patient education, peer or social support, and addressing barriers to adherence.⁵¹ For example, by providing support with weekly text messaging of “How are you?” and addressing the issues that patients reported in a large randomized treatment trial, adherence was significantly improved.⁵² In VHA patients with low health literacy, peer support or telephone coaching also has proven effective in increasing weight loss and glycemic control in patients with T2DM.^53,54 Providing multidisciplinary team support during intensive lifestyle intervention, providers can partner with patients to address questions or issues and applaud progress.

Effective VHA interventions

In an ethnically diverse population of patients with prediabetes, up to 7% weight loss was observed in the Diabetes Prevention Program (DPP).⁵⁵ In this study patients were randomized to placebo; metformin 850 mg twice daily; or a lifestyle-modification program in which they received one-on-one culturally sensitive, individualized lessons in diet, moderate exercise (≥ 150 minutes weekly), and behavior modification from case managers over 16 sessions. Lessons were reinforced in both group and individual sessions. This intervention was associated with an average of 6% weight loss at 6 months (half of participants attained 7% weight loss) and a 58% decrease in the rate of progression to T2DM over a nearly 3-year follow-up of this population with prediabetes compared with that of the placebo group.⁵⁵ Over a 15-year follow-up, the intensive lifestyle intervention group sustained a 27% decrease in the incidence of T2DM compared with that of the placebo group.⁵⁶ To emulate the success of the DPP in the VHA, a web-based DPP-like study in female veterans was performed with online coaching and daily weighing. This study achieved a 5.2% weight loss from baseline at 4 months.⁵⁷

 

To improve outcomes, the VHA MOVE! Weight Management Program has been revised to include more sustained intervention (16 sessions) and multiple modes for participating—in person, by telephone, via video, via MOVE! Coach phone app, or any combination.⁵⁸ Using shared decision making between patients with NAFLD and their providers, a customized MOVE! weight loss program can be developed to enable sustained intensive lifestyle intervention: hypocaloric diet, ≥ 150 minutes of moderate exercise weekly, and behavioral change.

In addition to intensive lifestyle intervention, a prospective study found that bariatric surgery significantly improved outcomes in patients with NASH, with most patients experiencing resolution of their NASH and nearly half exhibiting significantly improved fibrosis.²⁶ In the VHA, bariatric surgery has yielded excellent long-term outcomes, with 21% sustained weight loss from baseline (vs matched nonsurgical population) at 10 years postoperatively in patients undergoing Roux-en-Y gastric bypass.⁵⁹ Bariatric surgery also results in long-term remission of T2DM in most patients and significant improvement in hypertension and dyslipidemia.⁶⁰ The risks of bariatric surgery include 3% serious complications, 1% reoperation rates, and 0.4% 30-day mortality.^61,62 Bariatric surgery can be considered in patients with BMI > 40 or in patients with BMI > 35 who have comorbidities and do not have decompensated cirrhosis.^63,64

Beyond weight loss, more favorable liver-related outcomes and lower rates of advanced liver fibrosis are observed in those consuming filtered coffee; a reduction in liver steatosis also is observed with adherence to a Mediterranean diet.^65,66 In NAFLD, statins may improve liver chemistries and fibrosis; this class of medications can be used safely even in the presence of an elevated ALT.^11,67As a risk factor for chronic liver disease, alcohol consumption of ≥ 4 drinks per day or > 14 drinks per week for men or > 7 drinks per week for women should be avoided in patients with NAFLD.¹¹

Conclusion

Nonalcoholic fatty liver disease independently increases the risk of T2DM, cardiovascular disease and kidney disease. With its rates increasing in the VHA, earlier identification and intervention is warranted in patients at high risk (ie, those with metabolic syndrome, obesity, and T2DM).² 

In patients with metabolic syndrome and modest or no alcohol use, NAFLD can be identified by the presence of fatty liver on imaging in those in whom liver enzymes are measured and hepatitis B and C virus and secondary causes of fatty liver are excluded (aligning with the European Association of the Study of Liver Disease simple algorithm).¹⁶

NASH is more frequent in those with liver enzyme elevations or with an elevated FIB-4 and is associated with a long-term risk of cirrhosis. These patients merit referral to hepatology or gastroenterology for further evaluation and consideration of a liver biopsy to identify NASH. Patients with likely NAFLD without liver enzyme elevations can be further evaluated with FIB-4 scores to assess their probability of advanced liver fibrosis and potential need for referral to hepatology or gastroenterology.

Early NAFLD detection and intervention with intensive lifestyle modifications has the potential to avert progression to advanced fibrosis—and its associated increased overall and liver-related mortality, and impaired QOL.^3,16,18  Although FIB-4 is a validated predictor of advanced fibrosis, this score is not yet used nationally to identify and risk stratify NAFLD in the VHA. Additionally, the very low use of VHA diet/exercise programs in eligible patients contributes to NAFLD progression.⁶⁸ The cost-effective DPP has successfully yielded weight loss in patients with prediabetes and decreases in the incidence of T2DM through motivational interviewing and intensive lifestyle intervention.⁵⁵ 

By revising MOVE!, the VHA has enhanced its intensive lifestyle intervention program.

To improve NAFLD management, providers can successfully engage patients through motivational interviewing for intensive lifestyle intervention. Their resulting weight loss is enhanced with a personalized action plan, daily weighing, and peer support. When NAFLD is identified in patients with metabolic risk factors, the probability of advanced fibrosis is easily assessed in those with elevated FIB-4 scores who merit gastrointestinal referral.^33,37

In all those identified with NAFLD, disease information should be provided to patients and their families. Intensive lifestyle modification targeting a ≥ 7% weight loss is recommended; motivational interviewing can increase commitment to change and yield a customized action plan for sustained weight loss. Working with the support and encouragement of their team of primary care providers, dieticians, and MOVE! coaches, patients can actively engage to improve their NAFLD and overall health.

Nonalcoholic fatty liver disease (NAFLD) is a silent epidemic affecting nearly 1 in 3 Americans and is increasing within the Veterans Health Administration (VHA).^1,2 NAFLD independently increases the risk of type 2 diabetes mellitus (T2DM), cardiovascular disease, chronic kidney disease, cirrhosis, liver cancer, and death and impairs health-related quality of life (QOL).³ NAFLD primarily affects those with metabolic risk factors (prediabetes, T2DM, and metabolic syndrome) or obesity (Figure 1).^4,5 

In the US, 1 in 3 adults have prediabetes and 1 in 10 have T2DM (increasing to 1 in 4 aged ≥ 65 years).⁶ Among veterans, obesity affects 31% within 6 years postdeployment and 41% overall who receive VHA care.^7,8 Other patient characteristics associated with higher rates of NAFLD include Hispanic ethnicity and older age.^9-11

Among those with NAFLD, most have nonalcoholic fatty liver (NAFL), or simple steatosis, affecting > 5% of liver cells (Figure 2).¹² 

However, 25% to 30% exhibit nonalcoholic steatohepatitis (NASH), with steatosis, inflammation, hepatocyte injury, and often alanine aminotransferase (ALT) elevations.¹³About 4% of patients progress to cirrhosis and/or hepatocellular carcinoma (HCC) on 7- to 15-year follow-up (with 9% cirrhosis or end-stage liver disease rates in 1 recent study with up to 23-year follow-up).^1,14

In most patients (80%), NAFLD progresses slowly over decades. The progression is related to continuing insulin resistance.^15,16 Greater disease progression is seen in patients with T2DM or concomitant chronic liver disease (such as hepatitis C).^10,11,16 Patients with NAFLD who develop advanced fibrosis or cirrhosis experience increased rates of overall mortality, liver-related events, and liver transplantation.^1,9,17,18 Within the VHA, NAFLD is the third most common cause of cirrhosis and HCC, occurring at an average age of 66 and 70 years, respectively.¹⁹Less commonly, HCC also can occur in NAFLD without cirrhosis.²⁰

Although no pharmaceuticals are yet approved to treat NAFLD, even modest weight loss is beneficial. For example, weight loss > 4% improves fatty liver, ≥ 7% improves liver inflammation, and ≥ 10% decreases liver fibrosis (or scarring).^21-23 In patients with a prior lack of success with weight loss, weight loss medications may be beneficial for short-term use.²⁴ When comparing the effects of diet, exercise, obesity pharmacotherapy, and combinations for these approaches, intensive lifestyle modification with exercise had the greatest, most enduring benefit.²⁵ Additionally, bariatric (weight loss) surgery has significantly improved health and liver-related outcomes for patients with NASH.²⁶

In at-risk veterans, NAFLD has myriad negative effects on health and QOL. To improve its early identification and management in the VHA, we summarize strategies that all providers can use to screen and treat patients for this condition.

Screening for Advanced Fibrosis

Advanced fibrosis in NAFLD is diagnosed by analyzing adequately sized liver biopsies.^27,28 However, noninvasive approaches to quantify advanced fibrosis by imaging or use of a simple fibrosis prediction score also are available. Imaging modalities include measuring liver stiffness, using transient elastography (FibroScan, Waltham, MA) or magnetic resonance elastography.^1,29-31 Fibrosis prediction scores use common clinical and laboratory data to predict the presence or absence of advanced fibrosis (Table 1).²⁹ 

Of these, the fibrosis-4 (FIB-4) index requires only ALT, aspartate aminotransferase (AST), platelet count, and age to calculate the score and performs similarly to the NAFLD fibrosis score.^32-35 FIB-4 and the NAFLD fibrosis score are validated in ethnically diverse populations, recommended in evidence-based guidelines, and can be calculated using online calculators (eg, FIB-4).^11,16,33 The easily summed BARD score also detects NAFLD advanced fibrosis yet incorrectly identified advanced fibrosis in many patients without liver biopsy evidence of advanced fibrosis in a recent VHA study.^36,37 With increasing VHA rates of NAFLD, these scores are a simple way to identify patients with probable advanced fibrosis who may benefit from hepatology or gastroenterology consultation.²

 

Does This Patient Have NAFLD?

To identify NAFLD, patients with metabolic syndrome and modest or no alcohol use are first assessed for liver injury with ALT, AST, and complete blood count (Figure 3; Case 1).¹⁶ 

Among patients presenting with incidental liver enzyme elevations to primary care, NAFLD was the most common cause.³⁸

Next, common underlying liver diseases that cause liver injury should be excluded by hepatitis B and C virus serology.^11,16 Other underlying liver diseases are uncommon and should be assessed only if clinically indicated. 

After excluding secondary causes of fatty liver (eg, drugs causing steatosis, parenteral nutrition, severe malnutrition, etc), NAFLD is likely, particularly in those displaying fatty liver or steatosis on liver imaging (Table 2).^11,16

Evaluation of fasting glucose or hemoglobin A_1c (HbA_1c)can identify undiagnosed T2DM. NAFL, or simple steatosis, is independently associated with an increased risk of T2DM, cardiovascular and kidney disease, yet not overall mortality.¹⁶ Over 10 to 20 years, few patients (4%) with simple steatosis progress to cirrhosis.³⁹In contrast, NAFLD advanced fibrosis significantly increases overall and liver-related mortality and can be assessed with high probability by calculating the patient’s FIB-4, even in those with normal liver enzymes.^11,16 Patients with highly probable advanced fibrosis merit evaluation by hepatology or gastroenterology (Figure 3).

In NAFLD, simple steatosis can resolve, and NASH can significantly improve with 7% to 10% weight loss.^16,23,40 Patients with simple steatosis on imaging and normal liver enzymes should be monitored with periodic liver enzymes and fibrosis prediction scores (eg, FIB-4) and encouraged to pursue intensive lifestyle intervention.^16,33 Without weight loss and exercise interventions metabolic syndrome, T2DM, and NAFLD may progress.

Patients with combined liver steatosis and liver enzyme elevations may exhibit NASH and warrant an evaluation by a hepatologist or gastroenterologist for consideration of additional testing or liver biopsy.¹⁶While ALT elevations often have been used as a marker of NASH, ALT can be normal in NASH and in advanced fibrosis.^41,42 A liver biopsy is required to establish the diagnosis of NASH, which progresses to cirrhosis in 15% to 20% over a 10- to 20-year follow-up period (Case 2).³⁹ Fibrosis prediction scores also can evaluate the probability of advanced fibrosis in these patients.

Encouraging Patients to Pursue Intensive Lifestyle InterventionS

Most veterans wish to collaborate in their care (Table 3, Figure 4) yet experience many barriers, such as low health literacy, high rates of comorbidities, and ongoing drug/alcohol misuse.^43,44 

  To motivate patients to action to prevent the progression of NAFLD, patients must understand how it affects the development of T2DM, cardiovascular disease, and liver disease and the value of the intervention.  To enhance disease understanding, the VHA provides a simple 2-page patient information sheet about NAFLD and its treatment.⁴⁵ A 2-page pictorial patient education handout on NAFLD and its treatment is available as well (eAppendix)

Document

hunt_0119_e_appendix.pdf

Media Folder

FedPrac

.

In addition to patient education, motivational interviewing significantly improves weight loss, resulting in a 3.3 lb (1.5 kg) increased weight loss in the intervention group vs the control group in weight loss studies.⁴⁶By being supportive, empathic, and clearly sharing the rationale for change, motivational interviewing is a collaborative conversation to guide patients to strengthen their motivation and commitment to change.⁴⁷ It helps patients examine and address their ambivalence—most recognize they should exercise and lose weight, but it can be difficult.

To start the conversation, the health care provider can explain that NAFLD increases the risk of T2DM, heart disease, and liver injury or scarring and can be effectively treated (or improved) with modest weight loss and regular exercise (ie, 14 lb weight loss if 200 lb, or 21 lb weight loss if 300 lb). Exercise can start with a 5-minute walk and build to 30 minutes daily). Then, the provider can ask the following 4 questions:

 

1. Why would you want to lose weight and exercise?
2. How might you go about it in order to succeed?
3. What are the 3 best reasons for you to do it?
4. How important is it for you to make this change, and why? The provider can also ask the patient to quantify on a scale of 1 to 10: (a) How likely is it that they will make each required change? (b) How hard will each change be for them?
5. The provider then summarizes the patient’s reasons for wanting change, how he/she can effect change, what their best reasons are, and how to successfully change. The provider then asks a final question:
6. So what do you think you will do?

Most patients report feeling engaged, empowered, open, and understood with motivational interviewing. People are “persuaded by what they hear themselves say,” increasing motivation to change.⁴⁷

This personalized action plan facilitates successful health behavior change.⁴⁸ Action plans should integrate daily routines. For example, by placing the scale near the toothbrush, daily weighing is encouraged. Daily weighing is associated with significantly greater weight loss and less weight regain.⁴⁹ In a 6-month, randomized controlled weight loss trial in men and women, daily weighing (using a scale that automatically transmitted weight data), with weekly e-mails and tailored feedback yielded an overall 9% weight loss and increased use of exercise and diet behaviors associated with weight loss in comparison with those who weighed themselves less than weekly.⁵⁰ This simple daily measure seems to reinforce a patient’s action plan.

Adherence to an action plan significantly improves with patient education, peer or social support, and addressing barriers to adherence.⁵¹ For example, by providing support with weekly text messaging of “How are you?” and addressing the issues that patients reported in a large randomized treatment trial, adherence was significantly improved.⁵² In VHA patients with low health literacy, peer support or telephone coaching also has proven effective in increasing weight loss and glycemic control in patients with T2DM.^53,54 Providing multidisciplinary team support during intensive lifestyle intervention, providers can partner with patients to address questions or issues and applaud progress.

Effective VHA interventions

In an ethnically diverse population of patients with prediabetes, up to 7% weight loss was observed in the Diabetes Prevention Program (DPP).⁵⁵ In this study patients were randomized to placebo; metformin 850 mg twice daily; or a lifestyle-modification program in which they received one-on-one culturally sensitive, individualized lessons in diet, moderate exercise (≥ 150 minutes weekly), and behavior modification from case managers over 16 sessions. Lessons were reinforced in both group and individual sessions. This intervention was associated with an average of 6% weight loss at 6 months (half of participants attained 7% weight loss) and a 58% decrease in the rate of progression to T2DM over a nearly 3-year follow-up of this population with prediabetes compared with that of the placebo group.⁵⁵ Over a 15-year follow-up, the intensive lifestyle intervention group sustained a 27% decrease in the incidence of T2DM compared with that of the placebo group.⁵⁶ To emulate the success of the DPP in the VHA, a web-based DPP-like study in female veterans was performed with online coaching and daily weighing. This study achieved a 5.2% weight loss from baseline at 4 months.⁵⁷

 

To improve outcomes, the VHA MOVE! Weight Management Program has been revised to include more sustained intervention (16 sessions) and multiple modes for participating—in person, by telephone, via video, via MOVE! Coach phone app, or any combination.⁵⁸ Using shared decision making between patients with NAFLD and their providers, a customized MOVE! weight loss program can be developed to enable sustained intensive lifestyle intervention: hypocaloric diet, ≥ 150 minutes of moderate exercise weekly, and behavioral change.

In addition to intensive lifestyle intervention, a prospective study found that bariatric surgery significantly improved outcomes in patients with NASH, with most patients experiencing resolution of their NASH and nearly half exhibiting significantly improved fibrosis.²⁶ In the VHA, bariatric surgery has yielded excellent long-term outcomes, with 21% sustained weight loss from baseline (vs matched nonsurgical population) at 10 years postoperatively in patients undergoing Roux-en-Y gastric bypass.⁵⁹ Bariatric surgery also results in long-term remission of T2DM in most patients and significant improvement in hypertension and dyslipidemia.⁶⁰ The risks of bariatric surgery include 3% serious complications, 1% reoperation rates, and 0.4% 30-day mortality.^61,62 Bariatric surgery can be considered in patients with BMI > 40 or in patients with BMI > 35 who have comorbidities and do not have decompensated cirrhosis.^63,64

Beyond weight loss, more favorable liver-related outcomes and lower rates of advanced liver fibrosis are observed in those consuming filtered coffee; a reduction in liver steatosis also is observed with adherence to a Mediterranean diet.^65,66 In NAFLD, statins may improve liver chemistries and fibrosis; this class of medications can be used safely even in the presence of an elevated ALT.^11,67As a risk factor for chronic liver disease, alcohol consumption of ≥ 4 drinks per day or > 14 drinks per week for men or > 7 drinks per week for women should be avoided in patients with NAFLD.¹¹

Conclusion

Nonalcoholic fatty liver disease independently increases the risk of T2DM, cardiovascular disease and kidney disease. With its rates increasing in the VHA, earlier identification and intervention is warranted in patients at high risk (ie, those with metabolic syndrome, obesity, and T2DM).² 

In patients with metabolic syndrome and modest or no alcohol use, NAFLD can be identified by the presence of fatty liver on imaging in those in whom liver enzymes are measured and hepatitis B and C virus and secondary causes of fatty liver are excluded (aligning with the European Association of the Study of Liver Disease simple algorithm).¹⁶

NASH is more frequent in those with liver enzyme elevations or with an elevated FIB-4 and is associated with a long-term risk of cirrhosis. These patients merit referral to hepatology or gastroenterology for further evaluation and consideration of a liver biopsy to identify NASH. Patients with likely NAFLD without liver enzyme elevations can be further evaluated with FIB-4 scores to assess their probability of advanced liver fibrosis and potential need for referral to hepatology or gastroenterology.

Early NAFLD detection and intervention with intensive lifestyle modifications has the potential to avert progression to advanced fibrosis—and its associated increased overall and liver-related mortality, and impaired QOL.^3,16,18  Although FIB-4 is a validated predictor of advanced fibrosis, this score is not yet used nationally to identify and risk stratify NAFLD in the VHA. Additionally, the very low use of VHA diet/exercise programs in eligible patients contributes to NAFLD progression.⁶⁸ The cost-effective DPP has successfully yielded weight loss in patients with prediabetes and decreases in the incidence of T2DM through motivational interviewing and intensive lifestyle intervention.⁵⁵ 

By revising MOVE!, the VHA has enhanced its intensive lifestyle intervention program.

To improve NAFLD management, providers can successfully engage patients through motivational interviewing for intensive lifestyle intervention. Their resulting weight loss is enhanced with a personalized action plan, daily weighing, and peer support. When NAFLD is identified in patients with metabolic risk factors, the probability of advanced fibrosis is easily assessed in those with elevated FIB-4 scores who merit gastrointestinal referral.^33,37

In all those identified with NAFLD, disease information should be provided to patients and their families. Intensive lifestyle modification targeting a ≥ 7% weight loss is recommended; motivational interviewing can increase commitment to change and yield a customized action plan for sustained weight loss. Working with the support and encouragement of their team of primary care providers, dieticians, and MOVE! coaches, patients can actively engage to improve their NAFLD and overall health.

Nonalcoholic fatty liver disease (NAFLD) is a silent epidemic affecting nearly 1 in 3 Americans and is increasing within the Veterans Health Administration (VHA).^1,2 NAFLD independently increases the risk of type 2 diabetes mellitus (T2DM), cardiovascular disease, chronic kidney disease, cirrhosis, liver cancer, and death and impairs health-related quality of life (QOL).³ NAFLD primarily affects those with metabolic risk factors (prediabetes, T2DM, and metabolic syndrome) or obesity (Figure 1).^4,5 

In the US, 1 in 3 adults have prediabetes and 1 in 10 have T2DM (increasing to 1 in 4 aged ≥ 65 years).⁶ Among veterans, obesity affects 31% within 6 years postdeployment and 41% overall who receive VHA care.^7,8 Other patient characteristics associated with higher rates of NAFLD include Hispanic ethnicity and older age.^9-11

Among those with NAFLD, most have nonalcoholic fatty liver (NAFL), or simple steatosis, affecting > 5% of liver cells (Figure 2).¹² 

However, 25% to 30% exhibit nonalcoholic steatohepatitis (NASH), with steatosis, inflammation, hepatocyte injury, and often alanine aminotransferase (ALT) elevations.¹³About 4% of patients progress to cirrhosis and/or hepatocellular carcinoma (HCC) on 7- to 15-year follow-up (with 9% cirrhosis or end-stage liver disease rates in 1 recent study with up to 23-year follow-up).^1,14

In most patients (80%), NAFLD progresses slowly over decades. The progression is related to continuing insulin resistance.^15,16 Greater disease progression is seen in patients with T2DM or concomitant chronic liver disease (such as hepatitis C).^10,11,16 Patients with NAFLD who develop advanced fibrosis or cirrhosis experience increased rates of overall mortality, liver-related events, and liver transplantation.^1,9,17,18 Within the VHA, NAFLD is the third most common cause of cirrhosis and HCC, occurring at an average age of 66 and 70 years, respectively.¹⁹Less commonly, HCC also can occur in NAFLD without cirrhosis.²⁰

Although no pharmaceuticals are yet approved to treat NAFLD, even modest weight loss is beneficial. For example, weight loss > 4% improves fatty liver, ≥ 7% improves liver inflammation, and ≥ 10% decreases liver fibrosis (or scarring).^21-23 In patients with a prior lack of success with weight loss, weight loss medications may be beneficial for short-term use.²⁴ When comparing the effects of diet, exercise, obesity pharmacotherapy, and combinations for these approaches, intensive lifestyle modification with exercise had the greatest, most enduring benefit.²⁵ Additionally, bariatric (weight loss) surgery has significantly improved health and liver-related outcomes for patients with NASH.²⁶

In at-risk veterans, NAFLD has myriad negative effects on health and QOL. To improve its early identification and management in the VHA, we summarize strategies that all providers can use to screen and treat patients for this condition.

Screening for Advanced Fibrosis

Advanced fibrosis in NAFLD is diagnosed by analyzing adequately sized liver biopsies.^27,28 However, noninvasive approaches to quantify advanced fibrosis by imaging or use of a simple fibrosis prediction score also are available. Imaging modalities include measuring liver stiffness, using transient elastography (FibroScan, Waltham, MA) or magnetic resonance elastography.^1,29-31 Fibrosis prediction scores use common clinical and laboratory data to predict the presence or absence of advanced fibrosis (Table 1).²⁹ 

Of these, the fibrosis-4 (FIB-4) index requires only ALT, aspartate aminotransferase (AST), platelet count, and age to calculate the score and performs similarly to the NAFLD fibrosis score.^32-35 FIB-4 and the NAFLD fibrosis score are validated in ethnically diverse populations, recommended in evidence-based guidelines, and can be calculated using online calculators (eg, FIB-4).^11,16,33 The easily summed BARD score also detects NAFLD advanced fibrosis yet incorrectly identified advanced fibrosis in many patients without liver biopsy evidence of advanced fibrosis in a recent VHA study.^36,37 With increasing VHA rates of NAFLD, these scores are a simple way to identify patients with probable advanced fibrosis who may benefit from hepatology or gastroenterology consultation.²

 

Does This Patient Have NAFLD?

To identify NAFLD, patients with metabolic syndrome and modest or no alcohol use are first assessed for liver injury with ALT, AST, and complete blood count (Figure 3; Case 1).¹⁶ 

Among patients presenting with incidental liver enzyme elevations to primary care, NAFLD was the most common cause.³⁸

Next, common underlying liver diseases that cause liver injury should be excluded by hepatitis B and C virus serology.^11,16 Other underlying liver diseases are uncommon and should be assessed only if clinically indicated. 

After excluding secondary causes of fatty liver (eg, drugs causing steatosis, parenteral nutrition, severe malnutrition, etc), NAFLD is likely, particularly in those displaying fatty liver or steatosis on liver imaging (Table 2).^11,16

Evaluation of fasting glucose or hemoglobin A_1c (HbA_1c)can identify undiagnosed T2DM. NAFL, or simple steatosis, is independently associated with an increased risk of T2DM, cardiovascular and kidney disease, yet not overall mortality.¹⁶ Over 10 to 20 years, few patients (4%) with simple steatosis progress to cirrhosis.³⁹In contrast, NAFLD advanced fibrosis significantly increases overall and liver-related mortality and can be assessed with high probability by calculating the patient’s FIB-4, even in those with normal liver enzymes.^11,16 Patients with highly probable advanced fibrosis merit evaluation by hepatology or gastroenterology (Figure 3).

In NAFLD, simple steatosis can resolve, and NASH can significantly improve with 7% to 10% weight loss.^16,23,40 Patients with simple steatosis on imaging and normal liver enzymes should be monitored with periodic liver enzymes and fibrosis prediction scores (eg, FIB-4) and encouraged to pursue intensive lifestyle intervention.^16,33 Without weight loss and exercise interventions metabolic syndrome, T2DM, and NAFLD may progress.

Patients with combined liver steatosis and liver enzyme elevations may exhibit NASH and warrant an evaluation by a hepatologist or gastroenterologist for consideration of additional testing or liver biopsy.¹⁶While ALT elevations often have been used as a marker of NASH, ALT can be normal in NASH and in advanced fibrosis.^41,42 A liver biopsy is required to establish the diagnosis of NASH, which progresses to cirrhosis in 15% to 20% over a 10- to 20-year follow-up period (Case 2).³⁹ Fibrosis prediction scores also can evaluate the probability of advanced fibrosis in these patients.

Encouraging Patients to Pursue Intensive Lifestyle InterventionS

Most veterans wish to collaborate in their care (Table 3, Figure 4) yet experience many barriers, such as low health literacy, high rates of comorbidities, and ongoing drug/alcohol misuse.^43,44 

  To motivate patients to action to prevent the progression of NAFLD, patients must understand how it affects the development of T2DM, cardiovascular disease, and liver disease and the value of the intervention.  To enhance disease understanding, the VHA provides a simple 2-page patient information sheet about NAFLD and its treatment.⁴⁵ A 2-page pictorial patient education handout on NAFLD and its treatment is available as well (eAppendix)

Document

hunt_0119_e_appendix.pdf

Media Folder

FedPrac

.

In addition to patient education, motivational interviewing significantly improves weight loss, resulting in a 3.3 lb (1.5 kg) increased weight loss in the intervention group vs the control group in weight loss studies.⁴⁶By being supportive, empathic, and clearly sharing the rationale for change, motivational interviewing is a collaborative conversation to guide patients to strengthen their motivation and commitment to change.⁴⁷ It helps patients examine and address their ambivalence—most recognize they should exercise and lose weight, but it can be difficult.

To start the conversation, the health care provider can explain that NAFLD increases the risk of T2DM, heart disease, and liver injury or scarring and can be effectively treated (or improved) with modest weight loss and regular exercise (ie, 14 lb weight loss if 200 lb, or 21 lb weight loss if 300 lb). Exercise can start with a 5-minute walk and build to 30 minutes daily). Then, the provider can ask the following 4 questions:

 

1. Why would you want to lose weight and exercise?
2. How might you go about it in order to succeed?
3. What are the 3 best reasons for you to do it?
4. How important is it for you to make this change, and why? The provider can also ask the patient to quantify on a scale of 1 to 10: (a) How likely is it that they will make each required change? (b) How hard will each change be for them?
5. The provider then summarizes the patient’s reasons for wanting change, how he/she can effect change, what their best reasons are, and how to successfully change. The provider then asks a final question:
6. So what do you think you will do?

Most patients report feeling engaged, empowered, open, and understood with motivational interviewing. People are “persuaded by what they hear themselves say,” increasing motivation to change.⁴⁷

This personalized action plan facilitates successful health behavior change.⁴⁸ Action plans should integrate daily routines. For example, by placing the scale near the toothbrush, daily weighing is encouraged. Daily weighing is associated with significantly greater weight loss and less weight regain.⁴⁹ In a 6-month, randomized controlled weight loss trial in men and women, daily weighing (using a scale that automatically transmitted weight data), with weekly e-mails and tailored feedback yielded an overall 9% weight loss and increased use of exercise and diet behaviors associated with weight loss in comparison with those who weighed themselves less than weekly.⁵⁰ This simple daily measure seems to reinforce a patient’s action plan.

Adherence to an action plan significantly improves with patient education, peer or social support, and addressing barriers to adherence.⁵¹ For example, by providing support with weekly text messaging of “How are you?” and addressing the issues that patients reported in a large randomized treatment trial, adherence was significantly improved.⁵² In VHA patients with low health literacy, peer support or telephone coaching also has proven effective in increasing weight loss and glycemic control in patients with T2DM.^53,54 Providing multidisciplinary team support during intensive lifestyle intervention, providers can partner with patients to address questions or issues and applaud progress.

Effective VHA interventions

In an ethnically diverse population of patients with prediabetes, up to 7% weight loss was observed in the Diabetes Prevention Program (DPP).⁵⁵ In this study patients were randomized to placebo; metformin 850 mg twice daily; or a lifestyle-modification program in which they received one-on-one culturally sensitive, individualized lessons in diet, moderate exercise (≥ 150 minutes weekly), and behavior modification from case managers over 16 sessions. Lessons were reinforced in both group and individual sessions. This intervention was associated with an average of 6% weight loss at 6 months (half of participants attained 7% weight loss) and a 58% decrease in the rate of progression to T2DM over a nearly 3-year follow-up of this population with prediabetes compared with that of the placebo group.⁵⁵ Over a 15-year follow-up, the intensive lifestyle intervention group sustained a 27% decrease in the incidence of T2DM compared with that of the placebo group.⁵⁶ To emulate the success of the DPP in the VHA, a web-based DPP-like study in female veterans was performed with online coaching and daily weighing. This study achieved a 5.2% weight loss from baseline at 4 months.⁵⁷

 

To improve outcomes, the VHA MOVE! Weight Management Program has been revised to include more sustained intervention (16 sessions) and multiple modes for participating—in person, by telephone, via video, via MOVE! Coach phone app, or any combination.⁵⁸ Using shared decision making between patients with NAFLD and their providers, a customized MOVE! weight loss program can be developed to enable sustained intensive lifestyle intervention: hypocaloric diet, ≥ 150 minutes of moderate exercise weekly, and behavioral change.

In addition to intensive lifestyle intervention, a prospective study found that bariatric surgery significantly improved outcomes in patients with NASH, with most patients experiencing resolution of their NASH and nearly half exhibiting significantly improved fibrosis.²⁶ In the VHA, bariatric surgery has yielded excellent long-term outcomes, with 21% sustained weight loss from baseline (vs matched nonsurgical population) at 10 years postoperatively in patients undergoing Roux-en-Y gastric bypass.⁵⁹ Bariatric surgery also results in long-term remission of T2DM in most patients and significant improvement in hypertension and dyslipidemia.⁶⁰ The risks of bariatric surgery include 3% serious complications, 1% reoperation rates, and 0.4% 30-day mortality.^61,62 Bariatric surgery can be considered in patients with BMI > 40 or in patients with BMI > 35 who have comorbidities and do not have decompensated cirrhosis.^63,64

Beyond weight loss, more favorable liver-related outcomes and lower rates of advanced liver fibrosis are observed in those consuming filtered coffee; a reduction in liver steatosis also is observed with adherence to a Mediterranean diet.^65,66 In NAFLD, statins may improve liver chemistries and fibrosis; this class of medications can be used safely even in the presence of an elevated ALT.^11,67As a risk factor for chronic liver disease, alcohol consumption of ≥ 4 drinks per day or > 14 drinks per week for men or > 7 drinks per week for women should be avoided in patients with NAFLD.¹¹

Conclusion

Nonalcoholic fatty liver disease independently increases the risk of T2DM, cardiovascular disease and kidney disease. With its rates increasing in the VHA, earlier identification and intervention is warranted in patients at high risk (ie, those with metabolic syndrome, obesity, and T2DM).² 

In patients with metabolic syndrome and modest or no alcohol use, NAFLD can be identified by the presence of fatty liver on imaging in those in whom liver enzymes are measured and hepatitis B and C virus and secondary causes of fatty liver are excluded (aligning with the European Association of the Study of Liver Disease simple algorithm).¹⁶

NASH is more frequent in those with liver enzyme elevations or with an elevated FIB-4 and is associated with a long-term risk of cirrhosis. These patients merit referral to hepatology or gastroenterology for further evaluation and consideration of a liver biopsy to identify NASH. Patients with likely NAFLD without liver enzyme elevations can be further evaluated with FIB-4 scores to assess their probability of advanced liver fibrosis and potential need for referral to hepatology or gastroenterology.

Early NAFLD detection and intervention with intensive lifestyle modifications has the potential to avert progression to advanced fibrosis—and its associated increased overall and liver-related mortality, and impaired QOL.^3,16,18  Although FIB-4 is a validated predictor of advanced fibrosis, this score is not yet used nationally to identify and risk stratify NAFLD in the VHA. Additionally, the very low use of VHA diet/exercise programs in eligible patients contributes to NAFLD progression.⁶⁸ The cost-effective DPP has successfully yielded weight loss in patients with prediabetes and decreases in the incidence of T2DM through motivational interviewing and intensive lifestyle intervention.⁵⁵ 

By revising MOVE!, the VHA has enhanced its intensive lifestyle intervention program.

To improve NAFLD management, providers can successfully engage patients through motivational interviewing for intensive lifestyle intervention. Their resulting weight loss is enhanced with a personalized action plan, daily weighing, and peer support. When NAFLD is identified in patients with metabolic risk factors, the probability of advanced fibrosis is easily assessed in those with elevated FIB-4 scores who merit gastrointestinal referral.^33,37

In all those identified with NAFLD, disease information should be provided to patients and their families. Intensive lifestyle modification targeting a ≥ 7% weight loss is recommended; motivational interviewing can increase commitment to change and yield a customized action plan for sustained weight loss. Working with the support and encouragement of their team of primary care providers, dieticians, and MOVE! coaches, patients can actively engage to improve their NAFLD and overall health.