Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide. Nonalcoholic steatohepatitis, the progressive form of NAFLD, can lead to end-stage liver disease and hepatocellular carcinoma. However, the consequences of NAFLD are not confined to the liver. NAFLD is associated with an increased risk of cardiovascular disease (CVD) and is frequently associated with metabolic syndrome. Thus, there is a pressing need for the diagnosis and management of the comorbidities of NAFLD, including CVD. This review will guide clinicians in the assessment and management of metabolic disease and CVD in patients with NAFLD.
nonalcoholic fatty liver disease
Evaluation of Metabolic Comorbidities in Patients With NAFLD
The majority of patients with NAFLD exhibit features of metabolic syndrome. Therefore, clinicians must have a high index of suspicion and actively screen for metabolic syndrome. Metabolic syndrome is defined by having three or more of the following five components:
- Elevated triglycerides (>150 mg/dL).
- Low high-density lipoprotein (HDL) levels (<40 mg/dL in men and <50 mg/dL in women).
- Elevated fasting glucose levels (≥110 mg/dL).
- Hypertension (≥130/85 mm Hg or antihypertensive medications).
- Abdominal obesity (waist circumference > 102 cm in men and > 88 cm in women)
The evaluation should include fasting lipid, glucose, and insulin levels. In addition, blood pressure and hip/waist measurements should also be taken to evaluate patients for hypertension and abdominal obesity.
Patients should be questioned about symptoms of CVD, including resting and exertional chest pain, dyspnea, and claudication. Symptoms suggesting CVD should prompt a discussion with the primary care physician about a cardiac evaluation. Although routine noninvasive testing cannot be recommended, consideration should be given to calculating the Framingham risk score to identify NAFLD patients with an increased 10-year risk of coronary heart disease.
Management of Comorbidities and CVD
Dyslipidemia is an important risk factor for CVD and is highly prevalent in NAFLD patients. It is characterized by elevated low-density lipoprotein (LDL) levels as well as atherogenic dyslipidemia, which consists of hypertriglyceridemia, low HDL levels, and elevated small, dense LDL levels.
There has long been a reluctance to treat patients with liver disease with lipid-lowering therapy and specifically with 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors or statins because of concerns about hepatotoxicity. However, the incidence of serious hepatotoxicity with statins in patients with NAFLD is exceedingly low, and statins are safely used in patients with liver disease. Although the role of statins in the treatment of NAFLD itself remains unclear, the role of statins in the primary and secondary prevention of CVD is well established.
Statins are the initial treatment of choice for NAFLD patients. However, patients with NAFLD may demonstrate persistent atherogenic dyslipidemia, which may require additional treatment. Omega 3 fatty acids are an attractive option for NAFLD patients because of their minimal side-effect profile. In addition, early data suggest that omega 3 fatty acids may also improve steatohepatitis and clinical trials are ongoing. Niacin and fibrates can be used for the treatment of isolated hypertriglyceridemia and can be added to statin therapy.
Although NAFLD is associated with an increased risk of CVD, the target lipid goals for patients with NAFLD are not well established. We recommend following the Adult Treatment Panel III guidelines of the National Cholesterol Education Program for target LDL and atherogenic dyslipidemia goals (Table 1). An updated guidelines (ATP IV) is expected to release in late 2012.
|Patient Risk Factor||Treatment Target||Recommended Treatment|
|CVD or risk equivalentsa||LDL < 100 mg/dL||Lifestyle interventions and statin initiation|
|≥2 cardiovascular risk factorsb||LDL < 130 mg/dL||Lifestyle interventions and statin initiation|
|≤1 cardiovascular risk factor||LDL < 160 mg/dL||Lifestyle interventions and, if needed, statin initiation|
|Atherogenic dyslipidemia||HDL > 40 mg/dL and triglycerides < 150 mg/dL||Omega 3 fatty acids, nicotinic acid, and fibrates|
|Hypertension||<140/90 mm Hg (<130/80 mm Hg for diabetes or renal disease)||Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers|
Insulin Resistance and Diabetes
Nondiabetic NAFLD patients often have underlying insulin resistance, impaired fasting glucose, or impaired glucose tolerance, which may contribute to the increased risk of CVD. Patients with NAFLD and impaired glucose tolerance or impaired fasting glucose should be treated first with lifestyle interventions. If lifestyle changes prove insufficient, consideration can be given to the addition of metformin. Metformin decreases the progression to diabetes in patients with impaired glucose tolerance, but studies evaluating its efficacy in the treatment of nonalcoholic steatohepatitis have largely been negative, and metformin is not recommended for the treatment of NAFLD alone.[4, 5] Pioglitazone has also been shown to be beneficial in the management of insulin resistance and has led to histological improvements in patients with nonalcoholic steatohepatitis. However, recent concerns have emerged about increased risks of bladder cancer and congestive heart failure.
Diabetes mellitus is frequently associated with NAFLD. With the rapid development of new medications (including incretin-based therapy and sodium glucose transport protein 2 inhibitors), the management of diabetes is becoming increasingly complex and is beyond the scope of this review. We recommend working closely with a primary care physician and/or endocrinologist for diabetes management. All currently approved diabetes medications are safe in patients with compensated liver disease, and NAFLD should not limit a patient's therapeutic options.
Hypertension should be treated to prevent the development of CVD in NAFLD patients. Both angiotensin receptor blockers and angiotensin-converting enzyme inhibitors have been shown in animal models and cohort studies to reduce fibrosis progression in chronic liver disease. Although these results have not been confirmed in randomized controlled trials, if a patient requires treatment for hypertension, we recommend that these agents be preferentially used for achieving target goals. Recommended blood pressure targets for NAFLD are the same as those outlined by the Joint National Committee (Table 1).
The intentional loss of 10% of a patient's excess body weight over the course of a year is recommended via lifestyle changes, which may include caloric restrictions, reductions in the intake of carbohydrates, and an adherence to a balanced diet (including foods with a low glycemic index). Other recommendations include at least 3 hours of aerobic exercise weekly.
NAFLD Patients With CVD
Patients with NAFLD and diagnosed CVD should be managed similarly to those without liver disease. The presence of NAFLD should not prevent any necessary procedures, including cardiac catheterization and coronary artery bypass surgery. The presence of cirrhosis should prompt an evaluation of the functional status and the Child class by a hepatologist, but for patients without end-stage liver disease, no further evaluation is needed before cardiac procedures. Patients with CVD are often prescribed antiplatelet agents, including aspirin and clopidogrel. In patients with cirrhosis and known varices, a risk-benefit analysis should be undertaken between hepatology and cardiology, but the use of such agents is generally safe, and secondary measures can be taken to reduce the risk of gastrointestinal bleeding.
CVD and other metabolic comorbidities associated with NAFLD can lead to significant morbidity and mortality. An awareness of the diagnosis and management of these conditions can significantly improve the lives of patients with NAFLD.