The Journal for Nurse Practitioners
Volume 8, Issue 1 , Pages 45-50, January 2012

Nonalcoholic Fatty Liver Disease: Implications for Clinical Practice and Health Promotion

  • Bethany Croke, FNP-BC

      Affiliations

    • Bethany Croke, MS, FNP-BC, is a family nurse practitioner in primary care and community health at HealthFirst Family Care Center in Fall River, MA.
    • ,
  • Deborah Sampson, FNP-BC

      Affiliations

    • Deborah Sampson, PhD, APRN, FNP-BC, is a family nurse practitioner in urgent care, primary care, student health, and occupational health at Monadnock Community Hospital System in Peterborough, NH, and an assistant professor at the Connell School of Nursing at Boston College. In compliance with national ethical guidelines, the authors report no relationships with business or industry that would pose a conflict of interest.

Article Outline

Abstract 

Nonalcoholic fatty liver disease (NAFLD), a condition caused by fatty infiltration of the liver, in the absence of large alcohol consumption, that can result in liver failure. It is the leading cause of elevated liver enzymes in adults and of liver disease in children, and it is increasing in the United States commensurately with obesity. Initially an asymptomatic disease, diagnosis is based on risk factor assessment, laboratory findings, and imaging studies. Prevention and early intervention require lifestyle changes. Prognosis is typically good, especially early in the disease course.

Keywords:  insulin resistance , metabolic syndrome , nonalcoholic fatty liver disease , nonalcoholic steatohepatitis

 

Nonalcoholic fatty liver disease (NAFLD) is a term for a broad continuum of liver illnesses extending from the rather benign steatosis to the severe cryptogenic cirrhosis.1, 2, 3 Typically, patients with NAFLD have this problem independent of alcohol intake and its effects on the liver. Steatosis, or fatty infiltration of the liver, can progress to nonalcoholic steatohepatitis (NASH). Steatohepatitis, in turn, can progress to permanent liver damage in the form of cirrhosis or malignancy; 3% to 5% of patients with NAFLD progress to NASH, and 15% of those with NASH develop cirrhosis.4

NAFLD is the most common cause of elevated liver enzymes in American adults, and its prevalence is anticipated to increase as a result of the American obesity epidemic. Current prevalence estimates are widely regarded as conservative because patients with NAFLD are often asymptomatic, abnormalities are detected inadvertently, and diagnostic tests lack accuracy and noninvasiveness.5, 6 Ninety percent of patients with a body mass index (BMI) of 39 kg per m2 or greater have steatosis, while up to 8.6 million obese Americans may have NASH.1

The most significant risk factors for NAFLD include the components of metabolic syndrome: obesity, glucose intolerance or diabetes, hypertension, and dyslipidemia, particularly elevated triglycerides and low levels of HDL cholesterol.7 NAFLD itself is a risk factor for increased morbidity and mortality, cardiovascular disease and malignancy.8 Despite these facts, most patients have a good prognosis if the condition is caught in its early stages. Therefore, nurse practitioners (NPs) need to have the knowledge to identify, assess, and treat patients for NAFLD to ensure better patient outcomes.

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Epidemiology 

An estimated 20% to 30% of the American adult population has some form of NAFLD.1 Furthermore, approximations state that up to 80% of obese people have the disease.5 Fatty liver and NASH occur in both pediatric and adult patients, with the highest prevalence in the 40- to 49-year-old age group. It is the most common liver abnormality in children ages 2 to 19.9 The disease appears equally in men and women and across all ethnicities. In the United States the prevalence is higher in the Hispanic population compared to Caucasian and African American populations.

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Pathophysiology 

Two histological presentations of NAFLD occur: fatty liver and NASH. With fatty liver, infiltration of fat changes hepatocyte shape, resulting in swelling and nuclei displaced to the edge of the cell.4 This “ballooning” indicates cellular injury and degeneration. NASH is the progressive form of NAFLD, which is characterized by inflammation and heptocyte necrosis, and it can progress to cirrhosis.

Although the exact mechanism of NAFLD pathology is unknown, several hypotheses suggest that the liver damage is multifactorial. The multi-hit hypothesis describes proposed NAFLD pathology.6 The first insult, or hit, to the liver occurs from insulin resistance. This causes increased levels of fatty acids that result in fatty infiltration of the liver, or steatosis. These hits continue and the increasing fatty acids eventually cause apoptosis, or cell death, of hepatocytes.

Other hypotheses suggest that, after the first hit with insulin resistance and fatty infiltration, a second hit from a gut and adipose tissue-derived endotoxin may cause progression to NASH.10 The multiple-parallel hits hypothesis proposes that many insults to the liver happen concurrently, ultimately causing fatty infiltration and hepatic inflammation. Regardless of the hypothesis, progressive liver damage at the cellular level seems to stem from a combination of insulin resistance and fat deposit in the liver that ultimately result from obesity.

It is not entirely clear what causes progression from NAFLD to NASH, although insulin resistance appears to be a marker for both initiation of fatty liver disease and its progression to NASH. Other possible risk factors for progression include increasing weight, age progression, and an aspartate aminotransferase/alanine transaminase (AST/ALT) ratio > 1 (normal is < 1).11

Hepatic iron deposits, or hemochromatosis, may also be a causative factor for disease progression. The role of iron accumulation has been established for other chronic hepatic diseases, but its role in NAFLD and NASH remains unclear.12 Promising research links the more severe forms of NAFLD to iron deposits that occur exclusively in the reticuloendothelial system, while mild disease states show iron accumulation exclusively in hepatocytes.

Finally, there may be a genetic predisposition to NAFLD related to the risk factors of acquiring metabolic syndrome.13 Factors that tend to cluster in families include obesity, insulin resistance, type 2 diabetes, high triglyceride levels, and low HDL cholesterol levels. The familial clustering of NAFLD related to these comorbidities is also mediated by lifestyle and environmental factors, particularly diet and exercise. Therefore, it is not yet known whether NAFLD is related to genetic factors, learned behaviors, or a combination of both.

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Presentation 

Patients are typically asymptomatic, and abnormalities are found upon a routine liver enzyme test or an abdominal ultrasound for an unrelated illness. Early symptoms (Table 1), when they do occur, are typically nonspecific, such as fatigue and vague right upper quadrant pain. Some patients with progressed disease (ie, NASH or cirrhosis) may present with signs of serious liver damage, such as jaundice, anorexia, pruritis, and ascites. Upon physical exam 30%-100% of patients will be obese and 50% will have hepatomegaly.1 Less common physical findings include spider nevi and palmar erythema.

Table 1. Nonalcoholic Fatty Liver Disease Presentation
Early Adult Symptoms
•Asymptomatic

•Fatigue

•Right upper quadrant pain


Late Adult Symptoms
•Anorexia

•Ascites

•Jaundice

•Pruritis


Common Adult and Pediatric Symptoms
•Hepatomegaly

•Obesity


Rare Adult Symptoms
•Palmar erythema

•Spider nevi


Specific Pediatric Symptoms
•Fatigue

•Hepatomegaly

•Increased waist circumference

•Malaise

•Obesity with central adiposity

•Right-upper quadrant or epigastric pain


Pediatric NAFLD presentation is also typically asymptomatic in its early stages.14, 15 Like adults, symptoms include fatigue, malaise, and vague right upper or epigastric pain. The classic presentation is a boy, 11-13 years old, who is overweight or obese. Furthermore, greater than 90% of children with NAFLD have central adiposity contributing to their obesity, and hepatomegaly is a common finding.9 Acanthosis nigricans is also a common finding as a result of insulin resistance, and cardiovascular markers, such as hypertension and increased waist circumference, can coexist in children with NAFLD.16

In terms of laboratory findings, NAFLD is the most common cause of persistent ALT elevation in the absence of other chronic liver diseases. The ALT elevation is not excessive, usually 1 to 4 times the upper limit of normal. The AST may also be elevated, but the AST/ALT ratio is rarely > 2. Of important note, ALT levels do not correlate with the degree of steatosis or fibrosis. Other laboratory measures to consider are markers indicating decreased liver function in progressed disease, such as increased prothrombin time, decreased albumin levels, and increased serum bilirubin. Glucose levels and fasting lipid profiles may reveal comorbidities associated with NAFLD, such as diabetes and hypertriglyceridemia, respectively.

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Assessment 

All patients who are obese should be assessed for NAFLD because early identification and intervention is key to stopping disease progression and limiting liver damage. The patient history should focus on risk factors and other potential causes of liver disease (Table 2). Personal and family history of NAFLD, type 2 diabetes, metabolic syndrome, and hypertriglyceridemia should be ascertained.

Table 2. Patient Assessment of Nonalcoholic Fatty Liver Disease
Subjective
•Personal and family history of non-alcoholic fatty liver disease, type 2 diabetes, metabolic syndrome, hypertriglyceridemia, biliary tract disease

•Alcohol intake

•Risk factors for viral hepatitis: injection drug use, high-risk sexual behavior, blood transfusions

•Toxin exposure (eg, acetaminophen, alcohol)

•Medications: amiodarone, diltiazem, tamoxifen, tetracycline, valproate, methotrexate, steroids, highly-active antiretrovirals

•Rapid weight loss

•Diet and exercise habits


Objective
•Body mass index

•Obesity

•Hepatomegaly

•Liver function tests

•Fasting lipid panel

•Glucose


Because NAFLD is a diagnosis of exclusion, other causes of liver damage must be ruled out. Therefore, alcohol intake, risk factors for hepatitis B and C, autoimmune diseases, congenital causes, biliary tract disease, and exposure to toxins should be evaluated. A thorough review of patient medications is also necessary. Medications such as amiodarone, diltiazem, tamoxifen, tetracycline, valproate, methotrexate, and corticosteroids have all been linked to NAFLD. The use of highly-active antiretrovirals is of particular concern because of their tendency to cause severe insulin resistance and hyperlipidemia. Lastly, inquiries regarding weight loss efforts can also be insightful because rapid weight loss can cause both NAFLD and disease progression to NASH.

For the physical exam, the BMI should be measured and careful attention to subtle physical signs should be made, although it is unlikely that any will be found in the earliest stages of disease. If there is clinical suspicion, laboratory data will yield the most information; therefore ALT, AST, and alkaline phosphate levels and liver function tests should be ordered.17

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Diagnosis 

Many differential diagnoses cause elevated liver enzymes and must be ruled out. Alcoholic fatty liver disease (AFLD) usually presents with hepatomegaly and right upper quadrant tenderness; history reveals alcohol intake that exceeds 20 g/day (1.5 standard alcoholic drinks/day) for women and 30 g/day (2 standard alcoholic drinks/day) for men. The laboratory AST/ALT ratio is typically > 2, as well.

An autoimmune cause should be considered if the patient presents with symptoms of type 1 diabetes, Graves disease, ulcerative colitis, vasculitis, or Sjorgen's disease. Risk factors for viral hepatitis, such as illicit injection drug use, high-risk sexual behavior, and transfusions, should lead to evaluation for these diseases. Evidence of viral hepatitis usually can be identified from serology test results. Medications and toxins can also cause elevated liver enzymes, and symptoms vary based on the particular agent. Therefore, initial diagnostic tests to rule out other diseases and to assess the liver include a complete blood count, antinuclear antibody, erythrocyte sedimentation rate, liver function tests, viral hepatitis serology, and ultrasound of the liver.

Diagnosis of NAFLD has historically been made based on 3 criteria: abnormal hepatic histology, minimal alcohol consumption, and absence of viral hepatitis. If NAFLD is suspected in the presence of elevated liver enzymes, an imaging study should be ordered to detect the presence of fatty infiltrates. Ultrasound is typically used because of its lack of radiation exposure and its cost effectiveness compared to computed tomography scan and magnetic resonance imaging (MRI), respectively. MRI may be preferred despite its cost because of its superior sensitivity in detecting fat, especially since central obesity may result in poor ultrasound findings.

Finally, a liver biopsy is performed to confirm the findings and to assess disease status and potential progression to NASH. Liver biopsy is the only modality that accurately differentiates between fatty liver and NASH. Liver biopsy can also differentiate between NAFLD and alcoholic liver disease because histology findings in AFLD usually show greater cellular inflammation and hepatocellular injury.

In children, waist circumference typically correlates with the severity of NAFLD. Pediatric cases also have a different histological presentation compared to adults. Children show increased inflammation and fibrosis in the portal area, rather than in the lobules, and more severe fatty infiltration. Efforts are made to avoid invasive and risky procedures (liver biopsy) in children, but even the most highly-sensitive MRIs cannot accurately differentiate between fatty liver and NASH.

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Treatment and Management 

Treatment goals aim to prevent or reverse hepatic damage and to prevent progression of NAFLD to NASH and cirrhosis (Table 3). As with many treatments that are related to lifestyle change, diet and exercise remain the cornerstones of treatment for overweight individuals. A 10% reduction in body weight is an appropriate initial goal. Weight reduction should occur slowly to prevent paradoxical disease progression associated with rapid weight loss.

Table 3. Treatment and Management of Nonalcoholic Fatty Liver Disease
Nonpharmacological
•Slow, 10% reduction of body weight

•Healthy diet: low saturated fat, high fiber

•Exercise

•Avoidance of common hepatotoxins: alcohol, acetaminophen

•Patient education of condition


Pharmacological
Targeting dyslipidemia

•Fibrates

•Statins

Targeting insulin resistance

•Biguanides

•Thiazolidinediones

Other (strong effectiveness not yet proven)

•Betaine

•Ursodeoxycholic acid

•Vitamin E


Rarer Methods (after other methods fail)
•Gastric bypass

•Liver transplant


Nutritional counseling should include the importance of a diet low in saturated fats and high in fiber because this can improve insulin sensitivity. If BMI exceeds 35, more aggressive weight loss efforts may be warranted, such as gastric bypass. Such aggressive efforts should augment rather than replace weight loss programs, and the NP must review the relative risks and benefits of the procedure for each individual. In rare cases a liver transplant may be useful for patients with NASH. However, the disease can reoccur following transplantation, and fibrosis can develop rapidly if lifestyle changes and weight maintenance are not part of the overall regimen.

In patients with known diabetes, hemoglobin A1C levels should ideally be brought to under 7.0% through oral agents, insulin, or both. The lifestyle changes for fatty liver management will also help control diabetes. Two classes of oral diabetic agents, biguanides and thiazolidinediones, improve insulin sensitivity, but use of these drugs in patients with NASH and without diabetes remains experimental rather than therapeutic. Furthermore, their use in children with NAFLD has not been tested for effectiveness or safety.

Other pharmacological treatments include lipid-lowering agents and hepatoprotective drugs. Lipid-lowering medications aim to improve lipid profiles, particularly triglycerides, since fatty acids are elevated in NAFLD. Hyperlipidemia is also part of the constellation of diseases seen in metabolic syndrome. Effective drug choices include fibrates and statins. Although statins can cause liver injury, use in patients with modest liver enzyme elevation is not contraindicated as long as proper dosing and monitoring occur. The starting dose should be low; liver function tests should be measured after 2 weeks and then monthly for the first 3 months. Further monitoring intervals are left to provider discretion. If at any time the transaminase levels are 2 times greater than baseline, the statin should be discontinued.

Lastly, drugs such as betaine, vitamin E, and ursodeoxycholic acid, have been investigated for hepatoprotection, but strong evidence for their effectiveness remains to be found.

Patient education should be aimed at lifestyle habits that can prevent NAFLD and its progression. Both patients at risk for NAFLD and those with the diagnosis should be educated on diet and exercise, along with the importance of slow weight loss. Limiting the ingestion of common potential hepatotoxins, such as alcohol and acetaminophen, should also be reviewed.

Finally, because of the strong lifestyle factors contributing to the condition and its increasing prevalence in the pediatric population, NAFLD should be considered a family disease. The NP should involve all family members in treatment and patient education sessions, if possible. This will help strengthen support for the patient and help prevent disease in other family members, leading to better overall outcomes.

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Clinical Controversies 

Controversies exist regarding NAFLD diagnosis and classification. For example, there are no precise cutoff levels for the amount of alcohol intake that distinguishes between NAFLD and AFLD. Greater than 20 g/day is the generally accepted level that classifies AFLD, but there are no officially published and accepted guidelines. Furthermore, patient self-report of alcohol consumption may be a poor indicator of intake. Distinction between alcoholic liver disease and NAFLD is not always obvious, even if the patient only drinks small amounts of alcohol. In this instance, it is reasonable to ask the patient to abstain from alcohol and then reassess for a definitive diagnosis.

The use of liver biopsy in clinical practice also causes debate among health care providers. Most patients with NAFLD have a good prognosis; therefore, the risks of a liver biopsy seem to outweigh the clinical benefits. However, liver biopsy remains the only definitive way to distinguish fatty liver from NASH. The risks and benefits of biopsy therefore must be considered on an individual basis, taking into account the patient's risk for disease progression (high risk: BMI > 39, advanced age, AST/ALT ratio > 1), the optimal timing of the biopsy in relation to the diagnosis, and the potential for watchful waiting. Current research is examining the possibility of detecting disease severity through laboratory markers, namely AST, ALT, gamma-glutamyl transpeptidase (GGT), and insulin levels.18

Use of unnecessary invasive procedures in children has also been a concern in regard to NAFLD and liver biopsy. Despite attempts to predict disease severity through AST and GGT levels, liver biopsy remains the best tool for discerning between NAFLD and NASH in children.19 Other findings suggest that disease severity can possibly be predicted in the pediatric population by central obesity, elevated insulin levels, and lipid abnormalities.20

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Prognosis and Follow-Up 

Prognosis depends on the extent of liver damage at time of diagnosis. Fatty infiltration by itself is typically benign. NASH, as stated earlier, carries the risk of progression to cirrhosis, which is defined as irreversible liver damage. Providers should monitor patients closely for comorbidities and disease progression. Follow-up includes BMI, waist circumference, blood pressure, liver function tests, serum lipids, and blood glucose measurements every 6 months.21 An annual upper abdominal ultrasound examining the liver, gallbladder, and spleen should also be performed. Finally, providers should consider screening for cancer, complications of cirrhosis, and metabolic syndrome end-stage organ diseases, depending on the patient's risk factors and disease state.

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Conclusion 

As primary care providers that focus on patient education, health promotion, and disease prevention, NPs should use NAFLD as a teaching point for promoting healthy lifestyle habits in high-risk patients across all ethnicities and the lifespan. A healthy diet and exercise can help prevent NAFLD and metabolic syndrome. Because the condition is typically asymptomatic and its prevalence is increasing, primary care NPs need to be aware of NAFLD and its potential health consequences. Early detection is critical for good patient outcomes, and NAFLD should always be considered in the presence of elevated liver enzyme tests.

NPs should also understand available treatment modalities for NAFLD and understand the advantages and limitations of laboratory tests, imaging studies, and liver biopsies. Finally, NPs must remain current with research regarding the cause, progression, and best detection methods and treatments for NAFLD to provide the best care for patients.

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References 

  1. Bayard M , Holt J , Boroughs E . Nonalcoholic fatty liver disease . Am Fam Physician . 2006;73(11):1961–1968
  2. Angulo P . Nonalcoholic fatty liver disease . N Engl J Med . 2002;346:1221–1231
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PII: S1555-4155(11)00361-8

doi:10.1016/j.nurpra.2011.07.025

The Journal for Nurse Practitioners
Volume 8, Issue 1 , Pages 45-50, January 2012

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