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Nonalcoholic Fatty Liver Disease (NAFLD)

Daniel T. Lee, MD, MA and Anita Wong, MD Reviewed 06/2020
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Subject: Nonalcoholic Fatty Liver Disease (NAFLD)

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BASICS

  • A spectrum of fatty liver diseases not due to excess alcohol consumption ranging from nonalcoholic fatty liver (NAFL), to nonalcoholic steatohepatitis (NASH), to cirrhosis with hepatocyte injury with/without fibrosis

  • Leading cause of chronic liver disease; implicated in up to 90% of patients with asymptomatic, mild aminotransferase elevation not caused by alcohol, viral hepatitis, or medications

DESCRIPTION

  • NAFL (1)

    • Reversible condition in which large vacuoles of triglyceride fat accumulate in hepatocytes

    • Liver biopsy: fatty deposits in >5% of cells without hepatocellular injury (no hepatocyte ballooning, no necrosis, no fibrosis)

    • Alanine aminotransferase/aspartate aminotransferase (ALT/AST) enzymes usually normal but may be elevated, rarely >3 to 4 times upper limit normal (ULN)

    • Minimal risk of progressing to cirrhosis or liver failure

    • Synonym: steatosis

  • NASH: progressive form of NAFL (1)

    • Liver biopsy: fatty deposits in >5% of cells with hepatocellulary injury (ballooning, acute/chronic inflammation, ± fibrosis)

    • ALT and AST elevated, generally <3 to 4 times ULN

    • 30% with NASH may progress to fibrosis over 5 years, may progress to cirrhosis, liver failure, and rarely hepatocellular cancer

  • NASH cirrhosis

    • Presence of cirrhosis with current or previous histologic evidence of steatosis or steatohepatitis

EPIDEMIOLOGY

  • Nonalcoholic fatty liver disease (NAFLD): most common chronic liver disease in industrialized Western countries; usually benign, asymptomatic

  • Predicted to become the most frequent indication for liver transplantation by 2030 (2)

  • NASH may be symptomatic with progressive inflammation and fibrosis.

    • Predominant age: 40s to 50s; can occur in children

    • Predominant sex: male > female (slight)

Incidence

Estimates vary widely from 31 to 86 cases of NAFLD per 10,000 person-years to 29/100,000 person-years (1). 

Prevalence

  • United States estimate: 10–40%

  • Worldwide: 6–33%, median 25% (1)

  • Present in 58–74% of obese persons (BMI >30) and 90% of morbidly obese persons (BMI >39) (1)

  • Among individuals with type 2 diabetes mellitus, rate of 69–87%; in patients with dyslipidemia, rate of 50% (1)

ETIOLOGY AND PATHOPHYSIOLOGY

Primary mechanism is thought to be insulin resistance, leading to increased lipolysis, triglyceride synthesis, and increased hepatic uptake of fatty acids. 
  • NAFLD: excessive triglyceride accumulation in the liver and impaired ability to remove fatty acids

  • NASH: multiple hit theory that inflammation precedes steatosis in environmentally and genetically predisposed people. Multiple insults, including insulin resistance, hormones from adipose tissue, nutritional factors, endotoxins released by the gut microbiota, oxidative stress damage, and genetic factors. These “hits” act on liver parenchymal cells via toll-like receptors to lead to the progression of NASH (3).

Genetics

Largely unknown: Some familial clustering and increased heritability. NAFL: more first-degree relatives with cirrhosis than matched controls; NASH: 18% with affected first-degree relative. Carriers of hemochromatosis gene are more likely to be affected. Patatin-like phospholipase (PNPLA3) polymorphism implicated in NAFLD, hypertriglyceridemia, and insulin resistance (1,2). 

RISK FACTORS

  • Obesity (BMI >30), visceral obesity (waist circumference >102 cm for men or >88 cm for women), hypertension, dyslipidemia, high serum triglycerides and low serum high-density lipoprotein (HDL) levels, metabolic syndrome

  • Type 2 diabetes mellitus, cardiovascular disease, and chronic kidney disease (2)

  • Possible associations with hypothyroidism, hypopituitarism, hypogonadism, obstructive sleep apnea, pancreaticoduodenal resection, osteoporosis, psoriasis, and polycystic ovary syndrome (2)

  • Increasing age associated with increased prevalence, severity, advanced fibrosis, and mortality

  • High fructose intake linked to intestinal dysbiosis and metabolic stress (4)

  • Protein–calorie malnutrition; total parenteral nutrition (TPN) >6 weeks

  • Severe weight loss (starvation, bariatric surgery)

  • Organic solvent exposure (e.g., chlorinated hydrocarbons, toluene); vinyl chloride; hypoglycin A

  • Gene for hemochromatosis/other conditions with increased iron stores

  • Smoking

  • Drugs: tetracycline, glucocorticoids, tamoxifen, methotrexate, amiodarone, antiretroviral agents for HIV, valproic acid, fialuridine, many chemotherapy regimens, and nucleoside analogues

Pregnancy Considerations

Acute fatty liver of pregnancy: rare but serious complication in 3rd trimester. 50% of cases are associated with preeclampsia.

  • Symptoms: nausea, vomiting, headache, fatigue, right upper quadrant or epigastric pain, jaundice

  • Elevated ALT and AST >300 IU/L but usually <1,000 IU/L; elevated bilirubin

  • Liver biopsy confirms diagnosis (do not delay treatment for biopsy).

  • Early recognition and prompt delivery is key.

  • Recurrence is rare.

 
Pediatric Considerations
  • Pediatric NAFLD

    • Increasing prevalence of NAFLD among children. Parallels rise in pediatric obesity, with prevalence of 9.6% (1).

    • Reports of NAFLD as early as age 2 years and NASH-related cirrhosis as early as age 8 years.

    • Treat with intensive lifestyle modification.

    • Vitamin E of possible benefit.

  • Reye syndrome: fatty liver syndrome with encephalopathy usually following viral illness

    • Symptoms

      • Vomiting with dehydration

      • Confusion, progressive CNS damage

      • Hepatomegaly with extensive fatty vacuolization

      • Hypoglycemia

    • Etiology unknown; viral URIs and drugs (especially salicylates) have been implicated; mortality rate: 50%

    • Treat with mannitol, IV glucose, and FFP.

 

GENERAL PREVENTION

  • Avoid excess alcohol: ≤2 units per day (men); ≤1 unit per day (women)

  • Maintain appropriate BMI

  • Prevention and optimal management of diabetes

  • Avoid hepatotoxic medications

  • HAV and HBV vaccination if not immune

  • Pneumococcal and annual influenza vaccinations

COMMONLY ASSOCIATED CONDITIONS

Central obesity, hypertension, type 2 diabetes, insulin resistance, hyperlipidemia, preeclampsia in pregnancy, CVD and arrhythmias, hypothyroidism, hypogonadism, OSA (1,2

DIAGNOSIS

  • Routine screening not recommended.

  • Consider NAFLD in patients with asymptomatic aminotransferase elevations (1)[A].

  • Can occur with normal AST/ALT levels (1)[A]

  • NAFLD has no distinguishing historical/lab features to distinguish from other chronic liver disorders.

  • Index of suspicion is higher with risk factors such as metabolic syndrome, insulin resistance, or obesity.

  • May present as cryptogenic cirrhosis

  • Noninvasive biomarkers of steatosis/fibrosis are not sufficiently reliable; no validated test yet available.

  • Liver biopsy is the definitive diagnostic test but should only be considered if results will change management.

HISTORY

  • Typically asymptomatic

  • Possible fatigue and/or abdominal fullness

  • Vague right upper quadrant pain

  • History of medications, alcohol use, family history

PHYSICAL EXAM

Most common signs (all are infrequent) 
  • Liver tenderness

  • Mild to marked hepatomegaly

  • Splenomegaly

  • In advanced cases: cutaneous stigmata of chronic liver disease or portal hypertension (e.g., palmar erythema, spider angiomata, ascites)

DIFFERENTIAL DIAGNOSIS

  • Viral hepatitis

  • Alcoholic fatty liver

  • Drug- or toxin-induced hepatitis

  • Metabolic liver disease

  • Autoimmune hepatitis

  • Celiac disease

  • Muscle disease, if nonhepatic cause of elevated enzymes is possible

DIAGNOSTIC TESTS & INTERPRETATION

The diagnosis of NAFLD requires that there is hepatic steatosis (imaging or biopsy); no history of significant alcohol consumption; no other identifiable causes and no co-existing liver disease. 

Initial Tests (lab, imaging)

  • ALT and AST may be elevated.

    • Nonalcoholic, usually AST/ALT >1

    • If alcohol induced, usually AST/ALT ≥2

    • Nonspecific enzyme abnormalities may exist or may be normal with advanced cirrhosis (1,3).

  • Level of enzyme elevation does NOT correlate with degree of fibrosis (1).

  • Serum ferritin (1.5 times normal), alkaline phosphatase (2 to 3 times normal), and total/direct bilirubin may be elevated (1).

  • Severity and chronicity are characterized by defects in ability to produce plasma proteins (serum albumin, PT) and thrombocytopenia—marker for cirrhosis (1).

  • Lipids abnormalities are common and include elevated cholesterol, low-density lipoprotein (LDL), and triglyceride and decreased HDL (1).

  • Biomarkers of inflammation, increased oxidative stress, or hepatocyte apoptosis such as leptin, adiponectin, CRP, serum caspase, and cytokeratin 18 may help differentiate NASH from NAFLD (1)[B].

  • Serologic studies to exclude other causes of liver disease (celiac, α1-antitrypsin, iron, copper, Hepatitis A IgG, Hepatitis B Surface Antigen (HBsAg), Hepatitis B Surface Antibody, Hepatitis B core Antibody, Hepatitis C Antibody, anti-smooth muscle antibody, ANA, serum gammaglobulin) (1)[B]

  • Ultrasound (US) is first-line imaging modality for assessing liver chemistry abnormalities: Fatty liver is hyperechoic on US. MRI/CT may also be used; NAFLD has decreased hepatic attenuation on CT (1)[B].

Follow-Up Tests & Special Considerations

  • Other modalities can help noninvasively quantify fibrosis by estimating liver stiffness (1).

    • Clinical decision aids: NAFLD fibrosis score, FIB-4 index, APRI score

    • Serum biomarkers: Enhanced Liver Fibrosis panel, Fibrotest, Hepascore

    • Imaging: vibration controlled transient elastography (VCTE) or FibroScan, acoustic radiation force impulse (ARFI), magnetic resonance elastography (MRE) (5)[B]

  • No modality has been found to accurately distinguish and diagnose simple steatosis from steatohepatitis (5)[B].

Diagnostic Procedures/Other

Liver biopsy is the gold standard for diagnosis and prognosis—must have likelihood of changing management prior to biopsy (1)[B]. 

Test Interpretation

  • The NAFLD activity score (NAS) is used to grade diagnosis, based on three histologic features: steatosis (0 to 3), inflammation (0 to 3), and hepatocyte ballooning (0 to 2), for score between 0 and 8. NASH is very likely with scores ≥5 (3).

  • Staging scale (0 to 4) is based on fibrosis (1,3).

TREATMENT

  • Sustained weight loss (3–5% body weight) through lifestyle modification is most successful treatment (1,6)[A]. Weight loss for those who are overweight or obese is the only therapy that has good evidence of benefits and safety.

  • Bariatric surgery not proven to improve NASH (1)[B]

  • Aerobic exercise 3 to 5 times per week for 20 to 45 minutes with reduced calorie intake/diet modifications (1)[B]

  • Tight diabetes control (1,6)[B]

  • Treatment of metabolic syndrome—hypertension, dyslipidemia, and obesity (1,6)[B]

  • Avoid or limit alcohol consumption (6)[A].

  • Avoid hepatotoxic medications (1)[B].

MEDICATION

  • Currently no effective medication treatment (1,6)[A]

  • Some promising agents include the following:

    • Thiazolidinediones (pioglitazone): improves liver histology, only use with biopsy-proven NASH (1)[B]

    • Vitamin E 400-800 IU daily: long-term safety concerns at high doses; only use with biopsy-proven NASH (1)[C]

    • GLP-1 receptor agonists, exenatide and liraglutide

    • Pentoxifylline

    • Agents targeting apoptosis, fibrosis, and the gut microbiome are in early trials

  • Agents that have not shown benefit:

ISSUES FOR REFERRAL

Patients with persistent AST/ALT elevations 2 to 3 times ULN or fibrosis on biopsy benefit from hepatology consult (1)[A]. 

SURGERY/OTHER PROCEDURES

Bariatric procedures: NAFLD is not a contraindication in otherwise eligible obese patients. There is a lack of data to definitively assess benefits and harms of surgery in treating patients with NASH (1)[B]. 

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

  • Annual monitoring of LFTs (1,6)[B]

  • Consider surveillance with US or CT scan to evaluate for disease progression (6)[B]. Improvements provide motivation for lifestyle changes.

  • Routine liver biopsy is not recommended but may be repeated 5 years after baseline biopsy if progression of fibrosis is suspected (1,6)[B].

  • Hepatic fibrosis staging is the strongest predictor for all-cause and disease-specific mortality in patients with histologically confirmed NAFLD (2)[B].

DIET

Low in saturated and trans fat; low in simple carbohydrates; avoid excessive alcohol (protective or worsening effect of light/moderate consumption inconclusive). 

PATIENT EDUCATION

Extensive counseling on sustained lifestyle changes in nutrition, exercise, and alcohol use. 

PROGNOSIS

Within the spectrum of NAFLD, only NASH has been shown to be progressive, potentially leading to cirrhosis, hepatocellular carcinoma, cholangiocarcinoma, and/or liver failure: 
  • Cirrhosis develops in up to 20% of patients but may not always be present. Up to 42% of patients develop HCC without showing cirrhosis (3).

  • Transplantation is effective, but NASH may recur after transplantation due to ongoing risk factors.

COMPLICATIONS

Progressive disease may lead to decompensated cirrhosis and portal hypertension with complications such as ascites, encephalopathy, bleeding varices, and hepatorenal or hepatopulmonary syndromes. 

REFERENCES

1
Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology.  2018;67(1):328–357.
2
Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol.  2015;62(Suppl 1):S47–S64.
3
Borrelli A, Bonelli P, Tuccillo FM, et al. Role of gut microbiota and oxidative stress in the progression of non-alcoholic fatty liver disease to hepatocarcinoma: current and innovative therapeutic approaches. Redox Bio.  2018;15:467–479.
4
Sharma M, Mitnala S, Vishnubhotla RK, et al. The riddle of nonalcoholic fatty liver disease: progression from nonalcoholic fatty liver to nonalcoholic steatohepatitis. J Clin Exp Hepatol.  2015;5(2):147–158.
5
Lee SS, Park SH. Radiologic evaluation of nonalcoholic fatty liver disease. World J Gastroenterol.  2014;20(23):7392–7402.
6
Nascimbeni F, Pais R, Bellentani S, et al. From NAFLD in clinical practice to answers from guidelines. J Hepatol.  2013;59(4):859–871.

ADDITIONAL READING

  • Oseini AM, Sanyal AJ. Therapies in non-alcoholic steatohepatitis (NASH). Liver Int.  2017;37(Suppl 1):97–103.

  • Spengler EK, Loomba R. Recommendations for diagnosis, referral for liver biopsy, and treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Mayo Clin Proc.  2015;90(9):1233–1246.

  • Stahl EP, Dhindsa DS, Lee SK, et al. Nonalcoholic fatty liver disease and the heart: JACC state-of-the-art review. J Am Coll Cardiol.  2019;73(8):948–963.

SEE ALSO

Alcohol Use Disorder (AUD); Cirrhosis of the Liver; Diabetes Mellitus, Type 2; Metabolic Syndrome 

CODES

ICD10

K76.0 Fatty (change of) liver, not elsewhere classified 

ICD9

571.8 Other chronic nonalcoholic liver disease 

SNOMED

197315008 Non-alcoholic fatty liver (disorder) 

CLINICAL PEARLS

  • NAFLD is a major cause of liver disease. Spectrum ranges from NAFL to NASH, advanced fibrosis, and cirrhosis.

  • NAFLD is the most common chronic liver disease in children; there has been a parallel rise in childhood obesity and NAFLD.

  • Lifestyle changes with targeted weight loss are the cornerstones of therapy for NAFLD.

  • NAFLD is a common cause of asymptomatic mild serum aminotransferase elevation.

 
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