> Table of Contents > Nonalcoholic Fatty Liver Disease (NAFLD)
Nonalcoholic Fatty Liver Disease (NAFLD)
Jill T. Wei, MD
Daniel T. Lee, MD, MA
image BASICS
  • A spectrum of fatty liver diseases not due to excess alcohol consumption ranging from nonalcoholic fatty liver (NAFL) to steatohepatitis and 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 >30% of cells, 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 ULN
    • Minimal risk of progression to cirrhosis and liver failure
    • Synonym: steatosis
  • Nonalcoholic steatohepatitis (NASH): progressive form of NAFL (1)
    • Liver biopsy: fatty deposits in >50% of cells with ballooning, acute/chronic inflammation, ± fibrosis
    • ALT and AST elevated, generally <3 to 4 times ULN
    • May progress to cirrhosis, liver failure, and rarely hepatocellular cancer; 30% with NASH may progress to fibrosis over 5 years.
  • NASH cirrhosis (1)
    • Presence of cirrhosis with current or previous histologic evidence of steatosis or steatohepatitis
EPIDEMIOLOGY
  • NAFLD: most common chronic liver disease globally; 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: 30-40% (3)
  • Worldwide: 6-33%, median 20% (1)
  • Present in 58-74% of obese persons (BMI >30) and 90% of morbidly obese persons (BMI >39) (1)
  • Among individuals with T2DM, rate of 69-87%; in patients with dyslipidemia, rate of 50% (1)
ETIOLOGY AND PATHOPHYSIOLOGY
Primary mechanism is insulin resistance, which leads to increased lipolysis, triglyceride synthesis, and increased hepatic uptake of fatty acids.
  • NAFLD: excessive triglyceride accumulation in the liver and an impaired ability to remove fatty acids
  • NASH: “2-hit” hypothesis: (i) macrovesicular steatosis due to increased hepatic lipid synthesis, reduced transfer of lipids, and increased insulin resistance with hepatic oxidative stress and (ii) mitochondrial damage leading to impaired restoration of ADT stores, lipid peroxidation, and resultant inflammatory injury (1)
  • Other possible mechanism is lipotoxicity. Free fatty acid metabolites cause endoplasmic reticular stress, hepatocyte apoptosis, necrosis, and inflammation. Hepatocellular injury triggers fibrogenesis and inflammation, hastening disease progression (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 domain-containing 3 (PNPLA3) I148M polymorphism may play a role 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, cardiovascular disease, and chronic kidney disease (2)
  • Possible associations with hypothyroidism, hypopituitarism, hypogonadism, obstructive sleep apnea, pancreatoduodenal 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 (5)
  • Drugs: tetracycline, glucocorticoids, tamoxifen, methotrexate, 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 (6).
  • Symptoms: nausea, vomiting, headache, fatigue, right upper quadrant or epigastric gain, jaundice
  • Elevated ALT and AST >300 IU/L but usually <1,000 IU/L; elevated bilirubin
  • Liver biopsy confirms diagnosis but should not delay treatment.
  • Early recognition and prompt delivery is key
  • Recurrence is rare (6)
Pediatric Considerations
  • Increasing prevalence of NAFLD among children parallels rise in pediatric obesity.
  • 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 may be of possible benefit.
  • Reye syndrome: fatty liver syndrome with encephalopathy usually following viral illness
    • Vomiting with dehydration
    • Confusion, progressive CNS damage
    • Hepatomegaly with extensive fatty vacuolization
    • Hypoglycemia (7)
  • 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: ≤3 standard drinks/day (men); ≤2 standard drinks/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; HTN; type 2 diabetes; insulin resistance; hyerlipidemia; preeclampsia in pregnancy; CVD; hypothyroidism; hypogonadism; OSA (2)
image 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. Liver biopsy is the definitive diagnostic test but should only be considered when results are likely to change management.
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, for example, 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 are possible
DIAGNOSTIC TESTS & INTERPRETATION
  • Both ALT and AST may be elevated.
    • Nonalcoholic, usually ALT:AST >1
    • If alcohol-induced, usually AST:ALT ≥2
    • Nonspecific enzyme abnormalities may exist or may be normal with advanced cirrhosis (1).
  • 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 and direct bilirubin may be elevated (1).
  • P.719

  • Severity and chronicity are characterized by defects in ability to produce plasma proteins (serum albumin, PT) and thrombocytopenia (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 etiologies of liver disease, for example, celiac, &agr;-1-antitrypsin, iron, copper, HepA IgG, HepB SAg, HepC SAb, 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 (1)[B].
Follow-Up Tests & Special Considerations
  • Imaging modalities such as FibroScan (which detects tissue elasticity in cases of suspected hepatic fibrosis) and MR spectroscopy (to assess changes in hepatic fat) are currently being evaluated to better characterize NAFLD (8)[B].
  • No imaging modality can distinguish simple steatosis from steatohepatitis.
Diagnostic Procedures/Other
  • Liver biopsy is the gold standard for diagnosis. To perform procedure, biopsy must have likelihood of changing management (1)[B].
  • NAFLD fibrosis score age (>50 years), BMI (>30), platelet count, albumin, and AST/ALT ratio identifies patients at risk of developing fibrosis/cirrhosis (9)[B].
Test Interpretation
  • Liver biopsy is the gold standard for prognosis (1).
  • In NASH, steatosis, ballooning, and lobular inflammation are minimal criteria for diagnosis. Other common findings include mild to moderate portal inflammation, acidophil bodies, perisinusoidal zone 3 fibrosis, megamitochondria, and Mallory-Denk bodies (hyaline) in hepatocytes (1).
  • Staging is based largely on the extent of fibrosis (1).
image TREATMENT
  • Sustained weight loss through lifestyle modification of at least 3-5% of body weight is most successful treatment (1,9)[A].
  • Foregut bariatric surgery not yet proven to specifically treat NASH (1)[B]
  • Aerobic exercise 3 to 5 times weekly for 20 to 45 minutes with reduced calorie intake/diet modifications (1)[B]
  • Tight control of diabetes (1,9)[B]
  • Treatment of metabolic syndrome—hypertension, dyslipidemia, and obesity (1,9)[B]
  • Limit alcohol consumption (<21 drinks/week for men and <14 drinks/week for women) (9)[A].
  • Avoid hepatotoxic medications (1)[B].
MEDICATION
Currently no effective medication treatment (1,9)[A]
Several promising agents include the following:
  • Thiazolidinediones (pioglitazone) (1)[B]
  • Vitamin E (1)[B]
  • Other drugs studied in small studies (1,9,10)[B,C]
    • Statins, but study excluded cases with AST and AST >1.5 times normal limit
    • Gemfibrozil; omega-3 fatty acids
    • Angiotensin receptor blockers; probiotics
    • Obeticholic acid (bile acid derivative)
    • Ursodeoxycholic acid
ISSUES FOR REFERRAL
Persistent AST/ALT elevations 2 to 3 times above upper limit of normal without diagnosis or those with fibrosis on biopsy benefit from hepatology evaluation (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].
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
  • Annual monitoring of LFTs (1,9)[B]
  • Consider surveillance monitoring with US or CT scan to evaluate disease progression/improvement (9)[B]. Improvements can provide motivation for ongoing lifestyle changes.
  • Routine liver biopsy is not recommended but may be repeated 5 years after baseline biopsy if progression of fibrosis is suspected (1,9)[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 NALFD, only NASH has been shown to be progressive, potentially leading to cirrhosis, hepatocellular carcinoma, cholangiocarcinoma, and/or liver failure (11):
  • Cirrhosis develops in up to 15-20% of patients. Approximately 2-3% of patients with cirrhosis will develop HCC each year (3).
  • Transplantation is effective, but NASH may recur after transplantation due to ongoing risk factors.
REFERENCES
1. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 2012;142(7):1592-1609.
2. Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol. 2015;62(1)(Suppl):S47-S64.
3. 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.
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. Than NN, Newsome PN. A concise review of non-alcoholic fatty liver disease. Atherosclerosis. 2015;239(1):192-202.
6. Ahmed KT, Almashhrawi AA, Rahman RN, et al. Liver diseases in pregnancy: diseases unique to pregnancy. World J Gastroenterol. 2013;19(43):7638-7646.
7. Hurwitz ES, Nelson DB, Davis C, et al. National surveillance for Reye syndrome: a five-year review. Pediatrics. 1982;70(6):895-900.
8. Browning JD. New imaging techniques for non-alcoholic steatohepatitis. Clin Liver Dis. 2009;13(4):607-619.
9. Nascimbeni F, Pais R, Bellentani S, et al. From NAFLD in clinical practice to answers from guidelines. J Hepatol. 2013;59(4):859-871.
10. Ratziu V, Goodman Z, Sanyal A. Current efforts and trends in the treatment of NASH. J Hepatol. 2015;62(1)(Suppl):S65-S75.
11. White DL, Kanwal F, El-Serag HB. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol. 2012;10(12):1342-1359.e2.
Additional Reading
&NA;
  • Rinella ME. Nonalcholic fatty liver disease: a systematic review. JAMA. 2015;313(22):2263-2273.
  • Schwimmer JB, Pardee PE, Lavine JE, et al. Cardiovascular risk factors and the metabolic syndrome in pediatric nonalcoholic fatty liver disease. Circulation. 2008;118(3):277-283.
  • Thoma C, Day CP, Trenell MI. Lifestyle interventions for the treatment of non-alcoholic fatty liver disease in adults: a systematic review. J Hepatol. 2012;56(1):255-266.
See Also
&NA;
Alcohol Abuse and Dependence; Cirrhosis of the Liver; Diabetes Mellitus, Type 2; Metabolic Syndrome
Codes
&NA;
ICD10
K76.0 Fatty (change of) liver, not elsewhere classified
Clinical Pearls
&NA;
  • NAFLD: major cause of liver disease. Spectrum ranges from NAFL to NASH, advanced fibrosis, and cirrhosis.
  • NAFLD: most common chronic liver disease in children; 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.