II. Definition

  1. Nonalcoholic Fatty Liver Disease
    1. Spectrum of disorders of liver fat infiltration not due to Alcohol, medication or hereditary disorder
    2. Severity ranges from Steatosis to severe fibrosis (NASH)

IV. Epidemiology

  1. Most common cause of liver disease in western countries
    1. NAFLD Prevalence: 30% of U.S. population (17% in Framingham study)
    2. Nonalcoholic Steatohepatitis (NASH) occurs in up to 3-5% of the U.S. population
      1. Affects up to 66% of age >50 years with Obesity or Diabetes Mellitus
  2. Frequent cause of mild Liver Function Test Abnormality
    1. Most common cause of mildly abnormal ALT and AST in U.S. (accounts for up to 51% of cases)
  3. Most common cause of cryptogenic Cirrhosis (U.S. adult)
  4. More common in women

V. Pathophysiology

  1. Nonalcoholic Fatty Liver (hepatic Steatosis without inflammation)
    1. Insulin Resistance is a major inciting factor of hepatic Steatosis
    2. Lipotoxicity from free Fatty Acids
  2. Nonalcoholic Steatohepatitis (more severe, with risk of Cirrhosis)
    1. Hepatocyte injury with cell ballooning and inflammation
    2. Inflammatory factors include cytokines and oxidative stress
    3. Progresses to hepatic fibrosis and Cirrhosis, and increased risk of Hepatocellular Carcinoma

VI. Risk Factors

  1. Obesity
    1. NASH occurs in 66% of all obese patients (BMI>30) over age 50 years old
    2. Occurs in 90% of patients at BMI>39
  2. Hyperglycemia (75% of NASH patients)
    1. Metabolic Syndrome
    2. Type II Diabetes Mellitus
  3. Hyperlipidemia (especially Hypertriglyceridemia)
  4. Rapid weight loss
    1. Starvation
    2. Gastric Bypass
  5. Refeeding Syndrome
  6. Total Parenteral Nutrition
  7. Medications
    1. Amiodarone
    2. Diltiazem
    3. Antiretroviral Therapy (esp. Protease Inhibitors)
    4. Corticosteroids
    5. Tamoxifen

VII. Symptoms

  1. Asymptomatic in most cases
  2. Fatigue
  3. Malaise
  4. Right upper quadrant pain

VIII. Signs

  1. Hepatomegaly (50%)

X. Labs: Liver specific (first-line)

  1. Liver Transaminases (ALT, AST)
    1. Normal in some cases
    2. Typically 2-3 fold increase in transaminases
      1. If over 1000 consider other cause
        1. Viral Hepatitis
        2. Hepatotoxin exposure
    3. AST/ALT ratio <1 (not true in late disease)
      1. If AST exceeds ALT, consider Alcoholic Hepatitis
  2. Alkaline Phosphatase may be increased up to 2 fold
  3. Gamma-Glutamyltransferase (GGT) increased in some cases
    1. If over 2 times normal consider Alcoholic Hepatitis
  4. Cirrhosis screening (includes Liver synthetic function)
    1. Serum Bilirubin
    2. Serum Albumin
    3. Prothrombin Time

XII. Labs: Secondary causes - uncommon (consider if other testing negative)

  1. Autoimmune Hepatitis
    1. Antinuclear Antibody
    2. Smooth Muscle Antibody
    3. Consider liver and Kidney microsomal antibodies
  2. Alpha-1-Antitrypsin Deficiency
    1. Alpha-1-Antitrypsin
  3. Wilson Disease (consider in young patients, such as <30 years old, with liver disease)
    1. Ceruplasmin
    2. Consider 24 hour urinary copper

XIII. Imaging

  1. Right upper quadrant Ultrasound (Preferred first-line)
    1. Finding
      1. Increased liver echoes (fatty infiltrates)
    2. Disadvantages
      1. Does not determine disease severity
      2. Fibrosis and Steatosis are indistinguishable on Ultrasound
    3. Efficacy
      1. Test Sensitivity: 82-89%
      2. Test Specificity: 93%
  2. CT Abdomen (unenhanced)
    1. Precautions
      1. CT with contrast decreases the Test Specificity compared to unenhanced CT
    2. Advantages
      1. Better sensitivity than Ultrasound
      2. Better identification of other liver abnormalities
    3. Disadvantages
      1. CT-associated Radiation Exposure
      2. Higher cost than Ultrasound
    4. Efficacy
      1. Test Sensitivity: 88-95%
      2. Test Specificity: 90-99%
  3. MRI Abdomen
    1. Advantages
      1. Highest accuracy
    2. Disadvantages
      1. Expensive
    3. Efficacy: Steatosis
      1. Test Sensitivity: 96%
      2. Test Specificity: 93%
    4. Efficacy: Fibrosis
      1. Test Sensitivity: 94%
      2. Test Specificity: 73%

XIV. Diagnosis: Noninvasive Tests for Advanced Fibrosis in NAFLD patients

  1. AST/ALT ratio (AAR)
    1. Score 0.8 or higher is suggestive of NAFLD with liver fibrosis (Test Sensitivity: 74%, Test Specificity: 78%)
  2. AST/Platelet Count ratio index (APRI)
    1. AST/Platelet Count ratio index <0.3 to 0.5 excludes significant liver fibrosis or Cirrhosis
    2. AST/Platelet Count ratio index >1.5 rules in significant liver fibrosis or Cirrhosis
    3. Loaeza-del-Castillo (2008) Ann Hepatol 7(4):350-7 [PubMed]
  3. NAFLD Fibrosis Score (preferred)
    1. http://nafldscore.com/
    2. Liver fibrosis risk based on age, Hyperglycemia, BMI, Platelet Count, Serum Albumin, AST, ALT
    3. Score <-1.455 excludes advanced fibrosis while score >0.675 suggests advanced liver fibrosis (90% Test Sensitivity)
    4. Angulo (2007) Hepatology 45(4):846-54 [PubMed]
  4. Vibration-Controlled Transient Elastography (Fibroscan)
    1. Imaging study with high sensitivity for even mild liver fibrosis
    2. May be limited by operator experience and morbidly obese
    3. Myers (2012) Hepatology 55(1): 199-208 [PubMed]
  5. Alcoholic Liver Disease to NAFLD Index
    1. Used to distinguish Alcoholic Liver Disease from NAFLD (based on ALT, AST, MCV, height, weight, gender)
    2. https://www.mayoclinic.org/medical-professionals/model-end-stage-liver-disease/alcoholic-liver-disease-nonalcoholic-fatty-liver-disease-index
  6. BARD Score
    1. Score <2 has a strong Negative Predictive Value (90-97%) for NAFLD with fibrosis
  7. Fibrosis Probability Score (FIB-4 Index)
    1. Clinical score based on age, Platelet Count, AST and ALT
    2. Efficacy: Test Sensitivity: 85%, Test Specificity: 65%
  8. HAIR Score
    1. Severely obese (BMI >35 kg/m2) patient assessment for risk of Nonalcoholic Steatohepatitis (NASH)
    2. Assign one point each for Hypertension, elevated ALT, Insulin Resistance
    3. Score 2 or 3 predicts progressive liver injury
  9. Other tests
    1. See MRI Abdomen above
    2. Enhanced Liver Fibrosis panel (Test Sensitivity and Test Specificity approach 100%)
    3. FibroTest or FibroSure (Test Sensitivity: 15%, Test Specificity: 98%)
    4. Fibrometer (Test Sensitivity: 79%, Test Specificity: 96%)

XV. Diagnosis: Liver Biopsy

  1. Grades degree of fatty infiltration
    1. Hepatic Steatosis (fat accumulation in liver)
      1. Intracellular fat in >5% of hepatocytes
    2. Nonalcoholic Steatohepatitis (Steatosis AND liver cell injury and inflammation)
      1. Hepatocyte ballooning
      2. Mallory hyaline
      3. Perivenular inflammatory infiltrate (Lymphocytes, Neutrophils)
      4. Hepatocyte necrosis and apoptosis
      5. Hepatocyte fibrosis may be present
  2. Distinguishes NASH from other causes of liver injury and inflammation
    1. Autoimmune Hepatitis
    2. Alpha-1-Antitrypsin Deficiency
    3. Alpha-1-Antitrypsin
    4. Hemochromatosis
    5. Wilson Disease

XVI. Evaluation: Initial

  1. History and exam
    1. Consider comorbid history
      1. Premature COPD in alpha-1 antitrypsin deficiency
    2. Consider differential diagnosis (see above)
      1. Alcoholic Hepatitis
      2. Hepatoxic Medication
      3. Viral Hepatitis
    3. Consider Family History
      1. Hemochromatosis
      2. Wilson Disease
    4. Evaluate for likelihood of NASH
      1. Diabetes Mellitus or Metabolic Syndrome
      2. Body Mass Index
      3. Waist Circumference
  2. Labs
    1. Start with liver specific first-line labs and common secondary cause labs above
    2. Consider uncommon secondary cause labs as above (based on history, risk factors)
  3. Diagnostics
    1. Consider liver imaging (e.g. RUQ Ultrasound)

XVII. Management: Approach

  1. Step 1: Initial
    1. Confirm likelihood of NASH as underlying cause
    2. Start with initial evaluation as above, including confirmation of Liver Function Test Abnormality
    3. Institute lifestyle change (e.g. weight loss, Healthy Diet, Exercise, hyperlidemia management)
  2. Step 2: Month 6 (following lifestyle change)
    1. Repeat Liver Function Tests
    2. If Abnormal Liver Function Testing
      1. Consider liver imaging
      2. Evaluate with noninvasive tests for liver fibrosis (see above)
  3. Step 3: Gastroenterology referral indications (for evaluation and liver biopsy)
    1. Noninvasive tests suggest fibrosis (NAFLD Fibrosis Score)
    2. Persistently elevated Liver Function Tests despite interventions
    3. Suspected secondary cause of Steatosis other than NASH (e.g. Hemochromatosis, Autoimmune Hepatitis)

XVIII. Management

  1. See Prevention of Liver Disease Progression
  2. Weight Reduction
    1. Liver Function Tests improve or normalize with as little as 5-10% weight loss
    2. Fibrosis may not improve after weight loss
    3. Low to moderate fat intake and low carbohydrate
      1. Consider Mediterranean Diet
      2. Avoid high fructose corn syrup (beverages, foods)
    4. Consider Xenical which does improve liver enzymes and liver histology
    5. Physical Activity 150 to 200 minutes of moderate to vigorous Exercise
  3. Restrict Alcohol intake (2 standard drinks/day for men, 1/day for women)
  4. Maximize Glucose control
    1. Conditions
      1. Type II Diabetes Mellitus
      2. Metabolic Syndrome
    2. Medications: Glucophage (Metformin)
      1. Reduces transaminases, Steatosis in non-diabetics
    3. Medications: Glitazones
      1. Glitazones may be used if AST amd ALT <3x normal
      2. Monitor AST and ALT every 3 months
      3. Reduces transaminases, Steatosis in non-diabetics
  5. Lipid Reduction as needed with AntiHyperlipidemic
    1. AntiHyperlipidemic may be used if AST,ALT <3x normal
    2. Monitor AST and ALT every 3 months
    3. Statins (preferred) decrease transaminases, Steatosis
    4. Mixed results with Ursodeoxycholic Acid
  6. Control Hypertension
    1. Angiotensin Receptor Blockers
  7. Supplements that may offer benefit
    1. L-Carnitine
    2. Vitamin E 800 IU/day (variable efficacy)
    3. Avoid Milk Thistle (ineffective)
  8. References
    1. Musso (2010) Hepatology 52(1): 79-104 [PubMed]

XIX. Prognosis

  1. Nonalcoholic Fatty Liver (Hepatic Steatosis without inflammation)
    1. Rare progression to Cirrhosis
  2. Nonalcoholic Steatohepatitis (5% of general population, up to 66% of age >50 years with Diabetes Mellitus, Obesity)
    1. Hepatocellular Carcinoma: 1-5% risk
    2. Cirrhosis risk: 20% overall
      1. Advanced fibrosis in 15-30% of cases
      2. Advanced fibrosis progresses to Cirrhosis in 12-35%

XX. Complications

  1. Portal Hypertension
  2. Cirrhosis if associated with severe comorbid condition
    1. Morbid Obesity (BMI >30)
    2. Type II Diabetes Mellitus
    3. AST to ALT ratio >1
  3. Coronary Artery Disease
    1. Results in greatest morbidity
    2. Treat underlying Hyperlipidemia
  4. Diabetic Retinopathy
    1. Associated with increased Incidence in those with NAFLD and Diabetes Mellitus

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Related Studies

Ontology: Fatty Liver (C0015695)

Definition (MSHCZE) steatóza jater – nahromadění tuku v jaterních buňkách, časté při obezitě, alkoholismu, hyperlipoproteinemii, diabetu, těžké malnutrici; akutně u některých intoxikací, Reyově syndromu aj. Játra bývají zvětšená; s. je možné diagnostikovat morfologicky, je patrná i při sonografii (zvýšená echogenita při výraznějším postižení), bývají větš. změny jaterních testů vč. alkalické fosfatázy. Mikroskopicky se rozlišuje častější velkokapénková a malokapénková forma. (cit. Velký lékařský slovník online, 2013 http://lekarske.slovniky.cz/ )
Definition (MSH) Lipid infiltration of the hepatic parenchymal cells resulting in a yellow-colored liver. The abnormal lipid accumulation is usually in the form of TRIGLYCERIDES, either as a single large droplet or multiple small droplets. Fatty liver is caused by an imbalance in the metabolism of FATTY ACIDS.
Definition (CSP) yellow discoloration of the liver due to fatty degeneration of liver parenchymal cells.
Concepts Disease or Syndrome (T047)
MSH D005234
SnomedCT 197321007, 390002007, 5360002, 371330000
English Liver, Fatty, LIVER FATTY, LIVER FATTY CHANGE, LIVER FATTY DEGENERATION, LIVER FATTY INFILTRATION, LIVER FATTY METAMORPHOSIS, Fatty change of liver, Fatty infiltration of liver, Fatty changes in liver, Fatty Liver, fatty liver, fatty liver (diagnosis), Liver fatty change, Degeneration fatty liver, Liver fatty degeneration, Fatty liver infiltration, Infiltration fatty liver, Liver fatty infiltration, Liver fatty, Fatty liver metamorphosis, Liver fatty metamorphosis, Metamorphosis fatty liver, Hepatic lipidosis, Fatty liver, Fatty Liver [Disease/Finding], fatty livers, hepatic lipidosis, changes fatty liver, liver steatosis, fatty infiltration liver, change fatty liver, fatty liver metamorphosis, liver fatty change, liver fatty infiltration, hepatic steatosis, steatosis of liver, fatty liver infiltration, fatty change liver, Fatty change of liver (disorder), Fatty liver (disorder), Lipidosis of liver, degeneration; fatty, liver, degeneration; liver, fatty, fat; liver, fatty; degeneration liver, fatty; liver degeneration, infiltrate; liver, fatty, liver; degeneration, fatty, liver; fat, liver; infiltrate, fatty, hepatitic steatosis
French STEATOSE HEPATIQUE, Dégénérescence graisseuse du foie, Stéatose par infiltration, Infiltration graisseuse du foie, Stéatose avec métamorphose, Stéatose par infiltration graisseuse, Altération de la stéatose du foie, DEGENERESCENCE GRAISSEUSE DU FOIE, INFILTRATION GRAISSEUSE DU FOIE, METAMORPHOSE GRAISSEUSE DU FOIE, TRANSFORMATION GRAISSEUSE DU FOIE, Stéatose hépatique, Stéatose du foie
Spanish HIGADO GRASO, Hígado graso, Metamorfosis grasa de hígado, Transformación grasa de hígado, Infiltración grasa de hígado, Degeneración grasa del hígado, HIGADO, CAMBIO GRASO, HIGADO, INFILTRACION GRASA, HIGADO, METAMORFOSIS GRASA, hígado graso, lipidosis hepática, hígado graso (trastorno), Hígado Graso
German FETTLEBER, Leber, Verfettung, Infiltration, Fettleber, fettige Infiltration der Leber, Metamorphose, Fettleber, Leber, fettige Metamorphose, fettige Degeneration der Leber, fettige Metamorphose der Leber, Leber, fettige Degeneration, Leber, fettige Infiltration, LEBER FETTIGE DEGENERAT, LEBER FETTIGE INFILTRAT, LEBER FETTIGER UMBAU, LEBERSTEATOSE, Fettleber
Dutch leververvetting, leververvettingsverandering, vette lever infiltratie, leververvetting infiltratie, infiltratie van leververvetting, leververvettingsdegeneratie, leververvetting metamorfose, degeneratie vette lever, vette lever, vette lever metamorfose, metamorfose vette lever, degeneratie; lever, vettig, degeneratie; vettig, lever, infiltraat; lever, vettig, lever; degeneratie, vettig, lever; infiltraat, vettig, lever; vet, vet; lever, vettig; degeneratie lever, vettig; leverdegeneratie, Leversteatose, Leververvetting, Vetlever
Italian Infiltrazione grassa del fegato, Metamorfosi grassa del fegato, Trasformazione grassa del fegato, Degenerazione adiposa del fegato, Trasformazione adiposa del fegato, Infiltrazione lipidica epatica, Degenerazione grassa del fegato, Steatosi epatica
Portuguese Degenerescência gorda do fígado, Metamorfose de fígado gordo, Fígado gordo, Alteração gorda do fígado, Infiltração gorda do fígado, Metamorfose gorda do fígado, Infiltração de fígado gordo, Figado gordo, DEGENERESCENCIA GORDA DO FIGADO, GORDURA NO FIGADO, INFILTRACAO LIPIDICA NO FIGADO, METAMORFOSE LIPIDICA DO FIGADO, TRANSFORMACAO LIPIDICA DO FIGADO, Esteatose Hepática, Esteatohepatite, Fígado Gorduroso
Japanese 肝脂肪浸潤, 肝脂肪変性, カンシボウヘンセイ, カンシボウシンジュン, シボウカン, 脂肪肝
Swedish Fettlever
Finnish Rasvamaksa
Czech Hepatální steatóza, Jaterní steatóza, Degenerativní jaterní steatóza, Steatóza jater, ztučnělá játra, ztučnění jater
Polish Stłuszczenie wątroby, Choroba stłuszczeniowa wątroby
Hungarian Zsíros májdegeneratio, máj zsíros átalkulása, Máj zsíros infiltrációja, Zsíros máj metamorphosis, Zsíros máj infiltratio, Máj zsíros elváltozása, Zsíros máj, Zsírmáj, degeneratio adiposa hepatis, Máj zsíros infiltratioja, Máj zsíros metamorphosisa
Norwegian Fettlever

Ontology: Fatty degeneration (C0152254)

Definition (NCI) A morphologic finding indicating intracytoplasmic fat accumulation in the liver parenchyma.
Concepts Pathologic Function (T046)
SnomedCT 190803000, 29185008
English fatty change, fatty degeneration, fatty metamorphosis, steatosis, changes fatty, Fatty Change, Lipoid degeneration, Fatty change, Fatty metamorphosis, Steatosis, Fatty degeneration, Fatty degeneration (morphologic abnormality)
Spanish acumulación grasa intraparenquimatosa, degeneración grasa (anomalía morfológica), degeneración grasa, degeneración lipoidea, esteatosis, metamorfosis grasa

Ontology: Non-alcoholic Fatty Liver Disease (C0400966)

Definition (NCI) A term referring to fatty replacement of the hepatic parenchyma which is not related to alcohol use.
Definition (MSH) Fatty liver finding without excessive ALCOHOL CONSUMPTION.
Concepts Disease or Syndrome (T047)
MSH D065626
ICD10 K76.0
SnomedCT 197315008, 371329005, 5360002
English NAFLD - Nonalcoholic fatty liver disease, nonalcoholic fatty liver, nonalcoholic fatty liver (diagnosis), NAFLD - Nonalcoholic Fatty Liver Disease, Nonalcoholic fatty liver disease (NAFLD), non-alcoholic fatty liver, Nonalcoholic fatty liver disease, Nonalcoholic fatty liver (disorder), Nonalcoholic fatty liver, Liver, Nonalcoholic Fatty, Non-alcoholic Fatty Liver Disease, Fatty Liver, Nonalcoholic, Nonalcoholic Fatty Livers, Fatty Livers, Nonalcoholic, Livers, Nonalcoholic Fatty, Nonalcoholic Fatty Liver, Nonalcoholic Fatty Liver Disease, Non alcoholic Fatty Liver Disease, NAFLD, Non-alcoholic fatty liver, Non-alcoholic fatty liver (disorder)
Spanish esteatohepatitis no alcohólica, Hígado graso no alcohólico, hígado graso no alcohólico, hígado graso no alcohólico (trastorno), esteatosis hepática no alcohólica (trastorno), esteatosis hepática no alcohólica, hígado graso de causa no alcohólica
Czech Nealkoholická jaterní steatóza
Dutch niet-alcoholische leververvetting
French Stéatose hépatique non éthylique
German nicht-alkoholische Fettleber
Hungarian Nem-alkoholos zsírmáj
Italian Steatosi epatica non alcolica
Japanese 非アルコール性脂肪肝, ヒアルコールセイシボウカン
Portuguese Fígado gordo não alcoólico

Ontology: Steatohepatitis (C2711227)

Definition (MSH) Inflammation of the liver related to lipid accumulation in fatty liver.
Definition (MSHCZE) Mikroskopický obraz steatózy jater se známkami zánětu v periportálních oblastech infiltrace a vznikem lipogranulomů. (cit. Velký lékařský slovník online, 2013 http://lekarske.slovniky.cz/ )
Concepts Disease or Syndrome (T047)
MSH D005234
SnomedCT 442191002, 197321007
Italian Steatosi epatica
Dutch steatose lever, lever; steatose, steatose; lever, hepatische steatose
German Steatosis der Leber, Steatosis hepatis
Portuguese Esteatose hepática, Estenose hepática
Japanese 脂肪肝, シボウカン
English Liver steatosis, hepatic steatosis, Hepatic steatosis, Steatosis hepatic, Steatohepatitis (disorder), Liver Steatosis, Steatohepatitis, Steatosis, Liver, Steatoses, Liver, Steatosis of Liver, Steatohepatitides, Visceral Steatosis, Liver Steatoses, Visceral Steatoses, Steatoses, Visceral, Steatosis, Visceral, Steatosis of liver, Steatosis of liver (disorder), liver; steatosis, steatosis; liver
Czech Jaterní steatóza, steatohepatitida, steatóza jater, jaterní steatóza
Spanish esteatohepatitis, esteatohepatitis (trastorno), esteatosis hepática (trastorno), esteatosis hepática, Esteatosis hepática
French Stéato-hépatite, Stéatose viscérale, Stéatohépatite, Stéatose hépatique
Hungarian Máj steatosis, Steatosis hepatis
Norwegian Leversteatose

Ontology: Nonalcoholic Steatohepatitis (C3241937)

Definition (NCI) Fatty replacement and damage to the hepatocytes not related to alcohol use. It may lead to cirrhosis and liver failure.
Concepts Disease or Syndrome (T047)
MSH D065626
ICD10 K75.81
SnomedCT 442685003
English nonalcoholic steatohepatitis (diagnosis), nonalcoholic steatohepatitis, Nonalcoholic steatohepatitis, NASH - Nonalcoholic steatohepatitis, Nonalcoholic steatohepatitis (disorder), NASH - Nonalcoholic Steatohepatitis, Nonalcoholic steatohepatitis (NASH), Non-alcoholic steatohepatitis, Nonalcoholic Steatohepatitides, Steatohepatitis, Nonalcoholic, Nonalcoholic Steatohepatitis, Steatohepatitides, Nonalcoholic
Spanish esteatohepatitis no alcohólica (trastorno), esteatohepatitis no alcohólica, esteatosis hepática no alcohólica (trastorno), esteatosis hepática no alcohólica, Esteatohepatitis no alcohólica
Czech Nealkoholická steatohepatitida
German nicht-alkoholische Fettleber
Hungarian Nem-alkoholos steatohepatitis
Italian Steatoepatite non alcolica
Japanese 非アルコール性脂肪性肝炎, ヒアルコールセイシボウセイカンエン
Portuguese Esteatose hepática não alcoólica
Dutch niet-alcoholische steatohepatitis
French Stéatose hépatique non alcoolique