I. Indications

  1. Noninvasive Test for Evaluation for advanced fibrosis in Nonalcoholic Fatty Liver Disease

II. Criteria

  1. BMI: 28 or higher
    1. Score 1 point
  2. AST to ALT ration (AAR): 0.8 or higher
    1. Score 2 points
  3. Type 2 Diabetes Mellitus
    1. Score 1 point

III. Interpretation

  1. BARD Score less than 2 has a strong Negative Predictive Value for advanced hepatic fibrosis associated with Nonalcoholic Fatty Liver Disease

IV. Efficacy (for Total score 2 or higher)

VI. Definition

  1. Liver fatty infiltration without other cause identified (e.g. Alcohol)

VII. Epidemiology

  1. Most common cause of liver disease in western countries
    1. Affects up to 24% of U.S. patients (17% in Framingham study)
  2. Frequent cause of mild Liver Function Test Abnormality
    1. Most common cause of abnormal ALT and AST in U.S.
  3. Most common cause of cryptogenic Cirrhosis (U.S. adult)
  4. More common in women

VIII. Pathophysiology

  1. Insulin Resistance is a major inciting factor of hepatic Steatosis
  2. Inflammatory factors include cytokines and oxidative stress
  3. Progresses to hepatic fibrosis and Cirrhosis

IX. Risk Factors

  1. Obesity
    1. Occurs in 66% of all obese patients (BMI>30)
    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

X. Symptoms

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

XI. Signs

  1. Hepatomegaly (50%)

XIII. 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

XIV. Labs: Secondary causes - common

XV. 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
    1. Ceruplasmin
    2. Consider 24 hour urinary copper

XVI. 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%

XVII. 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 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 fibrosis or Cirrhosis
    2. AST/Platelet Count ratio index >1.5 rules in significant fibrosis or Cirrhosis
    3. Loaeza-del-Castillo (2008) Ann Hepatol 7(4):350-7
  3. BARD Score
    1. Score <2 has a strong Negative Predictive Value (90-97%) for NAFLD with fibrosis
  4. Other tests
    1. See MRI Abdomen above
    2. Enhanced Liver Fibrosis panel (Test Sensitivity and Test Specificity approach 100%)
    3. FIB-4 (Test Sensitivity: 85%, Test Specificity: 65%)
    4. FibroTest or FibroSure (Test Sensitivity: 15%, Test Specificity: 98%)
    5. Fibrometer (Test Sensitivity: 79%, Test Specificity: 96%)

XVIII. 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

XIX. 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. Hepatoxins
      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)

XX. 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, 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
    2. Persistently elevated Liver Function Tests despite interventions
    3. Suspected secondary cause of Steatosis other than NASH (e.g. Hemochromatosis, Autoimmune Hepatitis)

XXI. 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. Consider Xenical which does improve liver enzymes and liver histology
  3. Restrict Alcohol intake
  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 and Lopid 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 (variable efficacy)
  8. References
    1. Musso (2010) Hepatology 52(1): 79-104

XXII. Prognosis

  1. Hepatic Steatosis
    1. Rare progression to Cirrhosis
  2. Nonalcoholic Steatohepatitis (10%)
    1. Advanced fibrosis in 15-30% of cases
    2. Advanced fibrosis progresses to Cirrhosis in 12-35%
  3. Hepatitis occurs in 10% of patients
    1. Of the hepatitis group, a third develop Cirrhosis

XXIII. 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. Cardiovascular disease results in greatest morbidity
    1. Treat underlying Hyperlipidemia

Images: Related links to external sites (from Google)

Ontology: Fatty Liver (C0015695)

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 390002007, 371330000, 197321007, 5360002
English Liver, Fatty, LIVER FATTY, DEGENERATION FATTY LIVER, FATTY LIVER, Fatty metamorphosis, liver, INFILTRATION FATTY LIVER, LIVER FATTY CHANGE, LIVER FATTY DEGENERATION, LIVER FATTY INFILTRATION, LIVER FATTY METAMORPHOSIS, METAMORPHOSIS FATTY LIVER, Fatty change of liver, Fatty infiltration of liver, Fatty changes in liver, Fatty Liver, fatty liver, fatty liver (diagnosis), Fatty change of liver (disorder), 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, FATTY LIVER INFILTRATION, Fatty liver (disorder), 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, 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, Fatty change of liver, HIGADO, CAMBIO GRASO, HIGADO, INFILTRACION GRASA, HIGADO, METAMORFOSIS GRASA, hígado graso (trastorno), hígado graso, lipidosis hepática, Hígado Graso, Higado 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, Esteatohepatite, Esteatose Hepática, 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
Czech steatóza jater, Hepatální steatóza, Jaterní steatóza, Degenerativní jaterní steatóza, Steatóza jater
Finnish Rasvamaksa
Russian PECHENI ZHIROVAIA DISTROFIIA, ПЕЧЕНИ ЖИРОВАЯ ДИСТРОФИЯ
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

Ontology: Fatty degeneration (C0152254)

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