Nonalcoholic Fatty Liver

Aka: Nonalcoholic Fatty Liver, Nonalcoholic Steatohepatitis, Idiopathic Fatty Liver, Steatosis, Steatohepatitis, Fatty Liver, NASH, Nonalcoholic Fatty Liver Disease, NAFLD

1. 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)
2. See Also
   1. Acute Fatty Liver of Pregnancy
   2. Liver Function Test Abnormality
3. 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
4. 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
5. 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
6. Symptoms
   1. Asymptomatic in most cases
   2. Fatigue
   3. Malaise
   4. Right upper quadrant pain
7. Signs
   1. Hepatomegaly (50%)
8. Differential Diagnosis
   1. See Liver Function Test Abnormality
   2. Viral Hepatitis (Hepatitis B, Hepatitis C)
   3. Alcoholic Hepatitis
   4. Hepatotoxins
   5. Autoimmune Hepatitis
   6. Hereditary Hemochromatosis
   7. Wilson Disease
   8. Alpha-1-Antitrypsin Deficiency
9. 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
10. Labs: Secondary causes - common
    1. See Liver Function Test Abnormality
    2. Metabolic Syndrome and other causes of lipid abnormalities
       1. Hemoglobin A1C
       2. Fasting Glucose
       3. Lipid profile with Fasting serum Triglycerides, LDL Cholesterol and HDL Cholesterol
       4. Thyroid Stimulating Hormone
    3. Viral Hepatitis
       1. HBsAg
       2. xHCV
    4. Hemochromatosis
       1. Serum Ferritin
       2. Serum Iron
       3. Consider Hemochromatosis genetic testing (HFE)
11. 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
12. 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%
13. 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%)
14. 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
15. 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)
16. 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)
17. 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]
18. 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%
19. 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
20. References
    1. Angulo (2002) N Engl J Med 346:1221-31 [PubMed]
    2. Bayard (2006) Am Fam Physician 73:1961-68 [PubMed]
    3. Careyva (2016) Am Fam Physician 94(12): 980-6 [PubMed]
    4. Kumar (2000) Mayo Clin Proc 75:733-9 [PubMed]
    5. Oh (2017) Am Fam Physician 96(11): 709-15 [PubMed]
    6. Sanyal (2002) Gastroenterology 123:1705-25 [PubMed]
    7. Wilkins (2013) Am Fam Physician 88(1): 35-42 [PubMed]