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: 10-30% of U.S. population (17% in Framingham study)
      2. Nonalcoholic Steatohepatitis (NASH) accounts for up to one third of NAFLD cases
         1. Occurs in up to 3-5% of the U.S. population
         2. Affects up to 66% of age >50 years with Obesity or Diabetes Mellitus
         3. Risk of liver fibrosis, Cirrhosis and Hepatocellular Carcinoma
   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)
      1. By 2030, projected U.S. Prevalence 100 Million cases, will become the top indication for liver transplant
4. Types
   1. Nonalcoholic Fatty Liver (>5% hepatic Steatosis without inflammation)
      1. Insulin Resistance is a major inciting factor of hepatic Steatosis
      2. Lipotoxicity from free Fatty Acids
   2. Nonalcoholic Steatohepatitis (>5% hepatic Steatosis with Hepatic Injury and inflammation, 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 (33-66% will develop NAFLD)
      3. Polycystic Ovary Syndrome
   3. Hyperlipidemia (especially Hypertriglyceridemia)
      1. More than half of those with Hyperlipidemia will develop NAFLD
      2. High Triglyceride to HDL ratio is associated with up to 78% Prevalence of NAFLD
   4. Rapid weight loss
      1. Starvation
      2. Gastric Bypass
   5. Genetic Associations
      1. Patatin-Like Phospholipase Domain-Containing Protein 3 (PNPLA3)
         1. Associated with 2 fold increased risk of NAFLD with hepatic fibrosis
   6. Refeeding Syndrome
   7. Total Parenteral Nutrition
   8. Older age (Prevalence increases with age)
   9. Hispanic descent
   10. More common in women
   11. Obstructive Sleep Apnea
   12. Hypothyroidism
   13. HIV Infection
   14. Chemotherapeutic Agents
       1. Asparaginase
       2. Cisplatin
       3. Fluorouracil
       4. Irinotecan
       5. Methotrexate
       6. Tamoxifen
   15. Other Medications
       1. Amiodarone
       2. Diltiazem
       3. Antiretroviral Therapy (esp. Protease Inhibitors)
       4. Corticosteroids
       5. Cocaine
       6. Tetracyclines
       7. Valproic Acid
       8. NSAIDs
       9. Aspirin
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. Precautions
      1. Routine NAFLD screening for those at risk is not recommended in U.S.
      2. Liver Function Tests and Hepatic Ultrasound have insufficient NAFLD Test Sensitivity for screening
   2. 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 <0.8 (not true in late disease)
         1. If AST exceeds ALT, consider Alcoholic Hepatitis
   3. Alkaline Phosphatase may be increased up to 2 fold
   4. Gamma-Glutamyltransferase (GGT) increased in some cases
      1. If over 2 times normal consider Alcoholic Hepatitis
   5. 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. Hepatitis B Surface Antigen (HBsAg)
       2. Hepatitis C Virus Antibody (xHCV)
    4. Hemochromatosis (Bronze Diabetes with Arthritis, Heart Failure, Family History)
       1. Serum Ferritin
       2. Serum Iron
       3. Transferrin Saturation
       4. Complete Blood Count
       5. Consider HemochromatosisGenetic Testing (HFE)
11. Labs: Secondary causes - uncommon (consider if other testing negative)
    1. Autoimmune Hepatitis (esp. women, history of Thyroid disease)
       1. Antinuclear Antibody
       2. Smooth Muscle Antibody
       3. Consider liver and Kidney microsomal antibodies
    2. Alpha-1-Antitrypsin Deficiency
       1. Alpha-1-Antitrypsin total level
       2. Alpha-1-Antitrypsin Phenotype
    3. Wilson Disease (consider in <40 years old, with liver disease or neuropsychiatric disorder, Family History)
       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% (increases with greater fat infiltration)
          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 with elastography
       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 advanced fibrosis (Test Sensitivity: 74%, Test Specificity: 78%)
       2. Alternatively, Alcoholic Hepatitis also presents with AST > ALT
    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. Consider MR Elastography (or Fibroscan) for Fibrosis Score >-1.455
       5. Angulo (2007) Hepatology 45(4):846-54 [PubMed]
    4. Fibrosis Probability Score (FIB-4 Index, preferred)
       1. https://www.hepatitisc.uw.edu/page/clinical-calculators/fib-4
       2. Clinical score based on age, Platelet Count, AST and ALT
       3. Efficacy: Test Sensitivity: 85%, Test Specificity: 65%
       4. Score <1.45 excludes advanced fibrosis while score >3.25 suggests advanced liver fibrosis
       5. Consider MR Elastography (or Fibroscan) for Fibrosis Probability Score >1.45
    5. Magnetic Resonance Elastography (MR Elastography)
       1. MR Elastography score > 3.62 kPa is suggestive of advanced fibrosis
    6. Vibration-Controlled Transient Elastography (Fibroscan)
       1. MR Elastography is preferred (more accurate)
       2. Imaging study with high sensitivity for even mild liver fibrosis
       3. May be limited by operator experience and morbidly obese
       4. Fibroscan > 9.9 kPa is suggestive of advanced fibrosis
       5. Myers (2012) Hepatology 55(1): 199-208 [PubMed]
    7. 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
    8. BARD Score
       1. Score <2 has a strong Negative Predictive Value (90-97%) for NAFLD with fibrosis
    9. 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
    10. Other tests
        1. See MRI Abdomen with elastography 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. Non-invasive tests listed above are preferred (see complications)
    2. Indications
       1. Liver Disease etiology is unclear (distinguish NASH from conditions listed below)
       2. Increased risk of NASH or advanced fibrosis
    3. 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
    4. 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
    5. Complications of liver biopsy occur in >6% of patients
       1. Major Bleeding (4.5%)
       2. Death (1.6%)
15. Evaluation: Initial
    1. History and exam
       1. Consider comorbid history
          1. Premature COPD in alpha-1 antitrypsin deficiency
          2. Obesity
             1. Calculate Body Mass Index (BMI)
             2. Measure Waist Circumference
       2. Consider differential diagnosis (see above)
          1. Alcoholic Hepatitis
             1. Ask about excessive Alcohol use
          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
          1. Confirm Liver Function Test Abnormality
          2. Consider RUQ Ultrasound
       3. Institute lifestyle change (e.g. weight loss, Healthy Diet, Exercise, hyperlidemia management)
          1. See Interventions below
    2. Step 2: Month 6 (following lifestyle change)
       1. Repeat Liver Function Tests
       2. If Abnormal Liver Function Testing
          1. Consider liver imaging (RUQ Ultrasound) if not already done
    3. Step 3: Evaluate with noninvasive tests for liver fibrosis (see above)
       1. Perform scoring
          1. NAFLD Fibrosis Score (abnormal >-1.455) or
          2. Fibrosis Probability Score or FIB-4 Index (abnormal >1.45)
       2. Obtain Elastography Imaging if either score is abnormal
          1. Magnetic Resonance Elastography (MR Elastography, preferred)
             1. MR Elastography score > 3.62 kPa is suggestive of advanced fibrosis
          2. Vibration-Controlled Transient Elastography (Fibroscan)
             1. Fibroscan > 9.9 kPa is suggestive of advanced fibrosis
    4. Step 4: Gastroenterology referral indications (for evaluation and often liver biopsy)
       1. Noninvasive tests and inmaging suggest fibrosis (see Step 3)
       2. Persistently elevated Liver Function Tests despite interventions
       3. Suspected secondary cause of Steatosis other than NASH (e.g. Hemochromatosis, Autoimmune Hepatitis)
    5. Step 5: Monitoring
       1. Repeat liver transaminases at least every 2 years for those with hepatic Steatosis on imaging
17. Management: Interventions
    1. See Prevention of Liver Disease Progression
    2. Weight Reduction
       1. Single most effective and important intervention
       2. Liver Function Tests improve or normalize with as little as 5-10% weight loss
          1. Hepatic Steatosis improves with 3-5% weight loss
          2. NAFLD histopathologic changes improve with 7-10% weight loss
       3. Fibrosis may not improve after weight loss
       4. Low to moderate fat intake and low Carbohydrate
          1. Avoid high fructose corn syrup (beverages, foods)
          2. Consider Mediterranean Diet
             1. Zeiber-Sagi (2017) Liver Int 37(7): 936-49 [PubMed]
       5. Consider Xenical which does improve liver enzymes and liver histology
       6. Physical Activity 150 to 200 minutes of moderate to vigorous Exercise
       7. Consider Bariatric Surgery
          1. NASH resolved in 85% of 109 patients in one study
          2. Lassailly (2015) Gastroenterology 149(2): 379-88 [PubMed]
    3. Avoid Hepatotoxins
       1. Restrict Alcohol intake (2 standard drinks/day for men, 1/day for women)
       2. Eliminate Hepatotoxins
    4. Maximize Glucose control
       1. Conditions
          1. Type II Diabetes Mellitus
          2. Metabolic Syndrome
       2. Medications: Glucophage (Metformin)
          1. Recommended in Type II Diabetes
          2. Previously recommended to reduce transaminases and Steatosis in non-diabetics
             1. However, subsequent studies find no associated improvement in liver histology
       3. Medications: Glitazones
          1. Pioglitazone up to 30 mg orally daily
          2. Glitazones may be used if AST amd ALT <3x normal
          3. Monitor AST and ALT every 3 months
          4. Reduces transaminases, Steatosis in non-diabetics
             1. However, Glitazones also increase weight
             2. Not recommended in non-diabetics without biopsy proven NAFLD
       4. Medications: Incretin Mimetic (Liraglutide or Semaglutide)
          1. Appears to improve NASH, but still investigational as of 2020
          2. May also be considered in non-diabetic patients
    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
          1. Discontinue Statin if liver enzymes increase 2 fold at 3 months after starting medication
       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, risk of Prostate Cancer, Hemorrhagic CVA)
       3. Avoid Milk Thistle (ineffective)
       4. Omega-3 Fatty Acids have not been found effective in NAFLD
       5. Vitamin D Supplementation has not been found effective
    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. However NAFLD overall is associated with increased cardiovascular mortality risk
    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. Chalasani (2018) Hepatology 67(1): 328-57 [PubMed]
    5. Kumar (2000) Mayo Clin Proc 75:733-9 [PubMed]
    6. Oh (2017) Am Fam Physician 96(11): 709-15 [PubMed]
    7. Sanyal (2002) Gastroenterology 123:1705-25 [PubMed]
    8. Westfall (2020) Am Fam Physician 102(10): 603-12 [PubMed]
    9. Wilkins (2013) Am Fam Physician 88(1): 35-42 [PubMed]