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Nonalcoholic Fatty Liver
Aka: Nonalcoholic Fatty Liver, Nonalcoholic Steatohepatitis, Idiopathic Fatty Liver, Steatosis, Steatohepatitis, Fatty Liver, NASH, Nonalcoholic Fatty Liver Disease, NAFLD
- Definition
- Nonalcoholic Fatty Liver Disease
- Spectrum of disorders of liver fat infiltration not due to Alcohol, medication or hereditary disorder
- Severity ranges from Steatosis to severe fibrosis (NASH)
- See Also
- Acute Fatty Liver of Pregnancy
- Liver Function Test Abnormality
- Epidemiology
- Most common cause of liver disease in western countries
- NAFLD Prevalence: 10-30% of U.S. population (17% in Framingham study)
- Nonalcoholic Steatohepatitis (NASH) accounts for one third of NAFLD cases
- Occurs in up to 3-5% of the U.S. population
- Affects up to 66% of age >50 years with Obesity or Diabetes Mellitus
- Frequent cause of mild Liver Function Test Abnormality
- Most common cause of mildly abnormal ALT and AST in U.S. (accounts for up to 51% of cases)
- Most common cause of cryptogenic Cirrhosis (U.S. adult)
- By 2030, projected U.S. Prevalence 100 Million cases, will become the top indication for liver transplant
- Types
- Nonalcoholic Fatty Liver (>5% hepatic Steatosis without inflammation)
- Insulin Resistance is a major inciting factor of hepatic Steatosis
- Lipotoxicity from free Fatty Acids
- Nonalcoholic Steatohepatitis (>5% hepatic Steatosis with Hepatic Injury and inflammation, with risk of Cirrhosis)
- Hepatocyte injury with cell ballooning and inflammation
- Inflammatory factors include Cytokines and oxidative stress
- Progresses to hepatic fibrosis and Cirrhosis, and increased risk of Hepatocellular Carcinoma
- Risk Factors
- Obesity
- NASH occurs in 66% of all obese patients (BMI>30) over age 50 years old
- Occurs in 90% of patients at BMI>39
- Hyperglycemia (75% of NASH patients)
- Metabolic Syndrome
- Type II Diabetes Mellitus (33-66% will develop NAFLD)
- Polycystic Ovary Syndrome
- Hyperlipidemia (especially Hypertriglyceridemia)
- More than half of those with Hyperlipidemia will develop NAFLD
- High Triglyceride to HDL ratio is associated with up to 78% Prevalence of NAFLD
- Rapid weight loss
- Starvation
- Gastric Bypass
- Genetic Associations
- Patatin-Like Phospholipase Domain-Containing Protein 3 (PNPLA3)
- Associated with 2 fold increased risk of NAFLD with hepatic fibrosis
- Refeeding Syndrome
- Total Parenteral Nutrition
- Older age (Prevalence increases with age)
- Hispanic descent
- More common in women
- Obstructive Sleep Apnea
- Hypothyroidism
- HIV Infection
- Chemotherapeutic Agents
- Asparaginase
- Cisplatin
- Fluorouracil
- Irinotecan
- Methotrexate
- Tamoxifen
- Other Medications
- Amiodarone
- Diltiazem
- Antiretroviral Therapy (esp. Protease Inhibitors)
- Corticosteroids
- Cocaine
- Tetracyclines
- Valproic Acid
- NSAIDs
- Aspirin
- Symptoms
- Asymptomatic in most cases
- Fatigue
- Malaise
- Right upper quadrant pain
- Signs
- Hepatomegaly (50%)
- Differential Diagnosis
- See Liver Function Test Abnormality
- Viral Hepatitis (Hepatitis B, Hepatitis C)
- Alcoholic Hepatitis
- Hepatotoxins
- Autoimmune Hepatitis
- Hereditary Hemochromatosis
- Wilson Disease
- Alpha-1-Antitrypsin Deficiency
- Labs: Liver specific (first-line)
- Precautions
- Routine NAFLD screening for those at risk is not recommended in U.S.
- Liver Function Tests and Hepatic Ultrasound have insufficient NAFLD Test Sensitivity for screening
- Liver Transaminases (ALT, AST)
- Normal in some cases
- Typically 2-3 fold increase in transaminases
- If over 1000 consider other cause
- Viral Hepatitis
- Hepatotoxin exposure
- AST/ALT ratio <0.8 (not true in late disease)
- If AST exceeds ALT, consider Alcoholic Hepatitis
- Alkaline Phosphatase may be increased up to 2 fold
- Gamma-Glutamyltransferase (GGT) increased in some cases
- If over 2 times normal consider Alcoholic Hepatitis
- Cirrhosis screening (includes Liver synthetic function)
- Serum Bilirubin
- Serum Albumin
- Prothrombin Time
- Labs: Secondary causes - common
- See Liver Function Test Abnormality
- Metabolic Syndrome and other causes of lipid abnormalities
- Hemoglobin A1C
- Fasting Glucose
- Lipid profile with Fasting Serum Triglycerides, LDL Cholesterol and HDL Cholesterol
- Thyroid Stimulating Hormone
- Viral Hepatitis
- Hepatitis B Surface Antigen (HBsAg)
- Hepatitis C Virus Antibody (xHCV)
- Hemochromatosis (Bronze diabetes with Arthritis, Heart Failure, Family History)
- Serum Ferritin
- Serum Iron
- Transferrin Saturation
- Complete Blood Count
- Consider HemochromatosisGenetic Testing (HFE)
- Labs: Secondary causes - uncommon (consider if other testing negative)
- Autoimmune Hepatitis (esp. women, history of Thyroid disease)
- Antinuclear Antibody
- Smooth Muscle Antibody
- Consider liver and Kidney microsomal antibodies
- Alpha-1-Antitrypsin Deficiency
- Alpha-1-Antitrypsin total level
- Alpha-1-Antitrypsin Phenotype
- Wilson Disease (consider in <40 years old, with liver disease or neuropsychiatric disorder, Family History)
- Ceruplasmin
- Consider 24 hour urinary copper
- Imaging
- Right upper quadrant Ultrasound (Preferred first-line)
- Finding
- Increased liver echoes (fatty infiltrates)
- Disadvantages
- Does not determine disease severity
- Fibrosis and Steatosis are indistinguishable on Ultrasound
- Efficacy
- Test Sensitivity: 82-89% (increases with greater fat infiltration)
- Test Specificity: 93%
- CT Abdomen (unenhanced)
- Precautions
- CT with contrast decreases the Test Specificity compared to unenhanced CT
- Advantages
- Better sensitivity than Ultrasound
- Better identification of other liver abnormalities
- Disadvantages
- CT-associated Radiation Exposure
- Higher cost than Ultrasound
- Efficacy
- Test Sensitivity: 88-95%
- Test Specificity: 90-99%
- MRI Abdomen with elastography
- Advantages
- Highest accuracy
- Disadvantages
- Expensive
- Efficacy: Steatosis
- Test Sensitivity: 96%
- Test Specificity: 93%
- Efficacy: Fibrosis
- Test Sensitivity: 94%
- Test Specificity: 73%
- Diagnosis: Noninvasive Tests for Advanced Fibrosis in NAFLD patients
- AST/ALT ratio (AAR)
- Score 0.8 or higher is suggestive of NAFLD with advanced fibrosis (Test Sensitivity: 74%, Test Specificity: 78%)
- Alternatively, Alcoholic Hepatitis also presents with AST > ALT
- AST/Platelet Count ratio index (APRI)
- AST/Platelet Count ratio index <0.3 to 0.5 excludes significant liver fibrosis or Cirrhosis
- AST/Platelet Count ratio index >1.5 rules in significant liver fibrosis or Cirrhosis
- Loaeza-del-Castillo (2008) Ann Hepatol 7(4):350-7 [PubMed]
- NAFLD Fibrosis Score (preferred)
- http://nafldscore.com/
- Liver fibrosis risk based on age, Hyperglycemia, BMI, Platelet Count, Serum Albumin, AST, ALT
- Score <-1.455 excludes advanced fibrosis while score >0.675 suggests advanced liver fibrosis (90% Test Sensitivity)
- Consider MR Elastography (or Fibroscan) for Fibrosis Score >-1.455
- Angulo (2007) Hepatology 45(4):846-54 [PubMed]
- Fibrosis Probability Score (FIB-4 Index, preferred)
- https://www.hepatitisc.uw.edu/page/clinical-calculators/fib-4
- Clinical score based on age, Platelet Count, AST and ALT
- Efficacy: Test Sensitivity: 85%, Test Specificity: 65%
- Score <1.45 excludes advanced fibrosis while score >3.25 suggests advanced liver fibrosis
- Consider MR Elastography (or Fibroscan) for Fibrosis Probability Score >1.45
- Magnetic Resonance Elastography (MR Elastography)
- MR Elastography score > 3.62 kPa is suggestive of advanced fibrosis
- Vibration-Controlled Transient Elastography (Fibroscan)
- MR Elastography is preferred (more accurate)
- Imaging study with high sensitivity for even mild liver fibrosis
- May be limited by operator experience and morbidly obese
- Fibroscan > 9.9 kPa is suggestive of advanced fibrosis
- Myers (2012) Hepatology 55(1): 199-208 [PubMed]
- Alcoholic Liver Disease to NAFLD Index
- Used to distinguish Alcoholic Liver Disease from NAFLD (based on ALT, AST, MCV, height, weight, gender)
- https://www.mayoclinic.org/medical-professionals/model-end-stage-liver-disease/alcoholic-liver-disease-nonalcoholic-fatty-liver-disease-index
- BARD Score
- Score <2 has a strong Negative Predictive Value (90-97%) for NAFLD with fibrosis
- HAIR Score
- Severely obese (BMI >35 kg/m2) patient assessment for risk of Nonalcoholic Steatohepatitis (NASH)
- Assign one point each for Hypertension, elevated ALT, Insulin Resistance
- Score 2 or 3 predicts progressive liver injury
- Other tests
- See MRI Abdomen with elastography above
- Enhanced Liver Fibrosis panel (Test Sensitivity and Test Specificity approach 100%)
- FibroTest or FibroSure (Test Sensitivity: 15%, Test Specificity: 98%)
- Fibrometer (Test Sensitivity: 79%, Test Specificity: 96%)
- Diagnosis: Liver Biopsy
- Non-invasive tests listed above are preferred (see complications)
- Indications
- Liver Disease etiology is unclear (distinguish NASH from conditions listed below)
- Increased risk of NASH or advanced fibrosis
- Grades degree of fatty infiltration
- Hepatic Steatosis (fat accumulation in liver)
- Intracellular fat in >5% of hepatocytes
- Nonalcoholic Steatohepatitis (Steatosis AND liver cell injury and inflammation)
- Hepatocyte ballooning
- Mallory hyaline
- Perivenular inflammatory infiltrate (Lymphocytes, Neutrophils)
- Hepatocyte necrosis and apoptosis
- Hepatocyte fibrosis may be present
- Distinguishes NASH from other causes of liver injury and inflammation
- Autoimmune Hepatitis
- Alpha-1-Antitrypsin Deficiency
- Alpha-1-Antitrypsin
- Hemochromatosis
- Wilson Disease
- Complications of liver biopsy occur in >6% of patients
- Major Bleeding (4.5%)
- Death (1.6%)
- Evaluation: Initial
- History and exam
- Consider comorbid history
- Premature COPD in alpha-1 antitrypsin deficiency
- Obesity
- Calculate Body Mass Index (BMI)
- Measure Waist Circumference
- Consider differential diagnosis (see above)
- Alcoholic Hepatitis
- Ask about excessive Alcohol use
- Hepatoxic Medication
- Viral Hepatitis
- Consider Family History
- Hemochromatosis
- Wilson Disease
- Evaluate for likelihood of NASH
- Diabetes Mellitus or Metabolic Syndrome
- Body Mass Index
- Waist Circumference
- Labs
- Start with liver specific first-line labs and common secondary cause labs above
- Consider uncommon secondary cause labs as above (based on history, risk factors)
- Diagnostics
- Consider liver imaging (e.g. RUQ Ultrasound)
- Management: Approach
- Step 1: Initial
- Confirm likelihood of NASH as underlying cause
- Start with initial evaluation as above
- Confirm Liver Function Test Abnormality
- Consider RUQ Ultrasound
- Institute lifestyle change (e.g. weight loss, Healthy Diet, Exercise, hyperlidemia management)
- Step 2: Month 6 (following lifestyle change)
- Repeat Liver Function Tests
- If Abnormal Liver Function Testing
- Consider liver imaging (RUQ Ultrasound) if not already done
- Step 3: Evaluate with noninvasive tests for liver fibrosis (see above)
- Perform scoring
- NAFLD Fibrosis Score (abnormal >-1.455) or
- Fibrosis Probability Score or FIB-4 Index (abnormal >1.45)
- Obtain Elastography Imaging if either score is abnormal
- Magnetic Resonance Elastography (MR Elastography, preferred)
- MR Elastography score > 3.62 kPa is suggestive of advanced fibrosis
- Vibration-Controlled Transient Elastography (Fibroscan)
- Fibroscan > 9.9 kPa is suggestive of advanced fibrosis
- Step 4: Gastroenterology referral indications (for evaluation and often liver biopsy)
- Noninvasive tests and inmaging suggest fibrosis (see Step 3)
- Persistently elevated Liver Function Tests despite interventions
- Suspected secondary cause of Steatosis other than NASH (e.g. Hemochromatosis, Autoimmune Hepatitis)
- Step 5: Monitoring
- Repeat liver transaminases at least every 2 years for those with hepatic Steatosis on imaging
- Management: Interventions
- See Prevention of Liver Disease Progression
- Weight Reduction
- Liver Function Tests improve or normalize with as little as 5-10% weight loss
- Hepatic Steatosis improves with 3-5% weight loss
- NAFLD histopathologic changes improve with 7-10% weight loss
- Fibrosis may not improve after weight loss
- Low to moderate fat intake and low carbohydrate
- Avoid high fructose corn syrup (beverages, foods)
- Consider Mediterranean Diet
- Zeiber-Sagi (2017) Liver Int 37(7): 936-49 [PubMed]
- Consider Xenical which does improve liver enzymes and liver histology
- Physical Activity 150 to 200 minutes of moderate to vigorous Exercise
- Consider Bariatric Surgery
- NASH resolved in 85% of 109 patients in one study
- Lassailly (2015) Gastroenterology 149(2): 379-88 [PubMed]
- Avoid Hepatotoxins
- Restrict Alcohol intake (2 standard drinks/day for men, 1/day for women)
- Eliminate Hepatotoxins
- Maximize Glucose control
- Conditions
- Type II Diabetes Mellitus
- Metabolic Syndrome
- Medications: Glucophage (Metformin)
- Recommended in Type II Diabetes
- Previously recommended to reduce transaminases and Steatosis in non-diabetics
- However, subsequent studies find no associated improvement in liver histology
- Medications: Glitazones
- Glitazones may be used if AST amd ALT <3x normal
- Monitor AST and ALT every 3 months
- Reduces transaminases, Steatosis in non-diabetics
- However, Glitazones also increase weight
- Not recommended in non-diabetics without biopsy proven NAFLD
- Medications: Liraglutude
- Appears to improve NASH, but still investigational as of 2020
- Lipid Reduction as needed with AntiHyperlipidemic
- AntiHyperlipidemic may be used if AST,ALT <3x normal
- Monitor AST and ALT every 3 months
- Statins (preferred) decrease transaminases, Steatosis
- Discontinue Statin if liver enzymes increase 2 fold at 3 months after starting medication
- Mixed results with Ursodeoxycholic Acid
- Control Hypertension
- Angiotensin Receptor Blockers
- Supplements that may offer benefit
- L-Carnitine
- Vitamin E 800 IU/day (variable efficacy, risk of Prostate Cancer, Hemorrhagic CVA)
- Avoid Milk Thistle (ineffective)
- Omega-3 Fatty Acids have not been found effective in NAFLD
- Vitamin D Supplementation has not been found effective
- References
- Musso (2010) Hepatology 52(1): 79-104 [PubMed]
- Prognosis
- Nonalcoholic Fatty Liver (Hepatic Steatosis without inflammation)
- Rare progression to Cirrhosis
- However NAFLD overall is associated with increased cardiovascular mortality risk
- Nonalcoholic Steatohepatitis (5% of general population, up to 66% of age >50 years with Diabetes Mellitus, Obesity)
- Hepatocellular Carcinoma: 1-5% risk
- Cirrhosis risk: 20% overall
- Advanced fibrosis in 15-30% of cases
- Advanced fibrosis progresses to Cirrhosis in 12-35%
- Complications
- Portal Hypertension
- Cirrhosis if associated with severe comorbid condition
- Morbid Obesity (BMI >30)
- Type II Diabetes Mellitus
- AST to ALT ratio >1
- Coronary Artery Disease
- Results in greatest morbidity
- Treat underlying Hyperlipidemia
- Diabetic Retinopathy
- Associated with increased Incidence in those with NAFLD and Diabetes Mellitus
- References
- Angulo (2002) N Engl J Med 346:1221-31 [PubMed]
- Bayard (2006) Am Fam Physician 73:1961-68 [PubMed]
- Careyva (2016) Am Fam Physician 94(12): 980-6 [PubMed]
- Chalasani (2018) Hepatology 67(1): 328-57 [PubMed]
- Kumar (2000) Mayo Clin Proc 75:733-9 [PubMed]
- Oh (2017) Am Fam Physician 96(11): 709-15 [PubMed]
- Sanyal (2002) Gastroenterology 123:1705-25 [PubMed]
- Westfall (2020) Am Fam Physician 102(10): 603-12 [PubMed]
- Wilkins (2013) Am Fam Physician 88(1): 35-42 [PubMed]