Metabolic Liver Disease

Aka: Metabolic Liver Disease, Metabolic Dysfunction Associated Steatotic Liver Disease, Nonalcoholic Fatty Liver, Nonalcoholic Steatohepatitis, Idiopathic Fatty Liver, Steatosis, Steatohepatitis, Steatotic Liver Disease, Fatty Liver, NASH, Nonalcoholic Fatty Liver Disease, NAFLD, MASLD, MASH, MASLD and Increased Alcohol Intake, MetALD

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II. Definitions

  1. Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD)
    1. Previously known as Nonalcoholic Fatty Liver Disease (NAFLD)
    2. Spectrum of disorders of liver fat infiltration
      1. Severity ranges from Steatosis to Steatohepatitis to severe fibrosis (MASH or NASH)
    3. MASLD is the hepatic manifestation of Metabolic Syndrome
      1. Associated with at least one of 5 cardiometabolic risk factors (e.g. DM2, Htn, HTG, low HDL, Obesity)
      2. Not due to Alcohol (<3-4 drinks/day in men, <2-3 drinks/day in women)
      3. Not due to medication or hereditary disorder
    4. For brevity, this outline uses NAFLD/MASLD and NASH/MASH interchangeably (esp. when spelled out)
      1. Nonalcoholic Fatty Liver Disease is far shorter than the "new and improved" MASLD terms

III. Epidemiology

  1. Most common cause of liver disease in western countries
    1. MASLD Prevalence
      1. Global Overall: 30%
      2. U.S. Overall: 10-30% (17% in Framingham study)
      3. U.S. Age 50 to 59 years: 38%
        1. Affects up to 66% of age >50 years with Obesity or Diabetes Mellitus
    2. Nonalcoholic Steatohepatitis (NASH/MASH) accounts for up to one third of MASLD cases
      1. MASH affects up to 14% of U.S. population
      2. MASH Is a risk of Liver Fibrosis, Cirrhosis and Hepatocellular Carcinoma
        1. Significant fibrosis (>=F2) occurs in up to 3-6% of the U.S. population
  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

IV. Pathophysiology

  1. Energy Intake more than metabolic needs leads to increased free Fatty Acids
    1. Adipose fat storage capacity exceeded drives Insulin Resistance, inflammation and free Fatty Acids
    2. Increased Carbohydrate intake increases lipogenesis, Triglyceride and VLDL increases
  2. Free Fatty Acids lead to lipotoxic agents (e.g. ceramides, diacylglycerols, lysophosphatidic acids)
    1. Results in hepatocyte stress and inflammation (via Oxidants, inflammasomes)
  3. Hepatocyte inflammation, given NASH genetic predispositions, progresses to further hepatic complications
    1. Cirrhosis
    2. Hepatocellular Carcinoma

V. Types

  1. Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD, Nonalcoholic Fatty Liver)
    1. Definition: >5% hepatic Steatosis without inflammation
    2. Insulin Resistance is a major inciting factor of hepatic Steatosis
    3. Lipotoxicity from free Fatty Acids
  2. Metabolic Dysfinction associated Steatohepatitis (MASH, NASH, Nonalcoholic Steatohepatitis)
    1. Definition: >5% hepatic Steatosis with Hepatic Injury and inflammation (and risk of Cirrhosis)
    2. Hepatocyte injury with cell ballooning and inflammation
    3. Inflammatory factors include Cytokines and oxidative stress
    4. Progresses to Hepatic Fibrosis and Cirrhosis, and increased risk of Hepatocellular Carcinoma
  3. Hepatic Fibrosis
    1. Chronic hepatocyte injury and inflammation results in scarring with Hepatic Fibrosis
    2. Staging
      1. Stage F0: No fibrosis
      2. Stage F1: Mild fibrosis
      3. Stage F2: Moderate fibrosis
      4. Stage F3: Severe fibrosis
      5. Stage F4: Cirrhosis

VI. Risk Factors: Adults

  1. Obesity
    1. NASH occurs in 30% of patients with Obesity
      1. NASH effects 66% of all obese patients (BMI>30) over age 50 years old
      2. NASH occurs in 90% of patients at BMI>39
    2. Consider screening Liver Biopsy before Bariatric Surgery
      1. Significant fibrosis present in up to 1 in 12 patients undergoing Bariatric Surgery
      2. Cirrhosis in up to 1 in 25 patients undergoing Bariatric Surgery
  2. Hyperglycemia (75% of NASH patients)
    1. Metabolic Syndrome
    2. Type II Diabetes Mellitus (33-70% will develop MASLD, 30-40% MASH and 12-20% significant fibrosis)
    3. Type I Diabetes Mellitus (<25% of patients have MASLD)
    4. Polycystic Ovary Syndrome
  3. Hyperlipidemia (especially Hypertriglyceridemia)
    1. More than half of those with Hyperlipidemia will develop MASLD
    2. High Triglyceride to HDL ratio is associated with up to 78% Prevalence of MASLD
  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 MASLD/NAFLD with Hepatic Fibrosis
  6. Refeeding Syndrome
  7. Total Parenteral Nutrition
  8. Older age (Prevalence increases with age)
  9. Latino populations
  10. Obstructive Sleep Apnea
  11. Hypothyroidism
  12. HIV Infection
  13. Chemotherapeutic Agents
    1. Asparaginase
    2. Cisplatin
    3. Fluorouracil
    4. Irinotecan
    5. Methotrexate
    6. Tamoxifen
  14. 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

VII. Risk Factors: Children

  1. Overall NAFLD risk: 1 in 13 children
  2. Obesity (1 in 3 children)
  3. Prediabetes or Type 2 Diabetes Mellitus (50% of children)
  4. Polycystic Ovarian Syndrome (teen biologic females)

VIII. History

  1. Comorbidity history
    1. Premature COPD in Alpha-1 Antitrypsin Deficiency
    2. Diabetes Mellitus or Metabolic Syndrome
  2. Differential diagnosis (see below)
    1. Alcoholic Hepatitis
      1. Ask about excessive Alcohol use
    2. Hepatoxic Medication
    3. Viral Hepatitis
  3. Family History
    1. Hemochromatosis
    2. Wilson Disease

IX. Symptoms

  1. MASLD is asymptomatic in most cases
  2. Advanced liver disease
    1. See Cirrhosis
    2. Fatigue
    3. Malaise
    4. Right upper quadrant pain

X. Exam

  1. Metabolic Condition Findings
    1. Acanthosis Nigricans
    2. Overweight or Obesity
      1. Body Mass Index (BMI) >= 25 kg/m2 (or >23 kg/m2 in asian patients) OR
      2. Waist Circumference >=37 inches in men (>= 31.5 inches in women)
  2. Stigmata of liver disease
    1. Hepatomegaly (50%)
    2. Splenomegaly
    3. Spider Telangiectasia
    4. Ascites
    5. Palmar erythema
    6. Jaundice

XI. Differential Diagnosis

  1. See Liver Function Test Abnormality
  2. Comorbid second diagnosis (in addition to NASH) is found in 18% of cases
  3. Viral Hepatitis (Hepatitis B, Hepatitis C)
  4. Alcoholic Hepatitis
  5. Hepatotoxins (e.g. Methotrexate, Corticosteroids, TPN)
  6. Autoimmune Hepatitis
  7. Hereditary Hemochromatosis
  8. Wilson Disease
  9. Alpha-1-Antitrypsin Deficiency
  10. Rapid weight loss
  11. Celiac Disease
  12. Diabetes Mellitus
  13. Panhypopituitarism

XII. Associated Conditions

  1. See Metabolic Syndrome
  2. Type 2 Diabetes Mellitus
  3. Hypertension
  4. Hyperlipidemia
  5. Hypertriglyceridemia
  6. Obesity
  7. Chronic Kidney Disease
  8. Obstructive Sleep Apnea

XIII. 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. Precautions
      1. Transaminases are insufficient screening for advanced Liver Fibrosis (low Test Sensitivity and Test Specificity)
      2. Transaminases may be normal despite advanced Liver Fibrosis
      3. Transaminase elevations do not predict outcomes
    2. Typically 2-3 fold increase in transaminases
      1. If over 1000 consider other cause (e.g. Viral Hepatitis, Hepatotoxin exposure)
    3. AST/ALT ratio <0.8 may be consistent with MASLD (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

XIV. 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)

XV. 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

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% (increases with greater fat infiltration)
      2. Test Specificity: 93%
        1. False Positive Rate in some studies as high as 15% (leading to an overdiagnosis of NAFLD)
        2. Rowe (2018) Lancet Gastroenterol Hepatol 3(1): 66-72 [PubMed]
  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%

XVII. Diagnosis: Metabolic Liver Disease (MASLD)

  1. MASLD is the hepatic manifestation of Metabolic Syndrome
  2. Associated with at least one of the following 5 cardiometabolic risk factors
    1. Type 2 Diabetes Mellitus (or Prediabetes)
    2. Hypertension
      1. Blood Pressure >130/85 or on Antihypertensives
    3. Hypertriglyceridemia
      1. Serum Triglycerides >=150 mg/dl (or 1.69 mmol/L)
    4. Low HDL
      1. Men: HDL <40 mg/dl (or 1.43 mg/L)
      2. Women: HDL <=50 mg/dl (or 1.79 mg/L)
    5. Overweight or Obesity
      1. Body Mass Index (BMI) >= 25 kg/m2 (or >23 kg/m2 in asian patients) OR
      2. Waist Circumference >=37 inches in men (>= 31.5 inches in women)
  3. Other causes are excluded
    1. Not due to Alcohol (<3-4 drinks/day in men, <2-3 drinks/day in women)
    2. Not due to medication or hereditary disorder

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

  1. Lab findings (insufficient alone for NAFLD or NASH diagnosis)
    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]
  2. 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% (high Negative Predictive Value, low Positive Predictive Value)
    4. Not validated in age <35 years (consider elastography instead in this, younger population)
    5. Score <1.30 (<1.9-2 in age >65 years)
      1. Low risk for advanced Hepatic Fibrosis (NPV 95%)
    6. Score 1.3 to 2.67 (or 2 to 2.67 in age >65 years)
      1. Intermediate risk for advanced Hepatic Fibrosis
      2. Requires secondary assessment methods (e.g. elastography, Ultrasound)
    7. Score >2.67
      1. High risk for advanced hepatitc fibrosis
  3. NAFLD Fibrosis Score (preferred)
    1. https://www.mdcalc.com/calc/3081/nafld-non-alcoholic-fatty-liver-disease-fibrosis-score
    2. Liver Fibrosis risk based on age, Hyperglycemia, BMI, Platelet Count, Serum Albumin, AST, ALT
    3. Score <-1.455
      1. Low risk for advanced fibrosis
    4. Score -1.455 to 0.675
      1. Intermediate risk for advanced Hepatic Fibrosis
      2. Requires secondary assessment methods (e.g. elastography, Ultrasound)
    5. Score >0.675
      1. High risk for advanced Liver Fibrosis (90% Test Sensitivity)
    6. References
      1. Angulo (2007) Hepatology 45(4):846-54 [PubMed]
  4. Magnetic Resonance Elastography (MR Elastography, MRE)
    1. Most accurate for measuring Liver Fibrosis
    2. Preferred if BMI >36.65 kg/m2
    3. MR Elastography (MRE) score > 3.62 kPa is suggestive of advanced fibrosis
      1. MRE < 2.5 kPa: Normal (F0)
      2. MRE 2.5 to 3.5 kPa: Mild to moderate fibrosis (F1 to F2)
      3. MRE 3.5 to 4.0 kPa: Moderate to bridging fibrosis (F2 to F3)
      4. MRE 4.0 - 5.0 kPa: Advanced bridging fibrosis (F3 to F4)
      5. MRE = 5.0 kPa: Cirrhosis (F4)
    4. Tertiary Center Imaging Biomarkers (e.g. proton density fat fraction, iron corrected T1 mapping)
      1. Consider when other results are inconclusive for significant Hepatic Fibrosis
  5. Vibration-Controlled Transient Elastography (Fibroscan)
    1. MR Elastography is preferred (more accurate, but less available)
    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
      1. Low Risk <8 kPa
      2. Intermediate risk 8-12 kPa
      3. High risk >12 kPa
    5. References
      1. Myers (2012) Hepatology 55(1): 199-208 [PubMed]
  6. 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
  7. BARD Score
    1. Score <2 has a strong Negative Predictive Value (90-97%) for NAFLD with fibrosis
  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. NASHnext (NIS4 Algorithm)
    1. Proprietary test assigns composite score based on 4 markers (miR34a, a2M, YKL-40/CHI3L1 and Hemoglobin A1C)
    2. High risk NASH or advanced fibrosis predicted by score of 0.36 to 0.63 (moderate) or >0.63 (high risk)
    3. Only industry funded studies are available (needs further validation for significant clinical use)
    4. Hoffman and Chandler (2023) Am Fam Physician 108(4): 408-10 [PubMed]
  10. Other tests
    1. See MRI Abdomen with elastography above
    2. FibroTest or FibroSure (Test Sensitivity: 15%, Test Specificity: 98%)
    3. Fibrometer (Test Sensitivity: 79%, Test Specificity: 96%)
    4. Enhanced Liver Fibrosis panel
      1. Blood test to consider when elastography is unavailable
      2. Test Sensitivity and Test Specificity approach 100%

XIX. 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%)

XX. Evaluation

  1. Step 1: Initial
    1. Confirm likelihood of MASLD as underlying cause
      1. See diagnostic criteria for Metabolic Liver Disease as above
      2. Perform history and exam as above to identify comorbidities and stigmata of liver disease
      3. Evaluate differential diagnosis for Metabolic Liver Disease
    2. Obtain initial labs as above
      1. Confirm Liver Function Test Abnormality
      2. Start with liver specific first-line labs and common secondary cause labs above
      3. Consider uncommon secondary cause labs as above (based on history, risk factors)
    3. Obtain initial imaging
      1. Consider RUQ Ultrasound
    4. 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. Fibrosis Probability Score or FIB-4 Index OR
      2. NAFLD Fibrosis Score
    2. Interpretation
      1. Low Risk
        1. Fib-4 Score <1.30 (<1.9-2 in age >65 years)
        2. NAFLD Fibrosis Score <-1.455
        3. Repeat scoring every 2-3 years
          1. Obtain every 1-2 years if DM or Prediabetes, or >=2 metabolic risks
      2. Intermediate Risk
        1. Fib-4 Score 1.3 to 2.67 (or 2 to 2.67 in age >65 years)
        2. NAFLD Fibrosis Score -1.455 to 0.675
        3. Obtain Elastography Imaging if either score is abnormal
          1. Vibration-Controlled Transient Elastography (Fibroscan, most commonly used)
            1. Low Risk for advanced fibrosis <8 kPa (follow low risk repeat screening at intervals as above)
            2. Intermediate Risk for advanced fibrosis 10-12 kPa (refer to hepatology)
            3. High Risk for advanced fibrosis >12 kPa (refer to hepatology)
          2. Magnetic Resonance Elastography (MR Elastography, MRE, preferred if BMI>36)
            1. MR Elastography score > 3.62 kPa is suggestive of advanced fibrosis
            2. Follow low risk follow-up for MRE < 2.9 kPa (see above)
            3. Refer to hepatology for MRE >2.9 kPA
      3. High Risk
        1. Fib-4 Score >2.67
        2. NAFLD Fibrosis Score >0.675
        3. Refer to hepatology (or other MASLD specialist)
  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

XXI. Management: Interventions

  1. See Prevention of Liver Disease Progression
  2. Primary goals
    1. Cardiovascular disease prevention
    2. Cardiometabolic risk factor reduction
  3. Weight Reduction and related lifestyle changes
    1. Single most effective and important intervention
      1. Structured weight loss programs are most effective and are recommended
    2. Liver Function Tests improve or normalize with as little as 5-10% weight loss
      1. Hepatic Steatosis improves with 3-5% weight loss
        1. Improves, even with baseline normal BMI (18.5 to 24.9 kg/m2)
      2. MASH histopathologic changes improve with >7% weight loss
      3. Fibrosis may improve with >10% weight loss
    3. Low to moderate fat intake and low Carbohydrate
      1. Avoid high fructose corn syrup (beverages, foods)
      2. Consider Mediterranean Diet
        1. Most consistent dietary evidence for improving MASLD biomarkers, Steatosis and CAD risk factors
        2. Zeiber-Sagi (2017) Liver Int 37(7): 936-49 [PubMed]
    4. Physical Activity 150 to 200 minutes of moderate to vigorous Exercise per week
      1. However, MASLD improvements are also seen with <150 minutes/week
      2. Sung (2016) J Hepatol 65(4): 791-7 [PubMed]
    5. Consider Obesity Medications (e.g. GLP1 Agonists such as Semaglutide, Liraglutide, Tirzepatide)
    6. Consider Bariatric Surgery (e.g. Roux-en-Y Bypass, Sleeve Gastrectomy)
      1. NASH resolved in 85% of 109 patients in one study
      2. However, fibrosis may worsen in up to 1 in 8 patients undergoing Bariatric Surgery
        1. Benefits may be outweighed if Cirrhosis or stage 3 fibrosis is present
      3. References
        1. Lassailly (2015) Gastroenterology 149(2): 379-88 [PubMed]
  4. Avoid Hepatotoxins
    1. Eliminate Hepatotoxins
    2. Restrict Alcohol intake
      1. No or mild fibrosis (F0-1): Maximum 2 standard drinks/day for men, 1/day for women
      2. Moderate fibrosis (F2-4): No Alcohol intake
  5. Maximize Glucose control
    1. Conditions
      1. Type II Diabetes Mellitus
      2. Metabolic Syndrome (or Prediabetes)
    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: GLP-1 Agonist or Incretin Mimetic (Liraglutide or Semaglutide)
      1. Appears to improve NASH and very effective in assisting weight loss in Obesity
      2. Consider in Diabetes Mellitus with MASH
      3. Consider in non-diabetic patients, in noncirrhotic MASH with stage F2-3 fibrosis
        1. MASH resolves in 25% of patients on Semaglutide injection 2.4 mg/week for 72 weeks
        2. Petta (2025) Liver Int 45(11):e70407 +PMID: 41144918 [PubMed]
    4. 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
  6. 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
  7. Control Hypertension
    1. Angiotensin Receptor Blockers
  8. 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
  9. Refractory Cases with Fibrosis (medications employed by liver specialists)
    1. Resmetirom (Rezdiffra)
      1. Dose: 80-100 mg/day results in MASH resolution for 1 in 6 over 12 months
      2. Activates hepatic Thyroid Hormone receptor beta, increasing liver Fat Metabolism
      3. Expensive ($4000/month in 2026), with Drug Interactions (including Statins) and causes Diarrhea
      4. Tiwari (2025) Biomedicines 13(9):2079 +PMID: 41007643 [PubMed]
  10. References
    1. Musso (2010) Hepatology 52(1): 79-104 [PubMed]

XXII. Prognosis

  1. MASLD (or Nonalcoholic Fatty Liver, Hepatic Steatosis without inflammation)
    1. Rare progression to Cirrhosis
    2. However MASLD/NAFLD overall is associated with increased cardiovascular mortality risk
  2. Fib-4 Score as a marker of prognosis
    1. Low risk Fib-4 Score <1.30 (<1.9-2 in age >65 years)
      1. Associated with low risk for Cirrhosis or Hepatocellular Carcinoma in the subsequent 3 years
    2. High Risk Fib-4 Score >2.67
      1. Associated with increased all-cause mortality, liver-related mortality and cardiovascular mortality
    3. References
      1. Cholankeril (2023) J Hepatol 78(3): 493-500 [PubMed]
      2. Unalp-Arida (2017) Hepatology 66(1): 84-95 [PubMed]
  3. MASH (or Nonalcoholic Steatohepatitis)
    1. Prevalence
      1. Affects 5% of general population
      2. Affects up to 66% of age >50 years with Type 2 Diabetes Mellitus and Obesity
    2. Hepatocellular Carcinoma: 1-5% risk
      1. Risk is 3 fold higher in Type 2 Diabetes (better glycemic control reduces risk)
    3. Cirrhosis risk: 20% overall
      1. Advanced fibrosis in 15-30% of cases
      2. Advanced fibrosis progresses to Cirrhosis in 12-35%

XXIII. Complications

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

XXIV. 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. Musso (2017) JAMA Intern Med 177(5): 633-40 [PubMed]
  7. Oh (2017) Am Fam Physician 96(11): 709-15 [PubMed]
  8. Ohri (2026) Am Fam Physician 113(6): 578-85 [PubMed]
  9. Sanyal (2002) Gastroenterology 123:1705-25 [PubMed]
  10. Westfall (2020) Am Fam Physician 102(10): 603-12 [PubMed]
  11. Wilkins (2013) Am Fam Physician 88(1): 35-42 [PubMed]

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