New Title: Metabolic Dysfunction Associated Steatotic Liver Disease (MAFLD) – Diagnosis and Management

BACKGROUND:

Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) has replaced the term Non-Alcoholic Fatty Liver Disease. The change in nomenclature is due to the exclusionary nature of the diagnosis, the lack of recognition of the root cause of the condition, and the use of potentially stigmatizing terms37% of American adults and as many as 70% with T2DM have MASLD While usually asymptomatic, MASLD significantly increases the risk of cardiovascular disease, diabetes and liver disease including cirrhosis and liver cancer. Findings of hepatic steatosis on imaging and/or elevated liver function tests require evaluation for MASLD. Obese patients, especially those with metabolic issues (hypertension, (pre) diabetes, cardiovascular disease should all be evaluated for MASLD. Evaluation of MASLD starts with non-invasive blood test monitoring and measuring liver stiffness. Treatments of MASLD is multidisciplinary, including weight loss, alcohol evaluation, medications, evaluation and control of metabolic issues, and often referral to hepatologists, cardiologists, endocrinologists, dieticians, and sometimes bariatric surgeons.

Definitions
Clinical Presentation
Risk Factors
Evaluation
Treatment
Key Points
Learn More – Primary Sources

Definitions

Steatotic Liver Disease (SLD): hepatic steatosis due to various etiologies as below
Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD):
Criteria to meet MASLD:
- Presence of hepatic steatosis
- One or more Cardiometabolic Risk Factors i.e., BMI > 25 (or 23 if Asian | Waist Circumference>94 cm | Impaired Fasting Glucose or A1C ≥5.7 | T2DM | HTN | BP >130 | 85 | HLD or lipid lowering therapy | Low HDL e.g. < 40 mg/dL for males and < 50 mg/dL for females
- Alcohol consumption < 20g/day in females and <30 g/day for males

Metabolic Dysfunction and Alcohol-Associated Liver Disease (metALD):

Criteria met for MASLD but consumption of alcohol >140g/week for females and > 210 g/week for males
- Cryptogenic SLD: When patients do not qualify for MASLD or a specific alternative etiology
Metabolic Dysfunction-Associated Steatohepatitis: Aggressive form of MASLD, usually steatosis and elevated liver enzymes
- Liver biopsy may be needed to confirm this diagnosis
- Diagnosis implies minimal alcohol
  - <14 drinks week for women
  - <21 drinks per week in men

Alcohol-associated Liver Disease: Alcohol use is the only culprit
Specific Etiology SLD: Drug Induced Liver Injury| Monogenic Disease
Cryptogenic SLD: Etiology unknown
Liver fibrosis (i.e., liver scarring)
- Fibrosis correlates with increased risk of cirrhosis
- Mild to moderate fibrosis may be reversible
- Four stages, from minimal F1 to cirrhosis F4
Cirrhosis
- Severe, advanced state of fibrosis leading to distorted liver struction and function
- Not reversible
Decompensated cirrhosis
- Cirrhosis with any of the following
  - Hepatic encephalopathy
  - Ascites
  - Variceal bleeding
  - Hepatocellular carcinoma
  - Hepatorenal syndrome
- Failing liver may require transplant

Clinical Presentation

Hepatic Steatosis found incidentally on imaging done for non-liver causes
Abnormal LFT’s found on routine lab testing
Thrombocytopenia may be first sign of cirrhosis
Cirrhosis usually asymptomatic unless evidence of decompensated cirrhosis
Physical exam regarding liver is usually normal unless decompensated cirrhosis

Risk Factors

T2DM or prediabetes requires screening for MASLD
Patients with at least 2 manifestations of metabolic syndrome require screening:
- Hypertension
- Dyslipidemia especially high triglycerides and low HDL
- Central adiposity

Evaluation

History and Physical

Examine for signs of cirrhosis
- Jaundice
- Spider angiomas
- Gynecomastia
- Hepatosplenomegaly
- Caput medusae; dilated abdominal vein
- Testicular atrophy
- Clubbing
- Dupuytren’s contracture
- Hepatic encephalopathy (e.g., Sleep disturbance | Confusion | Asterixis)

Labs

Routine Labs
- CBC | CMP | lipid profile | TSH | INR | HbA1C
- Cardiovascular disease screening such as stress echo or cardiac CT
Screen for other liver diseases
- HCV antibody (HCV RNA if +ve) | HbsAg | HBsAb | HBcAB
- Autoimmune panel: Antinuclear antibody, Antimitochondrial antibodies (AMA), immunoglobulin IGG
- Ferritin | Alpha 1 anti-trypsin
- CRP, CRP, Anti smooth muscle Ab, Anti mitochondrial antibodies
FIB-4: Estimate amount of liver scarring fibrosis (see more “Learn More” below)
- Most popular noninvasive blood test for liver fibrosis
- Requires age, AST, ALT, platelet count

Imaging

Routine: Liver ultrasound
Liver stiffness measurement (LSM) via transient elastography (FibroScan)
- Best screening imaging test for fibrosis | Based on FIB-4 Score
  - Fib-4 <1.3: Not needed
  - FIB-4 of 1.3 to 2.67: Needed
  - Fib-4 >2.67: Consider FibroScan
- LSM risk assessment
  - <8 kPa: Low risk for liver fibrosis
  - 8 to 12 kPa: Indeterminate risk for significant liver fibrosis
  - >12 kPa: High risk for advanced fibrosis/cirrhosis

Additional Studies

Typically ordered by hepatologist
- Liver biopsy
- Magnetic Resonance Elastography (MRE) may be needed

Screen for Alcohol Use and Abuse

The Alcohol Use Disorders Identification Test (AUDIT) 10-item screening tool developed by WHO (see ‘Learn More – Primary Sources’ below)

CAGE Screening Tool (see “Learn More-Primary Sources’ below)

Treatment

Lifestyle Guidance

Exercise
Mediterranean diet
Avoid all alcohol if indeterminant to high-risk fibrosis
If overweight
- Advise structured weight loss plan
- Consider anti-obesity medication
- Consider bariatric surgery

Medications

In 2024 the US FDA approved resmetirom for the treatment of non-cirrhotic metabolic dysfunction associated steatohepatitis (MASH) with moderate to advanced fibrosis
- MASH w/o T2D and no cirrhosis: Vitamin E 800 IU daily
- Diabetics and MASH: Consider Semaglutide | Piotglitazone
- Obesity and MASH: Consider Liraglutide (Saxenda) or Semaglutide (Wegovy), both FDA approved for weight loss (not FDA approved for liver disease)
- Note: Wegovy and Ozempic are both brand names Semaglutide. Wegovy is FDA approved for weight loss whereas Ozempic is approved for treatment of T2DM. Wegovy has a higher dose available.
Do NOT combine liraglutide with semaglutide

KEY POINTS:

Liver fibrosis is the most important determination of the significance of MASLD
MASLD significantly increases risk of cardiovascular disease
11% of patients with fatty liver are at risk for advanced liver fibrosis
Elevated LFTs + fatty liver = higher risk of liver fibrosis
Statins
- If indicated, should be given
- No contraindication if LFTs are abnormal from NAFLD
- Soluble statins (simvastatin, atorvastatin) reduce risk of liver decompensation
- Contraindicated in decompensated cirrhosis
Specialist Referrals
- Hepatologist if indeterminant or advanced fibrosis
- Endocrinologist may be indicated for (pre)diabetes control
- Cardiologist for screening for cardiovascular disease
- Bariatric surgery consultation if indicated
- Liver cancer screening every 6 months if advanced fibrosis/cirrhosis