https://www1.racgp.org.au/ajgp/2021/october/updates-in-fatty-liver-disease

Definition

• Previously called NAFLD (Non-Alcoholic Fatty Liver Disease).
• Renamed MAFLD in 2020 to emphasise the underlying metabolic dysfunction.
• Diagnosis is based on
  • positive diagnostic criteria.
  • does not require exclusion of alcohol use before diagnosis.
  • allows recognition of dual pathology, for example MAFLD plus alcohol-related liver disease or viral hepatitis
• Can coexist with:
  • Alcohol-related liver disease
  • Hepatitis B or C
  • Other chronic liver diseases
• Caused by excessive fat accumulation in the liver due to metabolic dysfunction.

Epidemiology

• Affects approximately 1 in 4 Australian adults.
• Increasing prevalence in children.
• Up to 40% of patients are not obese (“lean MAFLD”).

Core pathophysiology

• MAFLD is primarily a disease of metabolic dysregulation.
• Main drivers:
  • Insulin resistance
  • Visceral adiposity
  • Increased free fatty acid flux to the liver
  • De novo hepatic lipogenesis
  • Mitochondrial dysfunction
  • Oxidative stress
  • Inflammatory cytokine activation
  • Gut microbiome changes
  • Genetic susceptibility
• Hepatic fat accumulation can lead to:
  • Simple steatosis
  • Steatohepatitis
  • Fibrosis
  • Cirrhosis
  • Liver failure
  • Hepatocellular carcinoma
• Approximately 5–10% progress to significant fibrosis over time.

Why fibrosis matters

• Fibrosis stage is the most important predictor of liver-related morbidity and mortality in MAFLD.
• Simple steatosis alone is usually lower risk.
• Advanced fibrosis or cirrhosis is associated with higher risk of:
  • Portal hypertension
  • Varices
  • Liver decompensation
  • Hepatocellular carcinoma
  • Liver-related death

Natural history

• MAFLD progression is usually slow.
• fibrosis progresses at approximately 0.12 stages per year on average.
• Around 1 in 5–10 people may develop liver fibrosis over time if not adequately managed.
• Progression risk is higher with:
  • Type 2 diabetes
  • Obesity
  • Older age
  • Hypertension
  • Dyslipidaemia
  • Ongoing alcohol intake
  • Coexisting liver disease
  • Established fibrosis
  • Persistent ALT/AST elevation
  • Metabolic syndrome

Important clinical concept: MAFLD is not only a liver disease

• Most patients with MAFLD do not die from liver disease.
• Most deaths are due to:
  • Cardiovascular disease
  • Extrahepatic malignancy
• Therefore management must focus on:
  • CVD risk reduction
  • Diabetes control
  • Weight management
  • BP control
  • Lipid control
  • Smoking cessation
  • Alcohol minimisation/avoidance

Risk factors

Major metabolic risk factors

• Central adiposity
• Overweight or obesity
• Insulin resistance
• Type 2 diabetes
• Atherogenic dyslipidaemia
• Hypertension
• Metabolic syndrome

Lifestyle risk factors

• High-calorie diet
• High saturated fat intake
• High cholesterol intake
• High-fructose soft drinks
• Highly processed foods
• Sedentary lifestyle
• Low physical activity

Other associated factors

• Sarcopenia
• Obstructive sleep apnoea
• Polycystic ovarian syndrome
• Hypothyroidism
• Hypopituitarism
• Hyperuricaemia
• Gut dysbiosis

Associated conditions to actively consider

• Cardiovascular disease
• Cerebrovascular disease
• Chronic kidney disease
• Obstructive sleep apnoea
• Osteoporosis
• Cancer
• Cognitive changes
• Type 2 diabetes
• PCOS
• Hypothyroidism

Lean MAFLD

• MAFLD can occur in patients with normal BMI.
• 40% of individuals with MAFLD may have normal weight by BMI criteria.
• This is clinically important because normal BMI does not exclude:
  • Visceral adiposity
  • Insulin resistance
  • Dyslipidaemia
  • Hypertension
  • Hepatic steatosis

Diagnostic approach

Who should be assessed?

• Assess adults with:
  • Type 2 diabetes
  • Obesity
  • Two or more metabolic risk factors, such as:
    • Hypertension
    • Dyslipidaemia
    • Prediabetes
    • Central adiposity
• Also consider assessment in lean patients with metabolic abnormalities.

Diagnostic criteria — practical concept

• Diagnosis requires evidence of:
  • Hepatic steatosis
  • Plus metabolic dysfunction
• Hepatic steatosis may be identified by:
  • Ultrasound
  • Elastography-based methods
  • MRI-based methods
  • Histology, if biopsy performed
• Metabolic dysfunction may be demonstrated by:
  • Overweight/obesity
  • Type 2 diabetes
  • Multiple metabolic risk abnormalities

First-line investigation

Liver ultrasound

• Liver ultrasound is recommended as the first-line test for hepatic steatosis.
• Advantages:
  • Accessible
  • Non-invasive
  • Relatively inexpensive
  • Detects moderate-to-severe steatosis
• Limitations:
  • Reduced sensitivity when steatosis is mild, especially <20% of hepatocytes.
  • Reduced performance in severe obesity, especially BMI >40 kg/m².
  • Does not reliably stage fibrosis.
  • A normal ultrasound does not fully exclude early fatty liver.

Baseline blood tests

• LFTs:
  • ALT
  • AST
  • GGT
  • ALP
  • Bilirubin
  • Albumin
• FBC:
  • Platelets are important for fibrosis/portal hypertension assessment.
• EUC/eGFR:
  • CKD is commonly associated.
• Fasting lipids
• HbA1c or fasting glucose
• INR if concern for advanced liver disease
• Ferritin and transferrin saturation
• Hepatitis B and C serology
• Consider autoimmune liver screen if atypical:
  • ANA
  • ASMA
  • AMA
  • Immunoglobulins
• Consider coeliac serology if clinically indicated
• Consider TSH, especially if hypothyroidism suspected

Need to assess for other liver diseases

• MAFLD can coexist with other liver diseases.
• Other causes should still be considered, especially:
  • Alcohol-related liver disease
  • Viral hepatitis
  • Haemochromatosis
  • Autoimmune hepatitis
  • Primary biliary cholangitis
  • Drug-induced liver injury
  • Wilson disease in younger patients if clinically suspicious
• Australian consensus recommendations state people with MAFLD should be assessed for other common causes of fatty liver and liver disease.

Alcohol and MAFLD

• MAFLD does not require alcohol exclusion for diagnosis.
• Alcohol may coexist as a second contributor.
• Dual pathology increases risk.
• Even “low safe-limit” alcohol intake may increase risk of cirrhosis and cancer in MAFLD
• Practical GP advice:
  • Document alcohol intake in standard drinks/week.
  • Screen for binge pattern.
  • Encourage reduction or abstinence, especially if fibrosis is present.

Fibrosis risk assessment

Why do fibrosis scoring?

• To identify patients at low risk who can stay in primary care.
• To identify patients needing:
  • Elastography
  • Hepatology/gastroenterology referral
  • Cirrhosis surveillance
• NFS is reasonable, but FIB-4 is simpler, more guideline-aligned in Australian primary care, and has excellent negative predictive value for ruling out advanced fibrosis.

FIB-4

Good rule-out test

• FIB-4 is mainly useful to exclude advanced fibrosis.
• A low FIB-4 has high negative predictive value; the Liver Foundation notes FIB-4 <1.3 has >95% NPV for advanced fibrosis

Parameters

• Age
• AST
• ALT
• Platelet count

Formula

• FIB-4 = age × AST / platelet count × √ALT

Interpretation

FIB-4 <1.3 → low risk, manage in primary care and repeat testing.

FIB-4 1.3–2.7 → indeterminate, do elastography or direct fibrosis test.

FIB-4 >2.7 → high risk, refer to hepatology/gastroenterology

Practical caution

• It is best used as a rule-out test for advanced fibrosis.
• Less reliable in:
  • Age <35 years
  • Age >65 years
• Can be falsely elevated in older patients because age is part of the formula.
• Do not use FIB-4 alone if there are clinical signs of cirrhosis or portal hypertension.
• If FIB-4 is indeterminate or high, move to:
  • Liver elastography/FibroScan
  • Direct fibrosis serum test, such as ELF or Hepascore
  • Specialist referral if second-line testing unavailable

NAFLD Fibrosis Score

Parameters

• Age
• AST
• ALT
• Platelets
• BMI
• Albumin
• Impaired fasting glucose or diabetes

Interpretation

• < –1.455
  • Significant fibrosis unlikely
• > 0.676
  • Significant fibrosis likely

Elastography

• Measures liver stiffness.
• More useful than ultrasound alone for fibrosis assessment.
• Can be performed as:
  • Transient elastography/FibroScan
  • Shear-wave elastography
  • ARFI/pSWE

Liver biopsy

• Gold standard for:
  • Diagnosis
  • Grading steatohepatitis
  • Staging fibrosis
• Not commonly used in routine primary care.
• Consider specialist discussion if:
  • Atypical presentation
  • Markedly elevated aminotransferases
  • Minimal metabolic burden despite significant liver injury
  • Suspected competing liver disease
  • Unclear diagnosis

Management principles

Overall management targets

• Reduce liver fat.
• Prevent fibrosis progression.
• Reduce cardiovascular risk.
• Treat metabolic comorbidities.
• Identify advanced fibrosis early.
• Prevent cirrhosis complications if present.

Primary-care management

• Most patients with MAFLD are best managed in primary care.
• Key components:
  • Lifestyle intervention
  • Weight management
  • Exercise prescription
  • Diabetes optimisation
  • Lipid management
  • BP management
  • Smoking cessation
  • Alcohol reduction
  • Medication review
  • Fibrosis risk stratification
  • Monitoring plan

Lifestyle intervention — evidence

Weight loss

• Weight loss reduces liver fat.
• Weight loss can improve:
  • Steatosis
  • Steatohepatitis
  • Fibrosis
  • Quality of life
• study of 293 patients showing improvement in liver fibrosis in approximately 90% of those achieving >10% weight loss, and fibrosis improvement in 45% of patients achieving >10% weight loss.
• Practical target:
  • Aim for gradual sustained weight loss.
  • A 500–1000 kcal/day deficit may achieve up to 1 kg/week weight loss.

Diet

• No single diet is clearly superior for MAFLD resolution.
• Practical advice:
  • Reduce total energy intake.
  • Reduce ultra-processed foods.
  • Reduce sugar-sweetened beverages.
  • Reduce fructose-containing soft drinks.
  • Reduce saturated fat.
  • Increase vegetables, legumes, whole grains, fibre.
  • Use Mediterranean-style dietary principles where suitable.
  • Avoid crash diets unless medically supervised.

Exercise

• Exercise reduces hepatic fat and improves cardiometabolic risk.
• There is no single agreed optimal type, intensity or volume.
• there appears to be a dose-dependent relationship between exercise volume and reduction in hepatic fat.
• A cited study found >250 minutes/week exercise produced greater reduction in hepatic steatosis than 150 minutes/week.
• Practical prescription:
  • Start where patient is capable.
  • Aim for at least 150 minutes/week moderate activity.
  • Consider progressing toward 250 minutes/week if feasible.
  • Include resistance training 2–3 times/week, especially with sarcopenia or diabetes risk.

Diabetes management

• Type 2 diabetes is a major risk factor for progression.
• Optimise:
  • HbA1c target individualised
  • Weight
  • BP
  • Lipids
  • CKD risk
• Metformin:
  • Useful for diabetes management.
  • Does not improve liver histology in MAFLD.
• GLP-1 receptor agonists:
  • Promising for weight loss and metabolic risk reduction.
  • May reduce liver fat, but not yet established as approved direct MAFLD therapy

Lipid management

• Dyslipidaemia should be treated according to cardiovascular risk.
• MAFLD is not a contraindication to statins.
• In most patients, cardiovascular benefit is central because CVD is a leading cause of death in MAFLD.
• Treat:
  • Elevated LDL-C
  • Hypertriglyceridaemia
  • Low HDL as part of metabolic syndrome management
• Use absolute CVD risk assessment where applicable.

Blood pressure management

• Hypertension is a key metabolic risk factor.
• Manage according to Australian hypertension/CVD risk guidance.
• Prioritise:
  • Accurate BP measurement
  • Home BP or ambulatory BP if needed
  • Lifestyle measures
  • Pharmacotherapy when indicated
  • CKD/diabetes risk modification

Smoking

• Smoking increases cardiovascular and cancer risk.
• Smoking cessation should be addressed as part of MAFLD management.

Alcohol

• Avoid or minimise alcohol.
• Stronger advice toward abstinence if:
  • Fibrosis present
  • Cirrhosis
  • Elevated LFTs
  • Heavy alcohol intake
  • Other liver disease
  • High HCC risk

Medication review

• Review medications that may contribute to steatosis or liver injury.
• long-term steatogenic medications including:
  • Corticosteroids
  • Valproic acid
  • Methotrexate
  • Amiodarone
• Do not stop these automatically.
• Consider:
  • Indication
  • Duration
  • Dose
  • Alternatives
  • Specialist input
  • Risk of destabilising underlying condition

Pharmacotherapy specifically for MAFLD

• No approved medication therapy specifically for MAFLD
• Australian Prescriber similarly emphasises management with fibrosis assessment, health behaviour change, comorbidity management, and HCC surveillance in cirrhosis.
• Metformin:
  • Does not improve liver histology.
• GLP-1 receptor agonists:
  • Promising, particularly where obesity/T2DM coexist.
  • Use based on diabetes/weight indications rather than as stand-alone MAFLD therapy unless specialist-directed.

Bariatric and metabolic therapy

• Bariatric/metabolic procedures can reduce:
  • Steatosis
  • Inflammation
  • Fibrosis
• systematic reviews/meta-analyses show resolution of hepatic steatosis in >75% of patients after bariatric/metabolic therapies.
• However:
  • Bariatric surgery should not be used solely because of MAFLD.
  • It may be appropriate if the patient meets obesity/metabolic surgery indications.

Monitoring

Low-risk MAFLD without fibrosis

• If no fibrosis and metabolic risk factors are stable:
  • Monitor every 2–3 years
  • Use non-invasive fibrosis scores such as FIB-4/NFS
  • Consider elastography if available or if risk changes

Higher-risk patients

• More frequent review if:
  • Type 2 diabetes
  • Worsening obesity
  • Rising ALT/AST
  • Platelet decline
  • Increasing FIB-4
  • Alcohol intake
  • CKD
  • OSA
  • Suspected fibrosis

Patients with fibrosis

• Stage 2–4 fibrosis should have non-GP specialist opinion.
• Specialist may guide:
  • Elastography interval
  • HCC surveillance
  • Variceal screening
  • Cirrhosis management
  • Need for biopsy
  • Clinical trial options

Cirrhosis surveillance

• Patients with cirrhosis require:
  • 6-monthly liver ultrasound
  • Alpha-fetoprotein
  • Endoscopy at some stage to assess/manage varices
  • Earlier endoscopy consideration if platelets <150 × 10⁹/L
  • Nutrition review
  • Bone health assessment
• Australian Prescriber also states HCC surveillance is required in patients with liver cirrhosis.

Referral indications

Refer to gastroenterology/hepatology if:

• FIB-4 high
• FIB-4 indeterminate with abnormal second-line test
• Elastography suggests significant fibrosis
• Suspected stage 2–4 fibrosis
• Cirrhosis suspected
• Platelets falling or <150 × 10⁹/L with liver disease
• Splenomegaly
• Low albumin
• Elevated INR
• Jaundice
• Ascites
• Encephalopathy
• Variceal bleed concern
• Persistent unexplained ALT/AST elevation
• Atypical pattern of LFT abnormality
• Coexisting viral hepatitis
• Significant alcohol use
• Possible autoimmune/metabolic/genetic liver disease
• Diagnostic uncertainty

Practical assessment checklist

History

• Alcohol intake:
  • Standard drinks/week
  • Binge pattern
  • Duration
• Metabolic history:
  • Weight gain
  • Waist circumference
  • Diabetes/prediabetes
  • Hypertension
  • Dyslipidaemia
  • PCOS
  • OSA symptoms
• Medication history:
  • Steroids
  • Valproate
  • Methotrexate
  • Amiodarone
  • Tamoxifen
  • Herbal/weight-loss products
• Family history:
  • Diabetes
  • Premature CVD
  • Liver disease
• Lifestyle:
  • Diet
  • Soft drinks/fructose
  • Ultra-processed foods
  • Physical activity
  • Sedentary work
• Liver decompensation symptoms:
  • Jaundice
  • Ascites
  • GI bleeding
  • Confusion
  • Pruritus
  • Easy bruising

Examination

• BMI
• Waist circumference
• BP
• Signs of insulin resistance:
  • Acanthosis nigricans
• Liver signs:
  • Hepatomegaly
  • Splenomegaly
  • Spider naevi
  • Palmar erythema
  • Ascites
  • Peripheral oedema
  • Muscle wasting
  • Bruising

Investigations

• LFT
• FBC
• EUC/eGFR
• Fasting lipids
• HbA1c
• INR if concern for advanced disease
• Hepatitis B/C screen
• Ferritin/transferrin saturation
• Ultrasound liver
• FIB-4 calculation
• Elastography if indicated/available

Red flags

• Jaundice
• Ascites
• Encephalopathy
• Haematemesis/melaena
• Unexplained weight loss
• Persistent marked ALT/AST elevation
• Low albumin
• High INR
• Thrombocytopenia
• Splenomegaly
• Liver mass
• Constitutional symptoms
• Strong family history of liver disease
• Young patient with unexplained liver disease

Patient explanation

• “Fat has built up in the liver because of metabolic factors such as insulin resistance, weight, cholesterol, blood pressure or diabetes.”
• “The main issue is not just the fat itself; we need to check whether there is liver scarring.”
• “Most people do not progress to cirrhosis, but those with fibrosis need closer monitoring.”
• “The most important treatment is reducing metabolic risk — weight, exercise, diabetes, cholesterol, blood pressure, smoking and alcohol.”
• “There is no specific tablet that cures MAFLD, but improving metabolic health can reduce liver fat and sometimes improve scarring.”

Summary

• MAFLD is common and increasing in Australia.
• It is diagnosed by hepatic steatosis plus metabolic dysfunction.
• It can occur even in normal-BMI patients.
• It can coexist with alcohol-related or viral liver disease.
• Fibrosis stage is the key prognostic factor.
• Ultrasound is first-line for steatosis.
• FIB-4/NFS and elastography help assess fibrosis risk.
• Most patients can be managed in primary care.
• Main treatment is lifestyle and cardiometabolic risk reduction.
• No approved direct pharmacotherapy exists for MAFLD.
• Patients with significant fibrosis or cirrhosis need specialist involvement.
• Cirrhosis requires 6-monthly HCC surveillance.