MASLD & MASH
Metabolic dysfunction-associated steatotic liver disease (MASLD) is hepatic steatosis associated with cardiometabolic risk factors, which can progress to its inflammatory subtype, metabolic dysfunction-associated steatohepatitis (MASH), characterized by lobular inflammation, hepatocyte ballooning, and risk of fibrosis.
| Exam domain | One-glance essentials |
|---|---|
| Definition / diagnosis |
|
| Epidemiology / risks |
|
| Core mechanism |
|
| Clinical picture |
|
| Investigations |
|
| Management |
|
| Complications |
|
| Prevention / follow-up |
|
| Exam traps |
|
References
[1] Lecture slides: GC 240. MASLD and Alcoholic Liver Disease.pdf [2] Senior notes: Block A - Gastroenterology Interactive Tutorial.pdf [3] Senior notes: Ryan Ho GI.pdf (MASLD/MASH and fibrosis sections)
MASLD & MASH (Metabolic Dysfunction-Associated Steatotic Liver Disease & Metabolic Dysfunction-Associated Steatohepatitis)
1. Definition & Terminology
Understanding the name changes is critical because exam questions may use old or new terminology interchangeably.
The condition we now call MASLD has undergone several name changes reflecting our evolving understanding:
| Era | Term | Abbreviation | Key Issue |
|---|---|---|---|
| Pre-2020 | Non-Alcoholic Fatty Liver Disease | NAFLD | "Non-alcoholic" is a diagnosis of exclusion; stigmatising |
| 2020 | Metabolic (dysfunction)-Associated Fatty Liver Disease | MAFLD | Proposed by international panel; uses positive diagnostic criteria (cardiometabolic risk factors) rather than exclusion of alcohol |
| 2023 (current) | Metabolic Dysfunction-Associated Steatotic Liver Disease | MASLD | Delphi consensus (multi-society); removes "fatty" (stigmatising); umbrella term under "Steatotic Liver Disease (SLD)" [1] |
MASLD is defined as the presence of hepatic steatosis (≥ 5% of hepatocytes contain fat on histology, OR imaging evidence of steatosis) PLUS at least one cardiometabolic risk factor (CMRF), in the absence of other causes of steatosis [1].
Breaking down the name:
- "Metabolic" = linked to metabolic syndrome (insulin resistance, obesity, dyslipidaemia, hypertension)
- "Dysfunction-Associated" = driven by metabolic dysfunction
- "Steatotic" = from Greek steatos (fat) — fat accumulation in the liver
- "Liver Disease" = a spectrum from simple steatosis to cirrhosis
MASLD is a spectrum [1]:
| Old Term | New Term (2023) | Definition |
|---|---|---|
| NAFL | MASL (Metabolic dysfunction-Associated Steatotic Liver) | Simple steatosis without significant inflammation or hepatocyte injury |
| NASH | MASH (Metabolic dysfunction-Associated Steatohepatitis) | Steatosis + lobular inflammation + hepatocyte ballooning ± fibrosis |
MASH = "steatohepatitis" = fat + inflammation + hepatocyte injury (ballooning). This is the progressive form that can lead to fibrosis, cirrhosis, and HCC [1].
GC Lecture Slide Terminology
The GC lecture slide uses "MASLD" and "MASH" as the current preferred terminology, while also referencing NAFLD/NASH as older terms. For exams, know both. The lecture explicitly titles the condition as "MASLD and Alcoholic Liver Disease" [1].
To diagnose MASLD, you need steatosis + ≥ 1 of the following CMRFs [1]:
- BMI ≥ 25 kg/m² (or ≥ 23 kg/m² for Asians) or waist circumference > 94 cm (M) / > 80 cm (F) in Caucasians; > 90 cm (M) / > 80 cm (F) in Asians
- Fasting glucose ≥ 5.6 mmol/L or HbA1c ≥ 5.7% or Type 2 DM or treatment for pre-diabetes/DM
- Blood pressure ≥ 130/85 mmHg or antihypertensive treatment
- Triglycerides ≥ 1.7 mmol/L or lipid-lowering treatment
- HDL-cholesterol < 1.0 mmol/L (M) / < 1.3 mmol/L (F) or lipid-lowering treatment
Key Conceptual Shift
MAFLD/MASLD is a positive, inclusive diagnosis — you identify metabolic risk factors. NAFLD was a diagnosis of exclusion (had to rule out alcohol, viral hepatitis, etc. first). Under the new framework, MASLD can coexist with other liver diseases (e.g., HBV + MASLD — very common in Hong Kong) [1][2].
Steatotic Liver Disease (SLD) is the overarching umbrella [1]:
| Subtype | Criteria |
|---|---|
| MASLD | Steatosis + ≥ 1 CMRF, no significant alcohol |
| MetALD | MASLD criteria + increased alcohol intake (women 140–350 g/wk; men 210–420 g/wk) — the overlap group |
| ALD | Steatosis + significant alcohol intake (> 350 g/wk women; > 420 g/wk men) |
| Specific aetiology SLD | Drug-induced, monogenic causes, etc. |
| Cryptogenic SLD | Steatosis without CMRF and without other known cause |
High Yield — MetALD
MetALD is a new category recognising that many patients have BOTH metabolic risk factors AND moderate alcohol use. This is very common in clinical practice and is now formally named [1].
2. Epidemiology
- MASLD is the most common chronic liver disease worldwide, affecting approximately 25–38% of the global adult population [1].
- Prevalence is rising in parallel with the obesity and type 2 DM epidemics.
- MASH affects roughly 3–5% of the general population (i.e., ~10–20% of those with MASLD progress to MASH).
- In Hong Kong, the prevalence of MASLD is approximately 25–30% of the general population [1][2].
- Concept of "lean MASLD": In Asia, a significant proportion of MASLD patients have BMI < 25 kg/m² but still have visceral adiposity and insulin resistance — use Asian-specific BMI cutoffs (≥ 23 kg/m²) [1].
- Dual liver disease is extremely common in HK: Many patients have HBV + MASLD concurrently [2][3].
- As noted in the GI Interactive Tutorial: "Dual liver disease → HBV cirrhosis, and MAFLD — Common in HK" [3].
- This accelerates progression to fibrosis and HCC.
High fructose foods → fatty liver [3]. Coffee → beneficial for fatty liver [3]. These are clinically relevant lifestyle points frequently examined.
- More common in men than women (pre-menopausal women relatively protected by oestrogen → oestrogen promotes subcutaneous rather than visceral fat distribution).
- Prevalence increases with age.
- Strong association with type 2 DM — up to 55–70% of T2DM patients have MASLD.
3. Risk Factors
| Risk Factor | Mechanism / Explanation |
|---|---|
| Obesity (especially central/visceral) | Visceral adipose tissue is metabolically active → releases free fatty acids (FFAs), pro-inflammatory cytokines (TNF-α, IL-6) → hepatic fat accumulation and inflammation |
| Type 2 Diabetes Mellitus | Insulin resistance → ↑ hepatic de novo lipogenesis, ↓ fatty acid β-oxidation, ↑ FFA delivery to liver |
| Dyslipidaemia (↑ TG, ↓ HDL) | Reflects metabolic syndrome; ↑ TG = ↑ VLDL production in liver |
| Hypertension | Part of metabolic syndrome; shared insulin resistance pathology |
| Metabolic syndrome | The clustering of the above; each component independently and synergistically increases MASLD risk |
| Risk Factor | Mechanism |
|---|---|
| High fructose diet | Fructose is metabolised almost exclusively by the liver → drives de novo lipogenesis (bypasses glycolytic regulation) → directly promotes hepatic steatosis [3] |
| Sedentary lifestyle | ↓ Energy expenditure → ↑ adiposity → insulin resistance |
| PCOS (Polycystic Ovarian Syndrome) | Hyperandrogenism + insulin resistance → visceral adiposity |
| Obstructive sleep apnoea | Intermittent hypoxia → oxidative stress → hepatic inflammation |
| Hypothyroidism | Thyroid hormone regulates hepatic lipid metabolism; deficiency → ↑ hepatic fat |
| Genetic factors | PNPLA3 (patatin-like phospholipase domain-containing 3) I148M variant — the most validated genetic risk factor; impairs lipid droplet remodelling in hepatocytes. TM6SF2 variant — impairs VLDL secretion, trapping fat in the liver |
| Drugs | Amiodarone, methotrexate, tamoxifen, corticosteroids, valproic acid — all can cause secondary steatosis |
| Rapid weight loss / starvation | Paradoxically causes steatosis (↑ peripheral lipolysis → flood of FFAs to liver) |
Lean MASLD — Don't Be Fooled by BMI
Up to 20% of MASLD patients in Asia are non-obese ("lean MASLD"). They still have visceral adiposity and insulin resistance. Always consider MASLD even in patients with normal BMI if they have other cardiometabolic risk factors. Use waist circumference as a better surrogate than BMI [1].
4. Anatomy & Function Relevant to MASLD
To understand MASLD from first principles, you need to understand normal hepatic fat handling:
Sources of hepatic fat (input):
- Dietary fat → absorbed as chylomicrons → chylomicron remnants taken up by liver
- Peripheral lipolysis → FFAs released from adipose tissue → delivered to liver via portal circulation (~60% of hepatic fat in MASLD comes from this source)
- De novo lipogenesis (DNL) → liver synthesises new fatty acids from carbohydrates (especially fructose and glucose) via acetyl-CoA → this pathway is markedly upregulated in MASLD (~25% of hepatic fat vs ~5% in normal subjects)
Disposal of hepatic fat (output):
- β-oxidation (mitochondrial) → fatty acids oxidised for energy
- VLDL secretion → triglycerides packaged with apolipoprotein B-100 and exported as VLDL particles
Steatosis occurs when input > output. In MASLD, there is both ↑ input (↑ peripheral FFA delivery + ↑ DNL) AND ↓ output (relative impairment of β-oxidation, and eventually saturated VLDL export capacity).
- Zone 3 (centrilobular / perivenular) is the zone most affected in MASLD/MASH.
- Why? Zone 3 receives blood last (lowest oxygen tension), has the highest concentration of CYP450 enzymes (more oxidative stress), and is the primary site of de novo lipogenesis.
- This is why steatosis and ballooning degeneration are characteristically zone 3-predominant in MASH.
- Fibrosis in MASH also starts in zone 3 → pericellular / "chicken-wire" fibrosis (around individual hepatocytes), in contrast to viral hepatitis where fibrosis starts around portal tracts.
5. Aetiology & Pathophysiology
The old "two-hit hypothesis" (1st hit = steatosis, 2nd hit = oxidative stress) has been superseded by the "multiple-hit" or "multiple parallel hits" hypothesis [1]:
Multiple factors act simultaneously and synergistically:
Step-by-Step Pathophysiology
- Insulin resistance is the core metabolic abnormality.
- In adipose tissue: insulin normally suppresses hormone-sensitive lipase (HSL). When insulin resistance develops, HSL is disinhibited → excessive lipolysis → flood of free fatty acids (FFAs) to the liver via portal vein.
- In the liver: insulin normally suppresses gluconeogenesis and promotes glycogen synthesis. With insulin resistance, there is paradoxical upregulation of de novo lipogenesis (DNL) via transcription factors SREBP-1c (sterol regulatory element-binding protein 1c) and ChREBP (carbohydrate-responsive element-binding protein).
- Why "paradoxical"? The liver becomes resistant to insulin's glucose-lowering effects but remains sensitive to insulin's lipogenic signalling — this is called "selective hepatic insulin resistance."
- The liver accumulates triglycerides as lipid droplets within hepatocytes.
- Defined histologically as ≥ 5% of hepatocytes containing macrovesicular fat.
- Simple steatosis is generally considered benign — most patients with MASL do NOT progress to MASH.
- However, it is NOT entirely innocent: it makes the liver vulnerable to second hits.
- Not all lipid species are equally harmful. Triglycerides stored in droplets are relatively inert (may even be protective by sequestering toxic lipid intermediates).
- The truly toxic species are:
- Free fatty acids (FFAs) — especially saturated FFAs like palmitate
- Diacylglycerols (DAGs)
- Ceramides
- Lysophosphatidylcholines
- Free cholesterol
- These toxic lipid intermediates cause:
- Mitochondrial dysfunction → ↑ reactive oxygen species (ROS) → oxidative stress
- Endoplasmic reticulum (ER) stress → unfolded protein response (UPR) activation
- Direct hepatocyte apoptosis and necrosis → release of damage-associated molecular patterns (DAMPs)
- Activation of the NLRP3 inflammasome → IL-1β, IL-18 release → sterile inflammation
- DAMPs released from injured hepatocytes activate Kupffer cells (resident hepatic macrophages) via pattern recognition receptors (TLRs, especially TLR4).
- Kupffer cells release pro-inflammatory cytokines: TNF-α, IL-6, IL-1β.
- Recruitment of monocyte-derived macrophages and neutrophils → lobular inflammation (the hallmark of MASH on histology).
- Gut-liver axis: gut microbiome dysbiosis in MASLD patients → increased intestinal permeability ("leaky gut") → translocation of bacterial products (e.g., lipopolysaccharide / LPS) via portal vein → activates hepatic TLR4 → amplifies inflammation.
- Chronic inflammation activates hepatic stellate cells (HSCs) — the key fibrogenic cell in the liver.
- Activated HSCs transdifferentiate into myofibroblasts → produce collagen types I and III → fibrosis.
- Fibrosis pattern in MASH: starts as perisinusoidal / pericellular ("chicken-wire") fibrosis in zone 3 → progresses to portal fibrosis → bridging fibrosis → cirrhosis.
- Fibrosis is the strongest predictor of liver-related morbidity and mortality in MASLD — not steatosis, not inflammation.
- Progressive fibrosis → cirrhosis (F4) → portal hypertension → decompensation (ascites, variceal bleeding, HE).
- MASLD-related HCC can develop even in the ABSENCE of cirrhosis — this is a critical distinction from most other liver diseases [3].
- Up to 20–30% of MASLD-HCC occurs in non-cirrhotic livers — thought to be due to the pro-oncogenic effects of chronic inflammation, oxidative DNA damage, and insulin/IGF-1 signalling.
HCC Surveillance in MASLD vs HBV
For HBV, HCC can occur without cirrhosis, so surveillance starts based on age/sex/family history (Male ≥ 40, Female ≥ 50, or cirrhosis, or family history of HCC) [3][4].
For MASLD, current guidelines recommend HCC surveillance primarily in patients with established cirrhosis (6-monthly USS ± AFP). The challenge is that MASLD-HCC can occur without cirrhosis, but screening non-cirrhotic MASLD patients is not currently cost-effective due to the enormous population at risk [1][3].
- ↓ Adiponectin (anti-inflammatory, insulin-sensitising) → loss of hepatoprotective effects.
- ↑ Leptin (pro-inflammatory, pro-fibrogenic) → directly activates HSCs.
- ↑ Resistin, ↑ Visfatin → promote insulin resistance and inflammation.
| Gene | Variant | Effect |
|---|---|---|
| PNPLA3 | I148M (rs738409 C>G) | Loss of function in lipid droplet remodelling → ↑ hepatic fat retention, ↑ risk of MASH, fibrosis, and HCC |
| TM6SF2 | E167K | Impairs VLDL secretion → fat trapped in liver (but lower cardiovascular risk due to ↓ circulating lipids — a trade-off) |
| MBOAT7 | rs641738 | Involved in phospholipid remodelling |
| HSD17B13 | rs72613567:TA | Protective variant → ↓ risk of MASH and fibrosis |
6. Classification
Histological Classification (NAS & SAF Scores)
| Component | 0 | 1 | 2 | 3 |
|---|---|---|---|---|
| Steatosis | < 5% | 5–33% | 34–66% | > 66% |
| Lobular inflammation (foci per 200× field) | None | < 2 | 2–4 | > 4 |
| Hepatocyte ballooning | None | Few | Many | — |
- NAS = sum of the 3 components (0–8).
- NAS ≥ 5 correlates with a histological diagnosis of MASH.
- NAS < 3 → unlikely MASH.
- NAS 3–4 → borderline.
Important: NAS was designed as a research tool for clinical trials, NOT as a diagnostic tool. The pathologist's overall pattern recognition (presence of ballooning + lobular inflammation + steatosis in a characteristic zone 3 pattern) is the gold standard for diagnosing MASH.
| Stage | Description |
|---|---|
| F0 | No fibrosis |
| F1 | Perisinusoidal / pericellular fibrosis in zone 3 (F1a = mild, F1b = moderate) or periportal fibrosis (F1c) |
| F2 | Perisinusoidal AND periportal fibrosis |
| F3 | Bridging fibrosis |
| F4 | Cirrhosis |
Fibrosis is King
Fibrosis stage is the single most important histological feature predicting liver-related outcomes (decompensation, HCC, death) and overall mortality in MASLD. Steatosis grade and inflammation activity are less predictive than fibrosis stage [1].
| Category | Description |
|---|---|
| MASL (simple steatosis) | Steatosis ± mild lobular inflammation, NO ballooning, NO significant fibrosis |
| MASH without significant fibrosis | Steatosis + ballooning + lobular inflammation, F0–F1 |
| MASH with significant fibrosis | F2–F3 |
| MASH-cirrhosis | F4, may be "burned-out MASH" where steatosis resolves but fibrosis/cirrhosis remains |
| MASLD-HCC | HCC arising in the setting of MASLD (with or without cirrhosis) |
7. Clinical Features
Most patients with MASLD are ASYMPTOMATIC [1]. The disease is typically discovered incidentally:
- Elevated liver enzymes on routine blood tests (health check)
- Hepatic steatosis found incidentally on ultrasound performed for other reasons
- During workup for metabolic syndrome components
As the GI Interactive Tutorial notes: "He is completely asymptomatic" — this is the classic MASLD presentation [3].
| Symptom | Pathophysiology | Notes |
|---|---|---|
| Asymptomatic (most common) | Fat accumulation and early inflammation do not stimulate pain fibres or cause sufficient functional impairment to produce symptoms | The liver parenchyma itself has no pain receptors |
| Fatigue / malaise | Unclear mechanism; possibly related to systemic inflammation (↑ TNF-α, IL-6), mitochondrial dysfunction, or associated sleep disturbances (OSA) | Non-specific; often attributed to other causes |
| Vague right upper quadrant discomfort / heaviness | Hepatomegaly → stretching of the liver capsule (Glisson's capsule), which IS innervated by sensory nerves | More common in MASH than simple steatosis |
| Symptoms of metabolic syndrome | The underlying metabolic dysfunction drives both MASLD and these symptoms | Polyuria/polydipsia (if DM), visual changes (diabetic retinopathy), chest pain (IHD) |
| Symptoms of advanced liver disease / cirrhosis (late) | Portal hypertension, synthetic failure | Abdominal distension (ascites), ankle swelling, confusion (HE), haematemesis/melaena (variceal bleeding), jaundice |
Signs (with pathophysiological basis)
| Sign | Pathophysiology |
|---|---|
| Hepatomegaly | Fat-laden hepatocytes enlarge → liver size increases; the liver edge may be palpable below the costal margin and is typically smooth and non-tender |
| Central obesity / ↑ waist circumference | Visceral adiposity — the metabolic driver of MASLD |
| Acanthosis nigricans | Hyperpigmented, velvety plaques typically in axillae, neck creases, groin — a cutaneous marker of insulin resistance (insulin stimulates keratinocyte and fibroblast proliferation via IGF-1 receptors) |
| BMI ≥ 25 (or ≥ 23 in Asians) | Reflects overall adiposity |
All the classical signs of chronic liver disease and portal hypertension apply:
| Sign | Pathophysiology |
|---|---|
| Jaundice | Impaired bilirubin conjugation and excretion by damaged/cirrhotic hepatocytes |
| Spider naevi (> 5 above nipple line is significant) | Oestrogen excess (impaired hepatic metabolism) → arteriolar vasodilation |
| Palmar erythema | Oestrogen excess → vasodilation of palmar arterioles |
| Gynaecomastia | ↑ Oestrogen (↓ hepatic clearance) + ↓ sex hormone-binding globulin production |
| Testicular atrophy | Oestrogen excess, ↓ testosterone |
| Dupuytren's contracture | More associated with ALD but can occur; mechanism unclear |
| Caput medusae | Porto-systemic collaterals via re-canalised paraumbilical veins due to portal hypertension |
| Ascites | Portal hypertension (↑ hydrostatic pressure in splanchnic capillaries) + hypoalbuminaemia (↓ oncotic pressure) + renal sodium retention (RAAS activation from splanchnic vasodilation → effective hypovolaemia) |
| Splenomegaly | Passive congestion from portal hypertension |
| Peripheral oedema | Hypoalbuminaemia + sodium/water retention |
| Hepatic encephalopathy (asterixis/flapping tremor, confusion) | Porto-systemic shunting → ammonia and other neurotoxins bypass hepatic detoxification → astrocyte swelling in the brain |
| Bruising / petechiae | ↓ Clotting factor synthesis (especially Factors II, VII, IX, X) + thrombocytopaenia (splenic sequestration from portal hypertension) |
| Leukonychia (white nails) | Hypoalbuminaemia |
| Clubbing | Hepatopulmonary syndrome (intrapulmonary shunting) — rare |
| Fetor hepaticus | Dimethyl sulphide (from failed hepatic metabolism of mercaptans) |
'Burned-Out' MASH
In advanced MASH-cirrhosis, the steatosis and inflammation may resolve ("burned-out MASH"), leaving behind only fibrosis/cirrhosis. On biopsy, there may be NO remaining steatosis, making the aetiology difficult to determine retrospectively. This is often labelled "cryptogenic cirrhosis" — and many cases of so-called cryptogenic cirrhosis are actually burned-out MASH [1]. Look for clues: metabolic syndrome, obesity, diabetes history.
When examining a patient suspected of MASLD:
- General inspection: Body habitus (central obesity), acanthosis nigricans, stigmata of chronic liver disease
- Abdominal examination: Hepatomegaly (smooth, non-tender), splenomegaly (if portal hypertension), ascites (shifting dullness, fluid thrill)
- Assess for metabolic syndrome: BP, waist circumference, BMI
- Look for complications: Signs of decompensation (jaundice, ascites, encephalopathy)
MASLD is a systemic disease — the leading cause of death in MASLD patients is cardiovascular disease, NOT liver disease [1].
| Association | Explanation |
|---|---|
| Cardiovascular disease (CVD) | #1 cause of death in MASLD — shared risk factors (metabolic syndrome) + systemic inflammation + atherogenic dyslipidaemia + endothelial dysfunction |
| Type 2 DM | Bidirectional relationship: insulin resistance causes MASLD; MASLD worsens hepatic insulin resistance → perpetuates DM |
| Chronic kidney disease (CKD) | Shared metabolic risk factors + hepatic inflammation may promote renal injury |
| Colorectal neoplasia | ↑ Risk of colorectal adenomas and carcinoma — possibly related to hyperinsulinaemia and insulin/IGF-1 signalling |
| Obstructive sleep apnoea | Bidirectional; OSA-related intermittent hypoxia worsens hepatic inflammation |
| PCOS | Hyperandrogenism + insulin resistance |
| Hypothyroidism | ↓ Thyroid hormone → ↓ hepatic lipid oxidation |
Leading Cause of Death in MASLD
The #1 cause of death in MASLD is CARDIOVASCULAR DISEASE, not liver-related death. This is because MASLD shares the same metabolic risk factors as atherosclerotic CVD. Liver-related mortality (cirrhosis, HCC) is the 2nd or 3rd cause of death. Therefore, cardiovascular risk assessment and management is paramount [1].
9. Non-Invasive Assessment of Steatosis and Fibrosis
While diagnosis and investigations will be covered in detail in the next section, the following non-invasive tools are essential to understand the clinical approach:
- Controlled Attenuation Parameter (CAP) on FibroScan/transient elastography [1][3]:
- 248–280 dB/m → mild-moderate steatosis
- > 280 dB/m → severe steatosis [3]
- Ultrasound: ↑ echogenicity of liver parenchyma compared to renal cortex ("bright liver")
- MRI-PDFF (proton density fat fraction): Gold standard for quantifying hepatic steatosis (research)
- Vibration-Controlled Transient Elastography (VCTE / FibroScan) [1][5]:
- Serum biomarkers: FIB-4, NAFLD Fibrosis Score (NFS), Enhanced Liver Fibrosis (ELF) panel
- Liver biopsy: remains the gold standard but invasive; indicated when diagnosis is uncertain or to stage disease
As stated in the jaundiced patient lecture: "Vibration controlled transient elastography — the non-invasive method to stage fibrosis… More stiff (27 kPa = F4), suggestive of more severe fibrosis" [5].
The GC lecture covers MASLD and Alcoholic Liver Disease together [1], reflecting their clinical overlap:
| Feature | MASLD | ALD | MetALD |
|---|---|---|---|
| Alcohol intake | Below threshold (< 140 g/wk F, < 210 g/wk M) | Above threshold (> 350 g/wk F, > 420 g/wk M) | In between |
| Metabolic risk factors | ≥ 1 CMRF required | May or may not have CMRFs | ≥ 1 CMRF + moderate alcohol |
| Histology | Macrovesicular steatosis, zone 3 predominant, ballooning, lobular inflammation, pericellular fibrosis | Identical histological features + Mallory-Denk bodies (more prominent), neutrophilic inflammation more pronounced, steatohepatitis | Overlap features |
| Pathophysiology overlap | Insulin resistance-driven | Alcohol metabolism generates acetaldehyde + ROS → direct hepatotoxicity; CYP2E1 induction → oxidative stress; also promotes gut permeability | Both mechanisms |
| Key distinguishing factor | Alcohol history | Alcohol history | Alcohol history |
Histological Overlap
It is impossible to distinguish MASLD from ALD purely on histology — both show macrovesicular steatosis, ballooning, lobular inflammation, Mallory-Denk bodies, and pericellular fibrosis. The distinction relies on clinical history (alcohol intake). This is why accurate alcohol history is essential [1].
11. Prognostic Scoring in Cirrhosis (Applicable to MASH-Cirrhosis)
Once a MASLD patient progresses to cirrhosis, the same prognostic scoring systems apply:
| Component | 1 point | 2 points | 3 points |
|---|---|---|---|
| INR | < 1.7 | 1.7–2.3 | > 2.3 |
| Albumin (g/L) | > 35 | 28–35 | < 28 |
| Bilirubin (μmol/L) | < 34 | 34–50 | > 50 |
| Ascites | None | Mild/controlled | Moderate-severe |
| Encephalopathy | None | Grade 1–2 | Grade 3–4 |
- Child A (5–6): Compensated cirrhosis
- Child B (7–9): Decompensated
- Child C (10–15): Decompensated (severe)
Limitations: subjective components (ascites, encephalopathy), manipulable (albumin infusion, ascites drainage) [5].
- Uses bilirubin, INR, creatinine — all objective, continuous variables.
- Used for liver transplant prioritisation and prognostication.
- Also useful in ACLF prognostication [5].
High Yield Summary
-
MASLD (formerly NAFLD) = hepatic steatosis + ≥ 1 cardiometabolic risk factor. MASH (formerly NASH) = steatosis + lobular inflammation + hepatocyte ballooning ± fibrosis.
-
Prevalence ~25–38% globally; ~25–30% in Hong Kong. Very common dual pathology with HBV in HK.
-
Insulin resistance is the central pathogenic driver → ↑ FFA delivery + ↑ de novo lipogenesis + ↓ β-oxidation → steatosis. Lipotoxicity from toxic lipid species → oxidative stress + ER stress + inflammasome activation → MASH → fibrosis → cirrhosis → HCC.
-
Most patients are asymptomatic. Diagnosis is often incidental (elevated ALT/GGT on health check, steatosis on USS).
-
Fibrosis stage is the strongest predictor of outcomes — not steatosis grade or inflammation.
-
CVD is the #1 cause of death in MASLD, not liver-related death.
-
MASLD-HCC can develop WITHOUT cirrhosis (unlike most other liver diseases except HBV).
-
FibroScan: > 12 kPa suggests cirrhosis; CAP: > 280 dB/m suggests severe steatosis.
-
Weight loss of 5–7% resolves steatosis; ≥ 10% can improve/reverse fibrosis [3].
-
Burned-out MASH = steatosis resolves but fibrosis/cirrhosis remains → often misclassified as "cryptogenic cirrhosis."
-
Lean MASLD exists in Asia (~20% of cases) — use Asian BMI cutoff ≥ 23 kg/m².
-
High fructose → fatty liver; Coffee → protective [3].
Active Recall - MASLD & MASH: Definition, Epidemiology, Risk Factors, Pathophysiology, Clinical Features
[1] Lecture slides: GC 240. MASLD and Alcoholic Liver Disease.pdf [2] Lecture slides: Gastroenterology Hepatology Introduction to GI:Hepatology investigations from the abnormal.pdf [3] Senior notes: Block A - Gastroenterology Interactive Tutorial.pdf [4] Senior notes: Block A - I am a hepatitis B carrier.pdf [5] Senior notes: Block A - A jaundiced and incoherent patient_ liver failure.pdf [6] Senior notes: Block A - Abdominal distension_ ascites and cirrhosis.pdf [7] Senior notes: Block A - Patients with non-viral chronic liver diseases.pdf
Differential Diagnosis of MASLD & MASH
The typical MASLD patient presents in one of two ways:
- Incidental finding of elevated liver enzymes (ALT, AST, GGT) on routine health check
- Incidental finding of hepatic steatosis on ultrasound performed for another reason
In both scenarios, the clinician's job is to systematically exclude other causes of elevated liver enzymes and/or hepatic steatosis before attributing the findings to MASLD. Remember: MASLD is now a positive diagnosis (requires steatosis + ≥ 1 CMRF) [1], but you still need to consider whether there is a concomitant or alternative liver disease.
Murtagh's Safe Diagnostic Model
As taught in the CFB lecture on differentiating the normal from the abnormal [8]: Be systematic in problem solving — What is the probability diagnosis? What serious disorders cannot be missed (red flags)? What conditions are often missed (pitfalls)? Could this patient have a 'masquerade'? Apply this framework to every patient with abnormal LFTs or steatosis.
Approach to the Differential Diagnosis
The differential diagnosis depends on the presenting problem. There are two main clinical entry points:
This is the most common presentation. The GI Interactive Tutorial case illustrates this perfectly: "A 53-year-old gentleman is found to have persistently elevated liver enzyme upon routine health check. ALT: 115, AST: 68, GGT: 102... He is completely asymptomatic. He is a non-drinker" [3].
Steatosis is found incidentally or during workup for metabolic syndrome.
Think of the differential in two tiers:
- Other causes of hepatic steatosis (conditions that cause fat in the liver — mimicking MASLD on imaging)
- Other causes of elevated liver enzymes (conditions that cause raised ALT/AST/GGT but may NOT cause steatosis — alternative diagnoses that could be missed)
Then consider the crucial concept of dual/concomitant liver disease — especially relevant in Hong Kong.
These conditions cause fat accumulation in the liver and can mimic or coexist with MASLD:
| Condition | Key Distinguishing Features | Why It Causes Steatosis |
|---|---|---|
| Alcoholic Liver Disease (ALD) | Alcohol history is the key distinguishing feature [1]. > 210 g/wk (M) or > 140 g/wk (F). AST:ALT ratio often > 2 (in ALD, mitochondrial damage preferentially releases AST; also alcohol depletes pyridoxal-5-phosphate needed for ALT synthesis). ↑↑ GGT (enzyme induction by alcohol). Histologically indistinguishable from MASLD [1] | Alcohol metabolism via alcohol dehydrogenase and CYP2E1 → acetaldehyde + NADH accumulation → shifts hepatic redox state → inhibits fatty acid β-oxidation + promotes lipogenesis |
| MetALD | The overlap category — patient has BOTH metabolic risk factors AND moderate alcohol intake (women 140–350 g/wk; men 210–420 g/wk) [1] | Dual mechanism: insulin resistance-driven DNL + alcohol-mediated inhibition of β-oxidation |
| Drug-induced steatosis | Temporal relationship with drug initiation. Common culprits: amiodarone (causes phospholipidosis — microvesicular steatosis), methotrexate, tamoxifen, corticosteroids, valproic acid, antiretrovirals (NRTIs — e.g., stavudine, zidovudine) | Varies by drug: amiodarone inhibits mitochondrial β-oxidation; corticosteroids promote insulin resistance + lipogenesis; valproic acid impairs mitochondrial function |
| Total parenteral nutrition (TPN) | ICU/hospitalised patients on prolonged IV nutrition | Excess glucose/lipid delivery → hepatic lipogenesis overwhelms export |
| Starvation / rapid weight loss | History of crash dieting, anorexia nervosa, bariatric surgery (early post-op) | Massive peripheral lipolysis → flood of FFAs to liver exceeding β-oxidation and VLDL export capacity |
| Lipodystrophy | Generalised or partial loss of subcutaneous fat (acquired or genetic). Paradoxical metabolic syndrome despite thin appearance | Without subcutaneous fat stores, FFAs cannot be stored peripherally → all diverted to liver + severe insulin resistance |
| Pregnancy-related | Acute fatty liver of pregnancy (AFLP) — 3rd trimester, microvesicular steatosis, can be fulminant. HELLP syndrome | Defect in mitochondrial fatty acid oxidation (LCHAD deficiency in fetus → accumulation of toxic long-chain fatty acid metabolites in maternal circulation) |
| Inborn errors of metabolism | Paediatric age group. Galactosaemia, hereditary fructose intolerance, glycogen storage diseases, urea cycle defects, fatty acid oxidation defects | Specific enzymatic defects in metabolic pathways → toxic metabolite accumulation and/or impaired energy metabolism in hepatocytes |
| Coeliac disease | May present with steatosis + elevated transaminases; check anti-tTG antibodies | Mechanism unclear; possibly related to intestinal permeability and altered gut-liver axis |
ALD vs MASLD — The Critical Distinction
You CANNOT distinguish ALD from MASLD on histology alone [1][7]. The distinction relies entirely on accurate alcohol history. Always quantify alcohol intake in standard drinks/grams per week. Be aware that patients frequently under-report alcohol consumption. AST:ALT ratio > 2 suggests ALD (but is not absolute). GGT is disproportionately elevated in ALD due to microsomal enzyme induction by alcohol.
Tier 2: Other Causes of Elevated Liver Enzymes (Alternative Diagnoses)
These conditions cause elevated ALT/AST but may NOT primarily cause steatosis. They must be excluded because they require different management:
| Condition | Key Features | HK Relevance |
|---|---|---|
| Chronic Hepatitis B (HBV) | The most common cause of chronic liver disease in Hong Kong (64–75% of cirrhosis) [6]. Check HBsAg, HBeAg/anti-HBe, HBV DNA. Very commonly coexists with MASLD ("dual liver disease") [3] | Endemic in HK; vertical transmission; can cause HCC without cirrhosis |
| Chronic Hepatitis C (HCV) | Check anti-HCV, if positive → HCV RNA. Less common in HK (~5–10% of cirrhosis) [6]. HCV itself can cause insulin resistance and steatosis (genotype 3 directly causes steatosis) | Less common than HBV in HK but important to exclude |
| Hepatitis D (HDV) | Only in HBV-positive patients (HDV needs HBsAg coat). Very rare in Chinese [4] | Low priority in HK |
| Hepatitis E (HEV) | Usually acute; can cause chronic hepatitis in immunocompromised. Check anti-HEV IgM | Increasing recognition, especially in immunosuppressed |
| Condition | Key Features | Distinguishing Tests |
|---|---|---|
| Autoimmune Hepatitis (AIH) | Young to middle-aged women (but can affect any age/sex). Hypergammaglobulinaemia (↑ IgG). May present with acute hepatitis flare. HCC is rare in AIH [7] | ANA, anti-SMA (smooth muscle antibody), anti-LKM-1. Liver biopsy: interface hepatitis, plasma cell-rich infiltrate |
| Primary Biliary Cholangitis (PBC) | Middle-aged women. Pruritus, fatigue. Cholestatic pattern (↑ ALP >> ALT). M2 isoform of antimitochondrial antibody (AMA) — highly specific for PBC [7]. Mayo score for PBC severity [7] | AMA-M2, ↑ IgM. Liver biopsy: florid duct lesion (granulomatous destruction of bile ducts) |
| Primary Sclerosing Cholangitis (PSC) | Young to middle-aged men. Strong association with IBD (especially UC). Cholestatic pattern. | pANCA, MRCP showing "beading" of intrahepatic/extrahepatic bile ducts (multifocal strictures and dilatations). No specific serological marker |
| Condition | Key Features | Why It Matters |
|---|---|---|
| Wilson's Disease | Young patients (< 40 years). Neuropsychiatric symptoms (can mimic Parkinson's — extrapyramidal copper deposition [7]). Kayser-Fleischer rings (slit lamp). Genetic test does not have to be positive — clinical diagnosis still valid if compatible [7]. Fulminant hepatic failure in Wilson's: young patient + Coombs-negative haemolytic anaemia [7] | Low ceruloplasmin, ↑ 24h urinary copper. Penicillamine can worsen neurological symptoms initially [7] |
| Hereditary Haemochromatosis | Older men (women protected by menstruation until menopause). "Bronze diabetes" — skin hyperpigmentation + DM + hepatomegaly. Arthropathy, cardiomyopathy | ↑ Transferrin saturation (> 45%), ↑ ferritin. HFE gene (C282Y, H63D). Liver biopsy: Perls' stain for iron |
| Alpha-1 Antitrypsin Deficiency | Young patient with emphysema + liver disease. Rare in Chinese (more common in Northern Europeans) | ↓ Alpha-1 antitrypsin level. PAS-positive, diastase-resistant globules on liver biopsy |
| Condition | Key Features |
|---|---|
| Drug-induced liver injury (DILI) | Temporal relationship with drug. Common culprits: paracetamol (dose-dependent), antibiotics (amoxicillin-clavulanate, isoniazid, rifampicin), statins, NSAIDs, TCM / herbal tea [4]. Can be hepatocellular, cholestatic, or mixed pattern |
| Thyroid disease | Hypothyroidism can cause elevated transaminases AND steatosis (↓ thyroid hormone → ↓ hepatic lipid metabolism). Hyperthyroidism can cause elevated ALT. Always check TFTs |
| Coeliac disease | Unexplained elevated transaminases; check anti-tTG IgA |
| Cardiac hepatopathy / congestive hepatopathy | Right heart failure → hepatic venous congestion → "nutmeg liver". ↑ ALT/AST, ↑ bilirubin. Look for JVP elevation, peripheral oedema, hepatomegaly |
| Adrenal insufficiency | Can cause mildly elevated transaminases. Usually other features present (hypotension, hyperkalaemia, hyponatraemia) |
Dual Liver Disease — Extremely Common in Hong Kong
In Hong Kong, many patients have concomitant HBV + MASLD [3][6]. This is a critical concept:
- A positive HBsAg does NOT exclude MASLD — you can have both.
- Dual pathology accelerates progression to fibrosis, cirrhosis, and HCC.
- The GI Interactive Tutorial explicitly states: "Dual liver disease → HBV cirrhosis, and MAFLD — Common in HK" [3].
- Under the new MASLD framework, coexistence with other liver diseases is formally recognised.
| Feature | MASLD | ALD | Viral Hepatitis | AIH | Wilson's | Haemochromatosis |
|---|---|---|---|---|---|---|
| Age | Any, ↑ with age | Any | HBV: any; HCV: middle-aged | Young-middle F | < 40 | > 40 M |
| Sex | M > F | M > F | Varies | F >> M | Equal | M >> F |
| Alcohol | Below threshold | Above threshold | Variable | Variable | Variable | Variable |
| BMI | Usually ↑ | Variable | Variable | Variable | Variable | Variable |
| AST:ALT ratio | Usually < 1 (ALT > AST) | Usually > 2 | Variable | Variable | Variable | Variable |
| Key test | CMRF + steatosis | Alcohol Hx | HBsAg, anti-HCV, HBV DNA | ANA, SMA, ↑ IgG | Ceruloplasmin, KF rings | Transferrin sat, ferritin |
| Histology | Zone 3 steatosis, ballooning, pericellular fibrosis | Identical to MASLD | Interface hepatitis, ground-glass hepatocytes (HBV) | Plasma cell-rich interface hepatitis | Copper staining | Iron staining (Perls') |
| HCC risk | In cirrhosis (can occur without) | In cirrhosis | HBV: even without cirrhosis | Rare | Rare | In cirrhosis |
Don't Miss These Pitfalls
-
Assuming all steatosis = MASLD: Always exclude ALD (alcohol history), drugs, and consider genetic causes in young patients.
-
Ignoring dual pathology: In HK, HBV + MASLD is extremely common [3]. A positive HBsAg does NOT mean the fatty liver is irrelevant.
-
AST:ALT ratio: In simple MASLD, ALT > AST (ratio < 1). If AST > ALT, think: (a) advanced fibrosis/cirrhosis in MASLD (as fibrosis progresses, AST rises relative to ALT because sinusoidal clearance of AST decreases), (b) ALD (ratio > 2), (c) muscle injury.
-
"Burned-out" MASH: Advanced MASH-cirrhosis may have no residual steatosis — often misclassified as cryptogenic cirrhosis [1]. Look for metabolic syndrome features to suspect MASH aetiology.
-
Missing Wilson's disease: Any patient < 40 years with unexplained liver disease should have ceruloplasmin checked. Genetic test does not have to be positive to diagnose — clinical criteria suffice [7].
-
Hypothyroidism: Always check TFTs in patients with unexplained elevated LFTs or steatosis — hypothyroidism is a treatable and reversible cause.
-
TCM/herbal supplements: Drug-induced liver injury from TCM and herbal tea is an important cause of hepatitis in HK [4]. Always ask specifically about supplements.
| Pattern | Predominant Enzyme | Think Of |
|---|---|---|
| Hepatocellular | ALT/AST >> ALP | MASLD, viral hepatitis, AIH, Wilson's, haemochromatosis, DILI (hepatocellular type) |
| Cholestatic | ALP/GGT >> ALT | PBC, PSC, biliary obstruction, drug-induced cholestasis |
| Mixed | Both elevated proportionally | Overlap syndromes, DILI (mixed type), infiltrative diseases |
| Isolated ↑ GGT | GGT only | Alcohol (enzyme induction), drugs (phenytoin, carbamazepine), MASLD, obesity |
In MASLD, the typical pattern is mildly elevated ALT (often 1–3× ULN), with ALT > AST, and ↑ GGT [3]. ALP and bilirubin are usually normal unless cirrhosis has developed.
High Yield Summary — Differential Diagnosis
-
Probability diagnosis in an overweight/obese patient with mildly elevated ALT and steatosis on USS = MASLD — but you MUST systematically exclude other causes.
-
ALD is histologically indistinguishable from MASLD — alcohol history is the ONLY way to differentiate. AST:ALT > 2 and ↑↑ GGT favour ALD.
-
Dual liver disease (HBV + MASLD) is extremely common in HK — always check HBsAg.
-
Check for viral hepatitis (HBsAg, anti-HCV), autoimmune markers (ANA, SMA, AMA), iron and copper studies (if < 40), TFTs, and drug/supplement history in every patient.
-
Wilson's disease: young patient, unexplained liver disease, Coombs-negative haemolytic anaemia in fulminant presentation, can mimic Parkinson's.
-
Burned-out MASH presents as cryptogenic cirrhosis — suspect if metabolic syndrome features present.
-
Always check TFTs — hypothyroidism is a reversible cause of steatosis and elevated transaminases.
-
In MASLD: ALT > AST (ratio < 1). If AST > ALT, consider advanced fibrosis, ALD, or muscle damage.
Active Recall - Differential Diagnosis of MASLD & MASH
References
[1] Lecture slides: GC 240. MASLD and Alcoholic Liver Disease.pdf [3] Senior notes: Block A - Gastroenterology Interactive Tutorial.pdf [4] Senior notes: Block A - I am a hepatitis B carrier.pdf [6] Senior notes: Block A - Abdominal distension_ ascites and cirrhosis.pdf [7] Senior notes: Block A - Patients with non-viral chronic liver diseases.pdf [8] Lecture slides: CFB (FM02) Introduction to common problems - Differentiating the normal from the abnormal.pdf
Diagnostic Criteria, Diagnostic Algorithm & Investigations for MASLD & MASH
1. Diagnostic Criteria for MASLD (2023 Multi-Society Delphi Consensus)
The current diagnostic framework uses positive, inclusion-based criteria rather than the old exclusion-based NAFLD approach.
To diagnose MASLD, you need ALL of the following [1]:
| Criterion | Details |
|---|---|
| 1. Evidence of hepatic steatosis | Any ONE of: USS showing diffuse hyperechoic texture ("bright liver"), FibroScan CAP ≥ 238 dB/m, CT/MRI evidence of steatosis, OR liver biopsy showing ≥ 5% steatotic hepatocytes |
| 2. At least ONE cardiometabolic risk factor | BMI ≥ 25 (≥ 23 Asian) or ↑ waist circumference; Fasting glucose ≥ 5.6 mmol/L or HbA1c ≥ 5.7% or T2DM; BP ≥ 130/85 mmHg or on Rx; TG ≥ 1.7 mmol/L or on Rx; HDL < 1.0 M / < 1.3 F or on Rx |
Under the new framework, MASLD does NOT require exclusion of all other liver diseases — it can coexist with HBV, HCV, etc. However, if the ONLY cause of steatosis is a specific aetiology (e.g. drug, monogenic), that is classified separately.
The alcohol thresholds determine classification [1]:
| Category | Alcohol Threshold |
|---|---|
| MASLD | < 140 g/week (F) or < 210 g/week (M) + ≥ 1 CMRF |
| MetALD | 140–350 g/week (F) or 210–420 g/week (M) + ≥ 1 CMRF |
| ALD | > 350 g/week (F) or > 420 g/week (M) |
How to Convert Standard Drinks to Grams of Alcohol
1 standard drink ≈ 10 g pure alcohol (HK standard). So:
- MASLD threshold: < 14 drinks/week (F) or < 21 drinks/week (M)
- A can of beer (330 mL, 5%) ≈ 13 g alcohol ≈ 1.3 standard drinks
- A glass of wine (150 mL, 12%) ≈ 14 g alcohol ≈ 1.4 standard drinks
MASH can ONLY be definitively diagnosed on liver biopsy [1][9]:
| Required Feature | Description |
|---|---|
| Hepatic steatosis | ≥ 5% of hepatocytes |
| Hepatocyte ballooning degeneration | Swollen, pale hepatocytes with loss of normal polygonal shape — the hallmark of hepatocyte injury |
| Lobular inflammation | Inflammatory cell infiltrates within the hepatic lobule (mixed, but predominantly mononuclear) |
All three must be present. Fibrosis is NOT required for the diagnosis of MASH but is separately staged (F0–F4).
Key Exam Point — Liver Biopsy is the ONLY Way to Diagnose MASH
Liver biopsy is the ONLY method to distinguish between simple steatosis (MASL) and steatohepatitis (MASH) [9]. Imaging and blood tests can identify steatosis and stage fibrosis non-invasively, but they CANNOT detect ballooning or lobular inflammation — which define MASH. This is why biopsy remains the gold standard despite being invasive.
Think of the MASLD diagnostic workup as answering three fundamental questions, in order:
3. Detailed Investigation Modalities
3A. Blood Tests
As taught by Prof. MF Yuen [10][11]: LFTs assess three distinct aspects of hepatic function:
- Cellular integrity → ALT, AST
- Synthetic capacity → Albumin, PT/INR
- Excretory function → Bilirubin, ALP, GGT
| Test | Typical Finding in MASLD | Interpretation / Pathophysiology |
|---|---|---|
| ALT | Mildly elevated (1–3× ULN) | ALT is predominantly cytoplasmic and liver-specific. Hepatocyte membrane injury from lipotoxicity → leakage of ALT into serum. In MASLD, ALT is usually higher than AST (ALT > AST, ratio < 1) [10] |
| AST | Mildly elevated, usually less than ALT | AST is found in liver (both cytoplasm and mitochondria) AND in muscle, heart, kidney. Less liver-specific than ALT. 4 conditions where AST > ALT: alcoholic hepatitis, HCC, congestive HF, ischaemic hepatitis [10] |
| GGT | Often elevated | GGT is a microsomal inducible enzyme [10]. In MASLD, it is induced by the metabolic milieu (insulin resistance, oxidative stress). Isolated ↑ GGT with normal ALP = fatty liver, alcohol, or drugs (phenytoin, carbamazepine) [10] |
| ALP | Usually normal | ALP rises in cholestatic disease (PBC, PSC, biliary obstruction). Normal ALP helps distinguish MASLD (hepatocellular pattern) from cholestatic disorders |
| Albumin | Normal in early disease; ↓ in cirrhosis | Albumin is synthesised exclusively by the liver (half-life ~21 days). Low albumin = impaired synthetic function = advanced disease |
| Bilirubin | Normal in early disease; ↑ in cirrhosis | Conjugation and excretion impaired when hepatocyte mass is significantly reduced |
| PT/INR | Normal in early disease; ↑ in cirrhosis | Liver synthesises clotting factors II, VII, IX, X (vitamin K-dependent) and fibrinogen. Factor VII has the shortest half-life (~6 hours), so PT rises early in acute liver injury |
High Yield — LFT Interpretation Framework
From the GI/Hepatology Investigations lecture [10]: Always interpret LFTs systematically:
- Is it hepatocellular (ALT/AST >> ALP) or cholestatic (ALP/GGT >> ALT)?
- What is the AST:ALT ratio? (> 2 = alcoholic hepatitis; approaching 1 with progression to cirrhosis)
- Is synthetic function preserved? (Albumin, PT)
- Is GGT disproportionately elevated? (Alcohol, drugs, fatty liver)
Important caveat: Normal ALT does NOT exclude MASLD or even MASH [1]. Up to 25% of patients with biopsy-proven MASH have normal ALT. This is why relying solely on ALT to screen for MASLD is insufficient.
| Test | Purpose |
|---|---|
| Fasting glucose | Screen for DM/pre-diabetes (≥ 5.6 mmol/L = IFG; ≥ 7.0 mmol/L = DM) |
| HbA1c | ≥ 5.7% = pre-diabetes; ≥ 6.5% = DM [12] |
| Fasting lipid profile | TG ≥ 1.7, HDL < 1.0 M / < 1.3 F = dyslipidaemia component of metabolic syndrome |
| Fasting insulin (if available) | HOMA-IR can quantify insulin resistance (HOMA-IR = [fasting insulin × fasting glucose] / 22.5). Not routinely done clinically but useful in research |
| Test | What It Shows |
|---|---|
| HBsAg | If positive → chronic HBV infection. Very important in HK [3][4]. Proceed with HBeAg, anti-HBe, HBV DNA |
| Anti-HCV | If positive → confirm with HCV RNA. HCV genotype 3 itself causes steatosis |
| Anti-HBc (IgG/IgM) | IgM = acute infection or reactivation; IgG = past exposure |
As covered extensively in the HBV lecture [4]: HBsAg +ve, Anti-HBs -ve, Anti-HBc +ve = acute or chronic HBV infection. Differentiate using IgM anti-HBc and timeline.
| Test | Condition Screened | Interpretation |
|---|---|---|
| ANA, Anti-SMA | Autoimmune hepatitis Type 1 | ANA/SMA positive in ~90% of AIH Type 1. Autoantibodies are not specific — require diagnostic criteria [7][11] |
| Anti-LKM-1 | Autoimmune hepatitis Type 2 | Rarer, less steroid-responsive [7] |
| AMA (M2 isoform) | PBC | M2 AMA is highly specific for PBC [7] |
| Immunoglobulins (IgG, IgM, IgA) | AIH (↑ IgG), PBC (↑ IgM) | Polyclonal hypergammaglobulinaemia in AIH |
| Ferritin, Transferrin saturation | Haemochromatosis | Transferrin sat > 45% → proceed to HFE genotyping. NB: Ferritin alone is non-specific (acute phase reactant, often ↑ in MASLD/metabolic syndrome without haemochromatosis) |
| Ceruloplasmin | Wilson's disease | Check in all patients < 40 years with unexplained liver disease. Low ceruloplasmin (< 0.2 g/L) is suggestive. Genetic test does not have to be positive for diagnosis [7] |
| Alpha-1 antitrypsin level | A1AT deficiency | Low levels; confirm with Pi typing |
| TFTs (TSH, fT4) | Hypothyroidism | Treatable cause of steatosis and elevated transaminases |
| Anti-tTG IgA | Coeliac disease | Unexplained elevated transaminases; more relevant in Western populations |
| Test | Purpose |
|---|---|
| AFP (alpha-fetoprotein) | HCC surveillance baseline. Normal < 12 ng/mL [3]. If mildly elevated (e.g. 15 ng/mL as in the GI tutorial case), warrants further imaging |
| CBP (Complete Blood Picture) | Thrombocytopaenia → suggests portal hypertension / hypersplenism (advanced disease). Macrocytosis (↑ MCV) → consider alcohol |
| Uric acid | Often elevated in metabolic syndrome |
3B. Non-Invasive Fibrosis Assessment
This is the most clinically important step because fibrosis stage is the strongest predictor of outcomes [1].
| Score | Components | Interpretation | Purpose |
|---|---|---|---|
| FIB-4 Index | Age, AST, ALT, platelet count. Formula: (Age × AST) / (Platelet count × √ALT) | < 1.3 = low risk (F0–F1); ≥ 1.3 = indeterminate; > 2.67 = high risk (F3–F4) | First-line triage in primary care. Rules out advanced fibrosis with high NPV |
| NAFLD Fibrosis Score (NFS) | Age, BMI, DM status, AST:ALT ratio, platelets, albumin | < -1.455 = low risk; > 0.676 = high risk | Alternative to FIB-4; slightly more complex |
| APRI | AST, platelet count | Less validated for MASLD specifically (better for HCV) | Occasionally used |
Clinical workflow: Use FIB-4 as the first-line screening tool. If FIB-4 < 1.3 → low risk, reassess in 2–3 years. If FIB-4 ≥ 1.3 → proceed to FibroScan (VCTE) or other second-line test.
FibroScan measures two parameters simultaneously [1][3][5]:
1. Liver Stiffness Measurement (LSM) — assesses fibrosis:
| LSM Value | Interpretation |
|---|---|
| < 8 kPa | Likely F0–F2 (no significant fibrosis) |
| 8–12 kPa | Indeterminate; may be F2–F3 |
| > 12 kPa | Suggestive of liver cirrhosis [3] |
| 27 kPa = F4 | As stated in the liver failure lecture [5] |
"Vibration controlled transient elastography — the non-invasive method to stage fibrosis… More stiff (27 kPa = F4), suggestive of more severe fibrosis" [5].
2. Controlled Attenuation Parameter (CAP) — assesses steatosis:
| CAP Value | Interpretation |
|---|---|
| < 238 dB/m | No significant steatosis |
| 248–280 dB/m | Mild-moderate steatosis [3] |
| > 280 dB/m | Severe steatosis [3] |
From the GI Interactive Tutorial: "CAP score 330 dB/m (248-280 dB/m suggestive of mild-moderate steatosis; > 280 dB/m suggestive of severe steatosis)" [3].
Limitations of FibroScan:
- Obesity (BMI > 30): may give unreliable readings; use XL probe
- Ascites: ultrasound waves cannot propagate through fluid → unreliable
- Acute inflammation/flare (e.g. ALT > 5× ULN): acutely oedematous liver is stiffer → falsely elevated LSM
- Congestive hepatopathy: raised CVP → liver congestion → falsely elevated
- Post-prandial: must be fasting (≥ 2–3 hours) — food increases hepatic blood flow → falsely elevated
- Serum markers of extracellular matrix turnover: hyaluronic acid, TIMP-1, PIIINP
- Proprietary test; good for excluding advanced fibrosis
- Used when FibroScan is unavailable or unreliable
| Modality | What It Shows | Strengths | Limitations |
|---|---|---|---|
| Ultrasound (USS) | Diffuse hyperechoic texture ("bright liver") compared to renal cortex [9]. May show hepatomegaly. Also used for HCC surveillance (6-monthly) [3] | Widely available, cheap, no radiation, operator-friendly | Cannot detect steatosis < 20–30%. Cannot distinguish MASL from MASH. Operator-dependent. Insensitive for fibrosis |
| FibroScan (VCTE) | LSM (fibrosis) + CAP (steatosis) simultaneously | Point-of-care, quick (~10 min), reproducible, non-invasive | See limitations above (obesity, ascites, inflammation) |
| CT | ↓ Hounsfield units of liver (fat is hypodense). Hepatic attenuation < spleen suggests steatosis | Can quantify steatosis; good for excluding masses | Radiation exposure. Cannot distinguish MASL from MASH. Not first-line for steatosis assessment |
| MRI-PDFF (Proton Density Fat Fraction) | Gold standard for non-invasive quantification of hepatic steatosis | Most accurate; can detect ≥ 5% steatosis; excellent for research/clinical trials | Expensive, limited availability, time-consuming |
| MR Elastography (MRE) | Liver stiffness (fibrosis staging) | Most accurate non-invasive method for fibrosis staging; less affected by obesity | Expensive, limited availability, requires specialised hardware |
USS for HCC Surveillance
Liver biopsy is the ONLY method to distinguish between steatosis (MASL) and steatohepatitis (MASH) [9].
Indications for liver biopsy in MASLD:
- Uncertain diagnosis despite non-invasive workup (e.g. coexisting autoimmune markers, unexplained LFT pattern)
- Discordant non-invasive test results (e.g. FIB-4 and FibroScan give conflicting fibrosis estimates)
- Suspected advanced fibrosis/cirrhosis with clinical implications (e.g. pre-transplant evaluation)
- Clinical trial enrolment (trials for MASH therapies require histological confirmation)
- Need to confirm MASH for treatment decisions (as specific pharmacotherapy for MASH emerges)
Histological features on biopsy [9]:
| Feature | Description | Scoring |
|---|---|---|
| Steatosis | Macrovesicular fat droplets in hepatocytes (large single droplet displacing nucleus peripherally, or multiple smaller droplets) | NAS: 0–3 based on % hepatocytes |
| Lobular inflammation | Inflammatory cell foci within the lobule (mononuclear cells predominant; some neutrophils) | NAS: 0–3 based on foci per field |
| Hepatocyte ballooning | Swollen, pale, rounded hepatocytes with wispy cytoplasm — pathognomonic of active hepatocyte injury | NAS: 0–2 |
| Mallory-Denk bodies | Eosinophilic cytoplasmic inclusions (damaged cytokeratin intermediate filaments) — seen in both MASH and ALD | Not scored in NAS but supportive |
| Fibrosis | Pericellular ("chicken-wire") in zone 3 → periportal → bridging → cirrhosis | Staged F0–F4 separately |
"Hepatic fat content tends to diminish with cirrhosis — NASH underdiagnosed in advanced liver disease" [9]. This is the "burned-out MASH" concept.
Risks of liver biopsy:
- Pain (~30%)
- Bleeding (~1:500 significant; ~1:10,000 fatal)
- Sampling error (~20–30% discordance between samples from different locations in the same liver — steatosis/inflammation can be patchy)
Once MASLD has progressed to cirrhosis, apply the same prognostic tools as for any other cirrhosis aetiology:
| Score | Components | Use |
|---|---|---|
| Child-Pugh | INR, Albumin, Bilirubin, Ascites, Encephalopathy [5] | Classify compensated (A) vs decompensated (B, C). Limitations: subjective (ascites, HE), manipulable [5] |
| MELD | Bilirubin, INR, Creatinine [5] | Transplant prioritisation, prognostication. Objective, continuous. Also useful in ACLF [5] |
- Always check HBsAg — HBV prevalence is very high; dual HBV + MASLD is the norm, not the exception [3][6]
- AFP baseline — even mildly elevated AFP (e.g. 15 ng/mL) in the context of dual HBV + MASLD warrants further imaging [3]
- FibroScan availability — widely available in HK public hospitals; the standard non-invasive fibrosis staging tool
- Ask about TCM / herbal supplements — a common but under-recognised cause of DILI in HK [4]
| Investigation Category | Specific Tests | Why |
|---|---|---|
| Confirm steatosis | USS, FibroScan CAP, MRI-PDFF | Establish the diagnosis |
| Assess metabolic status | Fasting glucose, HbA1c, lipid profile, BP, BMI/waist circumference | Confirm CMRFs for MASLD diagnosis |
| Exclude concomitant disease | HBsAg, anti-HCV, ANA/SMA/AMA, ferritin/TfSat, ceruloplasmin, TFTs, drug history | Identify dual pathology or alternative diagnosis |
| Stage fibrosis | FIB-4 → FibroScan LSM → ± liver biopsy | Fibrosis stage is the strongest outcome predictor |
| Screen for complications | OGD for varices (if cirrhotic), 6-monthly USS ± AFP for HCC | Early detection of life-threatening complications |
| Assess overall cardiovascular risk | ECG, ECHO if indicated, cardiovascular risk calculators | CVD is the #1 cause of death in MASLD |
High Yield Summary — Diagnosis & Investigations
-
MASLD diagnosis = hepatic steatosis (any modality) + ≥ 1 CMRF. No longer requires exclusion of all other liver diseases.
-
MASH can ONLY be diagnosed on liver biopsy — requires steatosis + ballooning + lobular inflammation. Non-invasive tests cannot detect ballooning.
-
LFTs in MASLD: mildly elevated ALT (usually ALT > AST), ↑ GGT, normal ALP/bilirubin/albumin in early disease. Normal ALT does NOT exclude MASH.
-
4 conditions where AST > ALT: alcoholic hepatitis (ratio > 2), HCC, congestive HF, ischaemic hepatitis [10].
-
Isolated ↑ GGT = fatty liver, alcohol, or drug induction (GGT is an inducible microsomal enzyme) [10].
-
FIB-4 index is the first-line fibrosis triage tool. < 1.3 = low risk; > 2.67 = high risk. Indeterminate → FibroScan.
-
FibroScan: LSM > 12 kPa suggests cirrhosis; CAP > 280 dB/m = severe steatosis [3][5].
-
Always check HBsAg in HK — dual HBV + MASLD is extremely common [3].
-
HCC surveillance for MASLD-cirrhosis: 6-monthly USS ± AFP [3].
-
Liver biopsy indications: uncertain diagnosis, discordant non-invasive tests, treatment decisions, clinical trials.
Active Recall - Diagnostic Criteria, Algorithm & Investigations for MASLD/MASH
References
[1] Lecture slides: GC 240. MASLD and Alcoholic Liver Disease.pdf [3] Senior notes: Block A - Gastroenterology Interactive Tutorial.pdf [4] Senior notes: Block A - I am a hepatitis B carrier.pdf [5] Senior notes: Block A - A jaundiced and incoherent patient_ liver failure.pdf [6] Senior notes: Block A - Abdominal distension_ ascites and cirrhosis.pdf [7] Senior notes: Block A - Patients with non-viral chronic liver diseases.pdf [9] Senior notes: Ryan Ho GI.pdf [10] Senior notes: Block A - Introduction to GI_Hepatology investigations (LFT, Endoscopy).pdf [11] Senior notes: Block A - Gastrointestinal Data Interpretation.pdf [12] Senior notes: Ryan Ho Chemical Path.pdf
Management Algorithm & Treatment Modalities for MASLD & MASH
Before diving into specifics, understand the strategic framework. MASLD management is guided by three overarching goals:
- Treat the metabolic milieu — because MASLD is a metabolic disease; treating the upstream drivers (obesity, insulin resistance, dyslipidaemia, hypertension) addresses the root cause
- Prevent and reverse liver-specific progression — halt the march from steatosis → MASH → fibrosis → cirrhosis → HCC
- Reduce overall mortality — which means aggressively managing cardiovascular risk, since CVD is the #1 cause of death in MASLD [1]
The management intensity is stratified by disease severity — particularly by fibrosis stage, because fibrosis is the strongest predictor of liver-related outcomes [1].
1. Lifestyle Modification — The Cornerstone for ALL Patients
Lifestyle modification is the foundation of MASLD management at every stage [1][3]. No pharmacotherapy replaces it.
This is the single most impactful intervention. The target depends on disease severity:
| Weight Loss Target | Expected Benefit | Rationale |
|---|---|---|
| 5–7% | Resolution of hepatic steatosis [3] | Even modest weight loss reduces hepatic de novo lipogenesis, improves insulin sensitivity, and reduces FFA delivery to the liver. 5% weight loss can reduce hepatic fat by ~30% |
| 7–10% | Resolution of MASH (steatohepatitis) | Greater reduction in hepatic inflammation and hepatocyte injury |
| ≥ 10% | Improvement or regression of fibrosis [3] | Fibrosis regression requires sustained reduction in hepatic stellate cell activation, which only occurs with more substantial metabolic improvement |
From the GI Interactive Tutorial [3]: "Resolution of fatty liver, BMI doesn't have to go back to 25 → reduce liver fat, weight loss of 5-7% is already sufficient in non-fibrosis patients. 10% in fibrosis patients → which is why GLP drugs work, they are shown to reduce weight by more than 10%"
The Challenge of Weight Loss
While the evidence is unequivocal that weight loss works, the hardest part is always ADHERENCE [13]. Only ~10% of patients achieve ≥ 10% weight loss through lifestyle alone. This is why pharmacological and surgical options are needed for many patients.
| Dietary Recommendation | Rationale |
|---|---|
| Mediterranean diet | Rich in monounsaturated fatty acids (olive oil), omega-3 PUFAs (fish), fibre, and polyphenols. Shown to reduce hepatic steatosis independent of weight loss. Anti-inflammatory effects |
| Reduce high fructose foods | "High fructose foods → fatty liver" [3]. Fructose is metabolised almost exclusively in the liver → directly drives de novo lipogenesis (bypasses normal glycolytic regulation via phosphofructokinase). Fructose-sweetened beverages are the worst offenders |
| ↑ Coffee intake | "Coffee → beneficial for fatty liver" [3]. Coffee contains polyphenols, caffeine, and kahweol/cafestol that reduce oxidative stress, inhibit hepatic stellate cell activation, and improve insulin sensitivity. Meta-analyses show dose-dependent reduction in fibrosis risk. 2–3 cups/day is beneficial |
| Reduce processed/ultra-processed foods | High in added sugars, refined carbohydrates, and trans fats — all promote insulin resistance and hepatic lipogenesis |
| Moderate caloric restriction | Caloric deficit of 500–1000 kcal/day → achieves ~0.5–1 kg/week weight loss |
| Alcohol | Keep below MASLD threshold (< 140 g/wk F, < 210 g/wk M). For patients with established fibrosis/cirrhosis, complete abstinence is recommended |
| Recommendation | Details | Rationale |
|---|---|---|
| 150–300 min/week moderate-intensity aerobic exercise | Brisk walking, cycling, swimming | Reduces hepatic fat even without significant weight loss (independent effect via ↑ fatty acid β-oxidation, ↑ insulin sensitivity). Also reduces cardiovascular risk |
| Resistance training 2–3×/week | Weight training, body-weight exercises | Increases muscle mass → ↑ glucose uptake → ↓ insulin resistance. Sarcopenia is a risk factor for worse MASLD outcomes |
| Reduce sedentary time | Break up prolonged sitting | Sedentary behaviour independently worsens insulin resistance |
2. Pharmacotherapy for MASLD/MASH
Key Principle — Who Needs Pharmacotherapy?
Pharmacotherapy is considered for patients with MASH and significant fibrosis (F2–F3), or those at high risk of disease progression (e.g. T2DM with elevated ALT). Patients with simple steatosis (MASL) without fibrosis generally do NOT need pharmacotherapy — lifestyle modification suffices [1].
| Feature | Details |
|---|---|
| Drug class | Thyroid hormone receptor beta (THR-β) selective agonist |
| Name breakdown | "Resmetirom" — targets the thyroid hormone receptor specifically in the liver |
| Mechanism | THR-β is highly expressed in hepatocytes. Activation of THR-β → ↑ hepatic fatty acid β-oxidation, ↓ de novo lipogenesis, ↓ hepatic fat content, ↓ atherogenic lipids (LDL, TG, Lp(a)). It mimics the beneficial metabolic effects of thyroid hormone on the liver WITHOUT systemic thyroid effects (does not affect THR-α in heart/bone) |
| Evidence | MAESTRO-NASH trial: significantly more patients achieved MASH resolution and fibrosis improvement at 52 weeks vs placebo |
| Indication | Adults with non-cirrhotic MASH with moderate to advanced fibrosis (F2–F3) |
| Contraindications | Decompensated cirrhosis; known hypersensitivity |
| Side effects | Diarrhoea, nausea. Monitor TFTs (may decrease TSH — expected pharmacological effect, not true hypothyroidism) |
| Key point | First drug specifically approved for MASH (March 2024). Represents a major milestone |
| Feature | Details |
|---|---|
| Drug class | Glucagon-like peptide-1 receptor agonists |
| Name breakdown | GLP-1 = "glucagon-like peptide 1" — an incretin hormone normally released by L-cells in the gut after eating. "Agonist" = activates the receptor |
| Key drugs | Semaglutide (Ozempic/Wegovy), liraglutide (Victoza/Saxenda) |
| Mechanism | GLP-1RA → (1) ↑ glucose-dependent insulin secretion, (2) ↓ glucagon secretion, (3) delayed gastric emptying → satiety, (4) central appetite suppression (hypothalamic GLP-1R) → significant weight loss (often > 10%) [3], (5) direct anti-inflammatory effects on liver, (6) ↓ hepatic de novo lipogenesis |
| Evidence | Semaglutide 2.4 mg weekly: STEP-NASH trial showed MASH resolution in ~59% vs ~17% placebo; improvement in fibrosis stage. Emerging evidence for MASLD, on top of DM and obesity [3] |
| Indication | Primarily approved for T2DM and obesity. Used off-label for MASH in patients with T2DM/obesity (dual benefit). Expected to gain MASH-specific indication |
| Contraindications | Personal or family history of medullary thyroid carcinoma; MEN2 syndrome; severe gastroparesis |
| Side effects | Nausea, vomiting, diarrhoea (GI side effects most common — due to delayed gastric emptying). Pancreatitis (rare). Gallstone formation (rapid weight loss) |
From the GI Interactive Tutorial [3]: "GLP-1 RA for the MAFLD → emerging evidence, on top of DM and obesity." "Which is why GLP drugs work, they are shown to reduce weight by more than 10%" [3].
| Feature | Details |
|---|---|
| Drug class | Dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist |
| Mechanism | Activates both GIP and GLP-1 receptors → superior weight loss (~20–25%) compared to GLP-1RA alone. Similar hepatic benefits as semaglutide but potentially more potent due to dual incretin action |
| Evidence | SYNERGY-NASH trial: impressive MASH resolution and fibrosis improvement. Also shown to achieve > 20% weight loss in SURMOUNT trials |
| Indication | T2DM, obesity. Under investigation for MASH-specific indication |
| Side effects | Similar to GLP-1RA (GI side effects) |
| Feature | Details |
|---|---|
| Drug class | Sodium-glucose co-transporter 2 inhibitors ("gliflozins") |
| Name breakdown | "SGLT2" = sodium-glucose linked transporter 2, located in the proximal convoluted tubule of the kidney. "Inhibitor" = blocks glucose reabsorption → glycosuria → caloric loss |
| Key drugs | Empagliflozin, dapagliflozin, canagliflozin |
| Mechanism for MASLD | ↓ Glucose reabsorption → glycosuria → mild weight loss + ↓ insulin levels → ↑ fatty acid oxidation. Also ↓ uric acid, ↓ BP. Ketogenesis promotion shifts hepatic metabolism toward fat oxidation |
| Evidence | Moderate evidence: reduces ALT, hepatic steatosis. Less robust evidence for fibrosis improvement compared to GLP-1RA/resmetirom |
| Indication | Primarily for T2DM, heart failure (HFrEF and HFpEF), CKD. Used adjunctively in MASLD patients with these comorbidities — dual benefit [14] |
| Contraindications | eGFR < 20 mL/min (reduced efficacy); T1DM (risk of euglycaemic DKA) |
| Side effects | UTI, genital mycotic infections (candida — glycosuria provides substrate), euglycaemic DKA (rare), Fournier's gangrene (very rare) |
GLP-1RA and SGLT2i — The Diabetes Drugs That Help the Liver
Both GLP-1RA and SGLT2i are primarily diabetes/obesity drugs that have significant hepatic benefits. In a patient with MASLD + T2DM, choosing these agents gives "two birds, one stone" — glycaemic control AND liver benefit. If the patient also has heart failure → prefer SGLT2i. If the patient needs maximum weight loss → prefer GLP-1RA or tirzepatide [3][14].
| Feature | Details |
|---|---|
| Drug class | Thiazolidinedione (TZD) — PPARγ agonist |
| Name breakdown | "Pioglitazone" — PPAR = peroxisome proliferator-activated receptor; γ = gamma isoform (predominantly in adipose tissue) |
| Mechanism | PPARγ activation → (1) ↑ adiponectin (anti-inflammatory, insulin-sensitising), (2) promotes fat redistribution from visceral/hepatic to subcutaneous depots, (3) ↑ fatty acid uptake by adipose tissue → ↓ FFA delivery to liver, (4) ↓ hepatic inflammation |
| Evidence | PIVENS trial (pioglitazone 30 mg): significantly improved MASH histology (steatosis, ballooning, inflammation) vs placebo. Also modest fibrosis benefit in some studies |
| Indication | MASH with T2DM — well-established benefit. Can be used in non-diabetic MASH but less commonly due to side effects |
| Contraindications | Heart failure (NYHA III–IV) — TZDs cause fluid retention → worsen HF. Active/history of bladder cancer (historical concern with pioglitazone). Osteoporosis in postmenopausal women |
| Side effects | Weight gain (2–4 kg — paradoxically, despite improving liver fat, because fat redistributes to subcutaneous depot). Fluid retention → peripheral oedema. ↑ Fracture risk in postmenopausal women. Potential bladder cancer risk (debated) |
| Feature | Details |
|---|---|
| Drug class | Fat-soluble antioxidant vitamin |
| Mechanism | Scavenges reactive oxygen species (ROS) → reduces oxidative stress → ↓ lipid peroxidation → ↓ hepatocyte injury and inflammation. Does NOT address the underlying metabolic driver (insulin resistance) |
| Evidence | PIVENS trial: Vitamin E 800 IU/day improved MASH histology in non-diabetic patients (43% MASH resolution vs 19% placebo). No benefit for fibrosis |
| Indication | Non-diabetic adults with biopsy-proven MASH |
| Contraindications | T2DM (not shown to be effective in diabetic MASH). Prostate cancer risk (SELECT trial raised concern at high doses). Avoid in patients with bleeding risk (theoretical anti-platelet effect at high doses) |
| Limitations | Does NOT improve fibrosis. Long-term safety concerns (↑ all-cause mortality at doses > 400 IU/day in some meta-analyses — debated). Not beneficial in diabetic patients |
| Agent | Mechanism | MASH Resolution | Fibrosis Improvement | Weight Effect | Best Candidate |
|---|---|---|---|---|---|
| Resmetirom | THR-β agonist | ✓✓ | ✓✓ | Neutral/mild ↓ | Non-cirrhotic MASH F2–F3 |
| Semaglutide | GLP-1RA | ✓✓ | ✓ | ↓↓ (> 10%) | MASH + obesity / T2DM |
| Tirzepatide | GIP/GLP-1RA | ✓✓ | ✓✓ | ↓↓↓ (> 15–20%) | MASH + obesity / T2DM |
| Pioglitazone | PPARγ agonist | ✓✓ | ✓ | ↑ (weight gain) | MASH + T2DM (no HF) |
| Vitamin E | Antioxidant | ✓ | ✗ | Neutral | Non-diabetic MASH only |
| SGLT2i | SGLT2 inhibitor | ✓ | ? | ↓ (mild) | MASH + T2DM + HF/CKD |
| Metformin | Insulin sensitiser | ✗ | ✗ | ↓ (mild) | T2DM (does NOT improve MASH histology) |
Metformin Does NOT Treat MASH
Metformin, despite being an insulin sensitiser, does NOT improve MASH histology (steatosis, inflammation, or fibrosis). It is still used for T2DM management and has cardiovascular benefit, but it should NOT be prescribed specifically for MASH treatment [1].
Since CVD is the leading cause of death in MASLD [1], aggressive cardiovascular risk management is mandatory:
| Risk Factor | Treatment | Notes |
|---|---|---|
| Dyslipidaemia | Statins | Statins are safe in MASLD/MASH (they do NOT worsen liver disease). In fact, statin use is associated with reduced hepatic fibrosis and lower HCC risk in observational studies. The mild ALT elevation sometimes seen with statins is usually transient and does NOT require discontinuation unless > 3× ULN persistently |
| Hypertension | ACEI/ARB preferred | ACEI/ARBs have additional benefits: ↓ portal pressure, possible anti-fibrotic effects (angiotensin II promotes hepatic stellate cell activation → RAS blockade may ↓ fibrosis) |
| T2DM | Metformin + GLP-1RA or SGLT2i [14] | Choose agents with dual metabolic and hepatic benefits |
| Smoking | Cessation | Smoking worsens fibrosis progression and increases HCC risk |
This is particularly important in Hong Kong where dual HBV + MASLD is common [3]:
| Concomitant Disease | Management |
|---|---|
| Chronic HBV | Antiviral therapy (entecavir or TDF/TAF) if meets treatment criteria [4]. Treat HBV according to standard guidelines: active viral replication (HBV DNA elevated) + elevated ALT + fibrosis [4]. HBV treatment for the HBV [3] |
| ALD overlap (MetALD) | Alcohol abstinence is the cornerstone [15]. Address both metabolic and alcohol components |
| Autoimmune hepatitis overlap | Steroids → azathioprine as per AIH guidelines [7] |
Once cirrhosis develops, management shifts to cirrhosis-specific care in addition to MASLD treatment:
| Component | Details |
|---|---|
| HCC surveillance | 6-monthly USS ± AFP [3]. For MASLD, surveillance is recommended when cirrhosis is established (unlike HBV where age/sex criteria also apply) |
| Variceal screening | OGD at diagnosis of cirrhosis. If no varices → repeat in 2–3 years (compensated) or 1 year (decompensated). If varices → non-selective beta-blocker (carvedilol preferred) or variceal band ligation |
| Portal hypertension management | Ascites: sodium restriction + spironolactone ± furosemide. SBP prophylaxis. Hepatic encephalopathy: lactulose ± rifaximin |
| Nutritional support | Avoid sarcopenia (protein intake 1.2–1.5 g/kg/day). Avoid prolonged fasting. Late evening snack to prevent overnight catabolism |
| Liver transplantation | Indicated for decompensated cirrhosis (Child B/C) or HCC meeting Milan/UCSF criteria [16][17]. MELD score used for transplant prioritisation [5]. MASLD/MASH is now the fastest-growing indication for liver transplantation worldwide. Post-transplant, metabolic syndrome must be aggressively managed to prevent recurrent MASLD in the graft |
| Feature | Details |
|---|---|
| Indications | BMI ≥ 40 without comorbidity, OR BMI ≥ 35 with comorbidity (e.g. diabetes, respiratory insufficiency) [13]. Lower threshold (BMI ≥ 30) now being suggested if significant comorbidity present [13] |
| Procedures | Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (most common now), adjustable gastric band (less common) |
| Efficacy for MASLD | Most potent intervention for weight loss (20–40% total body weight loss). Resolves steatosis in > 90%, MASH in ~80%, and improves fibrosis in ~50–65% of patients |
| Mechanism | Massive caloric restriction + gut hormone changes (↑ GLP-1, PYY; ↓ ghrelin) → dramatic insulin sensitisation + weight loss |
| Contraindications | Decompensated cirrhosis — perioperative mortality is unacceptably high in Child B/C. Compensated cirrhosis (Child A) may be cautiously considered at experienced centres |
| Caution | Rapid weight loss can paradoxically worsen steatosis/steatohepatitis transiently (massive peripheral lipolysis → FFA flood to liver). Monitor LFTs post-operatively |
From the obesity lecture [13]: "Surgery will get you the greatest amount of weight loss, but too invasive for many individuals. So principle is to keep developing drugs that can help narrow the treatment gap."
| Agent | Class | Mechanism | Status |
|---|---|---|---|
| Obeticholic acid (OCA) | FXR agonist | Farnesoid X receptor activation → ↓ bile acid synthesis, ↓ hepatic lipogenesis, anti-inflammatory. Pruritus is a major side effect [7] | Phase 3 complete (REGENERATE trial) but FDA did not approve due to safety concerns (pruritus, ↑ LDL). Still used for PBC |
| Lanifibranor | Pan-PPAR agonist (α/δ/γ) | Combines metabolic benefits of all PPAR isoforms | Phase 3 ongoing |
| Survodutide | Dual glucagon/GLP-1 RA | Glucagon receptor activation → ↑ hepatic fat oxidation + GLP-1 effects | Phase 2 promising |
| Pegozafermin | FGF21 analogue | FGF21 improves insulin sensitivity, ↓ lipogenesis, ↓ inflammation | Phase 2 promising |
| Agent | Evidence | Why Not |
|---|---|---|
| Metformin | Does NOT improve MASH histology | Despite being an insulin sensitiser, its hepatic effects are insufficient to reverse steatohepatitis |
| UDCA (ursodeoxycholic acid) | No benefit for MASLD/MASH | Effective for PBC but not MASH |
| Silymarin (milk thistle) | Insufficient evidence | Popular supplement but no rigorous RCT evidence for MASH |
| TCM / herbal remedies | "Definitely do not try TCM" [18] — no evidence of efficacy; risk of DILI | May worsen liver disease through hepatotoxicity |
| Glucose drip | "May actually induce patient to develop fatty liver" [18] | Excess glucose → substrate for de novo lipogenesis |
High Yield Summary — Management of MASLD & MASH
-
Lifestyle modification is the cornerstone for ALL patients: weight loss 5–7% resolves steatosis; ≥ 10% improves fibrosis [3].
-
Mediterranean diet, reduce fructose, increase coffee [3].
-
Pharmacotherapy indicated for MASH with significant fibrosis (F2–F3): (a) Resmetirom — first FDA-approved MASH drug (THR-β agonist), (b) GLP-1RA (semaglutide/tirzepatide) — emerging evidence, achieve > 10% weight loss [3], (c) Pioglitazone — for MASH + T2DM (avoid in HF), (d) Vitamin E 800 IU/day — for non-diabetic MASH only.
-
Metformin does NOT improve MASH histology — do not prescribe for MASH specifically.
-
CVD risk management is paramount: statins are safe and beneficial; ACEI/ARB preferred for hypertension.
-
Treat concomitant HBV in dual liver disease (common in HK) [3][4].
-
Bariatric surgery for BMI ≥ 40 (or ≥ 35 with comorbidity); most potent intervention but contraindicated in decompensated cirrhosis [13].
-
MASH-cirrhosis: HCC surveillance (6-monthly USS ± AFP), variceal screening, manage decompensation, assess for liver transplantation (MASLD is the fastest-growing transplant indication) [3].
-
Pioglitazone and saxagliptin increase heart failure risk — avoid in patients with HF [14].
-
Coffee is beneficial; high-fructose foods and TCM are harmful [3][18].
Active Recall - Management of MASLD & MASH
References
[1] Lecture slides: GC 240. MASLD and Alcoholic Liver Disease.pdf [3] Senior notes: Block A - Gastroenterology Interactive Tutorial.pdf [4] Senior notes: Block A - I am a hepatitis B carrier.pdf [5] Senior notes: Block A - A jaundiced and incoherent patient_ liver failure.pdf [7] Senior notes: Block A - Patients with non-viral chronic liver diseases.pdf [13] Senior notes: Block A - I am overweight, doctor_ obesity; Hyperlipidaemia.pdf [14] Senior notes: Block A - Deterioration of eyesight in a diabetic patient_ diabetic complications.pdf [15] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf [16] Senior notes: Maksim Surgery Notes.pdf [17] Senior notes: Ryan Ho GI.pdf [18] Senior notes: Block A - Jaundice after raw oysters_ acute hepatitis.pdf
Complications of MASLD & MASH
MASLD/MASH complications fall into two broad domains, and understanding this distinction is crucial for clinical management and exam answers:
- Hepatic / liver-related complications — arising from progressive liver disease (fibrosis → cirrhosis → decompensation → HCC)
- Extrahepatic / systemic complications — arising from the underlying metabolic dysfunction and systemic inflammation
The relative importance of each domain depends on disease stage:
| Stage | Primary Cause of Morbidity/Mortality |
|---|---|
| MASL / Early MASH (F0–F2) | Cardiovascular disease (extrahepatic) — liver-related mortality is negligible |
| Advanced MASH (F3–F4) / Cirrhosis | Liver-related complications become dominant (though CVD remains important) |
"CVD is the most common cause of death" in MASLD overall [1]. Liver-related mortality climbs steeply once fibrosis reaches F3–F4. This dual burden makes MASLD a truly systemic disease.
A. HEPATIC COMPLICATIONS
These are the complications that arise as MASH progresses to cirrhosis and portal hypertension. They are the same as for cirrhosis of any aetiology, but with some MASLD-specific nuances.
From the liver failure lecture [5]: 6 associated complications of liver failure: (1) Infections, (2) Variceal bleeding, (3) Ascites / SBP, (4) Hepatorenal syndrome, (5) Hepatic encephalopathy, (6) Coagulopathy. Plus (7) HCC — "a complication you must ask for during history for any patient with cirrhosis" [5].
This is the most feared complication and the one most unique to MASLD in terms of its atypical behaviour.
Pathophysiology — Why MASLD Causes HCC:
The path from MASLD to HCC involves multiple mechanisms operating in parallel:
- Chronic inflammation → sustained NF-κB and STAT3 signalling → promotes hepatocyte proliferation and survival of damaged cells → genomic instability
- Oxidative stress → ROS cause direct DNA damage (mutations, strand breaks, base modifications)
- Hyperinsulinaemia / IGF-1 axis → insulin and IGF-1 are potent mitogens → activate PI3K/Akt/mTOR and Ras/MAPK pathways → promote cell growth and inhibit apoptosis
- Altered gut microbiome → bacterial metabolites (deoxycholic acid) promote hepatic stellate cell senescence-associated secretory phenotype (SASP) → pro-tumorigenic microenvironment
- Epigenetic changes → DNA methylation and histone modification patterns altered by chronic metabolic stress
MASLD-Specific HCC Features:
| Feature | Explanation |
|---|---|
| HCC can occur WITHOUT cirrhosis | Up to 20–30% of MASLD-related HCC develops in non-cirrhotic livers. This is a critical difference from most other aetiologies (except HBV) [3]. The pro-oncogenic metabolic milieu (hyperinsulinaemia, inflammation) can drive carcinogenesis independent of the cirrhosis pathway |
| Often detected at later stage | Many MASLD patients are not in HCC surveillance programmes because: (a) they are not known to have cirrhosis (missed diagnosis), (b) current guidelines only recommend surveillance in established cirrhosis, (c) USS sensitivity is reduced in obese patients (body habitus limits visualisation) |
| More likely to be poorly differentiated | Possibly because delayed detection allows tumour evolution |
| Presence of underlying metabolic syndrome complicates treatment | Obesity, DM, CVD → higher perioperative risk for resection/transplant |
HCC Surveillance:
From the GI Interactive Tutorial [3]: "Surveillance of HCC, 6 months ultrasound." For HBV: "Male 40+, Female 50+, or underlying cirrhosis, or family history of HCC — since HBV can cause HCC without cirrhosis, jumps the barrier → have to be more stringent." For MASLD: "cirrhosis is one of the requirements" for HCC surveillance [3].
| Feature | Details |
|---|---|
| Modality | 6-monthly USS ± AFP [3][19] |
| Indication in MASLD | Established cirrhosis |
| Limitation | USS sensitivity is only ~60% in obese patients. Consider CT/MRI if USS quality is poor |
| AFP | USG has a higher sensitivity than AFP [19][20]. AFP alone misses ~40% of HCC (not all HCCs produce AFP). But combined USS + AFP is better than USS alone |
| Rationale for 6-month interval | HCC doubling time ≈ 3 months. 6-month interval provides better survival than 12-month, and no difference from 3-month interval [19][20] |
Prognosis of HCC — Why It Is Poor [19][20]:
4 reasons for poor prognosis in HCC:
- Present in the late stage — asymptomatic when tumour < 8 cm; NO nerve fibres in the liver
- Presence of underlying liver diseases — 80–100% of HCC has underlying cirrhosis
- Early venous permeation — high recurrence rate due to circulating tumour cells
- Field cancerisation effect — whole liver exposed to oncogenic influence
HCC Without Cirrhosis in MASLD — The Surveillance Gap
MASLD-HCC can develop without cirrhosis, yet current guidelines only recommend HCC surveillance in patients with established cirrhosis. This creates a surveillance gap: non-cirrhotic MASLD patients who develop HCC are not being screened. This is an unresolved challenge in clinical practice. Risk stratification tools are being developed to identify which non-cirrhotic MASLD patients warrant surveillance [3].
Pathophysiology:
Portal hypertension in MASLD-cirrhosis develops through the same mechanism as any other cirrhosis:
- Structural component — fibrosis and regenerative nodules distort sinusoidal architecture → ↑ intrahepatic resistance to portal blood flow
- Dynamic component — activated hepatic stellate cells (myofibroblasts) contract around sinusoids → further ↑ resistance. Endothelial dysfunction → ↓ intrahepatic NO production → vasoconstriction
- Splanchnic vasodilation — in response to ↑ portal pressure, splanchnic arterioles dilate (mediated by NO, VEGF, bacterial translocation-induced cytokines) → ↑ portal inflow → perpetuates portal hypertension
- Collateral formation — blood seeks low-resistance paths → porto-systemic collaterals at oesophagogastric junction (oesophageal varices), rectum (rectal varices), umbilicus (caput medusae), retroperitoneum
Clinical Consequence — Variceal Bleeding:
| Feature | Details |
|---|---|
| Mechanism | Varices are dilated, thin-walled veins under high pressure. When wall tension exceeds wall strength → rupture → life-threatening upper GI haemorrhage |
| Mortality | 15–20% per episode despite modern treatment |
| Screening | Screening OGD indicated for patients with cirrhosis [6]. Not needed if liver stiffness ≤ 15 kPa AND platelet count > 150 × 10⁹/L (no clinically significant portal hypertension) [6] |
| Highest risk varices | Red wale signs on OGD (red streak marks on variceal surface → indicate impending rupture) [6] |
| Prevention | Non-selective beta-blockers (carvedilol / propranolol / nadolol) — oral carvedilol has least side effects, give prophylactically before the first bleed; demonstrated efficacy for secondary prevention [6]. Side effects: hypotension, bradycardia. Alternatively: endoscopic variceal band ligation (EVL) |
| MASLD-specific | Patients with MASLD-cirrhosis may have portal hypertension at lower liver stiffness values due to concomitant sinusoidal fat accumulation and perisinusoidal fibrosis compressing sinusoids even before reaching F4 |
Pathophysiology of Ascites:
Ascites is the most common decompensating event in cirrhosis. It results from three interacting mechanisms:
- Portal hypertension → ↑ hydrostatic pressure in splanchnic capillaries → fluid transudation into peritoneal cavity
- Hypoalbuminaemia → ↓ oncotic pressure → fluid cannot be retained in the vascular compartment
- Renal sodium and water retention → splanchnic vasodilation → ↓ effective arterial blood volume → activation of RAAS, sympathetic nervous system, and ADH → avid sodium and water reabsorption by kidneys
Management of Ascites:
- Sodium restriction (< 2 g/day = ~80 mmol/day)
- Diuretics: spironolactone (aldosterone antagonist — blocks the RAAS-driven sodium retention) ± furosemide (loop diuretic)
- Large-volume paracentesis with albumin replacement for tense ascites
- Refractory ascites → TIPS (transjugular intrahepatic portosystemic shunt) — creates a shunt between portal and hepatic veins to decompress the portal system. Complication of TIPS → shunting toxic ammonia directly to the brain. Hence contraindication would be patients with hepatic encephalopathy [11]
Spontaneous Bacterial Peritonitis (SBP):
| Feature | Details |
|---|---|
| Definition | Infection of ascitic fluid without an identifiable intra-abdominal source |
| Pathophysiology | Bacterial translocation from the gut lumen → through oedematous, hyperpermeable intestinal wall → lymphatics → ascitic fluid. Impaired reticuloendothelial function and ↓ opsonisation (low ascitic fluid complement and protein) → inability to clear bacteria |
| Organisms | Mostly gram-negative (E. coli, Klebsiella), also gram-positive (Streptococcus, Enterococcus) |
| Diagnosis | Diagnostic paracentesis: ascitic fluid PMN count ≥ 250/mm³ (even before culture results) |
| Treatment | IV ceftriaxone or cefotaxime (empiric). IV albumin to prevent hepatorenal syndrome |
| Prophylaxis | Norfloxacin or ciprofloxacin for patients with prior SBP (secondary prophylaxis) or high-risk patients (ascitic protein < 15 g/L) |
Pathophysiology:
HRS is the end-stage of the circulatory dysfunction in cirrhosis — a functional renal failure with structurally normal kidneys:
- Severe splanchnic vasodilation → ↓ effective arterial blood volume → maximal activation of RAAS, SNS, ADH
- Renal vasoconstriction → ↓ renal perfusion → ↓ GFR → oliguria → rising creatinine
- Kidneys are structurally normal — if transplanted into a non-cirrhotic recipient, they function normally
| Type | Onset | Prognosis | Trigger |
|---|---|---|---|
| HRS-AKI (formerly Type 1) | Rapid (< 2 weeks, creatinine doubles to > 226 μmol/L) | Very poor — median survival ~2 weeks without treatment | Often triggered by SBP, GI bleeding, or large-volume paracentesis without albumin |
| HRS-CKD (formerly Type 2) | Gradual | Better than Type 1 but still poor | Refractory ascites |
Treatment:
- Volume expansion with IV albumin
- Vasoconstrictors: terlipressin (V1 receptor agonist → splanchnic vasoconstriction → ↑ effective arterial volume → ↑ renal perfusion) + albumin
- Definitive treatment: liver transplantation
Pathophysiology:
HE is a spectrum of neuropsychiatric manifestations caused by liver insufficiency and/or porto-systemic shunting:
- Porto-systemic shunting → ammonia and other neurotoxins (mercaptans, short-chain fatty acids, GABA-ergic substances) bypass hepatic detoxification → reach systemic circulation → cross blood-brain barrier
- Ammonia is the principal toxin — normally produced by gut bacteria (urease activity) and protein catabolism (~40% bacterial, ~60% from protein breakdown [5]). Normally converted to urea in the liver via the urea cycle. In cirrhosis, this conversion fails
- In the brain, astrocytes take up ammonia → convert glutamate to glutamine (via glutamine synthetase) → glutamine is osmotically active → astrocyte swelling → cerebral oedema → impaired neurotransmission
Grading (West Haven Criteria):
| Grade | Features |
|---|---|
| Minimal (Covert) | Normal clinical exam; detected only by psychometric tests (number connection, constructional apraxia) |
| Grade 1 | Subtle personality changes, shortened attention span, sleep disturbance |
| Grade 2 | Lethargy, disorientation, inappropriate behaviour, asterixis (flapping tremor). "Bedside usually grade 2, that's when patients realise symptoms and present" [11] |
| Grade 3 | Somnolent but arousable, marked confusion, "grade 3, grade 4 intubated in ICU" [11] |
| Grade 4 | Coma, unresponsive |
Confusion in Cirrhosis ≠ HE
"Key concept: confusion in cirrhosis does not mean HE. HE is a less common cause of confusion in cirrhosis. In fact, confusion in cirrhosis is still most commonly caused by head injury and drug-related" [5]. Other differentials: withdrawal state, infection, metabolic disturbance (hyponatraemia, hypoglycaemia). Always order CT brain and electrolyte panel for any cirrhotic patient with confusion. HE is a diagnosis by exclusion [5].
Diagnosis:
- HE is a diagnosis by exclusion — no single test is diagnostic [5]
- Arterial ammonia — supportive but "not always raised, may not correlate with severity; not all nitrogenous compounds are ammonia" [5]
- EEG abnormalities — diffuse slowing; useful for difficult cases or ICU patients [5]
- Psychometric tests — constructional apraxia (drawing a 5-point star), Reitan's test (number connection) [5]
- Clinical features — fetor hepaticus, flapping tremor [5]
Treatment:
From the GI Data Interpretation [11]: "Treatment for hepatic encephalopathy → since its effects are due to increased ammonia: (1) Decreased production → protein reduction, but not that useful since protein is crucial // or getting rid of the bacteria that produces the ammonia; (2) Increase removal → laxatives, shit it all out"
| Treatment | Mechanism | Notes |
|---|---|---|
| Lactulose | Non-absorbable disaccharide → (1) osmotic laxative → ↑ faecal nitrogen excretion ("shit it all out" [11]), (2) colonic bacteria ferment it to lactic acid → ↓ pH → converts NH₃ (absorbable) to NH₄⁺ (non-absorbable, trapped in lumen), (3) promotes growth of non-urease-producing bacteria | First-line. Titrate to 2–3 soft stools/day |
| Rifaximin | Non-absorbable antibiotic → ↓ ammonia-producing gut bacteria | Add-on to lactulose for prevention of recurrent HE. Minimal systemic absorption → minimal resistance |
| BCAA (branched-chain amino acids) | Provide alternative nitrogen disposal pathway; promote skeletal muscle ammonia detoxification. "BCAA also used as a form of treatment in hepatic encephalopathy, to increase ammonia removal" [10] | Adjunctive; modest benefit |
| Protein management | "Protein reduction not that useful since protein is crucial" [11] — sarcopenia worsens outcomes. Instead, distribute protein intake across meals. Vegetable and dairy protein preferred over meat protein | Do NOT restrict protein chronically — counterproductive |
| Treat precipitants | Infection, GI bleeding (→ protein load in gut), constipation, dehydration, electrolyte disturbance (hypokalaemia, hyponatraemia), sedatives/opioids | Identify and treat the trigger |
Infections in liver failure are very common [5]:
| Feature | Details |
|---|---|
| Mechanism | Reticuloendothelial dysfunction and reduced opsonisation [5] — the liver's Kupffer cells normally clear bacteria from portal blood. In cirrhosis, their function is impaired AND porto-systemic shunting bypasses hepatic filtration. Production of complement and opsonins (complement components) is also impaired |
| Common sites | Respiratory tract and urinary tract [5] |
| Organisms | Staph, Strep, gram-negative rods. Bacteraemia in up to 25% of fulminant hepatic failure patients. Fungal infection — especially Candida [5] |
| Clinical significance | Infection is a common precipitant of decompensation (variceal bleed, HE, HRS). Low threshold for investigation (blood cultures, urine culture, CXR, diagnostic paracentesis) and empiric antibiotics |
Pathophysiology:
The liver synthesises both pro-coagulant factors (Factors II, V, VII, IX, X, fibrinogen) AND anti-coagulant factors (Protein C, Protein S, antithrombin III). In cirrhosis, BOTH sides are reduced → a "rebalanced haemostasis" that is fragile:
| Feature | Explanation |
|---|---|
| Prolonged PT/INR | ↓ Synthesis of vitamin K-dependent factors (II, VII, IX, X). Factor VII has the shortest half-life (~6 hrs) so PT rises first |
| Thrombocytopaenia | Splenic sequestration (hypersplenism from portal hypertension) + ↓ thrombopoietin production (TPO made by hepatocytes) + marrow suppression (alcohol, if applicable) |
| Hyperfibrinolysis | ↓ Hepatic clearance of tPA; ↓ synthesis of antifibrinolytic proteins |
| Paradoxical thrombotic risk | ↓ Protein C, S, antithrombin III → prothrombotic tendency. Portal vein thrombosis occurs in 5–15% of cirrhotic patients |
The clinical consequence: cirrhotic patients bleed easily from varices and mucosal surfaces BUT also form clots (portal vein thrombosis, DVT). Conventional coagulation tests (PT, INR) do NOT reliably predict bleeding risk because they only measure pro-coagulant factors.
| Feature | Details |
|---|---|
| Definition | Pleural effusion (usually > 500 mL) in a cirrhotic patient without primary cardiac or pulmonary disease |
| Pathophysiology | Ascitic fluid tracks through microscopic diaphragmatic defects (typically right hemidiaphragm) into the pleural space. Negative intrathoracic pressure sucks fluid through these defects |
| Side | Right-sided in ~85% (right hemidiaphragm is thinner and has more congenital defects) |
| Management | Same as ascites (sodium restriction, diuretics). Therapeutic thoracentesis for symptomatic relief. TIPS for refractory cases. Do NOT place a chest drain (continuous protein/fluid loss → complications) |
B. EXTRAHEPATIC / SYSTEMIC COMPLICATIONS
These are driven by the metabolic dysfunction and systemic inflammation that underpin MASLD. They occur at ALL stages of disease and are responsible for the majority of mortality in non-cirrhotic MASLD.
| Feature | Details |
|---|---|
| Why | MASLD shares all the metabolic syndrome risk factors that drive atherosclerosis. Additionally, MASLD itself is an independent CVD risk factor — hepatic inflammation generates pro-atherogenic mediators (CRP, IL-6, TNF-α, PAI-1, fibrinogen), promotes atherogenic dyslipidaemia (↑ small dense LDL, ↑ TG, ↓ HDL), and causes endothelial dysfunction |
| Manifestations | Coronary artery disease (MI), cerebrovascular disease (stroke), peripheral arterial disease, heart failure (HFpEF particularly associated with MASLD — shared metabolic substrate) |
| Management | Statins (safe and beneficial), ACEI/ARB, anti-platelet agents where indicated, glycaemic control, smoking cessation, exercise |
| Feature | Details |
|---|---|
| Bidirectional relationship | MASLD → worsens hepatic insulin resistance → ↑ hepatic glucose output → promotes T2DM. T2DM → worsens hepatic steatosis and fibrosis. Each accelerates the other |
| Clinical significance | MASLD patients have ~2–5× higher risk of developing T2DM. Once T2DM develops, liver-related outcomes (fibrosis progression, HCC risk) worsen significantly |
| Feature | Details |
|---|---|
| Why | Shared metabolic risk factors + systemic inflammation + RAAS activation. MASLD is an independent risk factor for CKD (↑ albuminuria, ↓ GFR) |
| Management | SGLT2 inhibitors and ACEI/ARB provide dual benefit (renoprotection + hepatic benefit) |
| Feature | Details |
|---|---|
| Colorectal cancer | MASLD patients have ↑ risk of colorectal adenomas and carcinoma. Likely mediated by hyperinsulinaemia (insulin/IGF-1 signalling is mitogenic for colonocytes) and altered bile acid metabolism |
| Other cancers | ↑ Risk of breast, gastric, and pancreatic cancers — likely related to shared metabolic and inflammatory pathways |
| Feature | Details |
|---|---|
| Depression, anxiety, fatigue | Chronic systemic inflammation, fatigue, and the psychosocial burden of obesity and chronic disease contribute to significant psychiatric comorbidity |
| Reduced quality of life | Fatigue is the most common symptom and can be debilitating despite seemingly "mild" liver disease |
In Hong Kong, dual HBV + MASLD [3] creates unique complications:
| Complication | Explanation |
|---|---|
| Accelerated fibrosis progression | Dual insults (viral + metabolic) → synergistic stellate cell activation → faster progression to cirrhosis |
| Higher HCC risk | Both HBV (viral integration, HBx protein) and MASLD (hyperinsulinaemia, inflammation) independently promote hepatocarcinogenesis → additive risk |
| Diagnostic confusion | Elevated ALT: is it from HBV flare or MASH? Need to correlate with HBV DNA levels, viral markers, and metabolic parameters |
| Treatment complexity | Must manage both HBV (antivirals) AND MASLD (lifestyle, metabolic risk) simultaneously |
| Organ System | Complication | Mechanism |
|---|---|---|
| Liver | Cirrhosis, HCC, liver failure | Progressive fibrosis; chronic inflammation/hyperinsulinaemia → carcinogenesis |
| Portal system | Variceal bleeding, ascites, SBP, hepatic hydrothorax | Portal hypertension from distorted sinusoidal architecture |
| Brain | Hepatic encephalopathy | Porto-systemic shunting → ammonia/neurotoxin exposure |
| Kidney | Hepatorenal syndrome, CKD | Splanchnic vasodilation → ↓ effective circulating volume → renal vasoconstriction; shared metabolic risk |
| Blood | Coagulopathy, thrombocytopaenia | ↓ Factor synthesis, hypersplenism, rebalanced haemostasis |
| Immune | Infections (bacterial, fungal) | Reticuloendothelial dysfunction, ↓ opsonisation, bacterial translocation |
| Cardiovascular | MI, stroke, PAD, HFpEF | Metabolic syndrome, systemic inflammation, atherogenic dyslipidaemia |
| Metabolism | T2DM progression | Hepatic insulin resistance worsens glycaemic control |
| GI | Colorectal neoplasia | Hyperinsulinaemia, altered bile acids |
High Yield Summary — Complications of MASLD & MASH
-
CVD is the #1 cause of death in MASLD overall — liver-related mortality dominates only in advanced fibrosis/cirrhosis [1].
-
6 + 1 complications of liver failure [5]: Infections, variceal bleeding, ascites/SBP, hepatorenal syndrome, hepatic encephalopathy, coagulopathy — plus HCC ("must ask in history for any cirrhosis patient") [5].
-
MASLD-HCC can occur WITHOUT cirrhosis (20–30% of cases) — surveillance gap exists because guidelines recommend screening only in established cirrhosis [3].
-
HCC surveillance: 6-monthly USS ± AFP. HCC doubling time ~3 months. USS more sensitive than AFP alone [3][19].
-
Confusion in cirrhosis ≠ HE. Most commonly caused by head injury or drugs. HE is a diagnosis by exclusion. Always CT brain + electrolytes [5].
-
HE treatment: lactulose (titrate to 2–3 stools/day) ± rifaximin. Do NOT restrict protein — it causes sarcopenia and worsens outcomes [11].
-
TIPS for refractory ascites but contraindicated in HE (shunts ammonia to brain) [11].
-
Infections are very common in liver failure — reticuloendothelial dysfunction + reduced opsonisation. Common organisms: Staph, Strep, gram-negatives, Candida. Respiratory and urinary tract most common sites [5].
-
Coagulopathy in cirrhosis is "rebalanced" — both bleeding AND thrombosis can occur. PT/INR do not reliably predict bleeding risk.
-
Dual HBV + MASLD in HK accelerates fibrosis and HCC risk [3].
Active Recall - Complications of MASLD & MASH
References
[1] Lecture slides: GC 240. MASLD and Alcoholic Liver Disease.pdf [3] Senior notes: Block A - Gastroenterology Interactive Tutorial.pdf [5] Senior notes: Block A - A jaundiced and incoherent patient_ liver failure.pdf [6] Senior notes: Block A - Abdominal distension_ ascites and cirrhosis.pdf [10] Senior notes: Block A - Introduction to GI_Hepatology investigations (LFT, Endoscopy).pdf [11] Senior notes: Block A - Gastrointestinal Data Interpretation.pdf [19] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf [20] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf
High Yield Summary
-
MASLD (formerly NAFLD) = hepatic steatosis + ≥ 1 cardiometabolic risk factor. MASH (formerly NASH) = steatosis + lobular inflammation + hepatocyte ballooning ± fibrosis.
-
Prevalence ~25–38% globally; ~25–30% in Hong Kong. Very common dual pathology with HBV in HK.
-
Insulin resistance is the central pathogenic driver → ↑ FFA delivery + ↑ de novo lipogenesis + ↓ β-oxidation → steatosis. Lipotoxicity from toxic lipid species → oxidative stress + ER stress + inflammasome activation → MASH → fibrosis → cirrhosis → HCC.
-
Most patients are asymptomatic. Diagnosis is often incidental (elevated ALT/GGT on health check, steatosis on USS).
-
Fibrosis stage is the strongest predictor of outcomes — not steatosis grade or inflammation.
-
CVD is the #1 cause of death in MASLD, not liver-related death.
-
MASLD-HCC can develop WITHOUT cirrhosis (unlike most other liver diseases except HBV).
-
FibroScan: > 12 kPa suggests cirrhosis; CAP: > 280 dB/m suggests severe steatosis.
-
Weight loss of 5–7% resolves steatosis; ≥ 10% can improve/reverse fibrosis [3].
-
Burned-out MASH = steatosis resolves but fibrosis/cirrhosis remains → often misclassified as "cryptogenic cirrhosis."
-
Lean MASLD exists in Asia (~20% of cases) — use Asian BMI cutoff ≥ 23 kg/m².
-
High fructose → fatty liver; Coffee → protective [3].
High Yield Summary — Differential Diagnosis
-
Probability diagnosis in an overweight/obese patient with mildly elevated ALT and steatosis on USS = MASLD — but you MUST systematically exclude other causes.
-
ALD is histologically indistinguishable from MASLD — alcohol history is the ONLY way to differentiate. AST:ALT > 2 and ↑↑ GGT favour ALD.
-
Dual liver disease (HBV + MASLD) is extremely common in HK — always check HBsAg.
-
Check for viral hepatitis (HBsAg, anti-HCV), autoimmune markers (ANA, SMA, AMA), iron and copper studies (if < 40), TFTs, and drug/supplement history in every patient.
-
Wilson's disease: young patient, unexplained liver disease, Coombs-negative haemolytic anaemia in fulminant presentation, can mimic Parkinson's.
-
Burned-out MASH presents as cryptogenic cirrhosis — suspect if metabolic syndrome features present.
-
Always check TFTs — hypothyroidism is a reversible cause of steatosis and elevated transaminases.
-
In MASLD: ALT > AST (ratio < 1). If AST > ALT, consider advanced fibrosis, ALD, or muscle damage.
High Yield Summary — Diagnosis & Investigations
-
MASLD diagnosis = hepatic steatosis (any modality) + ≥ 1 CMRF. No longer requires exclusion of all other liver diseases.
-
MASH can ONLY be diagnosed on liver biopsy — requires steatosis + ballooning + lobular inflammation. Non-invasive tests cannot detect ballooning.
-
LFTs in MASLD: mildly elevated ALT (usually ALT > AST), ↑ GGT, normal ALP/bilirubin/albumin in early disease. Normal ALT does NOT exclude MASH.
-
4 conditions where AST > ALT: alcoholic hepatitis (ratio > 2), HCC, congestive HF, ischaemic hepatitis [10].
-
Isolated ↑ GGT = fatty liver, alcohol, or drug induction (GGT is an inducible microsomal enzyme) [10].
-
FIB-4 index is the first-line fibrosis triage tool. < 1.3 = low risk; > 2.67 = high risk. Indeterminate → FibroScan.
-
FibroScan: LSM > 12 kPa suggests cirrhosis; CAP > 280 dB/m = severe steatosis [3][5].
-
Always check HBsAg in HK — dual HBV + MASLD is extremely common [3].
-
HCC surveillance for MASLD-cirrhosis: 6-monthly USS ± AFP [3].
-
Liver biopsy indications: uncertain diagnosis, discordant non-invasive tests, treatment decisions, clinical trials.
High Yield Summary — Management of MASLD & MASH
-
Lifestyle modification is the cornerstone for ALL patients: weight loss 5–7% resolves steatosis; ≥ 10% improves fibrosis [3].
-
Mediterranean diet, reduce fructose, increase coffee [3].
-
Pharmacotherapy indicated for MASH with significant fibrosis (F2–F3): (a) Resmetirom — first FDA-approved MASH drug (THR-β agonist), (b) GLP-1RA (semaglutide/tirzepatide) — emerging evidence, achieve > 10% weight loss [3], (c) Pioglitazone — for MASH + T2DM (avoid in HF), (d) Vitamin E 800 IU/day — for non-diabetic MASH only.
-
Metformin does NOT improve MASH histology — do not prescribe for MASH specifically.
-
CVD risk management is paramount: statins are safe and beneficial; ACEI/ARB preferred for hypertension.
-
Treat concomitant HBV in dual liver disease (common in HK) [3][4].
-
Bariatric surgery for BMI ≥ 40 (or ≥ 35 with comorbidity); most potent intervention but contraindicated in decompensated cirrhosis [13].
-
MASH-cirrhosis: HCC surveillance (6-monthly USS ± AFP), variceal screening, manage decompensation, assess for liver transplantation (MASLD is the fastest-growing transplant indication) [3].
-
Pioglitazone and saxagliptin increase heart failure risk — avoid in patients with HF [14].
-
Coffee is beneficial; high-fructose foods and TCM are harmful [3][18].
High Yield Summary — Complications of MASLD & MASH
-
CVD is the #1 cause of death in MASLD overall — liver-related mortality dominates only in advanced fibrosis/cirrhosis [1].
-
6 + 1 complications of liver failure [5]: Infections, variceal bleeding, ascites/SBP, hepatorenal syndrome, hepatic encephalopathy, coagulopathy — plus HCC ("must ask in history for any cirrhosis patient") [5].
-
MASLD-HCC can occur WITHOUT cirrhosis (20–30% of cases) — surveillance gap exists because guidelines recommend screening only in established cirrhosis [3].
-
HCC surveillance: 6-monthly USS ± AFP. HCC doubling time ~3 months. USS more sensitive than AFP alone [3][19].
-
Confusion in cirrhosis ≠ HE. Most commonly caused by head injury or drugs. HE is a diagnosis by exclusion. Always CT brain + electrolytes [5].
-
HE treatment: lactulose (titrate to 2–3 stools/day) ± rifaximin. Do NOT restrict protein — it causes sarcopenia and worsens outcomes [11].
-
TIPS for refractory ascites but contraindicated in HE (shunts ammonia to brain) [11].
-
Infections are very common in liver failure — reticuloendothelial dysfunction + reduced opsonisation. Common organisms: Staph, Strep, gram-negatives, Candida. Respiratory and urinary tract most common sites [5].
-
Coagulopathy in cirrhosis is "rebalanced" — both bleeding AND thrombosis can occur. PT/INR do not reliably predict bleeding risk.
-
Dual HBV + MASLD in HK accelerates fibrosis and HCC risk [3].
Hepatitis E
Hepatitis E is an acute, typically self-limiting viral liver infection caused by the hepatitis E virus (HEV), transmitted primarily via the fecal-oral route through contaminated water, with particular severity in pregnant women.
MetALD
MetALD is steatotic liver disease with cardiometabolic risk factors plus increased alcohol intake in the overlap range between MASLD and ALD thresholds.