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	*MASLD = hepatic steatosis + ≥1 cardiometabolic risk factor; legacy terms: NAFLD/MAFLD ^[1] MASH = steatosis + lobular inflammation + hepatocyte ballooning*; fibrosis is not required ^[1]^[3]
Epidemiology / risks	Major drivers: central obesity, T2DM, dyslipidaemia and hypertension ^[1] *Use the Asian BMI threshold (≥23 kg/m²); remember lean MASLD—normal BMI does not exclude visceral adiposity ^[1] HBV + MASLD is common in Hong Kong* ^[2]
Core mechanism	Insulin resistance → ↑ adipose lipolysis/FFA delivery + ↑ hepatic de novo lipogenesis → steatosis ^[1] Lipotoxicity → mitochondrial/ER stress and Kupffer-cell inflammation → ballooning + MASH ^[1] Stellate-cell activation → zone 3 pericellular “chicken-wire” fibrosis → cirrhosis ^[1]^[3]
Clinical picture	*Usually asymptomatic*: incidental mild ALT/GGT elevation or bright liver on ultrasound ^[1]^[2] Possible fatigue, smooth hepatomegaly or vague RUQ discomfort; look for metabolic syndrome ^[1] Jaundice, ascites, variceal bleeding or encephalopathy imply advanced disease ^[3]
Investigations	Confirm steatosis with ultrasound/CAP/MRI; document cardiometabolic criteria and screen for HBV/HCV and other causes ^[1]^[2] FIB-4 first: < 1.3 = low risk; ≥1.3 → FibroScan/second-line assessment; fibrosis stage drives prognosis ^[1]^[3] *Only biopsy distinguishes MASL from MASH*: ballooning + lobular inflammation ^[3]
Management	*Lifestyle + cardiometabolic risk control are foundational: Mediterranean-style diet, exercise; treat DM, BP and lipids ^[1]^[2] Weight loss 5–7% improves steatosis; ≥10% may improve fibrosis* ^[2] Significant fibrosis/cirrhosis → specialist care, stage-directed therapy and portal-hypertension management ^[3]
Complications	MASH fibrosis → cirrhosis, portal hypertension, liver failure and HCC ^[1]^[3] *Cardiovascular disease is the leading cause of death overall*; also assess T2DM and CKD ^[1] HCC can occur without cirrhosis, but risk rises sharply with advanced fibrosis ^[1]
Prevention / follow-up	Sustained weight loss, exercise, reduced fructose intake and aggressive cardiovascular risk reduction ^[1]^[2] Reassess fibrosis periodically; cirrhosis → 6-monthly ultrasound ± AFP + variceal screening ^[2]^[3] Identify and treat concomitant HBV or harmful alcohol use; do not assume one aetiology ^[2]
Exam traps	*Normal ALT does not exclude MASLD or MASH; enzymes do not stage fibrosis ^[1] MASLD and ALD cannot be reliably separated histologically—quantify alcohol intake ^[1] “Burned-out” MASH may lose visible steatosis and present as cryptogenic cirrhosis ^[1]^[3] NAS supports activity grading but is not a stand-alone diagnostic test* for MASH ^[3]

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:
1. Mitochondrial dysfunction → ↑ reactive oxygen species (ROS) → oxidative stress
2. Endoplasmic reticulum (ER) stress → unfolded protein response (UPR) activation
3. Direct hepatocyte apoptosis and necrosis → release of damage-associated molecular patterns (DAMPs)
4. 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]:
- Measures liver stiffness in kPa
- > 12 kPa suggestive of cirrhosis ^[3]
- 27 kPa = F4 ^[5]
- The more stiff, the more severe the fibrosis ^[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

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

From the GI Interactive Tutorial ^[3]: For HCC surveillance in MASLD, perform 6-monthly USS ± AFP. Indications: MASLD with established cirrhosis. For HBV, the threshold is different: Male ≥ 40, Female ≥ 50, or cirrhosis, or family history of HCC — because HBV can cause HCC without cirrhosis ^[3].

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)

Pioglitazone Contraindications

Pioglitazone (TZD) and saxagliptin (DPP-4i) — both shown to have increased risk of heart failure ^[14]. Do NOT use pioglitazone in patients with established heart failure. This is directly mentioned in the DM complications lecture ^[14].

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].

MASLD & MASH

1. Definition & Terminology

Historical Evolution of Nomenclature

The Spectrum of MASLD

Cardiometabolic Risk Factors (CMRFs) — The "Positive Criteria"

New Umbrella: Steatotic Liver Disease (SLD)

2. Epidemiology

Global

Hong Kong & Asia-Pacific Context

Demographics

3. Risk Factors

Strong / Established Risk Factors

Other Risk Factors

4. Anatomy & Function Relevant to MASLD

Hepatic Lipid Metabolism — Why the Liver Accumulates Fat

Hepatic Architecture Relevant to Injury

5. Aetiology & Pathophysiology

The "Multiple-Hit" Hypothesis

Step-by-Step Pathophysiology

Step 1: Insulin Resistance — The Central Driver

Step 2: Hepatic Steatosis (MASL — Simple Steatosis)

Step 3: Lipotoxicity — The Bridge from Steatosis to Steatohepatitis

Step 4: Inflammation (MASH)

Step 5: Fibrogenesis

Step 6: Cirrhosis and HCC

Adipokine Imbalance

Genetic Susceptibility

6. Classification

Histological Classification (NAS & SAF Scores)

NAFLD Activity Score (NAS) — Still Widely Used

Fibrosis Staging (Modified Brunt / Kleiner)

Clinical Classification

7. Clinical Features

Overview

Symptoms (with pathophysiological basis)

Signs (with pathophysiological basis)

Early Disease (MASL / Early MASH)

Advanced Disease (MASH-Cirrhosis / Decompensated)

Key Examination Approach

8. Associated Conditions & Extrahepatic Manifestations

9. Non-Invasive Assessment of Steatosis and Fibrosis

Steatosis Assessment

Fibrosis Assessment

10. Relationship with Alcoholic Liver Disease (ALD)

11. Prognostic Scoring in Cirrhosis (Applicable to MASH-Cirrhosis)

Child-Pugh Score [5]

MELD Score [5]

Active Recall - MASLD & MASH: Definition, Epidemiology, Risk Factors, Pathophysiology, Clinical Features

References

The Clinical Scenario: Why Differential Diagnosis Matters

Approach to the Differential Diagnosis

Entry Point 1: Elevated Liver Enzymes (Hepatocellular Pattern: ALT/AST > ALP)

Entry Point 2: Hepatic Steatosis on Imaging

Systematic Differential Diagnosis Framework

Tier 1: Differential Diagnosis of Hepatic Steatosis

Tier 2: Other Causes of Elevated Liver Enzymes (Alternative Diagnoses)

Viral Hepatitis

Autoimmune Liver Diseases

Metabolic / Genetic Liver Diseases

Other Important Differentials

The Concept of Dual / Concomitant Liver Disease

Diagnostic Algorithm: Approaching the Patient with Suspected MASLD

Key Differentiating Features: Summary Table

Common Pitfalls in Differential Diagnosis

The Pattern of LFT Abnormalities Guides the Differential

Active Recall - Differential Diagnosis of MASLD & MASH

1. Diagnostic Criteria for MASLD (2023 Multi-Society Delphi Consensus)

Formal Diagnostic Criteria

Distinguishing MASLD from ALD and MetALD

Diagnostic Criteria for MASH (Histological Diagnosis)

2. The Three-Pillar Diagnostic Approach

3. Detailed Investigation Modalities

3A. Blood Tests

Liver Function Tests (LFTs)

Metabolic Profile — Essential for Confirming CMRFs

Viral Hepatitis Serology — Excluding Concomitant Disease

Autoimmune and Metabolic Workup

Other Blood Tests

3B. Non-Invasive Fibrosis Assessment

Serum-Based Scores — First-Line Triage