• SLD (all forms) affects approximately 25–38% of the global adult population
• MASLD alone accounts for ~25–30% of adults worldwide
• MetALD prevalence is estimated at 3–5% of the general adult population in Western studies, though precise figures vary because the category is newly defined
• The overlap is extremely common in clinical hepatology practice — up to 20–30% of patients initially labelled "NAFLD" in older cohorts would now reclassify as MetALD under the new criteria

• In Hong Kong, HBV remains the most common cause of cirrhosis (~64–75% by WHO pooled estimates) ^[3], but MASLD is rapidly rising
• The concept of concomitant liver disease is emphasized: many HBV carriers also have MASLD/MetALD ^[3][4]
• Hong Kong has a rising prevalence of metabolic syndrome (obesity ~30–40% of adults, diabetes ~10%) combined with a cultural context where moderate alcohol use (especially beer and wine) is increasingly common
• Dual liver disease (e.g., HBV cirrhosis + MAFLD) is common in HK ^[4]
• High fructose foods → fatty liver; Coffee → beneficial for fatty liver ^[4]

The liver is the body's largest solid organ (~1.5 kg), situated in the right upper quadrant. Understanding MetALD requires appreciating the hepatic lobule — the functional unit of the liver:

• Hepatic lobule: hexagonal arrangement with a central vein, portal triads at the periphery (hepatic artery, portal vein, bile duct)
• Hepatic acinus (of Rappaport): the functional microcirculatory unit, divided into three zones based on oxygen gradient:
  • Zone 1 (periportal): highest O₂, first to receive blood from portal triad; site of gluconeogenesis, fatty acid oxidation, cholesterol synthesis
  • Zone 2 (intermediate): transitional
  • Zone 3 (pericentral/centrilobular): lowest O₂, last to receive blood; site of lipogenesis, CYP450 metabolism (including alcohol metabolism via CYP2E1), glycolysis

Why does this matter for MetALD?

• Alcoholic steatosis/steatohepatitis classically affects Zone 3 (centrilobular) — this is where CYP2E1 is concentrated for ethanol metabolism, generating reactive oxygen species (ROS)
• MASLD/MASH steatosis can be panlobular but often starts in Zone 3 as well (due to lipogenesis occurring there)
• In MetALD, the dual insult means Zone 3 bears the brunt from both directions, accelerating injury

• Lipid metabolism: synthesis, packaging (VLDL), and oxidation of fatty acids
• Glucose metabolism: glycogen storage, gluconeogenesis, insulin clearance
• Detoxification: Phase I (CYP450, especially CYP2E1 for ethanol) and Phase II (conjugation)
• Protein synthesis: albumin, clotting factors (especially Factor VII with shortest half-life of ~6 hours), complement
• Bile synthesis and excretion: cholesterol excretion, fat-soluble vitamin absorption
• Immune function: Kupffer cells (resident macrophages) are critical in MetALD pathogenesis

This is essentially the pathophysiology of metabolic syndrome / insulin resistance:

• Metabolic syndrome: cluster of metabolic disorders due to insulin resistance ^[8]
• Cause: likely central obesity ^[8]
  • Adipocytes release large amounts of FFA → insulin resistance ^[8]
  • Adipocytes release adipokines → insulin resistance ^[8]
  • Physical inactivity: ↓AMPK activation → ↓glucose uptake + ↓FFA metabolism ^[8]

In Hong Kong specifically:

• Rising rates of obesity (30–40% overweight/obese by Asian BMI criteria)
• High prevalence of T2DM (~10% of adults)
• High fructose foods → fatty liver ^[4] — relevant given the dietary shift toward processed/sweetened foods
• Sedentary urban lifestyle

• Social/cultural alcohol consumption patterns in Hong Kong have increased
• Beer, wine, and spirits consumption among working-age adults
• Women may be under-recognized as moderate drinkers
• Alcohol thresholds for MetALD: 140–350 g/week (women), 210–420 g/week (men) ^[1]

While MetALD per se is defined by metabolic + alcohol drivers, in Hong Kong practice:

• Many patients have TRIPLE pathology: HBV + metabolic steatosis + moderate alcohol ^[3][4]
• This accelerates fibrosis progression and increases HCC risk synergistically
• HBV can cause HCC without cirrhosis (DNA integration and direct carcinogenesis), unlike MASLD where cirrhosis is usually required for HCC development ^[4]

Step by step:

1. Insulin resistance (driven by visceral adiposity, genetic susceptibility, sedentary lifestyle) → peripheral adipose tissue becomes resistant to insulin's anti-lipolytic effect → increased free fatty acid (FFA) release into portal circulation
2. Hyperinsulinaemia (compensatory) activates SREBP-1c (sterol regulatory element-binding protein 1c) in hepatocytes → de novo lipogenesis (DNL) ↑ → more triglyceride synthesis
3. Simultaneously, insulin resistance impairs fatty acid β-oxidation in hepatocyte mitochondria
4. Net result: triglyceride accumulation in hepatocytes → steatosis (fatty liver)
5. Accumulated lipids generate toxic lipid intermediates (diacylglycerols, ceramides, free cholesterol, lysophosphatidylcholines) → lipotoxicity → endoplasmic reticulum (ER) stress, mitochondrial dysfunction, oxidative stress
6. Injured hepatocytes release damage-associated molecular patterns (DAMPs) → activate Kupffer cells (resident macrophages) and recruit neutrophils → inflammation = steatohepatitis (MASH)

Step by step:

1. Ethanol metabolism occurs primarily in Zone 3 hepatocytes via:
   • ADH pathway (cytosol): ethanol → acetaldehyde → acetate (by ALDH2)
   • MEOS/CYP2E1 pathway (smooth ER): induced by chronic alcohol use; generates reactive oxygen species (ROS) as a byproduct
   • Catalase pathway (peroxisomes): minor role
2. Both ADH and CYP2E1 pathways increase the NADH/NAD⁺ ratio, which:
   • Inhibits fatty acid β-oxidation (needs NAD⁺)
   • Promotes lipogenesis
   • Inhibits gluconeogenesis
   • Result: steatosis
3. Acetaldehyde is directly toxic: forms protein adducts → triggers immune response, mitochondrial damage, collagen synthesis by stellate cells
4. CYP2E1-generated ROS → oxidative stress → lipid peroxidation → hepatocyte necrosis
5. Alcohol increases gut permeability ("leaky gut") → bacterial endotoxin (LPS) reaches liver via portal vein → activates Kupffer cells via TLR4 → release of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) → steatohepatitis

This is the crux of MetALD pathophysiology:

The common final pathway (regardless of whether the initial driver is metabolic, alcoholic, or both):

1. Hepatocyte injury (necrosis/apoptosis) → release of DAMPs and cytokines
2. Kupffer cell activation → TGF-β, PDGF, CTGF release
3. Hepatic stellate cell (HSC) activation: quiescent HSCs (storing vitamin A) → activated myofibroblast-like cells → produce type I and III collagen
4. Extracellular matrix (ECM) deposition in the space of Disse → capillarisation of sinusoids (loss of fenestrations) → impaired nutrient exchange
5. Progressive fibrosis (F1 → F2 → F3 → F4/cirrhosis)
6. Cirrhosis: diffuse distortion of liver architecture + formation of regenerative nodules, surrounded by fibrous bands ^[3]
7. Cirrhosis leads to → portal hypertension (increased intrahepatic resistance) → decompensation (ascites, variceal bleeding, hepatic encephalopathy, jaundice)

• In MetALD (as with MASLD), HCC generally requires cirrhosis as an intermediate step ^[4]
• This is in contrast to HBV, where HCC can occur without cirrhosis due to direct HBV DNA integration into host genome ^[4][5]
• Mechanisms of hepatocarcinogenesis in MetALD:
  • Chronic inflammation → repeated hepatocyte turnover → increased DNA replication errors
  • Oxidative DNA damage from ROS
  • Telomere shortening
  • Epigenetic alterations (DNA methylation, histone modification)
  • Activation of oncogenic signalling (NF-κB, STAT3, Wnt/β-catenin)

Note: The histological pattern in MetALD can show features of both MASH (zone 3 predominant steatosis, ballooning, lobular inflammation) and ASH (Mallory-Denk bodies, neutrophilic satellitosis, perivenular/pericellular fibrosis). This overlap can make histological distinction difficult, which is partly why the clinical MetALD category is useful.

Liver elastography (e.g., FibroScan / transient elastography) is the non-invasive clinical tool for fibrosis staging ^[4]:

CAP score (Controlled Attenuation Parameter) quantifies steatosis ^[4]:

Child-Pugh Score is used to subclassify cirrhosis ^[3]:

• Child A (5–6): Compensated cirrhosis ^[3]
• Child B (7–9): Decompensated cirrhosis ^[3]
• Child C (10–15): Decompensated cirrhosis (severe) ^[3]

When you encounter persistently elevated liver enzymes, the structured approach is to exclude all other causes before attributing findings to MetALD:

From the GI Interactive Tutorial Case 2: A patient with HBsAg positive AND CAP score 330 dB/m (severe steatosis) illustrates dual liver disease — HBV + MAFLD/MetALD. This is common in Hong Kong. ^[4]

Why dual pathology matters: Each insult independently drives fibrogenesis. A patient with HBV + MetALD has accelerated fibrosis progression compared to either alone. Both pathologies must be actively managed.

This is a critical "masquerade" that mimics MetALD:

• Common culprits: methotrexate, amiodarone, tamoxifen, corticosteroids, valproate, tetracycline — all can cause hepatic steatosis
• Herbal and traditional Chinese medicines — extremely relevant in Hong Kong; patients may not volunteer this information unless specifically asked
• Supplements, drugs should be specifically enquired about ^[4]
• Mechanism: direct hepatotoxicity, mitochondrial dysfunction, inhibition of β-oxidation, or promotion of lipogenesis — mimicking the metabolic arm of MetALD
• Key differentiator: temporal relationship between drug exposure and liver enzyme elevation; improvement after drug withdrawal

From the GI Interactive Tutorial Case 2: "A 53-year-old gentleman with persistently elevated liver enzymes upon routine health check — ALT 115, AST 68, GGT 102 — is completely asymptomatic. He is a non-drinker [in that case]." ^[4]

The approach:

1. Pattern recognition on LFT ^[10]:
   • Hepatitic pattern (ALT/AST predominant): MetALD, MASLD, ALD, viral hepatitis, AIH, Wilson's, haemochromatosis, DILI
   • Cholestatic pattern (ALP/GGT predominant): PBC, PSC, biliary obstruction, infiltrative disease, DILI (cholestatic subtype)
   • Mixed pattern: overlap — does not exclude any of the above
2. Quantify alcohol, assess metabolic risk factors → classify within SLD spectrum
3. Screen for viral, autoimmune, metabolic causes as above
4. Stage fibrosis non-invasively

When MetALD has already progressed to cirrhosis and the patient presents with decompensation (jaundice, ascites, encephalopathy):

• The differential for the cause of cirrhosis is wide (see table below)
• In Hong Kong, HBV is the most common cause of cirrhosis (~64–75%) ^[3]
• Must identify the aetiology because it determines specific management (e.g., antiviral therapy for HBV/HCV, immunosuppression for AIH, copper chelation for Wilson's)

Key concept: confusion in cirrhosis does NOT mean hepatic encephalopathy (HE). HE is actually a less common cause of confusion in cirrhosis. The most common causes are head injury and drug-related confusion ^[12].

Differential for confusion in cirrhosis:

1. Head injury (falls are common in cirrhotic patients — coagulopathy, sarcopaenia, postural hypotension) → order CT brain ^[12]
2. Drug-related (sedatives, opioids, benzodiazepines — impaired hepatic clearance) → urine toxicology ^[12]
3. Infection / sepsis (SBP, UTI, pneumonia — cirrhotic patients are immunocompromised)
4. Metabolic disturbance (hyponatraemia, hypoglycaemia, uraemia) → electrolyte panel ^[12]
5. Alcohol withdrawal / delirium tremens (relevant in MetALD/ALD patients)
6. Wernicke's encephalopathy (thiamine deficiency — consider in any patient with alcohol history)
7. Hepatic encephalopathy — a diagnosis by exclusion; no single diagnostic test ^[12]
   • Arterial ammonia: not always raised, may not correlate with severity ^[12]
   • EEG abnormalities: for difficult cases or ICU patients ^[12]
   • Psychometric tests: constructional apraxia (drawing a 5-point star), Reitan's number connection test ^[12]

Steatosis must be documented by at least one of the following:

• Imaging: ultrasound (echogenic liver), CT (low hepatic attenuation), MRI-PDFF (proton density fat fraction ≥ 5%)
• Liver elastography CAP score: steatosis grading ^[4]
  • 248–280 dB/m → mild-moderate steatosis (S1–S2) ^[4]
  • > 280 dB/m → severe steatosis (S3) ^[4]
• Histology: ≥ 5% of hepatocytes containing lipid droplets on liver biopsy (gold standard but invasive)
• Biomarkers: e.g., Fatty Liver Index (FLI) > 60 as a validated surrogate when imaging is unavailable

At least one of the following must be present ^[1]:

Practical conversion: 1 standard drink ≈ 10 g alcohol. So MetALD in men ≈ 21–42 standard drinks/week ≈ 3–6 drinks/day.

The diagnosis requires that other causes of steatotic liver disease have been reasonably excluded (viral hepatitis, autoimmune liver disease, Wilson's disease, haemochromatosis, drug-induced causes, etc.) — or if present, they are acknowledged as concomitant pathology ^[2][7].

This is the "liver screen" — a panel of tests to exclude other causes and identify dual pathology ^[4][7][13]:

Alcohol Biomarkers (Objective Assessment)

Since MetALD diagnosis hinges on alcohol intake quantification, objective biomarkers supplement self-report:

Fibrosis stage is the strongest predictor of liver-related outcomes in any form of SLD — more important than the degree of steatosis or inflammation. The question is: how far has the disease progressed?

Non-Invasive Fibrosis Assessment

A. Serum-Based Scores

Why use these? They are free, widely available, and can be calculated from routine blood tests. They serve as excellent first-line triage tools to identify patients who need further assessment. The key limitation is the "indeterminate" zone — many patients fall here and need a second test.

B. Imaging-Based Fibrosis Assessment

From the GI Interactive Tutorial Case 2: "Liver elastography: liver stiffness 15 kPa (> 12 kPa suggestive of liver cirrhosis); CAP score 330 dB/m (> 280 dB/m suggestive of severe steatosis)" ^[4] — this patient has both cirrhosis-level fibrosis AND severe steatosis, consistent with advanced MetALD or concomitant disease.

C. Liver Biopsy

Remains the gold standard for fibrosis staging but is reserved for specific indications:

• Discordant non-invasive test results
• Suspicion of concomitant liver disease requiring histological confirmation (e.g., autoimmune hepatitis)
• Clinical trial enrolment
• Pre-transplant assessment
• When steatohepatitis vs simple steatosis distinction will change management

Histological scoring systems:

• NAS (NAFLD Activity Score): steatosis (0–3) + lobular inflammation (0–3) + hepatocyte ballooning (0–2) = 0–8. NAS ≥ 4 is generally considered diagnostic of steatohepatitis. However, NAS was designed for clinical trials, not as a standalone diagnostic tool.
• SAF Score (Steatosis, Activity, Fibrosis): more modern, used in European centres
• Fibrosis stage (Kleiner): F0–F4 as previously described
• Alcoholic hepatitis scoring: Maddrey's Discriminant Function, ABIC score, Lille score — used if there is a flare of alcoholic hepatitis within MetALD

Ferritin is often elevated in MetALD patients, but this does NOT necessarily mean iron overload:

• Ferritin is an acute phase reactant — elevated in inflammation, metabolic syndrome, obesity, infection, malignancy
• In MetALD, hepatic inflammation drives ferritin elevation
• To differentiate true haemochromatosis from reactive hyperferritinaemia: check TSAT ( > 45% suggests true overload) ^[15]
• If TSAT is normal/low and ferritin is elevated → likely reactive (metabolic syndrome-related)

Four conditions where AST > ALT (must know) ^[10]:

1. Alcoholic hepatitis — AST:ALT > 2:1, AST almost never > 500 U/L
2. Hepatocellular carcinoma — check AFP, imaging
3. Congestive heart failure — check clinical context, USS liver shows engorged hepatic veins
4. Ischaemic hepatitis — profound shock, disproportionate LDH elevation

In MetALD: ratio is intermediate (1:1 to 2:1) because both metabolic (ALT-predominant) and alcohol (AST-predominant) drivers are present. Once cirrhosis develops from ANY cause, AST tends to exceed ALT (reduced hepatocyte ALT content in cirrhotic liver).

Prof emphasises: only when there is a physical entity causing the pathology is imaging helpful. In other cases, a diagnosis can be made using solely clinical and laboratory investigations. Don't expose patients to unnecessary radiation and don't clog up the wait times ^[10].

In MetALD:

• USS/FibroScan → very helpful (confirm steatosis, stage fibrosis, screen for portal hypertension/HCC)
• CT/MRI → reserve for specific indications (HCC characterisation, equivocal USS, pre-operative planning)
• MRCP/ERCP → only if cholestatic picture suggesting biliary pathology ^[10]

This is the single most impactful intervention for the metabolic component of MetALD.

Resolution of fatty liver does not require BMI returning to 25. Weight loss of 5–7% is already sufficient in non-fibrosis patients. 10% weight loss is needed in fibrosis patients — which is why GLP-1 drugs work, as they achieve > 10% weight reduction. ^[4]

Why does weight loss work?

• Reduces visceral adipose tissue → ↓ FFA flux to liver → ↓ steatosis
• Improves insulin sensitivity → ↓ hyperinsulinaemia → ↓ de novo lipogenesis (SREBP-1c pathway)
• Reduces inflammation (↓ TNF-α, ↓ IL-6 from adipocytes) → ↓ steatohepatitis
• Reduces gut-derived endotoxin translocation (improved gut barrier function)

This is the cornerstone for the alcohol component of MetALD. By definition, MetALD patients drink in the moderate-to-increased range (140–350 g/wk women, 210–420 g/wk men) ^[1].

Alcohol abstinence is the cornerstone of treatment of alcoholic liver disease. It can improve survival and potentially reverse histological injury. ^[16]

Alcohol cessation support:

• Brief intervention and motivational interviewing (first line for moderate drinkers)
• AUDIT-C screening tool for monitoring
• Pharmacotherapy for alcohol dependence (if applicable — though MetALD patients are typically moderate drinkers, not dependent):
  • Naltrexone — opioid antagonist; reduces craving and rewarding effects of alcohol. Contraindicated in acute hepatitis or hepatic failure (hepatotoxic at high doses)
  • Acamprosate ("acamprosate" = "a-camp-ros-ate" → think "anti-craving") — modulates GABA/glutamate balance; reduces withdrawal symptoms and craving. Renally excreted, safe in liver disease.
  • Disulfiram — aldehyde dehydrogenase (ALDH) inhibitor; causes accumulation of acetaldehyde after alcohol ingestion → unpleasant flushing, nausea, tachycardia ("disulfiram reaction"). Contraindicated in severe liver disease because it inhibits the very enzyme needed to clear acetaldehyde.
  • Baclofen — GABA-B agonist; evidence for reducing alcohol consumption in cirrhotic patients (one of the few drugs studied in this population)

Why does exercise work even without weight loss? Because exercise independently activates AMPK (AMP-activated protein kinase) in hepatocytes and skeletal muscle → promotes fatty acid β-oxidation and glucose uptake, reduces de novo lipogenesis, and improves mitochondrial function. This is a metabolic benefit separate from calorie balance.

Since MetALD by definition requires ≥1 cardiometabolic risk factor, these must be actively managed:

From the Nephrology Interactive Tutorial: "Ozempic / GLP-1 RA → semaglutide" is listed among the management options for diabetic nephropathy and vasculopathy ^[17], reflecting the broad cardiorenal-hepatic benefit of this drug class.

For MetALD patients with BMI ≥ 27 with comorbidities or ≥ 30 who have not responded to lifestyle modification ^[19]:

For patients who meet surgical criteria:

Surgery is considered eligible if BMI ≥ 40 without comorbidity, or BMI ≥ 35 with comorbidity (e.g., diabetes, respiratory insufficiency). Lower threshold if comorbidity present (now suggesting BMI ≥ 30). ^[19]

Contraindications for bariatric surgery in MetALD context:

• Decompensated cirrhosis (high surgical mortality — portal hypertension increases bleeding risk)
• Active alcohol dependence (relative contraindication; most bariatric programs require documented abstinence period)
• Severe coagulopathy

In Hong Kong, dual liver disease (e.g., HBV + MetALD) is common ^[3][4]. Each co-existing condition requires its own specific treatment:

A MetALD patient may present with an acute alcoholic hepatitis flare superimposed on chronic liver disease. This is a medical emergency with high short-term mortality.

Management of severe alcoholic hepatitis (DF ≥ 32):

Treatment for hepatic encephalopathy → since its effects are due to increased ammonia: ^[13]

• Decreased production → getting rid of the bacteria that produce ammonia (rifaximin)
• Increased removal → laxatives (lactulose), "shit it all out" ^[13]

Surveillance of HCC: 6-monthly ultrasound ^[4] For MetALD/MASLD: cirrhosis is one of the requirements for HCC surveillance ^[4] For HBV: Male ≥ 40, Female ≥ 50, or underlying cirrhosis, or family history of HCC ^[4]

• MetALD has a higher rate of fibrosis progression than either MASLD or ALD alone, because:
  • Both metabolic and alcohol pathways converge on hepatic stellate cell activation (via TGF-β from Kupffer cells + direct acetaldehyde-mediated activation)
  • Double suppression of β-oxidation → more severe steatohepatitis → more hepatocyte necrosis → more fibrogenesis
• Cirrhosis is defined histologically as diffuse distortion of liver architecture with formation of regenerative nodules, surrounded by fibrous bands (F4) ^[3]
• Once cirrhosis develops, further complications fall into two broad categories: portal hypertension and hepatocellular dysfunction

Six associated complications of liver failure: Infections, Variceal bleeding, Ascites / SBP, Hepatorenal syndrome, Hepatic encephalopathy, Coagulopathy (+HCC) ^[21]

• HCC surveillance is indicated for MetALD/MASLD patients with cirrhosis (6-monthly USS ± AFP) ^[4]
• For other causes of HCC such as MAFLD, cirrhosis is one of the requirements ^[4]
• This is in contrast to HBV, where HCC can occur without cirrhosis (via direct HBV DNA integration), so age-based surveillance criteria apply: Male ≥ 40, Female ≥ 50, or underlying cirrhosis, or family history of HCC ^[4]
• MetALD-related HCC has some unique features:
  • May present at larger size (compared to viral hepatitis HCC) because surveillance is less established/less systematic for SLD
  • Often occurs in patients without recognised cirrhosis (up to 20–30% of MASLD/MetALD-HCC arises in non-cirrhotic livers, though cirrhosis is the major risk factor)
  • Metabolic comorbidities (obesity, DM) may complicate surgical candidacy

Mechanisms of hepatocarcinogenesis in MetALD:

• Chronic inflammation → repeated hepatocyte necrosis and regeneration → ↑ DNA replication errors → oncogenic mutations accumulate
• Oxidative DNA damage from CYP2E1-generated ROS and lipid peroxidation products
• Insulin resistance → ↑ IGF-1 signalling → promotes hepatocyte proliferation
• Altered gut microbiome → secondary bile acid production → FXR pathway deregulation
• Acetaldehyde-DNA adducts → mutagenesis

A distinct syndrome where a patient with chronic liver disease (e.g., MetALD-cirrhosis) experiences an acute deterioration with multi-organ failure.

Precipitants: infection (most common), GI bleeding, active alcoholism (binge on top of MetALD), DILI, variceal bleeding, surgery

Prognostic factors for ACLF depend on 6 organ-specific factors ^[21]:

1. Cerebral: HE
2. Respiration: SaO₂/FiO₂
3. Circulation: Need for vasopressors
4. Liver: Bilirubin level
5. Coagulation: INR level
6. Kidney: Creatinine level

All 3 components of the MELD score (bilirubin, INR, creatinine) are present in the ACLF assessment → MELD score is still useful in prognosticating ACLF as well, not just for acute liver failure and transplant prioritisation ^[21]

• MetALD patients have all the cardiovascular risk factors clustered together: T2DM, hypertension, dyslipidaemia, obesity, insulin resistance
• Additionally, liver disease itself contributes to CVD:
  • Hepatic inflammation → systemic inflammation (↑ CRP, ↑ IL-6, ↑ TNF-α) → accelerated atherosclerosis
  • Dyslipidaemia pattern: ↑ TG, ↓ HDL-C, ↑ small dense LDL particles (most atherogenic subtype)
  • ↑ Coagulation factor production (fibrinogen, Factor VIII) → pro-thrombotic state
  • ↑ PAI-1 (plasminogen activator inhibitor-1) from steatotic liver → impaired fibrinolysis

Manifestations: ischaemic heart disease, stroke, peripheral arterial disease, heart failure

This is why statin therapy and aggressive CVD risk factor management are essential even in patients with liver disease — the liver concern should not prevent cardioprotective treatment.

• MetALD and T2DM have a bidirectional relationship:
  • Insulin resistance → hepatic steatosis (MetALD driver)
  • Hepatic steatosis → worsens insulin resistance (↑ hepatic glucose output, impaired insulin clearance) → accelerates T2DM
  • Progression: hyperinsulinaemic euglycaemia → impaired glucose tolerance → early T2DM (relative insulin deficiency) → late T2DM (absolute insulin deficiency from progressive β-cell loss due to glucotoxicity and lipotoxicity) ^[8]
• In cirrhosis: "hepatogenous diabetes" can develop even without pre-existing metabolic syndrome, because the cirrhotic liver cannot clear insulin properly (↑ portal-systemic shunting) and has impaired glycogen storage

• MetALD is an independent risk factor for CKD, through:
  • Shared risk factors (DM, HTN)
  • Systemic inflammation and oxidative stress
  • RAAS activation in cirrhosis → renal vasoconstriction
  • Hepatorenal syndrome (see above) in advanced disease

• Strongly associated with obesity/metabolic syndrome
• Intermittent nocturnal hypoxia → oxidative stress → worsens hepatic inflammation and fibrosis
• Creates a vicious cycle: OSA → worse liver disease → worse metabolic derangement → worse OSA

• Relevant if the MetALD patient is admitted and abruptly stops alcohol
• Spectrum (in order of timing):
  • 6–12 hours: tremor, anxiety, diaphoresis, tachycardia, insomnia (autonomic hyperactivity from CNS excitation — loss of GABA inhibition + glutamate excitation unmasked)
  • 12–24 hours: alcoholic hallucinosis (visual/auditory hallucinations with intact sensorium)
  • 24–48 hours: withdrawal seizures (generalised tonic-clonic)
  • 48–96 hours: delirium tremens (DT) — confusion, agitation, hallucinations, autonomic instability, fever. Mortality 5–15% if untreated.

AOS Psychiatry: "1 MCQ on medical situation — what is delirium vs delirium tremens. 1 MCQ on alcohol withdrawal — how to manage (complications: seizure etc)" ^[22]

Management of alcohol withdrawal:

• Benzodiazepines (chlordiazepoxide, diazepam, or lorazepam) — GABA-A agonists to replace the lost inhibitory tone
  • In cirrhosis: prefer lorazepam or oxazepam (metabolised by glucuronidation, NOT hepatic CYP450 → safer in liver disease)
  • Avoid long-acting benzodiazepines (diazepam) in severe liver disease — risk of accumulation
• Thiamine (vitamin B1) supplementation — MUST give before glucose to prevent Wernicke's encephalopathy
• Monitoring: CIWA-Ar score (Clinical Institute Withdrawal Assessment for Alcohol, revised) — guides benzodiazepine dosing

• Wernicke's encephalopathy: acute neurological emergency from thiamine deficiency
  • Triad: confusion, ophthalmoplegia (CN VI palsy), ataxia (classic triad present in < 30% of cases)
  • Pathology: haemorrhagic necrosis of mammillary bodies and periventricular grey matter
  • Treatment: IV thiamine (Pabrinex) BEFORE glucose — giving glucose without thiamine can precipitate or worsen Wernicke's (glucose metabolism consumes thiamine via the pentose phosphate pathway and TCA cycle)
• Korsakoff's syndrome: chronic, irreversible sequela if Wernicke's is not treated
  • Anterograde amnesia (cannot form new memories), confabulation (fabricates memories to fill gaps)
  • Pathology: persistent mammillary body atrophy

• Chronic alcohol consumption is directly toxic to cardiomyocytes → dilated cardiomyopathy → heart failure
• Mechanism: acetaldehyde damages myocyte mitochondria, disrupts calcium handling, causes myocyte apoptosis
• Reversible if alcohol is ceased early enough; otherwise progressive
• In MetALD, this compounds the already elevated cardiovascular risk from metabolic syndrome

• Alcohol is directly neurotoxic + chronic alcohol use → thiamine deficiency → impaired nerve metabolism
• Distal symmetrical sensorimotor polyneuropathy (glove-and-stocking distribution)
• Often overlaps with diabetic neuropathy in MetALD patients → difficult to disentangle clinically

• Alcohol is the major cause of both acute and chronic pancreatitis
• In MetALD patients, gallstones (from obesity/metabolic syndrome) are also a major cause of acute pancreatitis — so the dual aetiology applies to the pancreas as well as the liver
• Chronic pancreatitis → pancreatic exocrine insufficiency (steatorrhoea, malabsorption) and endocrine insufficiency (pancreatogenic diabetes — even harder to manage because both β-cells AND α-cells are destroyed) ^[23]