The 2024 EASL classification replaces NAFLD/NASH with MASLD/MASH and unifies all fatty liver under the umbrella term "Steatotic Liver Disease (SLD)." ^[1]

Cardiometabolic parameters that define MASLD ^[1]:

• Overweight or obese (BMI ≥ 23 kg/m² for Asians)
• Prediabetes or Diabetes (fasting glucose, HbA1c criteria)
• Hypertriglyceridemia
• Low HDL
• Hypertension

Assessment requires: (1) Detailed drinking history, (2) Cardiometabolic risk factors, (3) Drug history (corticosteroids / tamoxifen / valproate / methotrexate), (4) Concomitant liver disease, (5) Other causes (hypothyroid / PCOS / panhypopituitarism / bypass surgery / genetic), (6) LFTs (ALT/AST), (7) Platelet count. ^[1]

Why platelet count? Because thrombocytopenia is a surrogate marker for portal hypertension and advanced fibrosis (hypersplenism from portal HTN → splenic sequestration). It also feeds into the FIB-4 calculation.

The lecture opens with a 58-year-old male lab worker found jaundiced, drinking 1 bottle of whisky/day for 10+ years.

Key observations from his bloodwork:

• Bilirubin 145 μmol/L → significant hepatocellular dysfunction
• AST 278, ALT 191 → AST > ALT (ratio ~1.5:1) — classic for alcoholic hepatitis ^[1]
• GGT 1155 U/L → massively elevated; alcohol is the most potent inducer of GGT
• INR 1.9 → impaired synthetic function / coagulopathy
• Amylase 214 → mildly elevated; possible concomitant pancreatitis
• Splenomegaly on USG → portal hypertension / cirrhosis

His course: psychiatry input for alcohol abstinence, lorazepam for withdrawal, IV thiamine, nutritional support → LFTs improved by day 5. On day 6, haematemesis from esophageal variceal bleeding requiring banding → cirrhotic complication unmasked.

One Alcoholic Unit = One Standard Drink = 10 g Ethanol

Safety level (controversial): Men 20-30 g/day; Women 10-20 g/day. Binge drinking is harmful regardless of average intake.

If drinking 50-60 g/day ^[1]:

Why are these only gross estimations? Drinking histories are notoriously unreliable. Concomitant liver disease (viral hepatitis, metabolic syndrome) accelerates progression dramatically ^[1].

The lecture references the AUDIT (Alcohol Use Disorders Identification Test) endorsed by the HK Department of Health. This is a 10-question screening tool assessing hazardous/harmful drinking and dependence.

GGT can be > 1,000 U/L but is not specific. AST > ALT during hepatitis (AST usually < 400 U/L). Serum ethanol has a half-life of 4-5 hours. Phosphatidylethanol (PEth) is the most sensitive and specific biomarker.

Why is AST > ALT in alcoholic liver disease? Two reasons: (1) Alcohol causes mitochondrial damage (macromitochondria), and AST is predominantly mitochondrial; (2) Alcohol depletes hepatic pyridoxal 5'-phosphate (vitamin B6), which is a cofactor for ALT synthesis, so ALT production is relatively suppressed ^[2][3].

Alcohol causes multiple simultaneous presentations across organ systems.

Alcoholic liver disease: concomitant presentations to watch for ^[1]:

• Other organ involvement (psychiatric / CNS / cardiac / pancreatic)
• Poor nutritional status
• Alcoholic withdrawal (D2+ onward) — delirium tremens
• Infections
• Cirrhotic complications — variceal bleeding / ascites / SBP / HE

Alcoholic hepatitis: prolonged heavy drinking ( > 50-60 g/day). AST:ALT ratio ≥ 1.5:1 (AST seldom > 400 U/L). May have hepatic decompensation (↑INR, Bilirubin). ± abdominal discomfort / jaundice / low-grade fever. ± hemolysis (Zieve's syndrome).

Zieve's syndrome: A triad of alcoholic hepatitis + hyperlipidemia + hemolytic anemia. The hemolysis is thought to be caused by altered lipid composition of RBC membranes.

Must exclude ^[1]:

• Biliary obstruction (imaging)
• Other types of hepatitis (viral, autoimmune, drug-induced)

Why do these matter? Patients crossing these thresholds have high short-term mortality (~35-50% at 28 days without treatment) and are candidates for specific pharmacological intervention ^[1][5].

The cornerstone is ALCOHOL ABSTINENCE (check compliance!) and SUPPORTIVE CARE.

Supportive measures (very important) ^[1]:

1. Nutritional support:

   • Thiamine (IV) — prevents/treats Wernicke's encephalopathy. Must be given BEFORE glucose to avoid precipitating Wernicke's.
   • Folate, phosphate, magnesium replacement
   • Caloric support: Protein intake 1.2-1.5 g/kg/day — contrary to the old dogma of protein restriction (which is now discouraged except in severe HE)
   • Correct electrolytes

2. Assess infection risk — workup and treat aggressively

3. Manage liver-related complications if present:

   • Variceal bleeding → endoscopic banding
   • Ascites → diuretics, paracentesis
   • SBP → antibiotics
   • Hepatic encephalopathy → lactulose, rifaximin

4. Assess and manage other acute alcohol-related conditions:

   • Encephalopathy / Delirium tremens (typically D2+ after cessation) / Psychiatric
   • Pancreatitis

5. Assess for acute kidney injury

6. Assess need for ICU support (may be difficult — these patients can deteriorate rapidly)

For mDF ≥ 32 or MELD ≥ 21:

Why is glucocorticoid use a "difficult decision"? Alcoholic hepatitis patients are already immunocompromised (liver failure impairs opsonization, complement, and reticuloendothelial function). Adding steroids further increases infection risk. Active infection and GI bleeding are relative contraindications ^[1][6].

Lille score: Assessed at day 7 of steroid therapy. A Lille score > 0.45 indicates non-response → stop steroids (no benefit, only harm from continued immunosuppression).

Deceased Donor: Contraindicated in HK if last drink < 6 months. Living Donor: Can be considered if last drink ≥ 6 months; individualized. Need comprehensive psychosocial assessment. Issue of alcoholic relapse. Need to demonstrate commitment to abstinence.

A 74-year-old female, BMI 28.6, with poorly controlled T2DM (HbA1c 9.1%), CKD (eGFR 30), hypertension, dyslipidemia, minor CAD. Found to have a 4.8 cm HCC on CT — despite being HBsAg−, Anti-HCV−, Anti-HBc−. The liver had a lobular surface suggesting cirrhosis.

Teaching point: This patient developed HCC from MASLD/MASH-related cirrhosis without any viral hepatitis. She died 7 months after diagnosis. This case powerfully illustrates that MASLD is now a significant cause of HCC even without viral hepatitis ^[1].

30-35% prevalence in Asia. Main risk factors: Obesity/overweight (65%), T2DM (65-70%). 20% progress to MASH. Advanced fibrosis (F3): ~5-8%. Cirrhosis: ~3%. As sole liver disease: 11% of cirrhosis, 12% of HCC (much higher when concomitant with other liver diseases).

Why is this important? With rising obesity and diabetes in Asia (China's obesity prevalence went from 3.1% in 2004 to 8.1% in 2018; 52% of Chinese diabetics are untreated), MASLD is becoming one of the fastest-growing causes of liver disease and HCC ^[1].

"Burn-out" concept: In advanced MASLD cirrhosis, the fat disappears from the liver because the hepatocytes are replaced by fibrotic tissue. This makes it hard to diagnose MASLD retrospectively in a cirrhotic liver — hence the term "cryptogenic cirrhosis" may actually be burned-out MASLD ^[1].

Key: Exclude Advanced Fibrosis using FIB-4. Then confirm with elastography if needed.

FIB-4 is the most important test in MASLD. It should be part of T2DM complication screening.

FIB-4 Formula: Age × AST / (Platelet count × √ALT)

Why FIB-4? It uses routinely available blood tests (age, AST, ALT, platelets) — no additional cost. It has excellent negative predictive value for excluding advanced fibrosis ^[1].

VCTE thresholds (from EASL 2024 pathway shown in slides) ^[1]:

• VCTE ≥ 8 kPa → suspected significant fibrosis → consider pharmacotherapy
• VCTE ≥ 12 kPa → suggestive of cirrhosis ^[8]

Must assess both liver AND non-liver complications.

Cardiometabolic:

• T2DM / prediabetes (HbA1c, FBG)
• Obesity assessment
• Dyslipidemia
• Cardiovascular risk assessment

Other:

• OSA (obstructive sleep apnea) — strongly associated with MASLD
• Kidney disease — CKD is common in metabolic syndrome
• HCC surveillance for advanced fibrosis and cirrhosis: USG ± AFP
• Liver biopsy (occasionally, for diagnostic uncertainty)
• MRI-PDFF (research/specialist)

Weight loss is the cornerstone treatment.

Dietary strategies ^[1]:

• Hypocaloric diet ( < 1,000 kcal/day)
• Ketogenic diet (Carb: < 20-50 g/day)
• Time-restricted eating (uncertain evidence)
• Mediterranean diet pattern (high in olive oil, fish, vegetables)
• ↓ Ultra-processed foods (red meat)
• ↓↓ Sugar-sweetened beverages (fructose) — fructose is directly lipogenic in the liver via de novo lipogenesis
• Coffee!! (≥ 3 cups per day) — protective against fibrosis progression

Exercise ^[1]:

• > 150 min/week moderate intensity OR > 75 min/week high intensity
• Reduce sedentary time

Other: Reduce smoking and alcohol ^[1]

Treating co-morbidities is also important! The #1 cause of death in MASLD patients is cardiovascular disease, not liver disease. Managing hypertension, dyslipidemia, and diabetes aggressively is essential.

1. Alcohol Dehydrogenase (ADH) pathway (80%):

   • Ethanol → Acetaldehyde (+ NADH) → Acetate/Acetyl-CoA (via ALDH, also + NADH)
   • Excess NADH shifts redox state: impairs gluconeogenesis (→ hypoglycemia), impairs Krebs cycle (→ ketoacidosis), promotes fatty acid synthesis
   • Acetaldehyde forms protein adducts → immune activation → hepatocyte injury

2. Microsomal Ethanol-Oxidizing System (MEOS) (20%):

   • CYP2E1 oxidizes ethanol → acetate + reactive oxygen species (ROS)
   • ROS → lipid peroxidation → mitochondrial damage
   • CYP2E1 also metabolizes paracetamol → chronic alcoholics are more susceptible to paracetamol hepatotoxicity

3. Gut permeability: Alcohol increases intestinal permeability → endotoxin (LPS) enters portal circulation → Kupffer cell activation → TNF-α, IL-6 release → hepatic inflammation and fibrosis

Mallory-Denk bodies: Eosinophilic intracytoplasmic inclusions of damaged cytokeratin intermediate filaments. Not specific to alcohol (also seen in MASH, Wilson's, HCC) but suggestive of alcohol-induced injury ^[7].

Stem: "A 60-year-old man with known alcoholic liver cirrhosis was admitted for increased confusion. Arterial serum ammonia was noted at 115 μmol/L (normal: 6-47 μmol/L). Which of the following is MOST LIKELY to precipitate the patient's confusion?"

Options: A. Alcohol withdrawal | B. Bleeding gastric ulcer | C. Diagnostic paracentesis | D. Recent diagnosis of hepatocellular carcinoma

Correct Answer: B. Bleeding gastric ulcer

Rationale: GI bleeding is the most common precipitant of hepatic encephalopathy in cirrhosis. Blood in the GI tract → digested by gut bacteria → massive ammonia production → overwhelms the failing liver's capacity to clear it. Alcohol withdrawal causes confusion but would not explain the elevated ammonia. Diagnostic paracentesis does not typically precipitate HE. HCC is a cause of chronic liver deterioration but not an acute precipitant of the ammonia spike described.

Stem: "A 49-year-old man was diagnosed to have hepatitis C virus infection. He was also an intravenous drug addict. On physical examination, there was no stigmata of chronic liver disease, and hepatomegaly with the lower border of the liver measuring 3 cm below the right costal margin. His body mass index was 30 kg/m². Computed tomography did not reveal liver mass. Which of the following is the MOST LIKELY cause of hepatomegaly in his case?"

Options: A. Cirrhosis | B. Fatty liver | C. Hepatitis C virus infection | D. Hepatocellular carcinoma

Correct Answer: B. Fatty liver

Rationale: BMI 30 = obese. No stigmata of CLD (not cirrhosis). CT shows no mass (not HCC). HCV alone rarely causes significant hepatomegaly without cirrhosis. Fatty liver (steatosis from obesity/MASLD) is the most common cause of hepatomegaly in an obese patient. This tests the concept that MASLD/fatty infiltration is a very common concomitant finding.

Stem: "A 65-year-old man was admitted for fresh haematemesis... noted to have stigmata of chronic liver disease over the hands. Name three causes of cirrhosis apart from chronic viral hepatitis in this case."

Correct Answer (3 of the following for full marks):

• Alcoholic liver disease
• NASH / MASLD
• Autoimmune hepatitis
• Primary biliary cholangitis (PBC)
• Primary sclerosing cholangitis (PSC)
• Wilson's disease
• Hemochromatosis
• Alpha-1 antitrypsin deficiency
• Drug-induced (methotrexate, amiodarone)
• Budd-Chiari syndrome / cardiac cirrhosis

Discriminator: The question asks for causes "apart from chronic viral hepatitis." ALD and NASH/MASLD are the highest-yield answers after HBV/HCV in Hong Kong. Don't forget autoimmune hepatitis as a common examiner favorite.

Stem: "There are several contraindications for liver transplantation. Which of the following is a contraindication for liver transplantation?"

Options: A. Acute cholangitis | B. Alcoholic cirrhosis | C. Drug-induced hepatic failure | D. Hepatocellular carcinoma

Correct Answer: A. Acute cholangitis

Rationale: Active uncontrolled infection (like acute cholangitis/sepsis) is a contraindication to liver transplantation. Alcoholic cirrhosis (with abstinence), drug-induced hepatic failure, and HCC (within Milan criteria) are all INDICATIONS for transplant. This question tests that alcoholic cirrhosis is NOT an absolute contraindication — but the 6-month abstinence rule applies ^[1].

Stem: "A 33-year-old woman of unremarkable past health was noted to be jaundiced and with increased abdominal distension and mental confusion... AST > 3,000 U/L, ALT > 3,000 U/L, INR led... acute liver failure. Which of the following is MOST LIKELY to precipitate the patient's acute liver failure?"

Options: A. Acute hepatitis E | B. Intake of red wine 1 day prior to symptoms | C. Recent prescription of atorvastatin for dyslipidaemia | D. Recent prescription of oral corticosteroids for eczema

Correct Answer: A. Acute hepatitis E

Rationale: The massively elevated transaminases ( > 3000) point to acute viral or toxin-mediated injury. Red wine one day prior would not cause this degree of injury. Atorvastatin is safe and rarely causes fulminant failure. Oral corticosteroids don't cause acute liver failure. Acute HEV can cause fulminant hepatic failure, especially in pregnant women, though any young woman can be affected. This tests the concept that AST > 400 argues AGAINST alcoholic hepatitis and should prompt consideration of viral/drug/ischemic causes ^[1].