Cirrhosis is a chronic, irreversible liver disease characterized by diffuse hepatic fibrosis, destruction of normal architecture, and formation of regenerative nodules, leading to progressive hepatic dysfunction and portal hypertension.

Cirrhosis — Definition, Epidemiology, Risk Factors, Anatomy & Function, Etiology, Pathophysiology, Classification, and Clinical Features

Liver cirrhosis represents a late stage of progressive hepatic fibrosis, characterised by bridging fibrosis, distortion of hepatic architecture and formation of regenerative nodules ^[1]^[2]^[3].

Let's unpack this:

Fibrosis = deposition of extracellular matrix (mainly collagen I and III) in the liver parenchyma in response to chronic injury.
Bridging fibrosis = fibrous septa that connect portal tracts to each other or to central veins, disrupting normal lobular architecture.
Regenerative nodules = clusters of hepatocytes that regenerate within these fibrous bands but can no longer maintain normal sinusoidal flow or zonation.

The word "cirrhosis" comes from Greek kirrhos (κιρρός) meaning "tawny/orange-yellow," describing the gross appearance of the cirrhotic liver.

Cirrhosis is a histological definition (staged F1–F4, where F4 = cirrhosis) ^[4]. The staging refers to the METAVIR system:

Stage	Description
F0	No fibrosis
F1	Portal fibrosis without septa
F2	Portal fibrosis with few septa
F3	Numerous septa without cirrhosis (bridging fibrosis)
F4	Cirrhosis

Key Conceptual Point

Cirrhosis is NOT just "a scarred liver." It specifically requires BOTH architectural distortion AND regenerative nodule formation. Pure fibrosis without nodular regeneration (e.g., congenital hepatic fibrosis) is NOT cirrhosis. Similarly, drugs like methotrexate can cause hepatic fibrosis without true cirrhosis because they may not produce the distortion of architecture + nodule formation characteristic of cirrhosis ^[2]^[3].

Is Cirrhosis Reversible?

Probably — more and more evidence suggests that to some extent, yes. Can go from F4 to F0, if removing the underlying cause ^[4].

Depends on the etiology (HBV, HCV, alcohol) and severity of cirrhosis ^[4]:
- HBV cirrhosis: majority is reversible, but not all — requires long-term nucleoside-analogue therapy ^[4]
- HCV cirrhosis: some is reversible, but not all ^[4] — sustained virological response (SVR) with direct-acting antivirals can lead to regression
- Alcoholic cirrhosis: reversible with sustained abstinence, but depends on severity
Child A/B can have some benefit in reducing complications and hospitalisation; Child C has less impact ^[4]

The mechanism of reversal involves:

Removal of the injurious stimulus → cessation of stellate cell activation
Apoptosis of activated hepatic stellate cells
Matrix metalloproteinases (MMPs) degrade excess collagen
Remodelling of hepatic architecture toward normalcy

However, once cirrhosis is advanced (Child C) with extensive cross-linking of collagen and vascular remodelling, reversal becomes unlikely ^[4].

2. Epidemiology

3. Risk Factors

Factor	Mechanism
High HBV DNA viral load	Sustained hepatocyte injury → fibrosis progression
HBeAg positivity	Marker of high replication
Alcohol co-use	Synergistic hepatotoxicity
Co-infection (HCV, HDV, HIV)	Additive/synergistic liver damage
MASLD/obesity/metabolic syndrome	"Dual liver disease" — very common in HK ^[6]
Male sex	Faster fibrosis progression
Older age at acquisition	Less immune tolerance
Aflatoxin exposure	Mutagenic, synergistic with HBV for HCC

4. Anatomy & Function of the Liver (Relevant to Understanding Cirrhosis)

Function	Normal	In Cirrhosis
Synthetic	Produces albumin, clotting factors (I, II, V, VII, IX, X), complement, binding proteins	↓ Albumin → oedema, ascites; ↓ clotting factors → coagulopathy
Metabolic	Gluconeogenesis, lipid metabolism, drug metabolism (CYP450), urea cycle (NH₃ → urea), bilirubin conjugation	↑ Ammonia → encephalopathy; ↓ drug clearance; ↓ gluconeogenesis → hypoglycaemia
Excretory	Bile production and bilirubin excretion	↑ Bilirubin → jaundice
Immune/filtering	Kupffer cells clear portal bacteraemia	↓ Clearance → bacteraemia, ↑ infection risk
Haemodynamic	Low-resistance portal vascular bed	↑ Intrahepatic resistance → portal hypertension
Hormonal clearance	Metabolises oestrogen, aldosterone, ADH	↑ Oestrogen → gynaecomastia, spider naevi, palmar erythema; ↑ aldosterone/ADH → Na⁺/water retention

5. Etiology of Cirrhosis (Focus on Hong Kong)

Causes of liver cirrhosis ^[2]^[3]:

Letter	Cause
A	Alcohol
B	Biliary (PBC, PSC, secondary biliary cirrhosis)
C	Cryptogenic / Cardiac
D	Drugs (MTX, amiodarone)
E	Endocrine/metabolic (Wilson's, haemochromatosis, α1AT deficiency)
F	Fatty liver (MASLD/NASH)
G	Genetic (overlaps with E; also α1AT)
H	Hepatitis (B, C, autoimmune, D)

6. Pathophysiology of Cirrhosis

This is the single most important section to understand, because almost every clinical feature can be derived from first principles if you understand the pathophysiology.

6.2 Two Major Pathophysiological Consequences

Once cirrhosis is established, TWO interlinked processes drive all complications:

7. Classification of Cirrhosis

Type	Nodule size	Typical Causes
Micronodular	< 3 mm	Alcohol, haemochromatosis, biliary obstruction, Indian childhood cirrhosis
Macronodular	> 3 mm	Post-viral (HBV, HCV), autoimmune, Wilson's
Mixed	Both	Any cause in later stages

7.3 Prognostic Scoring Systems

The 2 main prognostic scoring systems for cirrhosis ^[1]:

Child-Pugh score
Model for End-stage Liver Disease (MELD) score

5 components ^[1]:

Parameter	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	34–51	> 51
Ascites	None	Mild/controlled	Moderate–severe/refractory
Encephalopathy	None	Grade 1–2	Grade 3–4

Mnemonic for Child-Pugh: "ABIEA" = Albumin, Bilirubin, INR, Encephalopathy, Ascites. Or alternatively "ABBIE" (Ascites, Bilirubin, Albumin (Bound), INR, Encephalopathy).

Classification ^[1]:

Class	Score	1-year survival	2-year survival
Child A	5–6	~100%	~85%
Child B	7–9	~80%	~60%
Child C	10–15	~45%	~35%

Limitations of Child-Pugh Score ^[1]:

Several parameters can be manipulated or are subjective:
- Albumin → after treatment (infusion), can be raised
- Ascites → after drainage, can be reduced
- Encephalopathy → not something that can be classified perfectly with numbers, subjective
Limited discrimination — only 8 levels between Child B and C
Same score for very different values of bilirubin, albumin, INR within a band

Alternative to Child-Pugh that addresses some limitations ^[1]:

3 parameters ^[10]:

Bilirubin
Creatinine
INR

Formula: MELD = 3.78 × ln(bilirubin mg/dL) + 11.2 × ln(INR) + 9.57 × ln(creatinine mg/dL) + 6.43

The higher the score, the worse the short-term survival ^[10].

Used for transplantation and priority for transplantation list — in HK, not a first-come-first-served principle ^[10].

Updated versions include MELD-Na (adds sodium, which better predicts mortality in patients with ascites/hyponatraemia) and MELD 3.0 (2022; adds sex, albumin, and updated Na weighting).

High Yield Exam Comparison

Feature	Child-Pugh	MELD
Parameters	5 (INR, albumin, bilirubin, ascites, encephalopathy)	3 (bilirubin, creatinine, INR)
Subjective components	Yes (ascites, encephalopathy)	No (all objective lab values)
Main use	General prognostication, guide management	Transplant listing priority
Limitation	Manipulable, limited range	Does not account for complications like variceal bleeding

Is it a must to wait until patients are symptomatic to diagnose cirrhosis? No — possible to catch early using vibration-controlled transient elastography (FibroScan) to measure liver stiffness ^[1].

More stiff (e.g., 27 kPa = F4), suggestive of more severe fibrosis ^[1].

Stiffness (kPa)	Interpretation
< 7	F0–F1 (minimal fibrosis)
7–12	F2–F3 (significant fibrosis)
> 12	Suggestive of liver cirrhosis ^[6]

Liver biopsy is generally not done anymore, rarely performed due to invasiveness — non-invasive measurements (FibroScan) are the standard of care ^[10].

FibroScan also measures CAP score (Controlled Attenuation Parameter) for steatosis ^[6]:

248–280 dB/m: mild–moderate steatosis
> 280 dB/m: severe steatosis

8. Clinical Features of Cirrhosis

The clinical features can be systematically understood through the two pathophysiological pillars: hepatocellular insufficiency and portal hypertension.

8.1 Symptoms

Symptom	Pathophysiological Basis
Fatigue, malaise, weakness	Impaired gluconeogenesis, amino acid metabolism, and overall metabolic failure; also ↑ cytokines (TNF-α, IL-6) from chronic inflammation
Easy bruising/bleeding	↓ Synthesis of clotting factors (II, V, VII, IX, X, fibrinogen); ↓ thrombopoietin → thrombocytopenia
Jaundice (yellow skin/sclera, dark urine, pale stools)	↓ Bilirubin conjugation and excretion by damaged hepatocytes; initially direct (conjugated) bilirubin predominates
Pruritus	Retention of bile salts in skin (cholestatic component); possibly lysophosphatidic acid and other pruritogens
Right upper quadrant dull ache	Distension of the liver capsule — liver parenchyma has no nerve fibres; only when there is inflammation and swelling does dull aching occur ^[7]
Anorexia, nausea, weight loss	GI congestion (portal HTN), ↑ cytokines, impaired bile salt secretion → fat malabsorption
Muscle wasting	Impaired protein synthesis; hyperammonaemia promotes muscle catabolism (muscles serve as secondary site for ammonia detoxification via glutamine synthesis)
Fetor hepaticus	Accumulation of dimethyl sulfide and mercaptans due to impaired hepatic metabolism; described as "sweetish, musty" smell on breath

Symptom	Pathophysiological Basis
Abdominal distension (ascites)	↑ Splanchnic hydrostatic pressure + ↓ oncotic pressure (hypoalbuminaemia) + Na⁺/H₂O retention (RAAS, ADH) → fluid accumulates in peritoneal cavity
Ankle/lower limb swelling (oedema)	↓ Oncotic pressure (hypoalbuminaemia) + ↑ aldosterone (failure to metabolise) → fluid redistribution to dependent areas
Haematemesis / melaena	Variceal bleeding — portosystemic collaterals develop at sites of anastomosis; oesophageal and gastric varices are most dangerous
Abdominal fullness, early satiety (from splenomegaly)	Pressure symptoms from enlarged spleen ^[11] — splenomegaly results from portal venous congestion → increased blood pooling in splenic sinusoids
Dyspnoea	Hepatic hydrothorax (transudation of ascitic fluid through diaphragmatic defects, usually right-sided); or hepatopulmonary syndrome (intrapulmonary vascular dilatations → V/Q mismatch)

Symptom	Pathophysiological Basis
Confusion, altered mental state	Accumulation of ammonia and other neurotoxins → astrocyte swelling, altered neurotransmission
Sleep-wake cycle reversal	Altered melatonin metabolism + altered GABAergic tone
Personality/behavioural changes	Subclinical encephalopathy affecting frontal lobe function
Asterixis (liver flap)	Actually a sign — involuntary flapping tremor due to impaired proprioceptive input to brainstem reticular formation
In severe cases: coma	Profound cerebral oedema and neurotoxicity

Symptom	Pathophysiological Basis
Loss of libido, amenorrhoea, erectile dysfunction	↑ Oestrogen (failure of hepatic clearance) + ↓ sex hormone-binding globulin metabolism; also hypothalamic-pituitary dysfunction
Symptoms of infections (fever, abdominal pain)	Impaired immune function (↓ complement, ↓ opsonisation, Kupffer cell dysfunction); SBP is a major concern

8.2 Signs

These are the examination findings you look for on inspection — particularly important for clinical exams.

Hands and Arms:

Sign	Pathophysiological Basis
Palmar erythema	Hyperdynamic circulation + ↑ oestrogen → arteriolar vasodilation in thenar and hypothenar eminences (areas rich in arteriovenous anastomoses)
Dupuytren's contracture	Associated with alcoholic liver disease specifically; fibrosis of palmar fascia (mechanism unclear, possibly related to oxidative stress/free radicals from alcohol metabolites)
Clubbing	Chronic hypoxia from hepatopulmonary syndrome / intrapulmonary shunting
Leuconychia (white nails)	Hypoalbuminaemia → impaired nail bed capillary perfusion
Terry's nails	White proximal nail bed with normal distal pink band — hypoalbuminaemia
Muehrcke's nails	Paired horizontal white bands — hypoalbuminaemia
Asterixis (liver flap)	Ask patient to dorsiflex wrists with arms outstretched — involuntary "flapping" due to impaired motor control from accumulation of neurotoxins (ammonia, etc.)
Spider naevi (spider angiomata)	↑ Oestrogen (impaired hepatic metabolism) → arteriolar vasodilation; characteristically fill from centre outward (central arteriole with radiating "legs"); clinically significant if > 5 spider naevi in distribution of SVC (face, neck, upper limbs, chest)

Head and Neck:

Sign	Pathophysiological Basis
Jaundice (scleral icterus)	Best detected in sclera under natural light; visible when bilirubin > 34–51 μmol/L
Parotid enlargement	Especially in alcoholic cirrhosis — mechanism uncertain; may relate to protein malnutrition or autonomic neuropathy
Fetor hepaticus	Breath smells musty/sweet — dimethyl sulfide accumulation
Temporal wasting	Muscle wasting from malnutrition and catabolism

Chest and Trunk:

Sign	Pathophysiological Basis
Spider naevi (SVC distribution)	As above — hyperoestrogenaemia
Gynaecomastia	↑ Oestrogen (failed hepatic clearance) + ↓ SHBG → ↑ free oestrogen relative to testosterone
Loss of body hair (axillary, pubic)	Hyperoestrogenaemia / hypogonadism
Caput medusae	Recanalisation of paraumbilical veins (portosystemic collateral) → visible dilated veins radiating from umbilicus; named after Medusa's snake-hair

Abdomen:

Sign	Pathophysiological Basis
Hepatomegaly (early) or shrunken liver (late)	Early: inflammation/steatosis → enlarged liver. Late: fibrotic contraction → small, hard, nodular liver edge
Splenomegaly	Portal hypertension → congestion of splenic sinusoids → splenomegaly; may be massive
Ascites (shifting dullness, fluid thrill)	Portal HTN + hypoalbuminaemia + Na⁺/H₂O retention (as detailed in pathophysiology section above)
Caput medusae (periumbilical)	Portosystemic collateral via recanalised umbilical vein
Venous hum / Cruveilhier-Baumgarten murmur	Turbulent blood flow through recanalised umbilical vein — auscultate over umbilicus

Lower Limbs:

Sign	Pathophysiological Basis
Bilateral pitting oedema	Hypoalbuminaemia + hyperaldosteronism → salt and water retention; gravity-dependent

Genitalia:

Sign	Pathophysiological Basis
Testicular atrophy	↑ Oestrogen + ↓ testosterone → gonadal suppression

Grade	Features
Subclinical	Impaired psychomotor testing only (number connection test)
Grade 1	Altered sleep pattern, impaired concentration
Grade 2	Lethargy, confusion, asterixis
Grade 3	Somnolence, marked confusion, incoherent speech
Grade 4	Coma

Constructional apraxia: inability to draw a five-pointed star — a bedside test for encephalopathy
Asterixis: the classic flapping tremor

Aetiology	Specific Clinical Clue
Alcohol	Dupuytren's contracture, parotid enlargement, peripheral neuropathy, cerebellar signs, features of chronic pancreatitis
HBV/HCV	May have no specific extra-hepatic signs; ask about risk factors
Wilson's disease	Kayser-Fleischer rings (copper deposited in Descemet's membrane of cornea — golden-brown ring seen on slit-lamp), extrapyramidal signs (dysarthria, dystonia, tremor), psychiatric symptoms ^[13]
Haemochromatosis	"Bronze diabetes" — skin hyperpigmentation, diabetes, cardiomyopathy, arthropathy (2nd/3rd MCP joints), hypogonadism
PBC	Xanthelasma, xanthomata, excoriations (pruritus), hyperpigmentation (melanin)
Autoimmune hepatitis	Young female, features of other autoimmune conditions (thyroiditis, Sjögren's, etc.)
MASLD	Obesity, metabolic syndrome features (central obesity, acanthosis nigricans)

While detailed investigations will be covered in later sections, understanding the typical biochemical patterns helps in understanding clinical features:

Liver Function Tests in Cirrhosis

Key LFT Interpretation ^[16]^[17]^[18]:

Parameter	Pattern in Cirrhosis	Why
ALT/AST	May be mildly elevated, normal, or even low in end-stage	Active hepatocyte injury elevates them; in end-stage, few hepatocytes left to release enzymes
AST:ALT ratio	Often > 1 in cirrhosis (reversal from normal < 1)	AST has shorter half-life and is also released from mitochondria of damaged hepatocytes; in alcohol, AST > ALT (typically 2:1) because alcohol depletes pyridoxal phosphate (B6) needed for ALT synthesis
ALP	Mild elevation	Biliary damage from peri-portal fibrosis
GGT	Elevated	Non-specific; particularly elevated in alcohol (GGT is an inducible enzyme) — isolated increase in GGT → inducible enzyme, alcohol ^[10]
Bilirubin	↑	Impaired conjugation and excretion
Albumin	↓	Impaired synthesis (half-life ~21 days, so changes are slow)
INR / PT	↑	↓ Synthesis of clotting factors; INR elevation suggests decompensation ^[10]
Globulins	↑	Polyclonal hyperglobulinaemia — impaired Kupffer cell clearance of antigens → chronic B cell stimulation

For acute hepatitis, the best parameters for monitoring progress and prognosis are PT/INR (reflects factor VII, half-life ~6 hours) ^[7]. If AST/ALT fall while INR worsens → suspect fulminant hepatitis (hepatocytes dying off, no more to release enzymes) ^[7].

High Yield Summary

Definition: Cirrhosis = late-stage fibrosis with bridging fibrosis, distortion of hepatic architecture, and regenerative nodules (F4 on METAVIR). Histological definition (F1–F4) ^[4].
Epidemiology (HK): HBV is by far the most common cause (~64–75%) ^[4]. HCV ~5–10%, alcohol > 5%. Dual liver disease concept (HBV + MASLD) is common ^[4].
Two pillars of pathophysiology: (a) Hepatocellular insufficiency → ↓ albumin, ↓ clotting factors, ↓ bilirubin clearance, ↑ ammonia, ↑ oestrogen. (b) Portal hypertension → varices, splenomegaly/hypersplenism, ascites.
Ascites mechanism: Portal HTN + hypoalbuminaemia + RAAS/ADH activation (peripheral arterial vasodilation hypothesis).
Compensated (Child A) vs Decompensated (Child B/C): Decompensation = jaundice, ascites, variceal bleeding, encephalopathy, HRS. Survival drops dramatically once decompensated ^[10].
Prognostic scores: Child-Pugh (5 parameters: INR, Albumin, Bilirubin, Ascites, Encephalopathy) vs MELD (3 parameters: Bilirubin, Creatinine, INR) ^[1]. MELD is more objective and used for transplant prioritisation.
Non-invasive assessment: FibroScan > 12 kPa suggestive of cirrhosis; liver biopsy rarely done nowadays ^[10].
Reversibility: Possible, especially if underlying cause removed (HBV antivirals, HCV cure, alcohol abstinence); depends on aetiology and severity ^[4].
Stigmata of CLD: Spider naevi, palmar erythema, gynaecomastia, jaundice, ascites, caput medusae, asterixis, splenomegaly, leuconychia — all explained by hepatocellular insufficiency and portal hypertension.
Risk factors for decompensation: Bleeding, dehydration, infection, obesity, alcoholism, medications ^[2]^[3].

Active Recall - Cirrhosis: Definition, Epidemiology, Pathophysiology & Clinical Features

This is the most common exam framing: "A patient has cirrhosis — what caused it?" The approach should be systematic. Anyone presenting with chronic liver disease and a history of alcoholism must exclude other causes — don't get fooled with alcoholic hepatitis, find out other things if possible ^[10].

High-Yield GC Lecture Principle

Concept of concomitant liver disease: many HBV patients in Hong Kong also possess overlapping MASLD — dual liver disease is common ^[4]^[6]. Never assume a single cause. Always screen for co-existing aetiologies.

Systematic Aetiological Differential

Use the mnemonic "ABCDEFGH" (from Part 1) expanded with clinical clues:

Category	Aetiology	Key Clinical/Lab Clue	Why This Clue Helps
A – Alcohol	Alcoholic liver disease / cirrhosis	Isolated increase in GGT → inducible enzyme, alcohol ^[10]; AST:ALT > 2:1; Dupuytren's, parotid swelling; drinking history ≥ 160 g/d for > 8 years ^[8]	GGT is induced by alcohol/drugs without needing actual biliary obstruction; alcohol depletes pyridoxal-5'-phosphate (vitamin B6), which is a cofactor for ALT synthesis → ALT synthesis is disproportionately reduced → AST:ALT > 2
B – Biliary	Primary biliary cholangitis (PBC)	M2 isoform of antimitochondrial antibody (AMA), highly specific for PBC ^[19]; ↑ALP, ↑GGT, ↑IgM; pruritus; middle-aged female (90–95%); xanthelasma ^[20]^[21]	PBC targets small intralobular bile ducts → cholestatic pattern. AMA-M2 targets the E2 subunit of pyruvate dehydrogenase complex on mitochondrial inner membrane
	Primary sclerosing cholangitis (PSC)	Cholangiographic strictures on MRCP; atypical pANCA; association with ulcerative colitis; ↑ALP, ↑GGT; young male ^[22]	PSC targets larger intra/extrahepatic bile ducts → multifocal strictures → biliary cirrhosis. Distinct from PBC which targets small ducts
	Secondary biliary cirrhosis	History of recurrent biliary obstruction (stones, stricture, surgery)	Chronic biliary obstruction → back-pressure injury to hepatocytes + cholestasis → biliary fibrosis
C – Cryptogenic	Cryptogenic cirrhosis	Most likely HBV carriers with loss of HBsAg (occult HBV) or undiagnosed MASLD ^[2]^[3]	Occult HBV: HBsAg-negative but HBV DNA detectable in liver tissue; "burnt-out" NASH: fat disappears as cirrhosis advances → steatosis absent on biopsy
	Cardiac	Right heart failure, MS/TR, constrictive pericarditis ^[2]^[3]	Back-pressure → hepatic venous congestion → centrilobular necrosis → "nutmeg liver" → congestive hepatopathy
D – Drugs	Drug-induced (methotrexate, amiodarone, nitrofurantoin, isoniazid)	Drug history; methotrexate monitoring LFTs	Methotrexate: direct hepatotoxicity from folate antagonism; amiodarone: phospholipidosis + steatohepatitis pattern
E – Endocrine / Metabolic	Wilson's disease	Kayser-Fleischer rings, extrapyramidal signs (can mimic Parkinson's) ^[13]^[19]; ↓ceruloplasmin; ↑24h urinary copper; onset 5–35 years; Coombs-negative haemolytic anaemia in fulminant presentation ^[19]	ATP7B mutation → copper cannot be exported → accumulates in hepatocytes → once hepatocytes rupture, free copper damages brain (basal ganglia), cornea (Descemet's membrane), kidneys
	Haemochromatosis	"Bronze diabetes": skin hyperpigmentation + DM; ↑ferritin, ↑transferrin saturation > 45%; arthropathy (2nd/3rd MCPs); cardiomyopathy; hypogonadism	HFE mutation (C282Y) → excess intestinal iron absorption → iron deposition in hepatocytes, pancreas, heart, joints, pituitary
	α1-antitrypsin deficiency	Young non-smoker with emphysema + cirrhosis; ↓serum α1-antitrypsin level; PiZZ phenotype ^[23]	Misfolded α1-antitrypsin accumulates in hepatocyte ER (PAS-positive, diastase-resistant globules) → hepatocyte injury. Lung: lack of circulating α1-AT → unopposed neutrophil elastase → emphysema
F – Fatty liver	MASLD / NASH	Obesity, metabolic syndrome, DM2, ↑BMI; dual liver disease with HBV common in HK ^[4]^[6]; FibroScan CAP score > 280 dB/m = severe steatosis ^[6]; "burnt out fatty liver disease" ^[10]	Insulin resistance → lipotoxicity → hepatocyte lipid accumulation → oxidative stress → inflammation (NASH) → fibrosis → cirrhosis. Fat content paradoxically ↓ in advanced cirrhosis
G – Genetic	(Overlaps with E above; also includes rare causes like galactosaemia, tyrosinaemia in paediatrics)	Family history; consanguinity	Paediatric causes accumulate toxic metabolites in hepatocytes
H – Hepatitis	Chronic HBV (most common in HK)	HBsAg+, HBV DNA; HBeAg positivity = higher risk ^[5]^[6]	Chronic immune-mediated hepatocyte destruction → fibrosis. HBV also integrates into host genome → direct oncogenic potential (can cause HCC even without cirrhosis)
	Chronic HCV	Anti-HCV+, HCV RNA; 20% clear spontaneously ^[10]; risk factors: IVDU, transfusion, MSM	HCV does NOT integrate into host DNA — oncogenesis requires cirrhosis as intermediate step (unlike HBV)
	Autoimmune hepatitis (AIH)	Young female; ↑IgG; ANA, ASMA (Type 1), anti-LKM1 (Type 2); HCC is rare in AIH ^[19]; exclude viral hepatitis first ^[24]	Autoimmune T-cell-mediated hepatocyte destruction; responds to immunosuppression (steroids ± azathioprine)
	Hepatitis D (HDV)	Only in HBV co-infection (HDV needs HBsAg as envelope); very rare in Chinese ^[5]	HDV superinfection accelerates fibrosis progression

Immunoglobulin Pattern — Classic Exam Point

Different liver diseases produce different immunoglobulin elevations ^[24]:

↑ IgG = Autoimmune hepatitis
↑ IgM = Primary biliary cholangitis (PBC)
↑ IgA = Alcoholic hepatitis

Why? In AIH, there is polyclonal B-cell activation with a dominant IgG response (T-helper driven). In PBC, the ongoing cholestasis and biliary immune response stimulates IgM production. In alcoholic liver disease, gut barrier dysfunction → increased exposure to enteric antigens → mucosal IgA response.

2. Differential Diagnosis of the Clinical Presentation — Mimics of Cirrhosis

Cirrhosis doesn't present as a single entity; it presents through its complications. Each major presentation has its own differential:

Differential diagnosis of hepatomegaly ^[25]^[26]^[27]:

Category	Causes	Clinical Clue to Distinguish
Enlargement of liver parenchyma	Fatty liver (ALD or NAFLD): firm, smooth ^[27]; Hepatitis (swollen hepatocytes); Storage diseases (glycogen storage, haemochromatosis)	USG shows diffuse hyperechogenicity in fatty liver vs. normal echogenicity in hepatitis
Infiltrative / neoplastic	HCC: hard, nodular liver with bruit (± CLD stigmata) ^[27]; Metastasis: hard, nodular with bruit (± features of primary tumour); Lymphoma, leukaemia, MPD; Amyloidosis	Arterial bruit over liver suggests hypervascular tumour; rock-hard nodular liver edge = malignancy until proven otherwise
Venous outflow obstruction	Right heart failure: firm, smooth, tender, ± pulsatile (if TR) ^[27]; Budd-Chiari syndrome; Constrictive pericarditis	Pulsatile hepatomegaly = tricuspid regurgitation (systolic pulsation transmitted from RA); tender = acute congestion
Biliary obstruction	PBC, PSC, biliary atresia	Cholestatic LFT pattern (↑ALP > ↑ALT)
Cysts	Simple cyst, polycystic liver disease	Nodular — polycystic kidney and liver disease ^[28]

Clinical approach to hepatomegaly — Physical examination ^[26]:

Hepatomegaly: assess size, tenderness, consistency, surface, edge, bruit
Irregular/hard → cancer (not only HCC!) ^[28]
Smooth → fatty liver, alcoholic cirrhosis, PBC (NOT chronic viral hepatitis unless superimposed pathology) ^[28]

Ascites has many causes beyond cirrhosis. The serum-ascites albumin gradient (SAAG) separates them:

SAAG ≥ 11 g/L (Portal HTN)	SAAG < 11 g/L (Non-portal HTN)
Cirrhosis (most common)	Peritoneal carcinomatosis
Right heart failure / constrictive pericarditis	Tuberculous peritonitis
Budd-Chiari syndrome	Nephrotic syndrome
Portal vein thrombosis	Pancreatic ascites
Myxoedema	Serositis (SLE)

Category	Cause	Distinguishing Feature
Hepatocellular	Cirrhosis itself; acute-on-chronic liver failure; drug hepatotoxicity; AIH flare	↑AST/ALT predominant; ↑INR; clinical context
Cholestatic	PBC, PSC, drug-induced cholestasis	↑ALP/GGT predominant; pruritus prominent
Obstructive	Choledocholithiasis, cholangiocarcinoma, pancreatic head cancer	Dilated CBD on USG; painless progressive jaundice (malignancy) vs. episodic painful (stones)
Haemolytic	Wilson's disease fulminant liver failure (Coombs-negative haemolytic anaemia ^[19]); hypersplenism	↑Unconjugated bilirubin; ↑reticulocytes; ↑LDH; ↓haptoglobin

Splenomegaly in a cirrhotic patient is usually from portal hypertension, but other causes should be considered:

Clinical features of splenomegaly ^[11]:

Pressure symptoms: abdominal fullness, early satiety
Symptoms related to pancytopenia → due to greater blood pooling in spleen
Features due to the underlying disease: stigmata of CLD, portal HTN features

Cause Category	Examples
Congestive	Cirrhosis/portal HTN (most common in HK), splenic/portal vein thrombosis, hepatic vein thrombosis
Infection	EBV, malaria, leishmaniasis, TB, infective endocarditis
Haematological	CML, myelofibrosis, lymphoma, CLL, haemolytic anaemias (thalassaemia)
Infiltrative	Amyloidosis, Gaucher's disease, sarcoidosis
Autoimmune	SLE, Felty's syndrome (RA + splenomegaly + neutropenia)

When you have a patient with cirrhosis and you are trying to determine the cause, certain clinical features are "discriminators":

Finding	Points Towards	Why
Dupuytren's contracture, parotid swelling	Alcoholic liver disease ^[25]^[26]	Dupuytren's: fibroblast proliferation from alcohol-related oxidative stress. Parotid: fatty infiltration/fibrosis/oedema, NOT hyperfunctioning ^[25]
Gynaecomastia, testicular atrophy, loss of body hair	Alcoholic liver disease or haemochromatosis ^[25]^[26]	Alcohol: direct gonadal toxicity + impaired hepatic extraction of androstenedione → ↑oestrogen. Haemochromatosis: iron deposition in pituitary → hypogonadotropic hypogonadism ^[25]^[26]
Finger clubbing	PBC ^[25]^[26]	Mechanism uncertain; possibly related to chronic cholestasis and hypoxia from hepatopulmonary syndrome
Kayser-Fleischer rings + extrapyramidal signs	Wilson's disease ^[13]^[19]	Copper deposition in Descemet's membrane (cornea) and basal ganglia
Xanthelasma, xanthomata	PBC	Cholestasis → impaired bile acid excretion → ↑serum cholesterol
Scratch marks	PBC, PSC, any cholestatic cause ^[25]^[26]	Bile salt retention in skin → pruritus
Bronze skin + diabetes + arthropathy	Haemochromatosis	Iron deposition in skin (melanin stimulation), pancreatic β-cells, synovium
Emphysema at young age + liver disease	α1-antitrypsin deficiency	Lack of α1-AT in lungs → elastase destruction; accumulation of misfolded α1-AT in liver → hepatocyte injury ^[23]
Fetor hepaticus	Severe hepatocellular decompensation; suggests underlying portosystemic shunt ^[25]^[26]	Dimethyl sulfide bypasses liver through portosystemic shunts → exhaled

Diagnosis of HE ^[29]^[30]:

Exclude other differentials first
Arterial ammonia: normally 40% produced by bacterial action, 60% directly from protein breakdown ^[30]
- Not always raised; may not correlate with severity of HE ^[30]
- Not all nitrogenous compounds are ammonia ^[29]
EEG abnormalities ^[30] — for difficult cases or ICU patients
Psychometric tests: constructional apraxia (drawing a five-pointed star), number connection (Reitan's) test ^[30]
Other clinical features: fetor hepaticus, flapping tremor ^[30]

Arterial ammonia is NOT diagnostic for HE — it is not always raised, may not correlate with the severity, and not all nitrogenous compounds are ammonia ^[29]^[30]. HE remains a clinical diagnosis of exclusion.

High Yield Summary

Two DDx tasks: (a) What caused the cirrhosis? (b) Is it actually cirrhosis or a mimic?
Aetiological workup is systematic: Viral → Alcohol → Metabolic/MASLD → Autoimmune → Biliary → Metabolic storage → Vascular/cardiac → Drug → Cryptogenic.
Dual/triple liver disease is common in HK (e.g., HBV + MASLD) ^[4]^[6] — always look for co-existing causes.
Anyone with CLD + alcoholism must have other causes excluded ^[10].
Immunoglobulin patterns: ↑IgG = AIH, ↑IgM = PBC, ↑IgA = Alcoholic ^[24].
Confusion in cirrhosis ≠ HE. HE is a diagnosis of exclusion. Most common causes of confusion in cirrhosis are head injury, drugs, withdrawal, infection, and metabolic disturbance ^[29].
Wilson's disease: Kayser-Fleischer rings + extrapyramidal signs; fulminant form = Coombs-negative haemolytic anaemia; penicillamine can initially worsen neuro symptoms ^[19].
PBC diagnosis: AMA-M2 + cholestatic biochemistry > 6 months + compatible histology (2 of 3 = probable) ^[20]^[21].
Hepatomegaly surface: irregular/hard = cancer; smooth = fatty liver, alcoholic cirrhosis, PBC; nodular = polycystic disease ^[28].
GGT is an inducible enzyme — isolated ↑GGT suggests alcohol or drugs, not necessarily biliary obstruction ^[10]^[18].

Active Recall - Differential Diagnosis of Cirrhosis

^[2] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Liver cirrhosis chapter, Etiology section) ^[3] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf (Liver cirrhosis chapter, Etiology section) ^[4] Lecture slides: GC 026. Abdominal distension_ascites and cirrhosis.pdf; Senior notes: Block A - Abdominal distension_ ascites and cirrhosis.pdf ^[5] Senior notes: Block A - I am a hepatitis B carrier.pdf ^[6] Senior notes: Block A - Gastroenterology Interactive Tutorial.pdf (Case 2) ^[8] Senior notes: Ryan Ho GI.pdf (Alcoholic cirrhosis, p. 306) ^[10] Senior notes: Block A - Gastrointestinal Data Interpretation.pdf (Case 2) ^[11] Senior notes: Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf ^[13] Senior notes: Adrian Lui Pediatrics Notes.pdf (Wilson Disease, p. 266) ^[18] Senior notes: Block A - Introduction to GI_Hepatology investigations (LFT, Endoscopy).pdf (GGT as inducible enzyme) ^[19] Senior notes: Block A - Patients with non-viral chronic liver diseases.pdf; Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (Wilson disease diagnosis, p. 384) ^[20] Lecture slides: Teaching Clinic - Non-viral chronic liver diseases (Prof. Yuen Man Fung) 2.pdf (PBC diagnosis criteria) ^[21] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (PBC chapter, p. 722–724) ^[22] Senior notes: Ryan Ho GI.pdf (PSC, p. 290) ^[23] Senior notes: Adrian Lui Pediatrics Notes.pdf (α1-antitrypsin deficiency, p. 269) ^[24] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Autoimmune hepatitis, immunoglobulin patterns, p. 732–734) ^[25] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Stigmata of CLD, p. 789–791) ^[26] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf (Stigmata of CLD, p. 443–445) ^[27] Senior notes: Ryan Ho Fundamentals.pdf (Differential diagnosis of hepatomegaly, p. 73) ^[28] Lecture slides: abdominal exam (MBBS IV) (student version).pdf (hepatomegaly description, p. 24) ^[29] Senior notes: Block A - A jaundiced and incoherent patient_ liver failure.pdf (Confusion in cirrhosis, p. 17) ^[30] Lecture slides: GC 025. A jaundiced and incoherent patient liver failure.pdf (Diagnosis of HE, p. 35)

2. Diagnostic Criteria — The Building Blocks

Liver function tests assess three distinct aspects of hepatic function: cellular integrity through ALT and AST levels, synthetic capacity via albumin and prothrombin time, and excretory function using bilirubin, ALP and GGT ^[18]^[35].

Parameter	Expected in Cirrhosis	Interpretation
ALT/AST	Mild ↑, normal, or even ↓ in end-stage	Fewer hepatocytes to release enzymes in burn-out phase
AST:ALT ratio	> 1 in cirrhosis of any cause	A ratio exceeding 2:1 strongly suggests alcoholic hepatitis ^[35]; in non-alcoholic cirrhosis AST:ALT > 1 due to mitochondrial AST release from damaged cells and reduced ALT clearance
Albumin	↓ (< 35 g/L is concerning; < 28 g/L = severe)	Half-life ~21 days — slow decline; reflects chronic synthetic failure
INR/PT	↑ — INR elevation suggests decompensation ^[10]	Factor VII (half-life ~6 hours) is the first to fall; INR is the best real-time marker of synthetic function
Bilirubin	↑	Impaired conjugation and excretion
ALP/GGT	Mild ↑	Biliary injury from peri-portal fibrosis; isolated increase in GGT → inducible enzyme, consider alcohol ^[10]^[18]
Globulins	↑ (polyclonal)	Impaired Kupffer cell clearance → chronic B-cell stimulation
Platelets	↓ — low platelet count, hypersplenism ^[10]	This is often the FIRST laboratory abnormality in compensated cirrhosis; due to splenic sequestration + ↓ thrombopoietin production by failing liver

AFP is not just a tumour marker — it is produced by regenerating liver cells → can also be an indicator of cirrhosis, which is characterised by the formation of abnormal regeneration nodules ^[5]. A mildly elevated AFP (< 200 ng/mL) in a cirrhotic patient does NOT automatically mean HCC, but warrants imaging surveillance.

2C. Non-Invasive Fibrosis Assessment

These are calculated from routine blood tests and are useful screening tools:

Score	Components	Interpretation
APRI (AST-to-Platelet Ratio Index)	AST, platelet count	APRI = (AST / upper limit of normal) × 100 / platelet count (×10⁹/L). Score > 1.0 suggestive of significant fibrosis; > 2.0 suggestive of cirrhosis
FIB-4	Age, AST, ALT, platelet count	FIB-4 = (Age × AST) / (Platelet × √ALT). Score < 1.45 = low probability of advanced fibrosis; > 3.25 = high probability

These are helpful for ruling OUT advanced fibrosis (high negative predictive value) but are not sufficient alone to confirm cirrhosis.

Ultrasound-based elastography technique for evaluation of liver stiffness and is very accurate in diagnosis of liver cirrhosis ^[31]^[32].

Performed using transducer-induced vibrations at low frequency and amplitudes in which the transmitted shear waves propagate through the liver parenchyma. Pulse-echo USG acquisition is used to follow the propagation of the shear wave and to measure its average speed ^[31]^[32].

How it works from first principles:

A mechanical impulse generates a shear wave through liver tissue
The stiffer the liver (more fibrosis), the faster the wave travels
Wave velocity is converted to liver stiffness in kilopascals (kPa)

Liver Stiffness (kPa)	METAVIR Stage	Interpretation
< 7	F0–F1	Minimal fibrosis
7–10	F2	Significant fibrosis
10–12	F3	Severe fibrosis
> 12 kPa	F4	Suggestive of liver cirrhosis ^[6]^[10]

Also measures CAP score (Controlled Attenuation Parameter) for steatosis ^[6]:

248–280 dB/m: mild–moderate steatosis
> 280 dB/m: severe steatosis

Limitations of FibroScan:

Falsely elevated by: acute hepatitis (inflammation → stiffness), post-prandial state, biliary obstruction, hepatic congestion (right heart failure), operator-dependent
Unreliable in: obesity (use XL probe), ascites (wave cannot propagate), narrow intercostal spaces
Requires ≥ 10 valid measurements with IQR/median < 30% for reliable result

2D. Imaging Criteria

4. Investigation Modalities — Systematic Breakdown

4A. Blood Investigations

Investigation	What to Look For	Why	Interpretation
CBC	Low platelet count → hypersplenism ^[10]; ↓Hb (anaemia of chronic disease, folate/B12 deficiency in alcoholics, GI bleeding); ↓WCC	Thrombocytopenia is often the earliest lab clue to cirrhosis; platelet < 150 × 10⁹/L in any chronic liver disease patient should raise suspicion	MCV: ↑ in alcoholic hepatitis (toxic alcohol alters RBC membrane lipid structures) ^[18]
LFT	AST, ALT, ALP, GGT, bilirubin, albumin, globulin	Classically used to give information on whether a patient's primary disorder is hepatitic or cholestatic in origin ^[18]	4 liver pathologies cause AST > ALT: alcoholic hepatitis, HCC, congestive heart failure, ischaemic hepatitis ^[18]
Clotting profile (PT/INR)	↑INR	Reflects factor VII synthesis (half-life ~6 hours) → sensitive real-time marker of hepatic synthetic function	INR > 1.5 in cirrhosis = concerning; used in both Child-Pugh and MELD
Ammonia (arterial)	↑ in hepatic encephalopathy	Normally ~40% produced by bacterial action on protein in gut, ~60% from direct protein breakdown ^[30]	Not always raised; may not correlate with severity of HE ^[30]; use for supportive evidence, not definitive diagnosis
Glucose	↓ in advanced cirrhosis	Impaired gluconeogenesis and glycogen stores depleted	Hypoglycaemia can be the presenting feature in fulminant liver failure

Investigation	Target Aetiology	Key Findings
HBsAg, Anti-HBs, Anti-HBc, HBeAg, Anti-HBe, HBV DNA	Chronic HBV	HBsAg+ with high HBV DNA → ↑ risk of cirrhosis and HCC ^[5]^[6]
Anti-HCV, HCV RNA	Chronic HCV	HCV RNA positive → active infection; 20% clear spontaneously ^[10]; genotype determines treatment duration
Alcohol history + GGT, MCV	Alcoholic liver disease	AST > ALT > 2:1; AST almost never > 500 U/L in alcoholic hepatitis ^[18]; ↑MCV ^[18]; isolated ↑GGT ^[10]^[18]
ANA, ASMA, anti-LKM1, IgG	Autoimmune hepatitis	Type 1: ANA + ASMA (90%); Type 2: anti-LKM1 ^[19]; ↑IgG is characteristic ^[24]
AMA-M2, IgM	PBC	M2 isoform of AMA highly specific for PBC ^[19]^[20]; ↑IgM ^[24]
Ceruloplasmin, 24h urine copper, slit-lamp exam	Wilson's disease	↓ Ceruloplasmin (< 20 mg/dL); ↑ 24h urine copper (> 40 mcg); Kayser-Fleischer rings on slit-lamp ^[37]; genetic test does not have to be positive ^[19]
Ferritin, transferrin saturation	Haemochromatosis	Transferrin saturation > 45% + ↑ ferritin; confirm with HFE gene testing (C282Y homozygosity)
α1-antitrypsin level + phenotyping	α1-antitrypsin deficiency	↓ serum level; PiZZ phenotype ^[23]
pANCA, MRCP	PSC	Atypical pANCA; MRCP shows multifocal strictures and beading ^[22]

High-Yield GC Interactive Tutorial Point

A patient with elevated liver enzymes: always consider alcohol, drugs, fatty liver as the initial differential even if asymptomatic ^[38]. The GC interactive tutorial case demonstrates a patient with HBsAg+ AND BMI 33.2 → dual liver disease (HBV + MASLD), common in HK ^[6]. Never stop at one diagnosis.

Marker	Use	Interpretation
AFP	HCC screening	Normal < 6 ng/mL (raised in 80% of HCC); false positive in pregnancy, germ cell tumour, cirrhosis, hepatitis ^[36]; mildly elevated AFP in cirrhosis without mass → regenerative nodules
CEA, CA 19-9	If cholangiocarcinoma or metastatic disease suspected ^[26]	Non-specific; CA 19-9 elevated in cholangiocarcinoma and biliary obstruction

Modality	Role	Key Findings in Cirrhosis
USG abdomen	First-line; screening; HCC surveillance	Irregular contour, surface nodularity, coarse echogenicity, right lobe atrophy, caudate hypertrophy; portal HTN signs: ↑ portal vein diameter, collaterals, ascites, splenomegaly ^[31]^[32]
Doppler USG	Assess portal vein flow direction/velocity; hepatic vein patency	Hepatofugal (reversed) portal flow = advanced portal HTN; absent hepatic vein flow = Budd-Chiari
FibroScan	Non-invasive fibrosis staging; standard of care ^[10]	> 12 kPa = suggestive of cirrhosis; CAP > 280 = severe steatosis ^[6]
CT abdomen	Not routinely used ^[31]^[32]; indicated for HCC characterisation, surgical planning	Triphasic CT: HCC shows arterial phase hyperenhancement with portovenous phase washout ^[36]
MRI	Iron overload quantification; portal vein thrombosis evaluation; hepatospecific contrast (Primovist) for indeterminate nodules ^[31]^[32]	T2* shortening with iron overload; Primovist hypointensity on hepatobiliary phase = HCC
OGD (oesophagogastroduodenoscopy)	Screen for oesophageal/gastric varices; portal hypertensive gastropathy	Varices graded: small (< 5 mm) vs large (> 5 mm); red wale marks = high rupture risk; snakeskin appearance = portal hypertensive gastropathy ^[33]

When ascites is present, diagnostic paracentesis is essential:

Test	Purpose	Key Values
Cell count + differential	Rule out SBP	SBP defined by ascitic fluid neutrophil count ≥ 250/mm³ ^[10]; culture not useful, usually negative → defined by checking the neutrophils ^[10]
Albumin	Calculate SAAG	SAAG = serum albumin – ascitic albumin. ≥ 11 g/L = portal hypertension (97% accuracy)
Total protein	Distinguish transudate from exudate; guides SBP prophylaxis	< 10 g/L = high risk of SBP (impaired opsonisation in ascitic fluid)
Culture (in blood culture bottles)	Identify organism if SBP	Positive in only ~40% of SBP cases; most commonly E. coli, Klebsiella, Streptococcus
Cytology	If malignant ascites suspected	Peritoneal carcinomatosis — NOT routine in cirrhotic ascites
Glucose, LDH, amylase	If secondary peritonitis suspected	Secondary peritonitis: glucose < 50 mg/dL, LDH > serum, polymicrobial

SBP — Requires High Suspicion

SBP may actually not have a lot of abdominal signs → since there is no perforation ^[10]. A cirrhotic patient with ascites who develops even subtle deterioration (new encephalopathy, renal impairment, unexplained fever) should have a diagnostic tap. Culture is not useful (usually negative) → diagnosis is made by checking the neutrophils (≥ 250/mm³) ^[10].

Histological appearance ^[31]^[32]:

Diffuse process affecting entire liver
Regenerative nodules of hepatocytes
Regenerative nodules separated by fibrous connective tissues

Special stains and what they detect:

Stain	Target	Aetiology
Masson's trichrome / Sirius red	Collagen (fibrosis extent)	All causes
Perl's Prussian blue	Iron	Haemochromatosis
PAS-diastase	α1-antitrypsin globules (PAS+, diastase-resistant)	α1-antitrypsin deficiency
Rhodanine / orcein	Copper / copper-binding protein	Wilson's disease
Victoria blue / immunohistochemistry for HBsAg	HBV surface antigen ("ground-glass hepatocytes")	Chronic HBV
H&E — plasma cell infiltrate	Interface hepatitis with plasma cells	Plasma cells infiltrating the liver → specific feature of autoimmune hepatitis ^[19]

Wilson's disease liver biopsy: diagnosis established when hepatic copper concentration ≥ 250 mcg/g dry weight; excluded when < 50 mcg/g; 50–250 mcg/g = indeterminate, requires genetic testing ^[37].

Aetiology	Specific Investigation	Finding
Wilson's disease	Slit-lamp examination	Kayser-Fleischer rings; sunflower cataract ^[37]
Wilson's disease	MRI brain	Most common finding: ↑ T2 signal in basal ganglia; "face of giant panda sign" ^[37]
Haemochromatosis	HFE genotyping	C282Y homozygosity; H63D compound heterozygosity
Haemochromatosis	MRI liver (T2*)	Shortened T2* from iron deposition
PBC	AMA-M2; diagnosis based on 3 criteria: presence of AMA, elevation of cholestatic markers > 6 months, histological features consistent — 2 out of 3 = probable diagnosis ^[20]
PSC	MRCP	Multifocal strictures with beading of intra/extrahepatic bile ducts ^[22]
AIH	Liver biopsy	Interface hepatitis with plasma cell infiltration ^[19]; lymphocytic infiltration; may show bridging necrosis → cirrhotic nodules in advanced disease
MASLD/NASH	Liver biopsy	NAFL: > 5% steatotic hepatocytes without ballooning and lobular inflammation; NASH: steatosis + ballooning degeneration + lobular inflammation ^[34]; hepatic fat content tends to diminish with cirrhosis → NASH underdiagnosed in advanced liver disease ^[34]

Once cirrhosis is confirmed, severity must be assessed:

Scoring System	Parameters	Use	Key Values
Child-Pugh	INR, Albumin, Bilirubin, Ascites, Encephalopathy ^[1]	General prognostication; guide management	A (5–6), B (7–9), C (10–15)
MELD	Bilirubin, Creatinine, INR ^[10]	Transplant listing priority; short-term mortality ^[10]	Higher = worse; in HK, not first-come-first-served ^[10]
MELD-Na	Bilirubin, Creatinine, INR, Sodium	Better predicts mortality in patients with hyponatraemia/ascites	Used in most transplant programmes since 2016

Investigation Tier	Tests	Purpose
Tier 1: Bedside	History, examination (stigmata of CLD)	Clinical suspicion
Tier 2: Blood — Baseline	CBC, LFT, INR, albumin, bilirubin	Confirm hepatic dysfunction; calculate Child-Pugh/MELD
Tier 2: Blood — Aetiology	Viral serology, autoimmune panel, metabolic screen, iron/copper/α1-AT	Identify cause
Tier 3: Non-invasive fibrosis	APRI, FIB-4, FibroScan	Stage fibrosis without biopsy
Tier 4: Imaging	USG (first-line), Doppler, CT (if HCC suspected), MRI (iron/indeterminate lesion)	Structural assessment, complications, HCC screening
Tier 5: Endoscopy	OGD	Variceal screening; portal hypertensive gastropathy
Tier 6: Ascitic tap	Cell count, albumin, culture	Rule out SBP; calculate SAAG
Tier 7: Biopsy	Liver biopsy (if indicated)	Gold standard histological confirmation; specific stains for aetiology

High Yield Summary

Liver biopsy = gold standard for cirrhosis diagnosis (diffuse process, regenerative nodules, bridging fibrosis) ^[31]^[32], but FibroScan (> 12 kPa) is now standard of care as non-invasive alternative ^[10].
LFT assesses 3 aspects: cellular integrity (ALT/AST), synthetic function (albumin, PT/INR), excretory function (bilirubin, ALP, GGT) ^[18]^[35].
4 conditions cause AST > ALT: alcoholic hepatitis (> 2:1, AST almost never > 500), HCC, CHF, ischaemic hepatitis ^[18].
Thrombocytopenia is often the first lab clue to compensated cirrhosis (hypersplenism) ^[10].
USG findings of cirrhosis: irregular contour, nodularity, coarse echogenicity, right lobe atrophy, caudate hypertrophy ^[31]^[32]. USG findings of portal HTN: ↑ portal vein diameter, collaterals, ↓ flow, ascites, splenomegaly ^[31]^[32].
SBP diagnosed by ascitic fluid neutrophil count ≥ 250/mm³ — culture is usually negative ^[10].
HCC surveillance: USG ± AFP every 6 months for all cirrhotics; HBV patients screened from age 40 (M) / 50 (F) even without cirrhosis ^[6].
PBC diagnosis: 2 of 3 criteria (AMA-M2+, cholestatic markers > 6 months, compatible histology) ^[20].
Wilson's disease: ↓ ceruloplasmin + KF rings + ↑ 24h urine copper; liver biopsy for hepatic copper ≥ 250 mcg/g = diagnostic ^[37].
AFP is NOT specific for HCC — also elevated in cirrhosis (regenerating nodules), hepatitis, pregnancy, germ cell tumours ^[36].

Active Recall - Diagnosis & Investigations of Cirrhosis

^[1] Lecture slides: GC 025. A jaundiced and incoherent patient liver failure.pdf (Child-Pugh components) ^[5] Senior notes: Block A - I am a hepatitis B carrier.pdf (AFP as marker of regeneration; cirrhosis development) ^[6] Senior notes: Block A - Gastroenterology Interactive Tutorial.pdf (Case 2 — FibroScan values, HCC surveillance, dual liver disease) ^[10] Senior notes: Block A - Gastrointestinal Data Interpretation.pdf (Case 2 — INR decompensation, GGT, SBP diagnosis, MELD, FibroScan) ^[18] Senior notes: Block A - Introduction to GI_Hepatology investigations (LFT, Endoscopy).pdf (LFT interpretation, AST:ALT ratio, GGT as inducible enzyme, alcoholic hepatitis pattern) ^[19] Senior notes: Block A - Patients with non-viral chronic liver diseases.pdf (AIH histology, PBC AMA-M2, Wilson's disease) ^[20] Lecture slides: Teaching Clinic - Non-viral chronic liver diseases (Prof. Yuen Man Fung) 2.pdf (PBC diagnostic criteria) ^[22] Senior notes: Ryan Ho GI.pdf (PSC diagnosis, p. 290) ^[23] Senior notes: Adrian Lui Pediatrics Notes.pdf (α1-antitrypsin deficiency, p. 269) ^[24] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Immunoglobulin patterns, p. 732–734) ^[26] Lecture slides: WCS 064 - A large liver - by Prof R Poon.pdf (Hepatomegaly investigations) ^[30] Lecture slides: GC 025. A jaundiced and incoherent patient liver failure.pdf (HE diagnosis, ammonia) ^[31] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Radiological tests in cirrhosis, p. 792–794) ^[32] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf (Radiological tests in cirrhosis, p. 446–448) ^[33] Senior notes: Ryan Ho GI.pdf (Diagnostic evaluation of cirrhosis, p. 314) ^[34] Senior notes: Ryan Ho GI.pdf (NAFLD diagnostic evaluation, p. 310) ^[35] Senior notes: Learning_Points_All_Lectures.txt (LFT learning points) ^[36] Senior notes: Maksim Surgery Notes.pdf (HCC investigations, AFP, triphasic CT, p. 124) ^[37] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (Wilson disease diagnostic criteria and liver biopsy, p. 384–386) ^[38] Lecture slides: GC_Interactive tutorial (GI-Liver case) student copy.pdf (Approach to elevated liver enzymes)

The management of cirrhosis is built on four pillars, and the approach differs fundamentally depending on whether cirrhosis is compensated or decompensated:

Pillar	Goal	When
1. Treat the underlying cause	Remove the injurious stimulus → halt fibrosis progression, allow regression	ALL stages
2. Prevent and screen for complications	Variceal screening, HCC surveillance, vaccination	Compensated + Decompensated
3. Manage complications	Ascites, varices, HE, SBP, HRS, HCC	Decompensated
4. Consider liver transplantation	Definitive cure when liver function is irreversibly compromised	End-stage / selected HCC

Cirrhosis is probably reversible — can go from F4 to F0 if removing the underlying cause ^[4]. HBV cirrhosis: majority reversible with long-term nucleoside-analogue therapy. HCV cirrhosis: some reversible with SVR. Alcoholic cirrhosis: dependent on abstinence and severity ^[4]. Child A/B can have benefit in reducing complications and hospitalisation; Child C has less impact ^[4].

3. Pillar 1: Treat the Underlying Cause (Aetiology-Specific Therapy)

Aims of treatment ^[5]^[39]:

Prevent/decrease cirrhotic complications AND HCC
Viral suppression: maximal suppression of HBV DNA → PCR undetectable
Viral eradication: loss of HBsAg (functional cure) — only achieved in < 10% ^[39]

Indications for treatment ^[5]^[39]:

Patients with cirrhosis with any detectable HBV DNA, irrespective of ALT levels ^[5]
Patients with family history of HCC or cirrhosis ^[5]
HBeAg+ patients with high HBV DNA but persistently normal ALT, if > 30 years old ^[5]
All patients regardless of HBeAg status with ALT > ULN, HBV DNA > 2,000 IU/mL, moderate necroinflammation/fibrosis (EASL 2017) ^[39]

Treatment endpoints ^[39]:

HBeAg seroconversion (for HBeAg+ patients) — insufficient as sole endpoint
HBsAg loss — most ideal endpoint, functional cure
HBV DNA undetectable by PCR — ideally permanently
Normalisation of ALT — ideally < ½ the upper limit of normal ^[39]

Drug choices:

Drug	Class	Key Points
Entecavir ("enteca-vir" → "enters" and blocks viral replication)	Nucleoside analogue	First-line; high potency, high genetic barrier to resistance; safe in pregnancy (now Category B)
Tenofovir disoproxil fumarate (TDF)	Nucleotide analogue	First-line; high potency, very high barrier to resistance; monitor renal function and bone density (can cause Fanconi syndrome)
Tenofovir alafenamide (TAF)	Nucleotide analogue (prodrug)	Improved renal and bone safety profile vs TDF; preferred in patients with renal impairment or osteoporosis
Pegylated interferon-α (PEG-IFN)	Immunomodulator	Finite course (48 weeks); higher rate of HBsAg loss; contraindicated in decompensated cirrhosis (risk of hepatic flare and failure)

Duration of therapy ^[10]:

If HBeAg+ at start: can potentially stop once quiescent (HBeAg seroconversion + undetectable DNA for ≥ 12 months) — but good practice to keep antivirals longer to prevent flare-ups ^[10]
If HBeAg– at start: need lifelong therapy unless HBsAg loss is achieved ^[10]

High-Yield Exam Point

Patients with cirrhosis and any detectable HBV DNA should receive lifelong nucleos(t)ide analogue therapy, irrespective of ALT levels ^[5]. This is a common exam question — the answer is to TREAT, regardless of ALT. The goal is to prevent decompensation and HCC.

Alcohol abstinence is the cornerstone of treatment — improves survival and potential reversal of histological injury ^[40].

Treatment	Indication	Details
Abstinence	ALL patients	Single most important intervention; support with addiction services, CBT, motivational interviewing
Nutritional support	ALL patients	Alcohol has high calorie content but poor nutritional value; good nutrition is critical; enteral feeding via fine-bore nasogastric tube may be needed in severely ill patients ^[40]; BCAA (branched-chain amino acids) also used as a form of treatment in hepatic encephalopathy, to increase ammonia removal ^[18]
Corticosteroids	Severe alcoholic hepatitis: Maddrey DF ≥ 32 or MELD > 20 ^[40]^[18]	Prednisolone 40 mg/d × 28 days; contraindicated in sepsis, active GI bleeding, renal failure, pancreatitis ^[40]; stop if bilirubin does not decrease at day 7 (Lille score > 0.45) — unlikely to reduce mortality ^[40]
Pentoxifylline	Severe alcoholic hepatitis (if steroids contraindicated)	Phosphodiesterase inhibitor with anti-TNF properties; monoclonal antibodies neutralising TNF-α (e.g., infliximab) should NOT be used — increased death from infection/renal failure ^[40]
Liver transplantation	Selected alcoholic cirrhosis	NOT performed for acute alcoholic hepatitis — increased surgical mortality and high recidivism ^[40]; typically requires ≥ 6 months of documented abstinence (though some centres now offer early transplant in selected non-responders)

Maddrey Discriminant Function = [4.6 × (PT – control PT in seconds)] + serum bilirubin (mg/dL) ^[18]^[40]. This determines whether steroids will benefit the patient.

Don't Give Steroids Lightly

Don't give steroids lightly without proper thinking and indications, since these patients are malnourished — they will not die from the hepatitis, but will instead die due to infections ^[18]. Always calculate the Maddrey DF or MELD first. If DF < 32, steroids provide no benefit and only add infection risk.

Resolution of fatty liver: BMI doesn't have to go back to 25 → weight loss of 5–7% is already sufficient in non-fibrosis patients; 10% in fibrosis patients ^[6].

Treatment	Details
Weight loss	5–7% for steatosis resolution; ≥ 10% for fibrosis regression ^[6]; caloric restriction + exercise
GLP-1 receptor agonists	Emerging evidence for MASLD, on top of DM and obesity ^[6]; semaglutide and liraglutide shown to reduce steatohepatitis; shown to reduce weight by > 10% ^[6] — which is why they work for fibrosis patients
Resmetirom (thyroid hormone receptor-β agonist)	First FDA-approved drug specifically for NASH with fibrosis (2024); reduces hepatic fat and fibrosis
Coffee	Beneficial for fatty liver ^[6] — epidemiological data consistently show ↓ fibrosis progression; likely via antioxidant and anti-inflammatory effects of chlorogenic acid
Avoid high fructose	High fructose foods → fatty liver ^[6]; fructose metabolised almost exclusively by liver → promotes de novo lipogenesis
Pioglitazone	Insulin sensitiser; improves histology in biopsy-proven NASH in non-diabetics; weight gain and fracture risk are limitations
Vitamin E (800 IU/d)	Antioxidant; improves histology in non-diabetic, non-cirrhotic NASH; concerns about long-term safety (↑ all-cause mortality, prostate cancer at very high doses)

Treatment of PBC ^[20]:

Component	Treatment	Details
Specific therapy	UDCA (ursodeoxycholic acid)	Very well tolerated, side effects are rare ^[19]; slows disease progression; 13–15 mg/kg/day; first-line
	Obeticholic acid (OCA)	FXR agonist; pruritus is a side effect ^[19] — if patient already has pruritus, may not consider adding ^[19]; if no initial pruritus, then can think of adding ^[19]; second-line if inadequate response to UDCA
Pruritus	Cholestyramine — drug of choice ^[20]	Oral anion exchange resin; binds bile acids → faecal excretion; 4 g daily → max 16 g daily; also potentially binds other drugs; ineffective in 10–20%; side effects: GI upset ^[20]
	Rifampicin — 2nd line ^[20]	Enzyme-inducing antibiotic; improves pruritus in cholestasis (150 mg bd or tds); potentially hepatotoxic ^[20]
	Opioid antagonists — 3rd line ^[20]	Naloxone (IV, very short half-life); naltrexone, nalmefene (oral, longer half-life) ^[20]
	Liver transplantation	For intractable cases ^[20]
Malnutrition	Fat malabsorption management	Reduction in dietary fat (~40 g/d); use of MCTs (digested/absorbed even with low bile acid concentration) ^[20]
	Fat-soluble vitamin supplementation	Vitamin D if biochemical cholestasis; parenteral vitamin K if PT increased ^[20]
Osteoporosis	Bone density monitoring, bisphosphonates	Cholestasis → impaired vitamin D metabolism + direct osteoblast toxicity from bile salts
Liver transplantation	Advanced decompensated PBC	Indications: advanced PBC with decompensated disease (Mayo risk score, serum bilirubin), intractable pruritus, severe osteoporosis ^[20]; 1-year survival 92%, 5-year survival 85%; recurrence rate 30% at 10 years ^[20]

Increased cholesterol in PBC will NOT increase atherosclerosis risk if the rise is due to HDL / lipoprotein X ^[19].

Treatment	Mechanism	Notes
Penicillamine (D-penicillamine)	Copper chelator; promotes urinary copper excretion	Causes worsened neurological symptoms in the first few days — patient is "used to" copper in brain; once penicillamine removes it, the body is not used to the shift ^[19]; side effects: hypersensitivity, proteinuria, bone marrow suppression
Trientine	Alternative copper chelator	Better tolerated than penicillamine; first-line in many centres
Zinc acetate	Blocks intestinal copper absorption by inducing metallothionein	Used for maintenance therapy or presymptomatic patients
Liver transplantation	Effective cure as it provides normal ATP7B in graft liver ^[13]	Indications: fulminant liver failure (coagulopathy + encephalopathy, Coombs-negative haemolytic anaemia, rapid deterioration within 8 weeks); decompensated cirrhosis refractory to medical therapy ^[13]

Treatment	Details
Phlebotomy	First-line; weekly venesection (500 mL = ~250 mg iron) until ferritin < 50 μg/L; then maintenance q2–4 months
Iron chelation (desferrioxamine, deferasirox)	Only if phlebotomy is contraindicated (e.g., severe anaemia, cardiac failure)
Avoid iron-rich foods, vitamin C supplements	Vitamin C enhances intestinal iron absorption
Screen first-degree relatives	HFE genotyping

4. Pillar 2: Prevention & Screening

All patients with cirrhosis should undergo OGD at diagnosis to screen for oesophageal/gastric varices.

Finding	Management
No varices	Repeat OGD in 2–3 years (compensated); annually if decompensated
Small varices, no red signs	Non-selective β-blocker (NSBB) OR repeat OGD in 1–2 years
Large varices or any red wale marks	Primary prophylaxis: NSBB (propranolol / carvedilol) OR endoscopic variceal ligation (EVL)

Non-selective beta-blockers (NSBBs):

Propranolol or nadolol: block β1 (↓ cardiac output) + β2 (allows unopposed α-mediated splanchnic vasoconstriction) → ↓ portal pressure
Carvedilol: NSBB + α1-blocker (additional intrahepatic vasodilation via ↑NO release) → superior portal pressure reduction; now often first-line
Target: resting heart rate 55–60 bpm or 25% reduction from baseline
Discontinue NSBBs in HRS-AKI ^[41] — in severely decompensated patients with refractory ascites, NSBBs may worsen haemodynamics ("window hypothesis")

5. Pillar 3: Manage Complications

Aspect	Details
Diagnosis	Ascitic fluid neutrophils ≥ 250/mm³; culture usually negative ^[10]
Treatment	IV ceftriaxone or cefotaxime (3rd-generation cephalosporins) × 5 days; IV albumin (1.5 g/kg on day 1, 1 g/kg on day 3) to prevent HRS
Primary prophylaxis	Norfloxacin 400 mg/d for: (a) ascitic protein < 15 g/L + advanced cirrhosis (Child ≥ 9, bilirubin ≥ 3, creatinine ≥ 1.2, Na ≤ 130); (b) history of GI bleeding
Secondary prophylaxis	Norfloxacin 400 mg/d indefinitely after first episode of SBP (recurrence rate ~70% at 1 year without prophylaxis)

Treatment	Mechanism	Details
Identify and treat precipitant	Remove trigger	GI bleeding, infection (SBP), constipation, sedatives, hypokalaemia, alkalosis, dehydration, excessive protein intake, portosystemic shunt
Lactulose ("lactu" = lactose derivative)	Osmotic laxative → ↑ colonic transit → ↓ ammonia absorption; acidifies colonic lumen (NH₃ → NH₄⁺ which is ionised and cannot cross mucosa)	Titrate to 2–3 soft stools per day; first-line for both treatment and secondary prophylaxis
Rifaximin ("rif" = rifamycin derivative; "ximin" = gut-selective)	Non-absorbable antibiotic → reduces ammonia-producing gut bacteria	Add to lactulose for secondary prophylaxis (significantly reduces recurrence); well tolerated
BCAA supplementation	Branched-chain amino acids (leucine, isoleucine, valine) serve as alternative substrate for ammonia detoxification in muscle	BCAA also used as a form of treatment in HE, to increase ammonia removal ^[18]; Aminoleban formula for chronic liver disease ^[42]
Avoid sedatives	Impaired hepatic drug clearance → exaggerated CNS depression	Benzodiazepines, opioids absolutely avoided
Protein intake	DO NOT restrict protein — worsens sarcopenia and mortality	Maintain 1.2–1.5 g/kg/d; plant-based and dairy protein may be better tolerated than meat protein

6. Pillar 4: Liver Transplantation

HCC and liver transplantation ^[44]^[36]:

Criteria	Details	Role
Milan criteria	Single lesion ≤ 5 cm OR ≤ 3 lesions each ≤ 3 cm; no gross vascular invasion; no nodal/distant metastasis ^[44]	Bonus score if fulfilled (> 75% 5-year survival) ^[44]
UCSF criteria	Single lesion ≤ 6.5 cm OR ≤ 3 lesions each ≤ 4.5 cm, sum ≤ 8.0 cm ^[44]	Drop-off criteria: only those fulfilled are included in the transplant list ^[44]
MELD score	Creatinine, bilirubin, INR ± Na	Prioritises the transplant list (benefit if score > 18) ^[44]; in HK, not first-come-first-served ^[10]

Bridging therapy ^[44]:

RFA or TACE can be used to shrink disease to fulfil transplant criteria and prevent tumour progression while waiting ^[44]

Five principles of management of acute liver failure ^[45]:

Supportive → standard ICU care
Identifying and removing/treating the insult — HBV → anti-HBV agents; paracetamol → N-acetylcysteine; mushrooms → activated charcoal ^[45]
Manage complications (cerebral oedema, coagulopathy, infection, metabolic derangement)
High-volume plasma exchange — wash away cytokines causing the liver failure; very expensive but useful; combination treatment ^[45]
Liver transplantation — the final line → after exhausting all other treatments ^[45]

High Yield Summary

Treat the cause: HBV cirrhosis with any detectable DNA → lifelong nucleos(t)ide analogues (entecavir/tenofovir) ^[5]. HCV → DAAs for cure (SVR) ^[10]. Alcohol → abstinence is cornerstone ^[40]. MASLD → weight loss 5-7% (steatosis) or ≥ 10% (fibrosis); GLP-1 RAs emerging ^[6].
AIH: Start steroid → taper within 4–12 weeks → lifelong azathioprine (check TPMT/NUDT15 first) ^[19].
PBC: UDCA first-line; cholestyramine for pruritus (drug of choice); rifampicin 2nd line; opioid antagonists 3rd line; transplant for intractable cases ^[20].
Ascites: Na restriction + spironolactone ± furosemide (100:40 ratio); refractory → large-volume paracentesis + IV albumin → TIPS.
Variceal bleeding: Restrictive transfusion (Hb < 7); terlipressin/octreotide + antibiotics before OGD; EVL is first-line endoscopic therapy ^[43].
HE: Identify/treat precipitant; lactulose (titrate 2–3 soft stools/day) + rifaximin for secondary prophylaxis; DO NOT restrict protein.
HRS: Exclude other causes; stop diuretics/NSBBs; IV albumin + terlipressin; definitive Mx = liver transplant ^[41].
Liver transplant: ≤ 65 years, Child C or HCC meeting Milan criteria; MELD score for prioritisation ^[44]. Contraindicated in active infection, active substance abuse ^[44].
HCC curative options: Resection, RFA, transplant. TACE if not curable; contraindicated in portal vein thrombosis ^[46].
Alcoholic hepatitis steroids: Only if Maddrey DF ≥ 32; stop if no bilirubin response at day 7 ^[40]^[18].

Active Recall - Management of Cirrhosis

^[4] Lecture slides: GC 026. Abdominal distension_ascites and cirrhosis.pdf; Senior notes: Block A - Abdominal distension_ ascites and cirrhosis.pdf (reversibility of cirrhosis) ^[5] Senior notes: Block A - I am a hepatitis B carrier.pdf (indications for HBV treatment in cirrhosis; treatment endpoints) ^[6] Senior notes: Block A - Gastroenterology Interactive Tutorial.pdf (Case 2 — MASLD weight loss targets, GLP-1 RAs, HCC surveillance, coffee, dual liver disease) ^[10] Senior notes: Block A - Gastrointestinal Data Interpretation.pdf (Case 2 — HCV SVR, MELD for transplant, SBP diagnosis, HBeAg and treatment duration) ^[13] Senior notes: Adrian Lui Pediatrics Notes.pdf (Wilson disease liver transplant indications, p. 268) ^[18] Senior notes: Block A - Introduction to GI_Hepatology investigations (LFT, Endoscopy).pdf (Maddrey DF, BCAA, alcoholic hepatitis steroid caution, AST:ALT patterns) ^[19] Senior notes: Block A - Patients with non-viral chronic liver diseases.pdf (AIH treatment, azathioprine TPMT/NUDT15, PBC UDCA/OCA, Wilson disease penicillamine, cholesterol in PBC) ^[20] Lecture slides: Teaching Clinic - Non-viral chronic liver diseases (Prof. Yuen Man Fung) 2.pdf (PBC treatment — UDCA, pruritus management, malnutrition, transplant indications/outcomes) ^[33] Senior notes: Ryan Ho GI.pdf (hepatic hydrothorax management, portal hypertensive gastropathy, p. 314) ^[36] Senior notes: Maksim Surgery Notes.pdf (HCC investigations, AFP, triphasic CT, curative options, p. 124–125) ^[39] Senior notes: Block A - I am a hepatitis B carrier.pdf (aims and endpoints of HBV treatment; EASL guidelines) ^[40] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Alcoholic liver disease treatment, p. 782–784; HCC treatment options, p. 843–845) ^[41] Senior notes: Block A - Abdominal distension_ ascites and cirrhosis.pdf (HRS-AKI management, p. 22) ^[42] Senior notes: Ryan Ho Fluids and Nutrition.pdf (Aminoleban for CLD, p. 9) ^[43] Senior notes: Block A - Coffee ground vomitus tarry stool upper GI bleeding.pdf (UGIB management principles, p. 13–15) ^[44] Senior notes: Maksim Surgery Notes.pdf (Liver transplant criteria — Milan, UCSF, MELD; bridging therapy; complications, p. 126–127) ^[45] Senior notes: Block A - A jaundiced and incoherent patient_ liver failure.pdf (Acute liver failure management, p. 24) ^[46] Senior notes: Ryan Ho Diagnostic Radiology.pdf (TACE contraindications, p. 86); Lecture slides: HCC and Gallstone acute cholangitis_Prof TT Cheung.pdf (Transplant indications for HCC)

3. Complication-by-Complication Detail

3A. Variceal Haemorrhage

3B. Ascites

3C. Spontaneous Bacterial Peritonitis (SBP)

3D. Hepatic Encephalopathy (HE)

Precipitant	Mechanism
GI bleeding	Protein load in gut → ↑ ammonia production by bacteria
Infection (SBP, UTI, pneumonia)	Cytokines synergise with ammonia; catabolism → ↑ nitrogen load
Constipation	Prolonged contact time for bacterial ammonia production
Sedatives/opioids	Impaired hepatic clearance → exaggerated CNS depression
Hypokalaemia	↑ Renal ammoniagenesis (K⁺ and H⁺ compete for secretion; hypokalaemia → alkalosis → NH₃ favoured over NH₄⁺ → crosses BBB more easily)
Alkalosis	Non-ionic NH₃ crosses BBB; ionic NH₄⁺ does not
Dehydration / over-diuresis	Concentrates ammonia; pre-renal impairment reduces renal ammonia excretion
Dietary protein excess	Increased substrate for ammonia
Portosystemic shunting (TIPS)	Bypasses liver entirely → uncleared ammonia reaches systemic circulation

Grade	Features
Minimal (covert)	Abnormal psychometric testing only
1	Altered sleep, impaired attention, ↓ computation
2	Lethargy, disorientation to time, asterixis, personality change
3	Somnolence, gross disorientation, bizarre behaviour, marked confusion
4	Coma

3E. Hepatorenal Syndrome (HRS)

Type	Old Name	Features
HRS-AKI	Type 1	Rapidly progressive; creatinine ≥ 1.5× baseline within 7 days or ≥ 26.5 μmol/L increase within 48 hours; often precipitated by SBP
HRS-CKD	Type 2	Slowly progressive; eGFR < 60 for > 3 months; associated with refractory ascites

Infections in liver failure are very common ^[48].

Mechanism: reticuloendothelial dysfunction and reduced opsonisation — liver failure impairs the ability to clear toxins; at the same time, production of complement and opsonins is impaired, meaning less immune defence ^[48].

Causative organisms ^[48]:

Bacteria — especially from the respiratory and urinary tract: Staph, Strep, gram-negative rods; bacteraemia in up to 25% of fulminant hepatic failure patients
Fungal infection — especially Candida (but bacterial still most common)

Common infections in cirrhosis:

Infection	Frequency	Notes
SBP	Most characteristic	Discussed above
UTI	Very common	Often asymptomatic; E. coli most common
Pneumonia	Common	↑ Risk from aspiration (encephalopathy) and immunocompromise
Bacteraemia	25% in fulminant cases	Often from gut translocation
Cellulitis	Common	Oedematous tissues + impaired immunity
Fungal	Less common but important	Candida; occurs in ICU setting, prolonged antibiotics

Pathophysiology

Cirrhosis affects ALL components of the coagulation system:

Component	Effect	Mechanism
Pro-coagulant factors	↓ Factors II, V, VII, IX, X, fibrinogen	↓ Hepatic synthesis
Anti-coagulant factors	↓ Protein C, Protein S, antithrombin III	Also ↓ hepatic synthesis
Fibrinolysis	↑ tPA (tissue plasminogen activator); ↓ plasminogen activator inhibitor	Hyperfibrinolysis
Platelets	↓ Number (hypersplenism + ↓ thrombopoietin) and ↓ function	Splenic sequestration + impaired TPO production
Vitamin K	↓ (malabsorption in cholestasis)	Fat-soluble vitamin malabsorption

The key concept: cirrhosis creates a "rebalanced haemostasis" — both pro- and anti-coagulant pathways are reduced in parallel. The INR overestimates bleeding risk because it only measures pro-coagulant factors. In reality, cirrhotic patients are at risk of BOTH bleeding AND thrombosis (e.g., portal vein thrombosis).

Common Exam Misconception

Students assume cirrhotic patients only bleed. In fact, cirrhosis creates a fragile, rebalanced haemostatic state. The INR is misleadingly prolonged because it only reflects pro-coagulant factor reduction, not the simultaneous reduction of anti-coagulant factors (protein C, S, antithrombin). Cirrhotic patients can and do develop thrombosis — most importantly portal vein thrombosis.

3H. Portal Vein Thrombosis (PVT)

3I. Hepatocellular Carcinoma (HCC)

Poor survival once cirrhosis becomes decompensated ^[10] — the transition from compensated to decompensated is the critical event. Each decompensating episode further worsens prognosis. MELD score guides transplant prioritisation.

High Yield Summary

Complications of cirrhosis can be separated into compensated (varices, PVT, HCC) and decompensated (ascites, SBP, HE, HRS, hepatic hydrothorax — on top of the compensated complications) ^[47].
Infections are very common in liver failure: mechanism is reticuloendothelial dysfunction and reduced opsonisation; bacteria from respiratory and urinary tract (Staph, Strep, GNR); fungal (Candida) ^[48].
SBP: diagnosed by ascitic neutrophils ≥ 250/mm³; culture usually negative; may have minimal abdominal signs; requires high suspicion ^[10].
Variceal bleed: use restrictive transfusion (Hb < 7); liberal strategy worsens rebleeding (increases portal pressure in cirrhosis); terlipressin/octreotide + antibiotics before OGD; EVL first-line ^[43].
HRS: functional renal failure (structurally normal kidneys); treat with IV albumin + terlipressin; spot urine Na < 10 suggestive; definitive Mx = transplant ^[41].
HE: diagnosis of exclusion; precipitants include GI bleed, infection, constipation, sedatives, hypokalaemia; treat with lactulose + rifaximin; DO NOT restrict protein ^[18].
Hepatic hydrothorax: right-sided; due to diaphragmatic defect; NEVER insert a chest drain ^[33].
HCC: 80% on cirrhotic liver; HBV has direct oncogenic effect (can cause HCC without cirrhosis); poor prognosis due to late presentation, underlying cirrhosis, early venous permeation, field cancerisation ^[36]^[50].
Coagulopathy: "rebalanced haemostasis" — BOTH pro- and anti-coagulant factors reduced; INR overestimates bleeding risk; patients can develop BOTH bleeding AND thrombosis (PVT) ^[31]^[32].
Hypersplenism requires 4 features: pancytopenia, splenomegaly, active marrow, reversal on splenectomy. Pancytopenia + splenomegaly alone is NOT sufficient ^[11].

Active Recall - Complications of Cirrhosis

High Yield Summary

Definition: Cirrhosis = late-stage fibrosis with bridging fibrosis, distortion of hepatic architecture, and regenerative nodules (F4 on METAVIR). Histological definition (F1–F4) ^[4].
Epidemiology (HK): HBV is by far the most common cause (~64–75%) ^[4]. HCV ~5–10%, alcohol > 5%. Dual liver disease concept (HBV + MASLD) is common ^[4].
Two pillars of pathophysiology: (a) Hepatocellular insufficiency → ↓ albumin, ↓ clotting factors, ↓ bilirubin clearance, ↑ ammonia, ↑ oestrogen. (b) Portal hypertension → varices, splenomegaly/hypersplenism, ascites.
Ascites mechanism: Portal HTN + hypoalbuminaemia + RAAS/ADH activation (peripheral arterial vasodilation hypothesis).
Compensated (Child A) vs Decompensated (Child B/C): Decompensation = jaundice, ascites, variceal bleeding, encephalopathy, HRS. Survival drops dramatically once decompensated ^[10].
Prognostic scores: Child-Pugh (5 parameters: INR, Albumin, Bilirubin, Ascites, Encephalopathy) vs MELD (3 parameters: Bilirubin, Creatinine, INR) ^[1]. MELD is more objective and used for transplant prioritisation.
Non-invasive assessment: FibroScan > 12 kPa suggestive of cirrhosis; liver biopsy rarely done nowadays ^[10].
Reversibility: Possible, especially if underlying cause removed (HBV antivirals, HCV cure, alcohol abstinence); depends on aetiology and severity ^[4].
Stigmata of CLD: Spider naevi, palmar erythema, gynaecomastia, jaundice, ascites, caput medusae, asterixis, splenomegaly, leuconychia — all explained by hepatocellular insufficiency and portal hypertension.
Risk factors for decompensation: Bleeding, dehydration, infection, obesity, alcoholism, medications ^[2]^[3].

High Yield Summary

Two DDx tasks: (a) What caused the cirrhosis? (b) Is it actually cirrhosis or a mimic?
Aetiological workup is systematic: Viral → Alcohol → Metabolic/MASLD → Autoimmune → Biliary → Metabolic storage → Vascular/cardiac → Drug → Cryptogenic.
Dual/triple liver disease is common in HK (e.g., HBV + MASLD) ^[4]^[6] — always look for co-existing causes.
Anyone with CLD + alcoholism must have other causes excluded ^[10].
Immunoglobulin patterns: ↑IgG = AIH, ↑IgM = PBC, ↑IgA = Alcoholic ^[24].
Confusion in cirrhosis ≠ HE. HE is a diagnosis of exclusion. Most common causes of confusion in cirrhosis are head injury, drugs, withdrawal, infection, and metabolic disturbance ^[29].
Wilson's disease: Kayser-Fleischer rings + extrapyramidal signs; fulminant form = Coombs-negative haemolytic anaemia; penicillamine can initially worsen neuro symptoms ^[19].
PBC diagnosis: AMA-M2 + cholestatic biochemistry > 6 months + compatible histology (2 of 3 = probable) ^[20]^[21].
Hepatomegaly surface: irregular/hard = cancer; smooth = fatty liver, alcoholic cirrhosis, PBC; nodular = polycystic disease ^[28].
GGT is an inducible enzyme — isolated ↑GGT suggests alcohol or drugs, not necessarily biliary obstruction ^[10]^[18].

High Yield Summary

Liver biopsy = gold standard for cirrhosis diagnosis (diffuse process, regenerative nodules, bridging fibrosis) ^[31]^[32], but FibroScan (> 12 kPa) is now standard of care as non-invasive alternative ^[10].
LFT assesses 3 aspects: cellular integrity (ALT/AST), synthetic function (albumin, PT/INR), excretory function (bilirubin, ALP, GGT) ^[18]^[35].
4 conditions cause AST > ALT: alcoholic hepatitis (> 2:1, AST almost never > 500), HCC, CHF, ischaemic hepatitis ^[18].
Thrombocytopenia is often the first lab clue to compensated cirrhosis (hypersplenism) ^[10].
USG findings of cirrhosis: irregular contour, nodularity, coarse echogenicity, right lobe atrophy, caudate hypertrophy ^[31]^[32]. USG findings of portal HTN: ↑ portal vein diameter, collaterals, ↓ flow, ascites, splenomegaly ^[31]^[32].
SBP diagnosed by ascitic fluid neutrophil count ≥ 250/mm³ — culture is usually negative ^[10].
HCC surveillance: USG ± AFP every 6 months for all cirrhotics; HBV patients screened from age 40 (M) / 50 (F) even without cirrhosis ^[6].
PBC diagnosis: 2 of 3 criteria (AMA-M2+, cholestatic markers > 6 months, compatible histology) ^[20].
Wilson's disease: ↓ ceruloplasmin + KF rings + ↑ 24h urine copper; liver biopsy for hepatic copper ≥ 250 mcg/g = diagnostic ^[37].
AFP is NOT specific for HCC — also elevated in cirrhosis (regenerating nodules), hepatitis, pregnancy, germ cell tumours ^[36].

High Yield Summary

Treat the cause: HBV cirrhosis with any detectable DNA → lifelong nucleos(t)ide analogues (entecavir/tenofovir) ^[5]. HCV → DAAs for cure (SVR) ^[10]. Alcohol → abstinence is cornerstone ^[40]. MASLD → weight loss 5-7% (steatosis) or ≥ 10% (fibrosis); GLP-1 RAs emerging ^[6].
AIH: Start steroid → taper within 4–12 weeks → lifelong azathioprine (check TPMT/NUDT15 first) ^[19].
PBC: UDCA first-line; cholestyramine for pruritus (drug of choice); rifampicin 2nd line; opioid antagonists 3rd line; transplant for intractable cases ^[20].
Ascites: Na restriction + spironolactone ± furosemide (100:40 ratio); refractory → large-volume paracentesis + IV albumin → TIPS.
Variceal bleeding: Restrictive transfusion (Hb < 7); terlipressin/octreotide + antibiotics before OGD; EVL is first-line endoscopic therapy ^[43].
HE: Identify/treat precipitant; lactulose (titrate 2–3 soft stools/day) + rifaximin for secondary prophylaxis; DO NOT restrict protein.
HRS: Exclude other causes; stop diuretics/NSBBs; IV albumin + terlipressin; definitive Mx = liver transplant ^[41].
Liver transplant: ≤ 65 years, Child C or HCC meeting Milan criteria; MELD score for prioritisation ^[44]. Contraindicated in active infection, active substance abuse ^[44].
HCC curative options: Resection, RFA, transplant. TACE if not curable; contraindicated in portal vein thrombosis ^[46].
Alcoholic hepatitis steroids: Only if Maddrey DF ≥ 32; stop if no bilirubin response at day 7 ^[40]^[18].

High Yield Summary

Complications of cirrhosis can be separated into compensated (varices, PVT, HCC) and decompensated (ascites, SBP, HE, HRS, hepatic hydrothorax — on top of the compensated complications) ^[47].
Infections are very common in liver failure: mechanism is reticuloendothelial dysfunction and reduced opsonisation; bacteria from respiratory and urinary tract (Staph, Strep, GNR); fungal (Candida) ^[48].
SBP: diagnosed by ascitic neutrophils ≥ 250/mm³; culture usually negative; may have minimal abdominal signs; requires high suspicion ^[10].
Variceal bleed: use restrictive transfusion (Hb < 7); liberal strategy worsens rebleeding (increases portal pressure in cirrhosis); terlipressin/octreotide + antibiotics before OGD; EVL first-line ^[43].
HRS: functional renal failure (structurally normal kidneys); treat with IV albumin + terlipressin; spot urine Na < 10 suggestive; definitive Mx = transplant ^[41].
HE: diagnosis of exclusion; precipitants include GI bleed, infection, constipation, sedatives, hypokalaemia; treat with lactulose + rifaximin; DO NOT restrict protein ^[18].
Hepatic hydrothorax: right-sided; due to diaphragmatic defect; NEVER insert a chest drain ^[33].
HCC: 80% on cirrhotic liver; HBV has direct oncogenic effect (can cause HCC without cirrhosis); poor prognosis due to late presentation, underlying cirrhosis, early venous permeation, field cancerisation ^[36]^[50].
Coagulopathy: "rebalanced haemostasis" — BOTH pro- and anti-coagulant factors reduced; INR overestimates bleeding risk; patients can develop BOTH bleeding AND thrombosis (PVT) ^[31]^[32].
Hypersplenism requires 4 features: pancytopenia, splenomegaly, active marrow, reversal on splenectomy. Pancytopenia + splenomegaly alone is NOT sufficient ^[11].

Cirrhosis

Cirrhosis — Definition, Epidemiology, Risk Factors, Anatomy & Function, Etiology, Pathophysiology, Classification, and Clinical Features

1. Definition

Is Cirrhosis Reversible?

2. Epidemiology

Global

Hong Kong — High Yield

Prevalence of HBV in Hong Kong

3. Risk Factors

Risk Factors for Developing Cirrhosis (from chronic liver disease)

Risk Factors for Decompensation of Existing Cirrhosis

4. Anatomy & Function of the Liver (Relevant to Understanding Cirrhosis)

Gross Anatomy

Microanatomy: The Hepatic Lobule & Sinusoid

Key Functions of the Liver (and how cirrhosis disrupts each)

5. Etiology of Cirrhosis (Focus on Hong Kong)

A. Liver Diseases (Parenchymal)

B. Biliary Diseases

C. Metabolic / "Endocrine" Diseases

D. Vascular Diseases

E. Drug-Induced

Mnemonic for Causes of Cirrhosis: "ABCDEFGH"

6. Pathophysiology of Cirrhosis

6.1 The Central Pathway: Chronic Injury → Fibrosis → Cirrhosis

6.2 Two Major Pathophysiological Consequences

6.2.1 Hepatocellular Insufficiency (Loss of Functioning Hepatocyte Mass)

6.2.2 Portal Hypertension

6.3 The Pathophysiology of Ascites — The "Underfill" (Peripheral Arterial Vasodilation) Hypothesis

6.4 The Pathophysiology of Hepatic Encephalopathy

6.5 The Pathophysiology of Hepatorenal Syndrome (HRS)

7. Classification of Cirrhosis

7.1 By Morphology (Historical, Less Clinically Used)

7.2 By Compensation Status — Compensated vs Decompensated

7.3 Prognostic Scoring Systems

7.3.1 Child-Pugh Score

7.3.2 MELD Score

7.4 Non-Invasive Assessment of Fibrosis/Cirrhosis

8. Clinical Features of Cirrhosis

8.1 Symptoms

A. Symptoms from Hepatocellular Insufficiency

B. Symptoms from Portal Hypertension

C. Symptoms from Hepatic Encephalopathy

D. Other Symptoms

8.2 Signs

A. Stigmata of Chronic Liver Disease (CLD)

B. Signs of Portal Hypertension Specifically

C. Signs of Hepatic Encephalopathy

D. Signs Specific to Certain Etiologies

8.3 Putting It All Together: The Abdominal Examination in Cirrhosis

9. Laboratory and Biochemical Patterns (Pre-Investigation Detail)

Liver Function Tests in Cirrhosis

10. Summary of Clinical Approach to Cirrhosis (Pre-DDx, Pre-Ix, Pre-Mx)

Active Recall - Cirrhosis: Definition, Epidemiology, Pathophysiology & Clinical Features

References

Differential Diagnosis of Cirrhosis

1. Differential Diagnosis of the Aetiology of Cirrhosis

Systematic Aetiological Differential

2. Differential Diagnosis of the Clinical Presentation — Mimics of Cirrhosis

2A. Differential Diagnosis of Hepatomegaly

2B. Differential Diagnosis of Ascites

2C. Differential Diagnosis of Jaundice in a Patient with Liver Disease

2D. Differential Diagnosis of Confusion in Cirrhosis

2E. Differential Diagnosis of Splenomegaly

3. Differential Diagnosis of Specific Aetiological Clues — Key Discriminators

4. Approach Algorithm for Aetiological Workup

5. Special Considerations for Wilson's Disease (Exam Favourite)

6. Hepatic Encephalopathy — The Diagnostic Pitfall Revisited

Active Recall - Differential Diagnosis of Cirrhosis

References

Diagnosis of Cirrhosis — Diagnostic Criteria, Algorithm, Investigation Modalities & Interpretation

1. Overarching Principle: How Do You "Diagnose" Cirrhosis?

2. Diagnostic Criteria — The Building Blocks

2A. Clinical Criteria

2B. Laboratory Criteria (Suggestive, Not Diagnostic)

2C. Non-Invasive Fibrosis Assessment

Serum-Based Scores

Transient Elastography (FibroScan)

2D. Imaging Criteria

USG Abdomen — First-Line Imaging

CT Abdomen