Signs and Symptoms of Heart Failure

Symptoms (What the Patient Reports)

• Dyspnea - the cardinal symptom; worsening shortness of breath on exertion or at rest
• Orthopnea - dyspnea when lying flat; patients sleep with heads elevated
• Paroxysmal nocturnal dyspnea (PND) - one of the most reliable indicators of HF; sudden breathlessness waking the patient from sleep
• Trepopnea - dyspnea when lying on the left side
• Tachypnea
• Cough (often dry, may be frothy pink in acute pulmonary edema)
• Cheyne-Stokes respiration - periodic/cyclic breathing, often noticed by family rather than the patient

• Fatigue and markedly diminished exercise capacity
• Somnolence or diminished mental acuity (low cardiac output to brain)

• Peripheral edema - ankles, legs, scrotum
• Increasing abdominal girth / bloating
• Weight gain (fluid) or weight loss (cardiac cachexia in advanced disease)
• Nocturia - nocturnal redistribution of fluid from dependent tissues

• Right upper quadrant pain - hepatic congestion
• Loss of appetite / early satiety - gut edema, hepatomegaly
• Palpitations
• Chest discomfort

Physical Signs (Examination Findings)

Key Diagnostic Pearls

• JVP elevation + S3 + peripheral edema is the classic triad pointing strongly to HF
• S3 gallop (third heart sound) reflects a dilated, volume-overloaded ventricle and has high specificity for elevated filling pressures
• Absence of dyspnea does not exclude HF - patients often reduce activity to avoid symptoms, masking the diagnosis
• BNP (B-type natriuretic peptide) elevation supports the diagnosis when the clinical picture is ambiguous; a 2025 meta-analysis (PMID: 40641207) confirmed its high diagnostic utility for HF in patients presenting with acute dyspnea

NYHA Functional Classification (Symptom-Based)

• Braunwald's Heart Disease, Tables 48.2 & 48.3
• Goldman-Cecil Medicine, Chapter 221

Differentiating HFpEF from HFrEF

1. The LVEF Cut-offs (Formal Definitions)

2. Clinical Profile: Who Gets Each?

3. Heart Sounds - the Most Useful Bedside Clue

4. Chest X-Ray

5. Echocardiographic Features

6. Pathophysiology Behind the Differences

• HFrEF: The problem is systolic - the ventricle cannot contract adequately. Cardiac output falls, the ventricle dilates and remodels, and neurohormonal activation (RAAS, SNS) worsens the cycle.
• HFpEF: The problem is diastolic - contraction is normal but the ventricle is stiff and cannot relax or fill properly. Resting hemodynamics may be near-normal, but during exercise or tachycardia (e.g., from AF), filling pressures spike dramatically, causing dyspnea. Because atrial contraction contributes disproportionately to filling of a stiff ventricle, loss of atrial kick in AF is particularly poorly tolerated. Patients also have a narrow "euvolemic window" - even modest fluid overload causes severe dyspnea, yet aggressive diuresis causes underfilling and hypotension.

7. BNP / NT-proBNP

8. Response to Therapy - A Diagnostic Clue in Retrospect

Quick Summary Table

Valvular Heart Diseases - Comprehensive Summary

1. MITRAL STENOSIS (MS)

Aetiology

• Rheumatic heart disease is by far the most common cause (rheumatic fever causes leaflet thickening, fusion of commissures, and chordal shortening)
• Rare: congenital, mitral annular calcification (MAC), carcinoid, SLE, mucopolysaccharidoses

Pathophysiology

• Obstruction to LV inflow raises left atrial (LA) pressure → LA enlargement → pulmonary venous hypertension → pulmonary oedema
• Reduced cardiac output at rest or on exertion
• LA enlargement predisposes to atrial fibrillation → loss of atrial kick worsens symptoms acutely
• AF + LA stasis = high thromboembolic risk (stroke, systemic embolism)
• Normal mitral valve area (MVA): 4-6 cm²; significant MS: <2 cm²; severe: <1 cm²

Symptoms

• Dyspnoea on exertion, orthopnoea, paroxysmal nocturnal dyspnoea
• Haemoptysis (rupture of bronchial veins)
• Palpitations (AF)
• Hoarseness (Ortner's syndrome - LA compresses left recurrent laryngeal nerve)
• Systemic embolism / stroke

Signs

• Malar flush (mitral facies) - plum-red cheeks from low CO + peripheral vasoconstriction
• Tapping apex beat (palpable S1)
• Loud S1 (if valve still mobile), opening snap (OS) - short S2-OS interval = more severe MS
• Low-pitched mid-diastolic rumble at the apex (best heard in left lateral position, after exertion)
• Presystolic accentuation (disappears in AF)
• Signs of pulmonary hypertension: loud P2, right ventricular heave, TR murmur

Investigations

• ECG: P mitrale (bifid P wave), AF; right axis deviation in pulmonary HTN
• CXR: LA enlargement (double right heart border, splaying of carina), Kerley B lines, pulmonary oedema
• Echo (definitive): MVA by planimetry or pressure half-time; assess leaflet mobility, calcification, subvalvular disease (Wilkins score for suitability of valvuloplasty)

Management

• Medical: diuretics for congestion; rate control for AF (beta-blocker, digoxin); anticoagulation for AF or prior embolism (warfarin preferred)
• Percutaneous balloon mitral valvuloplasty (PBMV/BMV): preferred for symptomatic severe MS if valve morphology favourable (low Wilkins score ≤8, no significant MR, no LA thrombus)
• Surgical: mitral commissurotomy or mitral valve replacement (MVR) if valve unsuitable for PBMV, or if significant MR co-exists
• PBMV success rates are lower in older patients and when valves are heavily calcified

2. MITRAL REGURGITATION (MR)

Aetiology

• Mitral valve prolapse (MVP) - most common cause in developed world (myxomatous degeneration)
• Rheumatic heart disease
• Infective endocarditis (leaflet destruction)
• Ruptured chordae tendineae (spontaneous or post-MI)
• Mitral annular calcification (MAC)
• Congenital cleft leaflet

• Dilated cardiomyopathy (annular dilation)
• Ischaemic MR (papillary muscle dysfunction/rupture)

Pathophysiology

• Regurgitant flow into LA during systole → LA volume overload → LA dilation
• LV also dilates (compensatory eccentric hypertrophy) to maintain forward CO
• Chronic: LV/LA both dilate; acute (ruptured chordae/papillary muscle): sudden LA pressure spike → acute pulmonary oedema (small non-compliant LA cannot buffer the volume)

Symptoms

• Chronic: often asymptomatic for years; eventually dyspnoea, fatigue, reduced exercise tolerance, AF
• Acute: sudden severe dyspnoea, pulmonary oedema (medical emergency)

Signs

• Pansystolic (holosystolic) murmur at apex, radiating to axilla
• Soft S1 (leaflets do not coapt properly)
• Loud P2 (with pulmonary hypertension)
• S3 gallop (from rapid LV filling)
• Displaced, hyperdynamic apex beat (volume-overloaded LV)
• In MVP: mid-systolic click followed by late systolic murmur

Investigations

• Echo (key): quantify regurgitant volume, EROA, vena contracta; assess LV function and dimensions; determine mechanism
• ECG: LA enlargement (P mitrale), LV hypertrophy, AF
• CXR: LA and LV enlargement, pulmonary congestion

Management

• Asymptomatic: monitor; surgery indicated when LVEF <60% or LVESD >4 cm (before irreversible LV dysfunction)
• Symptomatic severe MR: surgery - mitral valve repair preferred over replacement (preserves chordal apparatus, better LV function post-op)
• MVR if repair not feasible
• Transcatheter (MitraClip): edge-to-edge repair for high surgical-risk patients
• Secondary MR: optimise HF medical therapy first (GDMT); consider MitraClip if persistent and symptomatic

3. AORTIC STENOSIS (AS)

Aetiology

• Senile/calcific degenerative AS - most common in adults >65 years (calcification of tricuspid aortic valve)
• Bicuspid aortic valve (BAV) - congenital; presents 1-2 decades earlier (age 40-60); most common cause in younger adults
• Rheumatic AS - usually with MR/MS; rare in isolation

Pathophysiology

• Fixed obstruction to LV outflow → pressure overload → concentric LV hypertrophy (compensatory)
• Increased O2 demand + reduced coronary perfusion pressure → subendocardial ischaemia (angina)
• Hypertrophied LV is stiff, diastolic dysfunction; eventually systolic dysfunction
• Reduced CO → syncope on exertion
• Critical valve area <1.0 cm² (or <0.6 cm²/m² BSA); severe: mean gradient ≥40 mmHg, peak velocity ≥4 m/s

Symptoms - the Classic Triad (onset = poor prognosis without intervention)

Signs

• Harsh, ejection systolic murmur (crescendo-decrescendo), best at aortic area (2nd right intercostal space), radiating to carotids
• Slow-rising, low-amplitude carotid pulse (pulsus parvus et tardus) - less reliable in elderly due to arterial stiffness
• Heaving, sustained, non-displaced apex beat (pressure-loaded LV)
• Soft or absent A2 (aortic component of S2) when valve is heavily calcified
• S4 gallop (stiff, hypertrophied LV)
• Narrow pulse pressure

Investigations

• Echo (definitive): peak velocity, mean gradient, valve area by continuity equation; assess LV function, LVH, diastolic function
• ECG: LV hypertrophy (increased voltages, strain pattern), LBBB possible
• CXR: post-stenotic aortic dilation, calcification of aortic valve (on lateral view), LV enlargement (late)
• Low-flow, low-gradient AS: dobutamine stress echo to distinguish true severe AS from pseudo-severe AS

Management

• Asymptomatic: watchful waiting with regular echo; intervene when symptoms develop or LVEF <50%
• Symptomatic severe AS: intervention is mandatory
  • Surgical AVR (SAVR): preferred in younger patients (<65-75 years) and low surgical risk
  • Transcatheter AVR (TAVR): now recommended across all risk categories; preferred in older/high-risk patients; equivalent or superior outcomes vs SAVR in intermediate and high risk; lower risk of new-onset AF and faster recovery
  • Tissue (bioprosthetic) valve preferred in elderly (avoids anticoagulation); mechanical valve if <60 years
• No effective medical therapy to slow progression; avoid vasodilators (risk of hypotension)

4. AORTIC REGURGITATION (AR)

Aetiology

• Bicuspid aortic valve
• Rheumatic heart disease
• Infective endocarditis
• Calcific/degenerative disease

• Hypertension (most common in elderly)
• Marfan syndrome / connective tissue disorders
• Aortic dissection (Type A - surgical emergency)
• Syphilitic aortitis
• Ankylosing spondylitis, reactive arthritis

Pathophysiology

• Regurgitation during diastole → LV volume and pressure overload → eccentric LV hypertrophy (LV dilates and enlarges)
• Wide pulse pressure (high systolic from large SV + low diastolic from regurgitation)
• Chronic: LV compensates for years; eventually LV dysfunction develops (LVEF falls)
• Acute AR (dissection, endocarditis): LV has no time to dilate → acute LV diastolic pressure rise → pulmonary oedema; medical emergency

Symptoms

• Chronic: often asymptomatic for years; then exertional dyspnoea, orthopnoea, palpitations (awareness of forceful heartbeat), angina
• Acute: sudden severe dyspnoea, pulmonary oedema, haemodynamic collapse

Signs - the "Eponymous Signs" of AR (from wide pulse pressure)

• Early diastolic, high-pitched blowing murmur at left sternal border (lower = valvular; upper right = root disease)
• Austin Flint murmur: mid-diastolic rumble at apex (regurgitant jet hits anterior mitral leaflet, causing functional MS)
• Displaced, hyperdynamic apex beat; S3 when LV decompensates

Investigations

• Echo: quantify regurgitation (ERO, vena contracta, PHT); LV dimensions and EF
• ECG: LV hypertrophy
• CXR: cardiomegaly, aortic root dilation

Management

• Asymptomatic: monitor; intervene when LVEF <50% or LVESD >5 cm (chronic severe AR)
• Symptomatic: surgical AVR (SAVR or TAVR); TAVR increasingly used in high-risk patients
• Acute severe AR (e.g., dissection, endocarditis): emergency surgery; vasodilators (nitroprusside) as temporising bridge; do NOT use IABP (worsens AR)
• Vasodilators (nifedipine, ACE inhibitors) for chronic AR if symptomatic but not surgical candidate

5. TRICUSPID REGURGITATION (TR)

Aetiology

• Secondary (functional) - most common; right ventricular dilation from left-sided HF, pulmonary HTN, or cor pulmonale dilates the tricuspid annulus
• Primary: rheumatic (rare), infective endocarditis (especially IV drug users - right-sided), carcinoid syndrome (fibrous tricuspid and pulmonary leaflets), Ebstein's anomaly (congenital)

Pathophysiology

• Regurgitation into RA → RA/RV volume overload → systemic venous congestion

Symptoms & Signs

• Peripheral oedema, ascites, hepatomegaly, jaundice (congestive hepatopathy)
• Pulsatile liver (hepatic systolic pulsation)
• Elevated JVP with prominent cv wave
• Pansystolic murmur at lower left sternal border, increases with inspiration (Carvallo's sign - distinguishes TR from MR)
• Right ventricular heave

Management

• Treat underlying cause (left HF, pulmonary HTN)
• Diuretics for congestion
• Surgical tricuspid annuloplasty (repair) if severe TR at time of left-sided valve surgery; isolated TR surgery rarely done

6. TRICUSPID STENOSIS (TS)

• Almost always rheumatic and almost always associated with MS and MR
• Presents with right heart failure signs (JVP elevation, oedema, ascites) without pulmonary oedema
• Mid-diastolic murmur at lower left sternal border; increases with inspiration
• Large a wave in JVP
• Echo confirms; surgical valvotomy or TVR at time of mitral surgery

7. PULMONARY STENOSIS (PS)

• Usually congenital (isolated or as part of Fallot's tetralogy, Noonan syndrome)
• Acquired: carcinoid, rheumatic (rare)
• Children/young adults; well tolerated for years
• Ejection systolic murmur at upper left sternal border (pulmonary area); preceded by ejection click (mobile valve)
• Widely split S2; right ventricular heave
• Echo: gradient across pulmonary valve; assess RV function
• Management: percutaneous balloon valvuloplasty (excellent results for valvular PS); surgical valvotomy for subvalvular/supravalvular PS

8. PULMONARY REGURGITATION (PR)

• Usually secondary to pulmonary artery hypertension (functional; annular dilation)
• Primary: post-balloon valvuloplasty, endocarditis, carcinoid
• Graham Steell murmur: early diastolic, high-pitched at upper left sternal border (from pulmonary HTN)
• Treat underlying pulmonary HTN; pulmonary valve replacement if severe and causing RV failure (especially post-repaired ToF)

Comparative Summary Table

Key Principles Across All Valvular Lesions

1. Echo is the cornerstone of diagnosis and serial monitoring in all valve disease
2. Timing of intervention matters: act before irreversible LV (or RV) dysfunction develops, even in asymptomatic patients with certain thresholds (e.g., LVEF <50-60% in AR/MR, LVESD >4-5 cm)
3. AF complicates most left-sided lesions and dramatically increases thromboembolic risk
4. Infective endocarditis prophylaxis is recommended for high-risk procedures in patients with certain valve lesions (prosthetic valves, prior endocarditis, some congenital lesions)
5. Rheumatic fever prevention (penicillin prophylaxis) remains the cornerstone of preventing rheumatic valve disease progression in endemic regions
6. TAVR has transformed the management of AS and is increasingly applicable to other lesions

Pulmonary Edema

Definition

Pathophysiology

• Pulmonary capillary pressure normally ~7 mmHg
• Plasma colloid osmotic pressure ~28 mmHg
• This gives an acute safety factor of ~21 mmHg against pulmonary edema
• Once capillary pressure exceeds ~25-28 mmHg, fluid floods the interstitium and then alveoli

1. Interstitial phase - fluid accumulates in the peribronchial and perivascular spaces; Kerley B lines on CXR; early dyspnoea
2. Alveolar phase - alveoli flood; severe hypoxaemia; pink frothy sputum; the life-threatening stage

Classification & Causes

Type 1 - Cardiogenic (Hydrostatic / High-Pressure)

Type 2 - Non-Cardiogenic (Increased Permeability)

Other / Mixed Causes

• Neurogenic pulmonary edema - after intracranial events (SAH, TBI); catecholamine surge
• High-altitude pulmonary edema (HAPE) - hypoxic pulmonary vasoconstriction
• Re-expansion pulmonary edema - after drainage of large pleural effusion/pneumothorax
• Decreased oncotic pressure - hypoalbuminaemia (nephrotic syndrome, liver disease, protein-losing enteropathy)
• Lymphatic obstruction (rare)

Pathology (Robbins)

• Alveolar capillaries engorged
• Intra-alveolar transudate - pale pink granular material
• Alveolar microhaemorrhages
• Haemosiderin-laden macrophages ("heart failure cells") - from breakdown of extravasated RBCs
• Chronic: abundant haemosiderin, alveolar wall fibrosis and thickening → brown induration of the lung (firm, brown, soggy lungs); seen in chronic mitral stenosis

• Protein-rich exudate
• Hyaline membrane formation (diffuse alveolar damage)
• Inflammatory cell infiltration

Clinical Features

Symptoms

• Sudden-onset severe dyspnoea at rest
• Orthopnoea - cannot lie flat
• Paroxysmal nocturnal dyspnoea
• Pink frothy sputum (alveolar flooding with blood-tinged fluid) - pathognomonic
• Sensation of suffocation or drowning
• Palpitations, chest pain (if underlying MI/ACS)
• Anxiety and a sense of impending doom

Signs

Investigations

Immediate (Bedside)

• Pulse oximetry - severe hypoxaemia (SpO₂ often <90%)
• ECG - ST elevation/depression (ACS), AF, LVH, LBBB
• Chest X-Ray (CXR) - key findings:

Blood Tests

• BNP / NT-proBNP - markedly elevated in cardiogenic; normal/mildly elevated in non-cardiogenic; single most useful test to distinguish causes
• Troponin - if ACS precipitated the oedema
• ABG - type I respiratory failure (low PaO₂, normal or low PaCO₂ initially; rising CO₂ = tiring/impending arrest)
• FBC, U&E, LFTs (assess renal function, albumin)
• Echocardiography - identifies LV/RV dysfunction, valve pathology, pericardial effusion

Distinguishing Cardiogenic from Non-Cardiogenic

Management

Immediate - ALL Patients (LMNOP Mnemonic)

1. Oxygenation & Ventilation

• High-flow O₂ via non-rebreather mask (target SpO₂ 92-95%)
• CPAP / BiPAP (NIV) - reduces work of breathing, redistributes alveolar fluid to extraalveolar space, decreases preload AND afterload simultaneously; first-line for cardiogenic pulmonary oedema
• Mechanical ventilation with PEEP - if NIV fails or patient is obtunded; PEEP: (1) reduces preload and afterload, (2) redistributes lung water from alveolar to extraalveolar space, (3) prevents atelectasis
• High-flow nasal cannula (HFNC) may be used for non-CS hypoxaemic failure

2. Preload Reduction

• Furosemide (loop diuretic) - drug of choice; initial dose ≤0.5 mg/kg IV (higher 1 mg/kg if renal impairment or chronic diuretic use); also acts as a venodilator before diuresis begins
• Sublingual glyceryl trinitrate (GTN/nitroglycerin) - 0.4 mg × 3 every 5 min; then IV infusion 5-10 µg/min if still no improvement and BP allows; rapid preload reduction
• IV nitroprusside - potent venous and arterial vasodilator; useful with hypertension; requires arterial line for monitoring; avoid in reduced coronary perfusion states

3. Afterload Reduction

• ACE inhibitors - reduce both preload and afterload; recommended for hypertensive patients and acute MI with HF; reduce short- and long-term mortality in AMI
• IV nitroprusside (as above)

4. Inotropic Support (if hypotensive/low output)

• Dobutamine - positive inotrope; increases CO; vasodilation
• Dopamine - low dose: renal vasodilation; higher dose: inotrope + vasopressor
• Milrinone (PDE-3 inhibitor / inodilator) - 50 µg/kg bolus then 0.25-0.75 µg/kg/min; inotrope + vasodilator; useful in severe LV dysfunction
• Nesiritide (recombinant BNP) - arterial and venous vasodilator with diuretic properties; reserve for refractory cases; avoid in ischaemia/MI
• Digitalis - rarely used now; useful for rate control in AF with LV dysfunction and pulmonary oedema (no negative inotropic effect on AV node like beta-blockers)

5. Treat the Precipitant

• ACS/STEMI - primary PCI; in-hospital mortality 20-40% when STEMI is complicated by pulmonary oedema; rapid revascularisation is essential
• Arrhythmia - rate control or cardioversion
• Hypertensive crisis - IV nitroprusside or nitroglycerin
• Valve emergency (acute MR, AR) - emergency surgical repair

6. Renal Replacement Therapy

• Refractory volume overload despite maximal diuretics
• Metabolic acidosis pH <7.15-7.25
• Persistent hyperkalaemia
• Severe hypoxaemia
• In ESRD: emergency haemodialysis is the definitive treatment (dialysis, not diuretics)
• If hypotensive/requiring inotropes: continuous RRT (CRRT) better tolerated than intermittent HD

Non-Cardiogenic Pulmonary Oedema / ARDS

• Treat underlying cause (antibiotics for sepsis, control source)
• Lung-protective mechanical ventilation: low tidal volumes (6 mL/kg IBW), PEEP, plateau pressure <30 cmH₂O
• Conservative fluid strategy once haemodynamically stable
• No proven pharmacological therapy to reduce capillary permeability yet

Special Situations

Prognosis

• Acute cardiogenic pulmonary oedema: mortality depends on cause; AMI + pulmonary oedema = 20-40% in-hospital mortality
• Rapid treatment with NIV, diuretics, and nitrates substantially reduces need for intubation and improves outcomes
• Non-cardiogenic (ARDS): mortality 30-40% depending on severity and cause

Cirrhosis - Detailed Overview

1. DEFINITION

• Diffuse hepatocyte necrosis
• Replacement by fibrous scar tissue (collagen deposition)
• Formation of regenerative nodules surrounded by fibrous septa
• Distortion of normal hepatic architecture - both the lobular and vascular architecture are obliterated

2. CAUSES / AETIOLOGY

3. MECHANISM - PATHOGENESIS OF FIBROSIS

Fig. 74.1 - Pathogenesis of fibrosis in cirrhosis (Sleisenger & Fordtran)

Step-by-Step Mechanism:

• Damaged hepatocytes release damage-associated molecular patterns (DAMPs)
• Kupffer cells (liver macrophages) and endothelial cells are activated
• They release pro-inflammatory and pro-fibrotic cytokines: TGF-β1, PDGF, IL-1, TNF-α

• Kupffer cells, endothelial cells, and injured hepatocytes/cholangiocytes all signal to resting HSCs (also called Ito cells) and portal fibroblasts
• Resting HSCs (which normally store vitamin A in fat droplets) undergo transdifferentiation into myofibroblasts
• Activated myofibroblasts:
  • Produce vast amounts of Type I collagen and other extracellular matrix (ECM) proteins
  • Contract (contributing to increased intrahepatic resistance)
  • Are highly proliferative and resistant to apoptosis

• Progressive ECM accumulation in the perisinusoidal space of Disse
• Disrupts normal sinusoidal blood flow and hepatocyte nutrition
• Fibrous septa bridge portal tracts to central veins (bridging fibrosis)

• Regenerating hepatocytes form nodules but are encased in fibrosis
• Nodules have distorted blood supply → inadequate oxygenation and function

• Be deactivated back toward a quiescent state
• Undergo apoptosis or senescence
• Matrix metalloproteinases (MMPs) can break down excess collagen
• This is why treating the cause (e.g., antivirals for HBV/HCV, abstinence from alcohol) can cause regression of cirrhosis in some patients

Histological Stages of Fibrosis (METAVIR):

4. CONSEQUENCES OF ARCHITECTURAL DISTORTION

A. Portal Hypertension

• Normal portal pressure: 5-10 mmHg
• Cirrhosis increases intrahepatic resistance → portal pressure rises
• When portal pressure exceeds 12 mmHg (HVPG ≥12 mmHg), complications develop
• The portal system is valveless; collateral veins develop at sites where portal and systemic circulations communicate:
  • Gastroesophageal junction → oesophageal varices
  • Anal canal → anorectal varices
  • Falciform ligament / periumbilical → caput medusae
  • Retroperitoneum

B. Hepatocellular Failure

• Loss of functioning hepatocyte mass → impaired synthetic, metabolic, and detoxification functions
• Results in: jaundice, coagulopathy, hypoalbuminaemia, hypoglycaemia, hyperammonaemia

5. CLINICAL STAGES

6. SYMPTOMS

Early / Compensated

• Fatigue (most common, often the first symptom)
• Anorexia and weight loss
• Vague right upper quadrant discomfort
• Mild nausea
• Reduced exercise tolerance
• Muscle cramps (correlate with ascites and low MAP)

Late / Decompensated

• Jaundice - appears when bilirubin >2-3 mg/dL
• Abdominal distension (ascites)
• Peripheral oedema (ankle swelling)
• GI bleeding - haematemesis or malaena (varices)
• Confusion / altered behaviour (hepatic encephalopathy)
• Pruritus (in cholestatic disease - PBC, PSC)
• Reduced urine output (hepatorenal syndrome)
• Fetor hepaticus (sweet/musty breath from mercaptans and ammonia)

7. SIGNS ON EXAMINATION

General / Face

Hands

Skin / Trunk

Abdomen

Neurological

• Asterixis (bilateral, asymmetric flapping tremor of outstretched hands)
• Confusion, disorientation, drowsiness (hepatic encephalopathy grades I-IV)
• Constructional apraxia (inability to draw 5-pointed star)

8. COMPLICATIONS (in detail)

A. Ascites

• Most common complication (occurs in ~50% of patients within 10 years)
• Mechanism: Portal hypertension → splanchnic vasodilation (NO-mediated) → reduced effective arterial volume → RAAS + ADH activation → Na and water retention → peritoneal fluid accumulation; worsened by hypoalbuminaemia (low oncotic pressure)
• Diagnosis: SAAG (serum-ascites albumin gradient); SAAG ≥1.1 g/dL = portal hypertension
• Management:
  • Salt restriction (<2 g/day sodium)
  • Spironolactone (100-400 mg/day) ± furosemide (40-160 mg/day)
  • Large volume paracentesis (LVP) for tense ascites + albumin infusion 8 g per litre removed (for volumes >5 L)
  • TIPS (transjugular intrahepatic portosystemic shunt) for refractory ascites

B. Spontaneous Bacterial Peritonitis (SBP)

• Acute infection of ascitic fluid; no identifiable surgical source of infection
• Organisms: E. coli and Klebsiella (most common); gut translocation
• Diagnosis: Ascitic fluid PMN count >250 cells/mm³
• Presentation: Fever, abdominal pain, or unexplained deterioration (often subtle)
• Treatment: Cefotaxime 2 g IV every 8 hours for 5 days; albumin 1.5 g/kg on day 1, 1 g/kg on day 3 (prevents HRS)
• Secondary prophylaxis: Norfloxacin 400 mg/day (lifelong)
• Ascitic PMN >250 cells/mm³ = treat; do NOT wait for culture

C. Variceal Haemorrhage

• Oesophageal and gastric varices form when HVPG >10-12 mmHg
• Upper GI bleeding carries 10-15% mortality per episode
• Acute management:
  • Terlipressin (or octreotide/somatostatin) - vasoconstrictors to reduce portal pressure
  • IV antibiotics (ceftriaxone) - reduces bacterial infection and rebleeding
  • Endoscopic band ligation (EVL) - first-line for oesophageal varices
  • Balloon tamponade (Sengstaken-Blakemore tube) if bleeding not controlled
  • TIPS for refractory bleeding
• Primary prevention (before first bleed): Non-selective beta-blockers (propranolol, carvedilol, nadolol) reduce portal pressure; or EVL
• Secondary prevention: Combination of EVL + NSBB

D. Hepatic Encephalopathy (HE)

• Mechanism: Impaired liver detoxification → elevated blood ammonia → astrocyte swelling, cerebral oedema, neurotransmitter imbalance (increased GABA-A receptor activity, glutamate toxicity)
• Precipitants: GI bleeding, infection (SBP), hypokalaemia, constipation, dehydration, sedative drugs, renal failure, excess dietary protein
• Grades (West Haven Criteria):

  Grade	Features
  I	Mild confusion, sleep disturbance, impaired concentration
  II	Drowsiness, inappropriate behaviour, disorientation, asterixis
  III	Somnolence but rousable, gross disorientation, marked asterixis
  IV	Coma - unresponsive

• Treatment:
  • Identify and correct precipitants
  • Lactulose 30-60 g/day (acidifies colon → traps NH4+, reduces ammonia absorption; target 2-3 soft stools/day)
  • Rifaximin 400 mg every 8 hours (non-absorbable antibiotic reducing ammonia-producing gut flora)
  • Branched-chain amino acids (BCAA) IV infusion shown to have benefit
  • Dietary protein: do NOT restrict; give adequate protein (1.2-1.5 g/kg/day); preference for vegetable/dairy protein

E. Hepatorenal Syndrome (HRS)

• Renal failure occurring in advanced cirrhosis with ascites, without intrinsic kidney disease
• Mechanism: Profound splanchnic vasodilation → renal vasoconstriction → reduced GFR; rising creatinine
• HRS-1 (acute, rapidly progressive - previously AKI): creatinine doubles to >2.5 mg/dL within 2 weeks; median survival days-weeks without treatment
• HRS-2 (subacute, resistant ascites): creatinine 1.5-2.5 mg/dL; months
• Treatment: Terlipressin + albumin; TIPS; liver transplantation is definitive
• Increasing creatinine in liver failure = very poor prognostic sign; MAP is an independent predictor of mortality

F. Hepatocellular Carcinoma (HCC)

• All cirrhotic patients are at risk regardless of aetiology
• Incidence 1-5% per year in cirrhosis
• Surveillance: Liver ultrasound + AFP every 6 months
• Diagnosis: CT/MRI with contrast (arterial enhancement + portal-phase washout = diagnostic)
• Treatment: Curative (resection, ablation, transplant - Milan criteria) vs palliative (TACE, sorafenib)

G. Hepatic Hydrothorax

• Pleural effusion (usually right-sided) without cardiac/pulmonary disease
• Ascitic fluid passes through diaphragmatic defects
• Treat underlying ascites; TIPS if refractory

H. Hepatopulmonary Syndrome (HPS)

• Intrapulmonary vascular dilation → V/Q mismatch, hypoxaemia
• Platypnoea-orthodeoxia (worse when upright, better when supine) - opposite of orthopnoea
• Treatment: O₂ supplementation; liver transplantation is curative

I. Portopulmonary Hypertension

• Pulmonary arterial hypertension occurring in portal hypertension
• Dyspnoea, right heart failure
• Managed with pulmonary vasodilators; contraindication to transplant if severe

J. Coagulopathy

• Reduced synthesis of all clotting factors (except Factor VIII and vWF)
• Prolonged PT/INR; thrombocytopenia from hypersplenism
• Paradoxically: also hypercoagulable states (portal vein thrombosis) because protein C and S also fall

K. Other Complications

• Malnutrition and sarcopenia - universal; increased resting energy expenditure despite reduced fat and muscle mass
• Bone disease (hepatic osteodystrophy) - osteoporosis/osteomalacia from vitamin D malabsorption
• Infection - impaired phagocytic activity of the RES; bacterial infections (pneumonia, UTI, cellulitis, SBP, bacteraemia) are common and often the terminal event
• Hypersplenism - pancytopaenia from splenic sequestration
• Adrenal insufficiency - "hepatoadrenal syndrome"
• Erectile dysfunction

9. INVESTIGATIONS

Bloods

Non-Invasive Fibrosis Markers

• FIB-4 score (age × AST / platelets × √ALT)
• APRI score (AST/platelet ratio index >2 suggests cirrhosis)
• Transient elastography (FibroScan) - measures liver stiffness; superior to APRI; now preferred non-invasive method

Imaging

• Ultrasound: Nodular liver surface, splenomegaly, ascites, collateral vessels; Doppler for portal vein flow and portal hypertension
• CT / MRI: Better assessment of liver architecture, HCC screening, portal vein thrombosis
• Upper GI endoscopy: Surveillance for oesophageal varices

Liver Biopsy (Gold Standard for Staging)

• Percutaneous, transjugular (if coagulopathy/ascites), or laparoscopic
• Masson trichrome stain highlights collagen/fibrosis in blue
• Gives aetiology, activity (inflammation), and stage (fibrosis grade)
• Now often deferred in favour of non-invasive methods

Prognostic Scoring

10. LIFESTYLE MEASURES

11. TREATMENT

A. Treat the Underlying Cause (Disease-Modifying)

B. Manage Portal Hypertension

• Non-selective beta-blockers (NSBBs): Propranolol 40-80 mg BD or Carvedilol 6.25-12.5 mg OD; reduce cardiac output and splanchnic vasodilation; primary prevention of variceal haemorrhage; also used for secondary prevention
• TIPS (Transjugular Intrahepatic Portosystemic Shunt): Creates a shunt between portal and hepatic vein; reduces portal pressure; used for:
  • Refractory ascites
  • Refractory variceal bleeding
  • HRS type 1
  • Risk of worsening HE post-TIPS (contraindicated in grade III-IV HE)

C. Manage Ascites

• Salt restriction + diuretics (spironolactone first-line ± furosemide)
• LVP for tense ascites + albumin replacement
• TIPS for refractory ascites
• Avoid: ACE inhibitors, ARBs, NSAIDs (worsen renal function)

D. Prevent and Treat Infections

• Prophylactic antibiotics: Norfloxacin for secondary SBP prophylaxis; consider primary prophylaxis in high-risk patients (ascitic protein <1.5 g/dL with renal dysfunction)
• Vaccinations (see lifestyle section)
• Low threshold to investigate and treat infections

E. Treat Hepatic Encephalopathy

• Lactulose + rifaximin (as above)
• Correct precipitants
• BCAA supplementation
• Zinc supplementation (cofactor for urea cycle enzymes)

F. Treat Coagulopathy

• For active bleeding: Cryoprecipitate preferred over FFP (replaces fibrinogen + coagulation factors); platelet transfusion (target >50,000 before procedures)
• Elevated INR alone is NOT a contraindication to paracentesis
• Vitamin K: useful only if cholestatic cause (fat-soluble vitamin malabsorption); does NOT help in hepatocellular failure

G. Liver Transplantation - Definitive Treatment

• Indicated for:
  • MELD score ≥15 (risk of death without transplant exceeds risk with it)
  • Refractory ascites
  • Spontaneous bacterial peritonitis (history of)
  • HRS type 1 (with terlipressin as bridge)
  • Recurrent variceal haemorrhage
  • HCC within Milan criteria (single ≤5 cm or up to 3 nodules ≤3 cm, no vascular invasion)
  • HE grade III-IV unresponsive to treatment
• Contraindications: active alcohol/substance use, extrahepatic malignancy, severe cardiopulmonary disease, uncontrolled sepsis
• 5-year survival post-transplant: ~70-75%

Summary: The Cirrhosis "Web"

Chronic liver injury (alcohol/virus/fat/autoimmune)
         ↓
Hepatocyte necrosis → Kupffer cell activation → TGF-β, PDGF
         ↓
Hepatic stellate cell activation → Myofibroblast
         ↓
Collagen deposition → Bridging fibrosis → Cirrhosis
         ↙                      ↘
Hepatocellular failure        Portal hypertension
(↓albumin, ↑INR,           (varices, ascites, HE,
jaundice, HE, HRS)           SBP, HRS)
         ↘                      ↙
            Death or Liver Transplant

Transverse Myelitis (TM) - Brief Summary

Definition

Aetiology / Associations

Pathogenesis

• Unknown mechanism; presumed autoimmune
• Postinfectious cases: molecular mimicry or bystander immune activation
• Anti-AQP4 antibodies attack water channels on astrocyte foot processes at the blood-brain barrier → inflammation and necrosis
• Thoracic cord most commonly affected (60-70%); cervical cord rarely
• Progression: 66% reach maximal deficit within 24 hours; some progress over days to weeks

Clinical Features - The Classic Triad

• Back pain at the level of the lesion (common early symptom)
• Low-grade fever (especially post-infectious)
• Abnormalities are typically bilateral but may be asymmetrical

Investigations

Differential Diagnosis

• Multiple sclerosis (partial/asymmetric cord lesion)
• Spinal cord compression (disc, tumour, haematoma) - must rule out urgently with MRI
• Spinal epidural abscess (SEA)
• Spinal cord infarction (vascular)
• Vitamin B12 deficiency (subacute combined degeneration)
• Primary/metastatic spinal neoplasm

Treatment

TM vs. MS Lesion - Key Distinction

Prognosis

• Most patients with idiopathic TM have at least partial recovery, beginning within 1-3 months; maximal improvement by 3-6 months
• 30% - good recovery (near-normal function)
• 25% - fair recovery (moderate disability)
• 30% - poor outcome (severe disability)
• 15% mortality at 5 years
• Poor prognostic signs: rapid onset to nadir, complete deficits, LETM, NMOSD, back pain at onset
• Risk of conversion to MS: similar to optic neuritis - cumulative probability builds over 2-5 years