11.3 Cirrhosis & Complications of Portal Hypertension

Cirrhosis is the irreversible end-stage histopathological consequence of chronic liver injury, characterized by diffuse nodular parenchymal regeneration surrounded by dense fibrous septa. Decompensated cirrhosis—defined by the emergence of ascites, variceal haemorrhage, hepatic encephalopathy, or hepatorenal syndrome—carries high short-term mortality and requires rigorous mastery of physiological mechanisms and emergency management protocols.

---

1. Cirrhosis Assessment & Prognostic Scoring

Pathophysiology of Portal Hypertension

Portal hypertension is defined by an elevation in the Hepatic Venous Pressure Gradient (HVPG >5 mmHg), calculated as the wedged hepatic venous pressure minus the free hepatic venous pressure:

• Clinically Significant Portal Hypertension (CSPH): Defined as HVPG >=10 mmHg, at which threshold portosystemic collateral vessels (gastro-oesophageal varices, caput medusae) form and ascites can accumulate.
• Variceal Bleeding Risk: Escalate significantly when HVPG >=12 mmHg.
• Underlying Haemodynamic Drivers:
  1. Increased Intrahepatic Resistance: Fixed structural architectural distortion (sinusoidal fibrosis, collagen deposition in the space of Disse, regenerative nodules) combined with active dynamic sinusoidal vasoconstriction (deficiency of endothelial nitric oxide [eNOS] and overproduction of endothelin-1 and thromboxane A2 by activated hepatic stellate cells).
  2. Hyperdynamic Splanchnic Circulation: Excessive endothelial production of nitric oxide (NO) within the splanchnic arterial bed induces profound splanchnic arterial vasodilation, increasing portal venous inflow into the obstructed hepatic vascular bed.

Child-Pugh Score (Child-Turcotte-Pugh [CTP])

Stratifies liver functional reserve and perioperative mortality based on 5 parameters (each scored 1, 2, or 3 points):

• Child-Pugh Class A (5–6 points): Well-compensated disease; 1-year survival ~100%, 2-year survival ~85%.
• Child-Pugh Class B (7–9 points): Significant functional compromise; 1-year survival ~80%, 2-year survival ~60%.
• Child-Pugh Class C (10–15 points): Decompensated disease; 1-year survival ~45%, 2-year survival ~35%.

Model for End-Stage Liver Disease (MELD / MELD-Na)

• Formula & Mechanics: A continuous mathematical model calculated using natural logarithms of four objective laboratory variables: Serum Bilirubin, Serum Creatinine, International Normalized Ratio (INR), and Serum Sodium (MELD-Na).
• Clinical Purpose: Primary tool used internationally for liver transplant organ allocation and predicting short-term (90-day) waitlist mortality.

---

2. Ascites & Spontaneous Bacterial Peritonitis (SBP)

Pathophysiology of Ascites Formation

Splanchnic arterial vasodilation decreases effective arterial blood volume (EABV), triggering baroreceptor unloading. This provokes marked neurohumoral activation of the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system (SNS), and non-osmotic secretion of arginine vasopressin (ADH). Avid renal tubular retention of sodium and water, combined with reduced oncotic pressure (hypoalbuminaemia) and elevated sinusoidal hydrostatic pressure, forces transudation of fluid across the hepatic capsule into the peritoneal space.

Diagnostic Paracentesis & SAAG

Diagnostic paracentesis is mandatory in every cirrhotic patient presenting with new-onset ascites or admitted to hospital with clinical decompensation (fever, abdominal pain, encephalopathy, worsening renal function, or GI bleed).

• Serum-Ascites Albumin Gradient (SAAG): $\text{SAAG} = \text{Serum Albumin} - \text{Ascitic Fluid Albumin} \quad (\text{measured simultaneously})$
  • High SAAG (>=11 g/L): Diagnostic of portal hypertension (accuracy >97%).
    • Ascitic Fluid Total Protein <25 g/L: Cirrhotic ascites (sinusoidal capillarization prevents albumin leakage).
    • Ascitic Fluid Total Protein >=25 g/L: Cardiac ascites (congestive cardiac failure, constrictive pericarditis; intact sinusoids permit protein-rich hepatic lymph to enter peritoneum) or Budd-Chiari syndrome (early stage).
  • Low SAAG (<11 g/L): Excludes portal hypertension; indicates non-portal hypertensive peritoneal pathology:
    • Peritoneal carcinomatosis (ovarian, gastric, colon cancer)
    • Tuberculous peritonitis (elevated ascitic adenosine deaminase [ADA])
    • Nephrotic syndrome (massive urinary protein loss)
    • Pancreatic ascites (massively elevated ascitic amylase)
    • Biliary peritonitis / chylous ascites

Spontaneous Bacterial Peritonitis (SBP)

• Definition & Pathogenesis: Bacterial infection of ascitic fluid occurring without an identifiable surgically treatable intra-abdominal source. Driven by bacterial translocation from the intestinal lumen into mesenteric lymph nodes, followed by haematogenous seeding into ascitic fluid with deficient antibacterial opsonic activity.
• Diagnostic Criteria:
  • Ascitic fluid polymorphonuclear leukocyte (neutrophil) count >=250/mm3 (>=0.25 x 10^9/L).
  • Exam Rule: Ascitic fluid culture into blood culture bottles is positive in only ~50% of cases (culture-negative neutrocytic ascites). Antimicrobial therapy must NEVER be delayed while awaiting culture results!
• Microbiology: Monomicrobial infection driven by enteric Gram-negative bacilli: Escherichia coli (~50%), Klebsiella pneumoniae (~20%), followed by Gram-positive cocci (Streptococcus pneumoniae, Enterococcus species). Polymicrobial flora or high protein (>10 g/L), low glucose (<2.8 mmol/L), and high LDH suggests secondary bacterial peritonitis (gut perforation), mandating urgent CT imaging.
• Emergency Treatment:
  • Antimicrobial Therapy: First-line empirical therapy is intravenous cefotaxime (2 g TDS) or co-amoxiclav (1.2 g TDS) for 5–7 days. (Piperacillin-tazobactam or meropenem if nosocomial or in septic shock).
  • Intravenous Albumin Protocol: Human Albumin Solution (20%) administered at 1.5 g/kg body weight within 6 hours of diagnosis, followed by 1.0 g/kg on day 3. Expands effective arterial volume, suppresses systemic nitric oxide release, prevents precipitous renal hypoperfusion, and slashes the incidence of hepatorenal syndrome from 30% to 10%, reducing in-hospital mortality from 29% to 10% (Sort et al. trial).
• Antimicrobial Prophylaxis:
  • Secondary Prophylaxis: Mandatory after a single episode of SBP; lifelong oral ciprofloxacin (500 mg daily) or co-trimoxazole (trimethoprim-sulfamethoxazole 160/800 mg daily).
  • Primary Prophylaxis: Indicated in cirrhotic patients with acute upper GI bleeding (IV ceftriaxone 1 g daily for 7 days), or in patients with ascitic total protein <15 g/L accompanied by severe liver dysfunction (Child-Pugh >=9 and bilirubin >=50 umol/L) or renal impairment (creatinine >=106 umol/L, urea >=10.7 mmol/L, or sodium <=130 mmol/L).

---

3. Hepatorenal Syndrome (HRS)

Pathophysiology

Hepatorenal syndrome is a functional, prerenal form of acute kidney injury developing in patients with advanced cirrhosis and portal hypertension. Massive splanchnic arterial vasodilation triggers extreme systemic arterial underfilling, unleashing maximal compensatory activation of the renin-angiotensin system, sympathetic nervous system, and endothelin. This provokes intense, sustained intrarenal vasoconstriction and cortical hypoperfusion despite completely intact, structurally normal renal parenchyma.

Classification of HRS

• HRS-AKI (formerly Type 1 HRS): Rapidly progressive acute kidney injury defined by an increase in serum creatinine of >=50% within 48 hours to >=26.5 umol/L (0.3 mg/dL) or a doubling of baseline serum creatinine within 2 weeks. Frequently precipitated by SBP, large-volume paracentesis without albumin, or GI bleeding. Untreated median survival is <2 weeks.
• HRS-CKD (formerly Type 2 HRS): Insidious, slowly progressive renal decline (eGFR <60 mL/min/1.73m2 for >3 months); characteristically associated with refractory ascites.

International Club of Ascites (ICA) Diagnostic Criteria for HRS-AKI

All of the following criteria must be satisfied:

1. Diagnosis of cirrhosis with ascites.
2. Diagnosis of AKI according to ICA-AKI criteria (creatinine rise >=26.5 umol/L within 48 h, or >=50% increase from baseline within 7 days).
3. No response after at least 48 hours of diuretic withdrawal and intravenous plasma volume expansion with Human Albumin Solution (1 g/kg body weight/day, up to a maximum of 100 g/day).
4. Absence of circulatory shock.
5. No current or recent exposure to nephrotoxic medications (NSAIDs, aminoglycosides, iodinated radiocontrast).
6. Absence of macroscopic signs of structural kidney injury: absence of significant proteinuria (<500 mg/day), absence of microhaematuria (<50 RBCs per high-power field), and normal bilateral renal ultrasonography.

Pharmacological Management

• First-Line Medical Therapy: Intravenous terlipressin (synthetic vasopressin V1 receptor agonist; continuous infusion starting at 2 mg/day up to 12 mg/day, or IV bolus 1 mg 4–6 hourly) combined with intravenous 20% albumin (20–40 g/day). Terlipressin induces selective splanchnic arterial vasoconstriction, shifting splanchnic pooling back into the systemic circulation, increasing effective circulating arterial volume, suppressing endogenous neurohumoral vasoconstrictors, and restoring renal cortical blood flow.
• Alternative (ICU setting): Intravenous noradrenaline continuous infusion (titrated to raise mean arterial pressure by >=15 mmHg) plus albumin.
• Definitive Treatment: Orthotopic liver transplantation. Reverses the portal hypertension and splanchnic vasodilation; intrinsic renal function typically normalizes post-transplant.

---

4. Hepatic Encephalopathy (HE)

Pathophysiological Mechanisms

Hepatic encephalopathy is a reversible neuropsychiatric syndrome resulting from portosystemic shunting (collaterals or radiological TIPS) and hepatocellular failure. Nitrogenous neurotoxins absorbed from the gastrointestinal tract bypass hepatic clearance via the urea cycle and enter the cerebral circulation:

1. Ammonia (NH3) Toxicity: Ammonia is generated in the gut from dietary protein catabolism and bacterial urease hydrolysis of urea. Lipid-soluble NH3 crosses the blood-brain barrier.
2. Astrocyte Swelling & Cerebral Oedema: Within cerebral astrocytes, ammonia is detoxified exclusively by glutamine synthetase, which condenses ammonia with glutamate to form glutamine. Accumulation of intracellular glutamine exerts a potent osmotic effect, drawing water into astrocytic foot processes (cytotoxic brain oedema), inducing mitochondrial dysfunction, generating reactive oxygen species, and disturbing blood-brain barrier integrity.
3. Neurotransmission Alterations: Ammonia and neurosteroids upregulate the inhibitory GABA-A / benzodiazepine receptor complex, enhancing GABAergic tone and causing central nervous system depression.

West Haven Clinical Staging of Hepatic Encephalopathy

• Grade 1: Mild confusion, shortened attention span, euphoria or anxiety, sleep rhythm inversion (daytime somnolence, nocturnal insomnia), impaired addition and subtraction.
• Grade 2: Lethargy, apathy, mild disorientation for time, obvious personality changes, inappropriate behaviour, easily elicitable asterixis (flapping tremor).
• Grade 3: Somnolence to semi-stupor, responsive to verbal commands, marked confusion, gross disorientation for place and time, bizarre behaviour, hyperreflexia, clonus, positive Babinski sign.
• Grade 4: Coma (unresponsive to verbal or noxious stimuli), decerebrate posturing, flaccidity.

Precipitating Factors (The Core Diagnostic Priority)

Hepatic encephalopathy rarely occurs spontaneously in stable cirrhosis. A rigorous search for triggers is essential:

• Constipation: Prolonged colonic transit time enhances bacterial degradation of stool and ammonia absorption.
• Gastrointestinal Haemorrhage: Upper GI bleeding delivers a massive protein load (haemoglobin) to the intestinal lumen, metabolized into massive ammonia surges.
• Infections: Spontaneous bacterial peritonitis, urinary tract infection, pneumonia; systemic inflammation and TNF-alpha enhance cerebral sensitivity to ammonia.
• Electrolyte & Acid-Base Imbalances:
  • Hypokalaemia: Promotes renal tubular ammoniagenesis and causes compensatory cellular extrusion of potassium in exchange for hydrogen ions, producing intracellular acidosis and systemic alkalosis.
  • Metabolic Alkalosis: Converts polar ammonium ($NH_4^+$) into non-polar, lipid-soluble ammonia ($NH_3$) [$NH_4^+ \rightleftharpoons NH_3 + H^+$], promoting rapid diffusion across the blood-brain barrier.
• Dehydration & Prerenal Azotaemia: Over-diuresis reduces renal excretion of urea and promotes metabolic alkalosis.
• Sedatives: Benzodiazepines, opioids, z-drugs (directly potentiate GABAergic neurotransmission).
• TIPS Insertion: Shunts portal blood directly into systemic circulation; ~30% develop new or worsening HE.

Management Strategy

1. Identify & Treat Precipitating Factors: Discontinue diuretics, treat infection with antibiotics, eradicate GI bleeding, and correct hypokalaemia.
2. First-Line Pharmacotherapy — Lactulose:
   • Mechanism: Synthetic non-absorbable disaccharide fermented by colonic bacteria into lactic and acetic acid, reducing colonic luminal pH (<5.0). Acidification protonates gaseous ammonia ($NH_3$) into polar ammonium ($NH_4^+$), which is membrane-impermeant and trapped in the bowel lumen for faecal evacuation ("ammonia trapping"). Also exerts an osmotic cathartic effect.
   • Dosage & Titration: Oral or NG lactulose (20–30 mL TDS/QDS), titrated meticulously to achieve 2 to 3 soft bowel motions per day. Clinical warning: Over-titration causes severe diarrhoea, dehydration, hypernatraemia, and paradoxical worsening of encephalopathy!
3. Second-Line / Secondary Prevention — Rifaximin:
   • Mechanism: Oral, non-absorbable broad-spectrum rifamycin derivative (<0.4% systemic absorption). Modulates gut microbiota by eradicating ammonia-producing enteric flora.
   • Indication: Added to lactulose at a dose of 550 mg twice daily for secondary prevention in patients who have experienced >=2 episodes of overt hepatic encephalopathy.