Complications of cirrhosis: HE, HRS and varices

• Cirrhosis is not just scarring: portal pressure rises, blood shunts past the liver, and the liver stops making the proteins on which haemostasis and kidney perfusion depend.
• Hepatic encephalopathy (HE) is a reversible brain syndrome from ammonia and other gut-derived toxins; it starts with subtle attention and sleep problems and can progress to coma.
• Hepatorenal syndrome (HRS) is functional kidney failure: the kidneys themselves are structurally normal, but splanchnic vasodilation has starved them of perfusion.
• Varices are collateral veins at the gastro-oesophageal junction; their bleeding is a medical emergency with high six-week mortality.
• Coagulopathy of cirrhosis is “rebalanced”: both clotting and anticoagulant factors fall, so the INR is prolonged yet patients can clot or bleed.
• In every case the key is to treat the precipitant (infection, bleeding, constipation, dehydration, drugs), not only the end-organ sign.

By the end of this page you should be able to:

1. Explain the pathogenesis of hepatic encephalopathy, hepatorenal syndrome, varices and coagulopathy from portal hypertension and hepatic failure.
2. Grade hepatic encephalopathy with the West Haven criteria and list its precipitants and differential diagnoses.
3. Apply the International Club of Ascites (ICA) criteria for hepatorenal syndrome and choose first-line therapy.
4. Screen for and prevent first variceal bleeding, and manage an acute variceal bleed step by step.
5. Interpret coagulation tests in cirrhosis and avoid unnecessary plasma transfusion before procedures.
6. Plan low-resource and special-group management, and state the prognosis of each complication.

Cirrhosis is diffuse fibrosis with nodular regeneration that distorts the liver architecture and obstructs portal venous inflow. Portal hypertension is a hepatic venous pressure gradient (HVPG) of 5 mmHg or more; clinically significant portal hypertension (CSPH) is an HVPG of 10 mmHg or more and marks the stage at which varices, ascites, encephalopathy and renal dysfunction become likely.^[1] This topic deals with four of those decompensations and uses the AASLD/EASL terminology compensated advanced chronic liver disease (cACLD) for patients in whom cirrhosis is inferred from non-invasive tests rather than biopsy.^[4]

Hepatic encephalopathy (HE) is reversible cerebral dysfunction caused by liver failure and/or portosystemic shunting.^[2] Type A occurs with acute liver failure, type B with a portosystemic shunt without intrinsic liver disease, and type C is the common cirrhotic form. Overt HE produces asterixis, disorientation, somnolence or coma. Minimal (covert) HE causes subtle deficits in attention, executive function, sleep, balance and driving performance.

Hepatorenal syndrome–acute kidney injury (HRS-AKI) is a functional AKI in a patient with cirrhosis and ascites: the kidneys are structurally intact, but intense renal vasoconstriction follows splanchnic vasodilation.

Varices are dilated portosystemic collateral veins, most often at the distal oesophagus and proximal stomach. They are graded endoscopically as small or large.^[7]

Coagulopathy of cirrhosis is not a single deficiency. The liver makes fewer clotting factors II, V, VII, IX, X and XI, but also fewer anticoagulant proteins (proteins C and S, antithrombin), while factor VIII and von Willebrand factor rise because hepatic clearance falls.^[6] The result is rebalanced but fragile haemostasis with both bleeding and thrombosis risk.

Hepatic encephalopathy affects up to 40% of patients with cirrhosis within five years and is covert in 25 to 80% of them depending on Child class.^[3] In an older Korean series varices were found at screening endoscopy in 52% of patients with cirrhosis.^[7] Incidence of a first variceal bleed is about 12% per year overall, 5% with small varices and 15% with large varices.^[7] Hepatorenal syndrome develops in about 8% of patients with ascites annually and, once established, has a median survival of about two weeks without definitive treatment.^[3]

Decompensation is the turning point: median survival after incident overt HE is about 0.92 years and after ascites about 1.1 years.^[3] Six-week mortality after a variceal bleed is about 17.7%.^[3] These figures are blunt population averages; individual outcomes depend on age, comorbidity and treatment of the underlying cause.

Most cirrhosis is due to alcohol use disorder, chronic hepatitis B or C, or metabolic dysfunction-associated steatotic liver disease, often overlapping.^[3] Superimposed liver injury (alcoholic hepatitis, acute viral hepatitis, HBV flare, drug-induced liver injury) is the commonest precipitant of a sudden decompensation.^[1] Bacterial infection, major surgery and hepatocellular carcinoma can also precipitate decompensation in a patient with CSPH.^[1]

Increased intrahepatic resistance raises portal pressure. Splanchnic vasodilation (nitric oxide) and hyperdynamic circulation further increase portal inflow. When portal pressure rises above about 10 mmHg, collaterals open. Ammonia and other toxins bypass hepatic clearance, so the liver fails to detoxify them.^[2]

The liver clears ammonia generated by gut bacteria and dietary protein through the urea cycle. In cirrhosis, hepatocellular failure and portosystemic shunting let ammonia accumulate. Ammonia crosses the blood-brain barrier; astrocytes convert it to glutamine, which causes osmotic swelling, oxidative stress and altered neurotransmission.^[2] Dysbiosis and increased intestinal permeability drive this process, and inflammation means HE can develop at modest ammonia levels during infection.^[2][3]

Splanchnic arterial vasodilation produces effective arterial hypovolaemia. Baroreceptor activation triggers the renin-angiotensin-aldosterone system, sympathetic nerves and vasopressin, causing intense renal cortical vasoconstriction. The kidneys are structurally normal and functional. Superimposed insults (volume depletion, infection, bleeding, nephrotoxins, large-volume paracentesis without albumin) convert compensated haemodynamics into overt AKI.^[2]

Collateral veins develop where portal and systemic circulations communicate, driven by portal pressure. Wall tension depends on pressure and radius, so larger, thinner and more pressured varices bleed. Gastric varices may bleed at portal pressures as low as 6 to 8 mmHg because they empty through gastrorenal shunts.^[4]

Reduced hepatocellular mass lowers synthesis of procoagulant factors (II, V, VII, IX, X, XI) and of anticoagulant proteins (proteins C and S, antithrombin), while factor VIII and von Willebrand factor rise. Platelet counts fall from hypersplenism and reduced thrombopoietin, but increased von Willebrand factor compensates partly. Fibrinolysis and dysfibrinogenemia worsen with advancing disease, and thrombocytopenia is usually moderate (counts often below 100,000 per mm3, rarely under 30,000 to 40,000).^[5][6] The net picture is “rebalanced” haemostasis: prolonged INR and aPTT, yet normal or increased thrombin generation and a genuine risk of venous thromboembolism.^[5][6]

The West Haven criteria grade HE 0 to 4.^[3] Most authorities treat grade 2 or more as overt HE; minimal HE is grade 0 to 1.

Minimal HE increases the risk of motor vehicle crashes.^[3] Because mental state genuinely fluctuates, a patient who has had overt HE, or has minimal HE with impaired attention and reaction time, should not drive until clinically recovered and formally reassessed.^[3]

Precipitants of HE include gastrointestinal bleeding, infection (especially spontaneous bacterial peritonitis, urinary and respiratory infection), constipation, diarrhoea/dehydration, hypokalaemia, renal impairment, hyponatraemia, diuretic overuse, benzodiazepines/opioids/sedatives, alcohol, transjugular intrahepatic portosystemic shunt (TIPS) or surgical shunts, and excessive dietary protein in combination with any of the above.^[1][2]

Differential diagnosis of altered mental state in cirrhosis: hypoglycaemia, hyponatraemia, azotaemia, alcohol withdrawal or intoxication, sedative/opioid effect, hypoxia/hypercapnia (hepatopulmonary syndrome), Wernicke-Korsakoff syndrome, intracranial haemorrhage or infection, non-convulsive status, and sepsis.^[2] Asterixis is not HE-specific; renal failure and respiratory failure also cause it.

Patients present with rising creatinine, oliguria and sodium retention in the setting of cirrhosis and ascites. The urine is bland and the sodium is low. Crucially there are no signs of shock and no nephrotoxic insult. The sediment is inactive: little or no proteinuria and no microscopic haematuria, and renal ultrasound is normal.^[2]

HRS-AKI criteria (International Club of Ascites, 2014)^[2]:

1. Cirrhosis with ascites.
2. AKI by ICA criteria: rise in serum creatinine of at least 0.3 mg/dL within 48 hours or at least 50% from baseline within 7 days.
3. No response after 2 days of diuretic withdrawal and volume expansion with albumin 1 g/kg.
4. No shock.
5. No current or recent nephrotoxic drug use.
6. No structural kidney disease: proteinuria under 500 mg/day, no more than 50 red cells per high-power field, normal renal ultrasound.

Distinguishing HRS from prerenal azotaemia (responds to fluids) and acute tubular necrosis (granular casts, high sodium, high fractional excretion of sodium, tubular injury biomarkers such as neutrophil gelatinase-associated lipocalin) is essential; the three can look similar early.^[2]

Varices cause no symptoms until they bleed. Bleeding presents as haematemesis, melaena or haematochezia with hypovolaemia. Risk of a first bleed rises with size, wall thickness, red wale (cherry-red) signs and decompensated (Child-Pugh B/C) cirrhosis; large varices in Child-Pugh C carry the highest short-term risk.^[4] Patients with portal hypertensive gastropathy present with chronic occult bleeding or acute haemorrhage. Gastric varices (especially cardiofundal GOV2 and isolated GV1) bleed less often but more heavily and at lower portal pressure.^[4]

Routine blood tests show prolonged INR and aPTT without bleeding. Clinically, bleeding is usually from a high-pressure source (varices, portal hypertensive gastropathy) rather than from the coagulopathy itself; thrombosis (portal vein, deep veins) can also occur.^[5][6]

HE is a clinical diagnosis; serum ammonia is not required and correlates poorly with grade. Ammonia may support the diagnosis when high, but normal values do not exclude HE and high values occur without encephalopathy (for example, during constipation or high protein intake). Imaging of the brain is used when focal signs, head injury or diagnostic doubt exist. Psychometric tests diagnose minimal HE: the psychometric hepatic encephalopathy score (PHES), the EncephalApp Stroop test, and simple bedside tools such as the animal naming test.^[1]

HRS is diagnosed by the criteria above; creatinine is itself a poor marker of renal function in cirrhosis. Biomarkers (urinary NGAL, cystatin C) may help distinguish HRS from acute tubular necrosis but are not universally available.^[2]

Varices are diagnosed by upper gastrointestinal endoscopy. Screening is recommended at cirrhosis diagnosis, then every 2 to 3 years if compensated and disease is controlled, every 1 to 2 years if decompensated or disease uncontrolled.^[7] Non-invasive risk stratification: a patient who is not a candidate for non-selective beta-blockers should undergo variceal screening endoscopy if liver stiffness is at least 20 kPa or the platelet count is at most 150,000/mm3; if liver stiffness is 25 kPa or more, CSPH is likely.^[1]

Coagulation assessment in cirrhosis includes full blood count, INR, aPTT and fibrinogen. Alcohol-induced or cholestatic patients need vitamin K status assessment where deficiency is plausible. Severity scores (Child-Pugh, MELD/MELD-Na) predict mortality and guide thresholds for TIPS futility.^[3]

The first step is to find and treat the precipitant: stop constipating drugs, give fluids, correct potassium, start antibiotics for suspected infection, control bleeding.^[1][2]

• Lactulose is first-line. Give 10 to 20 g orally two or three times daily (or via nasogastric tube/rectal enema when the patient cannot swallow) and titrate to two to three soft stools daily. Over-treatment causes diarrhoea, hypovolaemia and worsening renal function.^[3]
• Rifaximin 550 mg twice daily is added for recurrent overt HE, intolerance to lactulose, or prophylaxis around elective TIPS (start two weeks before).^[1][2]
• Nutrition should not be restricted: 1.25 g of protein per kilogram of actual body weight daily, with a late-evening snack of over 250 kcal, and correction of zinc and vitamin deficiencies.^[3]
• Branched-chain amino acids and zinc are reasonable adjuncts in malnourished patients; L-ornithine L-aspartate, glycerol phenylbutyrate and sodium benzoate are second-line options.^[2]
• Refractory HE from large portosystemic shunts may respond to shunt embolisation.^[2]

Grade 3 to 4 HE needs airway protection, with lactulose by enema and intravenous fluids.^[1]

Prevention is as important as treatment: give albumin with spontaneous bacterial peritonitis, avoid nephrotoxins (NSAIDs, aminoglycosides, contrast exposure), and give albumin after large-volume paracentesis.^[2][3]

For suspected HRS-AKI: withdraw diuretics, expand volume with albumin 1 g/kg for two days, then reassess. If criteria persist:

• Terlipressin 0.85 mg intravenously every 6 hours (increase per local label if no response), combined with albumin, is first-line where available.^[3]
• Norepinephrine 0.5 to 3 mg per hour by intravenous infusion is the alternative in intensive care.^[3]
• Midodrine plus octreotide is weaker evidence and mainly used when terlipressin is unavailable.^[2]
• Renal replacement therapy (dialysis) as a bridge to liver transplantation.
• TIPS may help selected patients with refractory ascites/renal failure.
• Liver transplantation is definitive; consider combined liver-kidney transplant if renal recovery is unlikely.^[2]

Monitor for respiratory failure with terlipressin: check oxygen saturation before and during treatment and avoid in hypoxia or volume overload; albumin should be used cautiously.^[4]

Screen all patients with cirrhosis. If no varices and disease controlled, repeat endoscopy every 2 to 3 years; if uncontrolled, every 1 to 2 years. Small varices in a high-risk patient (decompensated cirrhosis, red signs) warrant prophylaxis.^[7]

Non-selective beta-blockers (NSBBs) are first-line for CSPH. Carvedilol is preferred: 12.5 mg once daily (start 6.25 mg, increase after three days).^[3][4] Propranolol starts at 40 mg twice daily and can be increased to 160 mg twice daily, aiming for a resting heart rate of 55 beats per minute; nadolol starts at 20 to 40 mg once daily (maximum 160 mg daily without ascites, 80 mg with ascites).^[3][7] Hold NSBBs or reduce the dose if systolic blood pressure falls under 90 mmHg, severe bradycardia, advanced heart block, severe asthma or decompensation with poor perfusion occur.^[4][7]

Where NSBBs are contraindicated or not tolerated, endoscopic band ligation is usedwith repeated sessions until eradication, then surveillance endoscopy.^[7] Gastric varices in high-risk patients (large cardiofundal varices with red wale signs or Child-Pugh B/C) may receive cyanoacrylate in experienced centres; balloon-occluded retrograde or antegrade transvenous obliteration (BRTO/BATO) and TIPS are not used for primary prophylaxis of gastric varices.^[1][4]

This is an emergency requiring airway, haemodynamic and sepsis care.

1. Resuscitation: restrictive transfusion with target haemoglobin 7 to 8 g/dL; avoid over-resuscitation, which raises portal pressure.^[1][4]
2. Vasoactive drug immediately: octreotide 50 micrograms intravenous bolus then 25 to 50 micrograms per hour; or terlipressin 2 mg intravenously every 4 to 6 hours for the first 24 to 48 hours, then 1 mg every 4 to 6 hours.^[4] Continue up to 3 to 5 days (guidelines differ).^[1][4]
3. Antibiotics immediately: ceftriaxone 1 g every 24 hours for up to 5 days (or according to local resistance).^[4][7]
4. Endoscopy within 12 hours (up to 24 hours if unstable): band ligation for oesophageal varices; cyanoacrylate or endoscopic ultrasound-guided coil obliteration for gastric varices.^[4]
5. Pre-emptive TIPS within 24 to 72 hours for Child-Pugh C with score 10 to 13 or Child-Pugh B with score over 7 and active bleeding at index endoscopy.^[1][4]
6. Balloon tamponade or self-expanding metal stent only as a bridge to TIPS or transplantation.
7. Bleeding that fails combined drug and endoscopic therapy is best managed by salvage TIPS.^[1]
8. Proton pump inhibitors should be stopped once a variceal source is confirmed, unless there is another indication.^[4]

Coagulation management in active bleeding: variceal bleeding is driven by portal pressure, not by the INR. Fresh frozen plasma does not correct the coagulopathy and may worsen portal hypertension through volume overload. Platelet counts above 50,000 per mm3 or an INR under 1.5 should not be corrected. Fibrinogen can be corrected to over 100 mg/dL with cryoprecipitate during active bleeding. Recombinant factor VIIa and tranexamic acid are not recommended.^[1][4]

• No routine plasma transfusion before paracentesis, endoscopy or biopsy: conventional tests (INR, aPTT) do not predict procedural bleeding in cirrhosis.^[5]
• A platelet count above 50,000 is generally not corrected before procedures; EASL allows platelet transfusion or thrombopoietin-receptor agonists (such as avatrombopag or lusutrombopag) case by case in high-risk procedures where local haemostasis is not possible and the count is very low.^[5]
• Vitamin K does not reliably correct the INR of cirrhosis, because the problem is reduced hepatocyte synthesis, not vitamin deficiency. Routine vitamin K is not recommended.^[6]
• Anticoagulation is not contraindicated in cirrhosis on approved indications; it may improve outcomes. Direct oral anticoagulants are appropriate in Child-Pugh A and B but not C cirrhosis.^[1]
• Venous thromboembolism prophylaxis should be used as for other hospitalised patients.^[5]
• Prothrombin complex concentrates, recombinant factor VIIa and antifibrinolytics are not routine; factor concentrates have no outcome benefit in this setting and can be thrombogenic.^[5]
• Viscoelastic testing (thromboelastography/ROTEM) can guide resuscitation without more product use, though it is not universally available.^[5]

• Hepatopulmonary syndrome: intrapulmonary vasodilation causing hypoxaemia; bubble (contrast) echocardiography supports diagnosis; liver transplantation is the only definitive therapy.^[3]
• Portopulmonary hypertension: raised pulmonary pressure; requires right-heart assessment and specialist vasodilator therapy and transplant evaluation.^[3]
• Hepatic hydrothorax: pleural effusion in the absence of cardiac disease; managed like ascites, sometimes with TIPS.^[3]
• Cirrhotic cardiomyopathy: subclinical systolic/diastolic dysfunction and prolonged QT, unmasked by stress, infection or TIPS.^[3]
• Hyponatraemia: dilutional; strict fluid management and slow correction to avoid central pontine myelinolysis.^[3]
• Malnutrition and sarcopenia: common and worsen outcomes; aim for 1.25 g of protein per kilogram of actual body weight per day plus micronutrients and exercise.^[3]
• Hepatocellular carcinoma: screen with biannual ultrasound and alpha-fetoprotein in all cirrhosis.^[3]

Child-Pugh and MELD scores stratify risk. The highest-risk single events are variceal bleeding and HRS (median survival about two weeks). Minimal HE independently predicts falls, hospitalisation and death. Transplantation resets the outlook for refractory cases.

Preventing decompensation is the real goal. Treat the underlying cause (antiviral therapy, alcohol abstinence, weight management). For patients with CSPH, NSBBs reduce decompensation and probably improve survival.^[1] Use TE and platelets to decide who needs endoscopy. Prophylactic antibiotics reduce mortality and rebleeding in upper gastrointestinal bleeding and should be standard for all cirrhotic bleeders.^[1][4] Intravenous albumin is indicated for SBP, for large-volume paracentesis and with terlipressin for HRS-AKI.^[1][2]

• Children: cirrhosis is often due to congenital or biliary disease; varices are managed by paediatric specialists, and primary sclerosing cholangitis / transplant pathways differ.
• Pregnancy: variceal management and drug choices need obstetric and hepatology teams; carvedilol and terlipressin require individualised risk assessment.
• Older adults: NSAIDs, sedatives and constipation are common precipitants of both HE and renal injury; drug review is high-yield.
• Acute-on-chronic liver failure (ACLF): grade 3 HE (coma), mechanical ventilation, renal support and infection predominate; nutrition and transplant planning are urgent.

• HE is a clinical diagnosis: the mental status, flapping tremor and clinical context are enough; serum ammonia is helpful only if available.
• Use the cheapest psychometric tools (animal naming test) for minimal HE, or skip testing and focus on driving advice in at-risk patients.
• A stethoscope, clinical assessment and the 12-hour endoscopy target save more lives than unavailable CT scans. Where TE is unavailable, endoscopy is the screening test for varices.^[4]
• Where terlipressin is unavailable, use norepinephrine or midodrine plus octreotide; where banding is unavailable, NSBBs and meticulous avoidance of precipitants still matter.
• Albumin may be unaffordable; prioritise SBP and HRS, and use the 1 g/kg expansion for HRS diagnosis.
• Keep every resected specimen for histology where surgery is available; refer early for transplant.

• CSPH (HVPG over 10 mmHg) is the biological starting point for all four complications.
• Hepatic encephalopathy is reversible; always search for infection, bleeding, constipation, hypokalaemia, drugs and shunts.
• Ammonia is a clue, not a required test, for HE.
• Lactulose is titrated to two to three soft stools; do not starve the patient of protein.
• Hepatorenal syndrome is functional kidney injury; albumin (1 g/kg for up to two days) must precede the diagnosis.
• Terlipressin plus albumin improves HRS reversal; the cure is liver transplantation.
• Varices are graded; screen at diagnosis of cirrhosis and repeatedly thereafter.
• Carvedilol 12.5 mg daily is the preferred NSBB for primary prophylaxis with CSPH.
• Acute variceal bleeding needs vasoactive drug, antibiotics and endoscopy within 12 hours; restrictive transfusion is safer.
• Plasma does not correct INR and may worsen portal hypertension; plasma only for active bleeding.
• Raised INR in cirrhosis reflects loss of synthesis, not vitamin K deficiency; do not give vitamin K routinely.
• Rebalanced haemostasis means both clotting and bleeding are possible.
• Other decompensations (hepatopulmonary syndrome, portopulmonary hypertension, hepatic hydrothorax, cardiomyopathy, hyponatraemia, malnutrition, HCC) demand vigilance and early referral.

Cirrhosis and portal hypertension; ascites and spontaneous bacterial peritonitis; alcohol-related liver disease; hepatitis B and D; hepatitis C; hepatocellular carcinoma; gastrointestinal bleeding; primary biliary cholangitis; malnutrition in liver disease.