Portal Hypertension Pharmacotherapy

Portal hypertension is a rise in portal venous pressure, defined by a hepatic venous pressure gradient of 6 mmHg or more, and clinically significant when it reaches 10 mmHg or more. It causes varices, ascites, hepatic encephalopathy and hypersplenism. Pharmacotherapy aims to reduce portal pressure and prevent first bleeding, control acute bleeding, and prevent rebleeding.

Causes. Cirrhosis, schistosomiasis, non-cirrhotic portal fibrosis, portal vein thrombosis and hepatic venous outflow obstruction.

Mechanism of therapy. Non-selective beta blockers reduce cardiac output and splanchnic inflow. Carvedilol also lowers intrahepatic resistance through alpha-1 blockade. Vasoactive drugs cause splanchnic vasoconstriction in acute bleeding.

Risk stratification. Large varices, red signs on endoscopy and Child-Pugh C raise bleeding risk.

Primary prevention. Offer a non-selective beta blocker or endoscopic band ligation to patients with medium or large varices. Give a non-selective beta blocker to patients with small varices with red signs or Child-Pugh C disease. Carvedilol is preferred where available.

Non-selective beta blockers.

Acute variceal bleeding.

• Resuscitate with a restrictive transfusion strategy: transfuse at a haemoglobin under 70 g/L, aiming for 70 to 90 g/L.
• Start a vasoactive drug as soon as bleeding is suspected and continue for 2 to 5 days: terlipressin 2 mg intravenously every 4 hours until bleeding is controlled, then 1 mg every 4 hours; or octreotide 50 micrograms intravenous bolus then 50 micrograms/hour; or somatostatin 250 micrograms bolus then 250 micrograms/hour.
• Give ceftriaxone 1 g intravenously once daily for up to 7 days.
• Give erythromycin 250 mg intravenously 30 to 120 minutes before endoscopy if no QT prolongation.
• Perform endoscopy within 12 hours with band ligation.

Secondary prevention. Combine a non-selective beta blocker (carvedilol, propranolol or nadolol at the doses given for primary prevention) with repeated band ligation until varices are eradicated.

Early transjugular intrahepatic portosystemic shunt. Consider within 72 hours, ideally 24 hours, for Child-Pugh C 10 to 13, or Child-Pugh B over 7 with active bleeding at endoscopy.

Not advised. Tranexamic acid, routine recombinant factor VIIa, and fresh frozen plasma to correct INR.

Proton pump inhibitors. Give for a short course after band ligation and stop when ulcers heal. Long-term use increases infection and encephalopathy risk.

Non-cirrhotic and schistosomal portal hypertension. Non-selective beta blockers and band ligation are used on the same indications. Praziquantel 40 mg/kg orally as a single dose treats active schistosomiasis but does not reverse established periportal fibrosis.

Contraindications to beta blockers. Severe asthma, second or third degree heart block, severe bradycardia, systolic blood pressure under 90 mmHg, and decompensated heart failure.

Terlipressin cautions. Ischaemic heart or peripheral vascular disease, oxygen saturation under 90%, and pregnancy.

Pregnancy. Propranolol and carvedilol may continue with foetal growth monitoring. Band ligation is preferred before conception. Terlipressin is contraindicated; octreotide may be used for acute bleeding.

Breastfeeding. Propranolol and nadolol are compatible with monitoring of the infant; carvedilol data are limited.

Older adults. Greater risk of bradycardia and hypotension; titrate more slowly.

Kidney impairment. Reduce nadolol dose when creatinine clearance is under 50 mL/min. Propranolol and carvedilol need no adjustment.

Interactions. Verapamil and diltiazem with beta blockers cause bradycardia and block. Beta blockers mask hypoglycaemia in insulin-treated patients.

Monitoring. Resting heart rate and blood pressure at each titration step. Creatinine, sodium and ascites status every 1 to 4 weeks during titration, then every 3 months.

Stopping thresholds. Reduce or stop non-selective beta blockers for systolic blood pressure under 90 mmHg, sodium under 130 mmol/L, acute kidney injury, or spontaneous bacterial peritonitis, and restart cautiously when stable. Do not stop abruptly in patients with ischaemic heart disease.

Referral and escalation. Refer urgently to endoscopy and critical care for gastrointestinal bleeding with haemodynamic instability. Refer for transjugular intrahepatic portosystemic shunt assessment after failure of first-line therapy or for refractory ascites, and for transplant assessment at first decompensation.