Pharmacological management of portal hypertension: current status and future

By Zhu-Qing Gao, Ying Han, Lei Li, and Hui-Guo Ding
Department of Gastroenterology and Hepatology, Beijing You’an Hospital Affiliated to Capital Medical University, Beijing 100069, China
Correspondence to: Prof. Hui-Guo Ding, E-mail: dinghuiguo@ccmu.edu.cn

Portal hypertension (PHT) is the driving force behind some of the most severe complications of cirrhosis, including life-threatening esophagogastric variceal bleeding (EVB), fluid buildup in the abdomen (ascites), brain dysfunction (hepatic encephalopathy), heart problems (cirrhotic cardiomyopathy), and kidney failure (acute kidney injury and hepatorenal syndrome, AKI-HRS). For people with cirrhosis, these complications can lead to death or the need for a liver transplant—and EVB remains one of the deadliest.

To diagnose and monitor PHT, doctors rely on the hepatic venous pressure gradient (HVPG), measured via a transjugular-hepatic vein balloon catheterization. This test is the most widely accepted way to assess portal pressure (PP), the key factor in PHT.

The Goal of Pharmacological Treatment

The main aim of PHT medications is to lower portal pressure and prevent complications. PP depends on two things: how much blood flows into the portal vein (portal blood flow) and how hard it is for blood to pass through the liver (hepatic vascular resistance). Current drugs target either:

Reducing portal blood flow: By constricting blood vessels in the gut (splanchnic vasoconstriction) or blocking overactive hormone systems (like the renin-angiotensin-aldosterone system).
Decreasing hepatic resistance: By fighting liver scarring (fibrosis), shrinking abnormal regenerative nodules, or stopping harmful blood vessel growth (angiogenesis).

First-Line Drugs for Acute Complications

For acute variceal bleeding (AVB)—a sudden, life-threatening bleed from enlarged veins in the esophagus or stomach—three drugs are first-line: terlipressin, somatostatin (SMT), and octreotide. These drugs work by tightening blood vessels in the gut, which lowers blood flow to the varices (enlarged veins) and stops bleeding.

Combining these drugs with endoscopic therapy (like band ligation to tie off varices) improves outcomes. A meta-analysis of 30 randomized controlled trials (3,344 patients) found that terlipressin plus endoscopic ligation had a lower 5-day treatment failure rate and reduced the need for blood transfusions compared to terlipressin alone.

These drugs also help with AKI-HRS—a serious kidney complication in people with cirrhosis and ascites. Recent evidence shows terlipressin combined with albumin (a blood protein) is more effective than midodrine (a blood pressure drug) plus octreotide. Giving terlipressin and albumin early can significantly improve kidney function—and it works just as well as noradrenaline to reverse AKI-HRS.

Long-Term Treatment: Non-Selective Beta-Blockers (NSBBs)

For long-term management of cirrhotic PHT, non-selective beta-blockers (NSBBs) like propranolol and carvedilol are the gold standard. They prevent first-time (primary) and repeat (secondary) EVB and lower the risk of liver decompensation (when the liver stops working properly).

But NSBBs have limitations:

Only 30–40% of patients have a “response” (meaning their HVPG drops enough to reduce risk).
They can cause harmful side effects: A meta-analysis found NSBBs increase the risk of portal vein thrombosis (PVT)—a blood clot in the portal vein—and AKI. The odds ratio was 4.62 (95% confidence interval 2.50–8.53), meaning the risk is more than four times higher. This happens because NSBBs slow portal vein blood flow.

Carvedilol, a newer NSBB, helps people who don’t respond to propranolol. It not only lowers portal blood flow but also reduces liver resistance. However, it can disrupt the delicate balance of blood flow in cirrhosis, which may increase mortality.

New Drugs: Promising Directions

Researchers are testing several innovative therapies for PHT:

Statins

Statins—best known for lowering cholesterol—show promise for NASH-related cirrhosis (non-alcoholic steatohepatitis, a type of liver disease linked to obesity). They improve the function of the liver’s tiny blood vessels (sinusoidal endothelial cells) and reduce liver resistance by blocking a protein called Rho-associated kinase and activating nitric oxide synthase (an enzyme that relaxes blood vessels).

Anticoagulants

Low-molecular-weight heparin and direct-acting anticoagulants (DOACs) help dissolve PVT clots without causing extra bleeding. They also lower EVB risk in people with cirrhosis and PVT. An observational study found DOACs are safe and effective for preventing PVT, delaying liver damage, and improving outcomes—especially in compensated cirrhosis (where the liver still works well). More research is needed to find the best type and dose for decompensated cirrhosis (liver failure).

Other Emerging Therapies

Drugs like pioglitazone (for diabetes), sorafenib (for cancer), PX20606 (a new compound), tetrahydrobiopterin (a nutrient), antioxidants, and supplements (caffeine, green tea polyphenols) have shown benefits in animal models or small human studies. But larger trials are needed to confirm their value.

Non-Cirrhotic Portal Hypertension (NCPH)

Non-cirrhotic portal hypertension (NCPH) is a rare type of PHT caused by liver blood vessel diseases or systemic conditions. Unlike cirrhotic PHT, people with NCPH have normal liver function and normal or low HVPG—but they still get ascites, an enlarged spleen (splenomegaly), and EVB. NCPH is often misdiagnosed as cirrhotic PHT, but endoscopic and drug therapies (like those used for AVB) are safe and effective.

Conclusion

Pharmacological management is the backbone of PHT care—whether it’s caused by cirrhosis or NCPH. For acute variceal bleeding, terlipressin, SMT, and octreotide are first-line. For long-term cirrhotic PHT, propranolol and carvedilol are recommended—but their risks (like PVT) mean doctors must monitor patients closely.

The biggest unmet need is new drugs that can lower portal pressure more effectively without harmful side effects. Researchers are making progress with statins, anticoagulants, and other therapies—but more studies are needed to confirm their safety and efficacy, especially for NCPH.

This work was supported by grants from the State Key Projects Specialized on Infectious Diseases (No. 2017ZX10203202-004), the National Natural Science Foundation (No. 81970525), the Beijing Natural Science Foundation Program and Scientific Research Key Program of Beijing Municipal Commission of Education (No. KZ201810025037), and the Beijing Municipal Administration of Hospitals’ Ascent Plan (No. DFL20151602).

Conflicts of interest: None.

doi.org/10.1097/CM9.0000000000001004

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