Pharmacological Management of Portal Hypertension: Current Status and Future
Portal hypertension (PHT) is a critical condition that serves as the catalyst for severe complications in cirrhosis, including esophagogastric variceal bleeding (EVB), ascites, hepatic encephalopathy, cirrhotic cardiomyopathy, acute kidney injury, and hepatorenal syndrome (AKI-HRS). These complications can lead to mortality or increase the necessity for liver transplantation. Among these, EVB remains one of the most lethal complications of PHT. The primary method for assessing portal pressure (PP) and PHT is the hepatic venous pressure gradient (HVPG), measured via transjugular hepatic vein balloon catheterization. The pharmacological management of PHT aims to reduce PP and prevent PHT-related complications. Given that PP is determined by portal blood flow and hepatic vascular resistance, current drugs primarily target the modulation of increased liver blood flow, such as reducing hyperdynamic circulation, renin-angiotensin-aldosterone system activation, vascular hyperplasia, and collateral circulation formation, or decreasing intravascular resistance, such as inhibiting liver fibrosis, regenerative nodules, and angiogenesis.
In the context of PHT, arterial vasodilation occurs in both the splanchnic and systemic circulation, activating neurohumoral and vasoconstrictive systems. This leads to sodium and water retention, increased blood volume, and increased cardiac output. Drugs like terlipressin, somatostatin (SMT), octreotide, and non-selective beta-blockers (NSBBs) decrease portal venous inflow through splanchnic vasoconstriction. However, the interaction between vasoactive substances and contractile cells often results in abnormal liver microcirculation and PHT development, presenting new targets for future pharmacological management.
In clinical practice, SMT and octreotide are commonly used to treat PHT-induced acute variceal bleeding (AVB), either independently or in combination with urgent endoscopic therapy. A meta-analysis of 30 randomized controlled trials involving 3344 patients indicated that terlipressin combined with endoscopic variceal ligation had a lower 5-day treatment failure rate and transfusion requirement compared to terlipressin alone. Furthermore, the combination of SMT/octreotide and endoscopic therapy is effective in controlling AVB. The efficacy of these drugs combined with alpha-adrenergic receptor activators, such as noradrenaline and midodrine, has also been evaluated in the treatment of AKI-HRS. Recent evidence suggests that the efficacy of terlipressin with albumin is superior to midodrine combined with octreotide. The timely use of terlipressin and albumin significantly improves AKI-HRS in cirrhotic patients with ascites. This approach is also as effective as noradrenaline in reversing AKI-HRS in cirrhotic patients with PHT.
NSBBs are the mainstream drugs for long-term treatment in cirrhotic patients with PHT, used to prevent primary and secondary EVB and reduce the risk of hepatic decompensation. However, only 30% to 40% of patients treated with long-term NSBBs achieve a response to reduce HVPG. NSBBs may also lead to undesirable outcomes, such as portal vein thrombosis (PVT) and AKI, in a portion of cirrhotic patients due to significantly decreased portal vein velocity. Although carvedilol treatment achieves a good hemodynamic response in propranolol non-responders, it may disrupt the delicate hemodynamic balance in cirrhotic patients and increase mortality.
Several new drugs, including statins, anticoagulants, pioglitazone, sorafenib, PX20606, tetrahydrobiopterin, antioxidants, and supplementary treatments such as caffeine and green tea polyphenol, have been reported to benefit PHT patients or animal models. Among these, statins are promising in managing PHT in non-alcoholic steatohepatitis-related cirrhosis by improving liver sinusoidal endothelial cell function and reducing intrahepatic resistance through inhibition of Rho-associated kinase signaling and activation of endothelial nitric oxide synthase. Low-molecular-weight heparin or direct-acting anticoagulants (DOACs) are capable of increasing PVT recanalization without extra bleeding and decreasing the incidence of EVB in cirrhotic patients with PVT. An observational study shows that DOACs are safe and effective in preventing PVT, delaying hepatic decompensation, and improving prognosis in patients with cirrhosis. However, further studies are needed to determine the optimal type of anticoagulant and dose in patients with compensated and decompensated cirrhosis.
Non-cirrhotic portal hypertension (NCPH) is a disease entity due to rare hepatic sinus-portal vascular diseases or systemic diseases. NCPH is characterized by normal liver function, normal or low HVPG, ascites, splenomegaly, and a high occurrence of EVB. It is noteworthy that NCPH can be easily misdiagnosed as cirrhotic portal hypertension. For NCPH-induced EVB, endoscopic and drug therapies are safe and effective in current clinical practice.
In summary, pharmacological management is the mainstay of PHT in cirrhotic or NCPH patients. Terlipressin, SMT, and octreotide are the first-line drugs for treating AVB in patients with PHT. Propranolol and carvedilol are recommended for the long-term treatment of cirrhotic PHT. Whether these drugs, especially NSBBs, are also safe and efficient in NCPH patients requires further investigation. Novel therapeutic drugs that could effectively reduce PP are needed in clinical practice.
doi.org/10.1097/CM9.0000000000001004
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