How does liver disease cause pulmonary hypertension?

From the Guidelines

Liver disease can cause pulmonary hypertension through a condition called portopulmonary hypertension (POPH), which occurs when chronic liver disease leads to portal hypertension, triggering changes in the pulmonary vasculature. The mechanism begins with the development of portal hypertension, where blood flow through the liver is obstructed, causing blood to be shunted through collateral vessels. This shunting allows vasoactive substances that would normally be metabolized by the liver to enter the pulmonary circulation. These substances, including endothelin-1, serotonin, and inflammatory cytokines, cause pulmonary vasoconstriction and vascular remodeling. Additionally, the increased blood flow to the lungs from portosystemic shunting creates a hyperdynamic circulatory state that puts stress on the pulmonary vasculature. Over time, these changes lead to pulmonary arterial smooth muscle hypertrophy, endothelial dysfunction, and in-situ thrombosis, resulting in increased pulmonary vascular resistance and elevated pulmonary arterial pressure.

The severity of POPH doesn't necessarily correlate with the severity of liver disease, and it can develop in patients with various forms of chronic liver disease, most commonly cirrhosis. According to the most recent guidelines 1, treatment typically involves pulmonary vasodilators such as phosphodiesterase-5 inhibitors, endothelin receptor antagonists, or prostacyclins, while addressing the underlying liver disease. Vasomodulator therapy should be offered to all LT candidates with porto-pulmonary hypertension and mean pulmonary arterial pressure >35 mmHg and pulmonary vascular resistance >3 Wood units. It is also recommended that a mean pulmonary arterial pressure >45 mmHg despite vasomodulator treatment should be considered as an absolute contraindication to LT 1.

Key points to consider in the management of POPH include:

• The use of vasomodulatory treatments to improve pulmonary haemodynamics
• The importance of careful perioperative attention to avoid right ventricular failure from acutely elevated pulmonary artery pressure or sudden increase in right ventricular preload
• The consideration of liver transplantation in patients with POPH responding to medical therapy with pulmonary vasodilators and with mean pulmonary arterial pressure ≤35 mmHg
• The need for a thorough evaluation to exclude other underlying or contributing factors such as chronic recurrent thromboembolic disease, previously undetected congenital heart disease, collagen vascular disease, or prior IV drug abuse.

Overall, the management of POPH requires a multidisciplinary approach, taking into account the severity of the underlying liver disease, the presence of other comorbidities, and the potential risks and benefits of different treatment strategies.

From the Research

Liver Disease and Pulmonary Hypertension

Liver disease can cause pulmonary hypertension through several mechanisms, including:

• Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH) are two pulmonary vascular complications of liver disease 2
• Increased pulmonary vascular resistance (PVR) may be initiated by pulmonary vasoconstriction, altered levels of circulating mediators, or shear stress, and can eventually lead to the classic vascular remodeling (plexiform lesion) that characterizes POPH 3
• Portal hypertension is a prerequisite for the diagnosis of POPH, although the severity of pulmonary hypertension is unrelated to the severity of portal hypertension or the nature or severity of liver disease 3

Pathophysiology

The pathophysiology underlying HPS and POPH is distinct, but patients with either condition may be limited by dyspnea 2.

• HPS is characterized by pulmonary vascular dilatation and abnormal gas exchange 4
• POPH is a process defined by pulmonary hypertension associated with portal hypertension 4
• The imbalance of vasoactive substances in pulmonary vessels is a putative mechanism for the pathogenesis of both entities 4

Diagnosis and Treatment

A careful evaluation of concomitant symptoms, the physical examination, pulmonary function testing and arterial blood gas analysis, and echocardiographic, imaging, and hemodynamic studies is crucial to establishing (and distinguishing) these diagnoses 2.

• There is no effective medical treatment for HPS 2
• Although liver transplantation can resolve HPS, there appears to be worse survival even with transplantation 2
• Targeted medical therapies may improve functional status and allow successful transplantation in a small number of select patients with POPH 2, 3
• Pulmonary vasodilator therapy includes oral, inhaled, and parenteral agents, and one or more of these agents may significantly lower pulmonary artery pressures to the point that liver transplantation becomes possible 3

Prognosis

The presence of either HPS or POPH increases the risk of morbidity and mortality in patients with underlying liver disease 2.

• Patients with POPH had comparable post-liver transplantation survival rates but were significantly more likely to have graft failure 5
• Both pre-liver transplantation mean pulmonary artery pressure (MPAP) and PVR predicted post-liver transplantation survival in POPH, with a pre-liver transplantation PVR of ≥1.6 WU, more than doubling the hazard for mortality 5