Human internal organs, computer artwork.

A group of Chinese researchers recently published a study to better understand the relationship between liver function and idiopathic pulmonary arterial hypertension (PAH). They conducted a retrospective, longitudinal study with 407 newly diagnosed idiopathic PAH patients at the Shanghai Pulmonary Hospital in China, with all-cause mortality as their primary endpoint. 

The findings of their study illustrated the mysterious but irrefutable relationship between liver dysfunction and PAH. Among their discoveries was that 77.6% of patients had abnormal liver function tests (LFTs) at baseline. In addition, PAH patients with liver dysfunction had a worse prognosis than those with normal liver function parameters. Individuals with isolated albumin deficiency also had a poorer prognosis compared to individuals with normal LFTs. 

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“Our study provided a comprehensive evaluation of the prevalence and prognostic importance of LFT abnormalities in idiopathic PAH,” Luo et al wrote. However, they conceded that “the mechanisms linking LFT and poor outcomes in idiopathic PAH are still unclear.”

Nickel et al, in a separate study, attempted to go further in elucidating how liver abnormalities occur in PAH. We will be exploring this complex relationship in this article. 

A Systemic Circulatory Disease

“In severe idiopathic PAH patients, which may be similar to chronic congestive heart failure, we proposed that elevated right heart filling pressure (including right atrial pressure) and central venous pressures are transmitted through the hepatic veins and into the small hepatic venules,” Luo and colleagues wrote.

“The effect of this transmitted pressure is passive congestion of the liver resulting in elevated hepatic venous pressure, which can impair the delivery of oxygen and nutrients to hepatocytes, leading to hepatocyte necrosis with subsequent atrophy of liver cells and edema of the peripheral area.”

This explanation of how PAH eventually leads to liver dysfunction represents conventional medical wisdom. In the introduction of their study, Nickel and colleagues provided a similar flowchart of how PAH causes liver dysfunction: elevated blood pressure in the lung circulatory system negatively impacts the right ventricle, leading to right ventricular failure, which then puts pressure on the liver, leading to congestive hepatopathy and a deranged liver profile. 

“More recently, PAH has been recognized as a multi-organ systemic disease, with abnormalities in the systemic circulation, central and peripheral nervous system, kidneys, skeletal muscle, and immune system,” Nickel et al wrote. In other words, PAH is not just a problem of the pulmonary circulation; it has wide-ranging implications for the whole body, and particularly the liver—the largest solid organ in the adult human body. 

In Luo et al’s study, they discovered that an abnormal liver profile featured heavily among PAH patients. The natural explanation for this is that hepatic venous congestion causes a rise in cholestatic liver enzymes, such as bilirubin and alkaline phosphatase (ALP), as well as albumin deficiency. 

“Disturbance of hepatic venous outflow can lead to interstitial and cellular edema that can impair the uptake and secretion of bilirubin, bile acids, and other substances,” explained Nickel and colleagues. Albumin deficiency can be caused by hepatic congestion due to right heart pressure overload. 

Read more about PAH patient education 

In summary, the culprit of liver dysfunction in PAH is congestive hepatopathy due to right heart failure. When hepatic congestion becomes chronic, cirrhosis may occur. Decades of increased venous pressure may also lead to hepatocellular carcinoma.

Therapeutic Approaches

What kinds of therapies are available to tackle challenges to the liver in patients with PAH? One of the major problems here is that most drugs undergo hepatic metabolism and clearance; hence, liver dysfunction ends up impairing their efficacy.

Among the drugs commonly used to treat liver dysfunction are inhaled iloprost and oral treprostinil, which are prescribed at lower doses in patients with hepatic impairment (they are not typically prescribed in severe hepatic impairment, such as Child-Pugh class C). 

In addition, physicians will need to manage abnormal lipid metabolism in PAH. “It is well established that patients with PAH have abnormal concentrations of circulating lipids and lipoproteins,” Nickel et al wrote. “The exact etiology of these changes and the clinical implications are less well defined.” 

This is because the liver plays a central role in protein, fat, and carbohydrate metabolism. (In fact, the liver plays such a diverse role in maintaining homeostasis that scientists are beginning to recognize its central importance in maintaining health and well-being.) 

“Decreased HDL levels and other lipid abnormalities in PAH might in part be related to chronic inflammation or may have a biological role in the pathobiology of PAH, rather than simply be a consequence of obesity or the metabolic syndrome,” wrote Nickel and colleagues. This means that physicians will have to closely monitor PAH patients’ lipid profiles and treat dyslipidemia if present. 

Interconnected Systems 

It is clear from both academic studies and clinical experience that PAH often leads to problems with the liver, even if scientists have not fully unraveled all their intricate connections. Luo et al conceded that even though a test as simple as LFTs may be helpful in determining both the severity and prognosis of PAH patients, “long-term and larger sample studies are needed to . . . elucidate the mechanism and interaction between liver function and idiopathic PAH.” 


Nickel NP, Galura GM, Zuckerman MJ, et al. Liver abnormalities in pulmonary arterial hypertension. Pulm Circ. Published online October 21, 2021. doi:10.1177/20458940211054304

Luo C, Wu W, Wu C, et al. Liver dysfunction in idiopathic pulmonary arterial hypertension: prevalence, characteristics and prognostic significance, a retrospective cohort study in China. BMJ Open. Published online September 7, 2021. doi:10.1136/bmjopen-2020-045165