Subtle liver problems may contribute to lung inflammation in PAH: Study
Findings support complex communication between organs along an axis
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Subtle liver problems may contribute to the development of pulmonary arterial hypertension (PAH), suggesting complex communication between the lungs and liver along a so-called lung-liver axis, according to a study.
Some people with PAH but no known liver disease showed signs of mild liver dysfunction, enhanced lung-related inflammatory processes, and worse PAH-related outcomes. Researchers hypothesized that these abnormalities could contribute to the changes in lung blood vessels that characterize PAH.
“Our observations support a lung-liver axis in PAH even in the absence of liver disease, warranting further study,” the team wrote.
The study, “Exploring the Lung–Liver Axis in Pulmonary Arterial Hypertension,” was published in Comprehensive Physiology.
Some PAH patients have underlying liver disease
PAH is a type of pulmonary hypertension, or high blood pressure in the lungs. Narrowing of the pulmonary arteries, which are major blood vessels that supply the lungs, causes PAH. Inflammation and a process called pulmonary vascular remodeling contribute to this narrowing. In pulmonary vascular remodeling, lung blood vessels change their structure, forcing the heart to work harder.
Sometimes, people with PAH have underlying liver disease or conditions affecting other organs. However, exactly how other organs contribute to the condition is still a matter of debate.
“While PAH is increasingly recognized as a multisystem disease, the degree to which pulmonary vascular remodeling is perpetuated by inter-organ crosstalk in PAH is unknown,” the researchers wrote.
In the present study, a team in the U.S. aimed to identify contributions of the liver to PAH in people without known liver disease. They included 25 participants with PAH, who had a median age of 61. About three-quarters were women.
Patients with lower MELD-Na scores performed better on walking test
For each participant, the team calculated the Model for End-Stage Liver Disease Sodium (MELD-Na) score. MELD-Na is a tool that quantifies the severity of liver disease and helps predict liver-related outcomes. The researchers separated participants into two groups — one with high MELD-Na scores (12 or higher) and one with low MELD-Na scores (lower than 12).
They then compared disease-related outcomes for participants depending on MELD-Na scores. This included pulmonary vascular resistance (PVR), a measurement of how difficult it is for blood to move from the heart to the lungs.
“The MELD-Na score was predictive of PVR among PAH patients with no clinical liver disease,” they noted.
Additionally, participants with lower MELD-Na scores performed significantly better on the six-minute walk distance (6MWD) test. This standard measure of exercise capacity assesses how far a person can walk in six minutes. Low-MELD-Na participants had a median 6MWD of 411 meters (449 yards), indicating less impairment than high-MELD-Na participants, who had a median distance of 353 meters (386 yards).
[These experiments suggest] evidence of a lung-liver axis in PAH independent of primary liver disease in both human PAH tissues and two small animal models.
Next, the team analyzed gene activity in cells lining the pulmonary arteries of these participants. They found that participants with higher MELD-Na scores also had more activity in inflammation-related genes. Activity of the IL6 gene tended to be higher in high-MELD-Na participants, and this was also affecting a network of related genes implicated in processes such as vascular remodeling and oxidative damage.
“Directed by our network analysis, we next examined whether a similar pro-inflammatory signature existed in the livers of two small animal models of PH,” the researchers wrote.
Both animal models showed signs of liver inflammation and scarring. While one model has a known connection to liver disease, the other does not. The inflammation suggests that even without overt liver problems, subtle dysfunction may exist in that model.
Finally, the team tested samples from the livers of 12 individuals — three controls without PAH or liver disease, four with PAH but no known liver disease, and five with PAH and liver disease.
As expected, the group with PAH and liver disease had significantly more scarring than the control group. People with PAH but no liver disease showed an intermediate amount of scarring. Statistical analysis didn’t reveal significant differences between these participants and either of the other groups, but this could be due to the low number of participants, the team noted.
Taken together, these experiments suggest “evidence of a lung-liver axis in PAH independent of primary liver disease in both human PAH tissues and two small animal models,” the researchers wrote.
The study had several limitations, the scientists said, including that MELD-Na is designed for people with known liver disease and does not comprehensively capture liver function.
Future research could help clarify how the liver and lungs interact in this context and how these interactions change over the course of PAH disease.
