Hilary DuBrock, MD - phaware® interview 398

Jan 10, 2023

Pulmonologist and PH clinician from the Mayo Clinic, Hilary DuBrock, MD discusses portopulmonary hypertension, a type of pulmonary arterial hypertension that develops in the setting of portal hypertension and liver disease.

Dr. Hilary DuBrock:
Hi. I'm Dr. Hilary DuBrock, and I'm a pulmonologist and a PH clinician at Mayo Clinic in Rochester, Minnesota, and today I'm going to talk about portopulmonary hypertension.

Portopulmonary hypertension, which we often abbreviate as POPH, is a type of pulmonary arterial hypertension or Group 1 PH. As we know, PAH can be associated with different conditions, like connective tissue disease, HIV, congenital heart disease, or portal hypertension, and portopulmonary hypertension refers to PAH that develops in the setting of portal hypertension and liver disease.

We know that PH is high pressure in the pulmonary artery, but what is portal hypertension?

Well, portal hypertension refers to elevated pressure within the portal veins, which is most commonly caused by cirrhosis or scarring in the liver. In addition POPH, portal hypertension can also lead to problems like ascites or fluid buildup in the stomach, esophageal varices, which are dilated blood vessels in the esophagus which can bleed, and an enlarged spleen.

Portopulmonary hypertension affects approximately 5-8% of patients with liver disease who undergo evaluation for a liver transplant and accounts for approximately 5-15% of all cases of pulmonary arterial hypertension. POPH is classified as Group 1 PAH because it's similar to other types of pulmonary arterial hypertension like idiopathic PAH, and is generally treated in the same way. Similar to idiopathic pulmonary arterial hypertension, we treat portopulmonary hypertension with medications that target the nitric oxide, endothelin, and prostacyclin pathways. Although we classify and treat pulmonary hypertension the same as idiopathic PAH, there are a few important differences which I'd like to highlight.

First of all, our knowledge regarding treatment of portopulmonary hypertension is actually fairly limited, since patients with portopulmonary hypertension and liver disease were excluded from the majority of PAH clinical trials. We generally think, however, that PAH therapy is safe and effective based on small studies, but there's just less robust evidence regarding PAH therapy and portopulmonary hypertension. POPH patients were excluded from clinical trials due to concerns such as safety of medications in the setting of liver disease.

Recently, a randomized control clinical trial called PORTICO was completed specifically in patients with portopulmonary hypertension. This was a study of macitentan, an oral endothelin receptor antagonists, versus placebo. Patients in the study could be treated with other classes of PAH therapy, as well.

So what did they find?

Well, macitentan resulted in a significant improvement in pulmonary vascular resistance or narrowing of the pulmonary blood vessels by 35% after 12 weeks of treatment. This was the primary outcome, so the study met its primary endpoint. Unfortunately, macitentan was not associated with improvements in six-minute walk distance, but we also know that other factors, such as liver disease severity, could impact six-minute walk distance, as well. Notably, there were no liver-related safety concerns in the study, importantly.

Another important distinction between idiopathic pulmonary arterial hypertension and portopulmonary hypertension is that some patients with POPH may benefit from liver transplantation. Remarkably, liver transplant can obviously cure the liver disease, but it can also lead to improvements in portopulmonary hypertension. Liver transplant obviously isn't a cure for other types of PAH, but in portopulmonary hypertension addressing the underlying cause of the PAH, the portal hypertension, can actually result in improvement and sometimes even resolution of pulmonary hypertension. In fact, about half of patients are able to come off all PAH therapy and don't have any evidence of PAH on follow-up testing following liver transplant, suggesting that their pulmonary hypertension can potentially be cured, as well.

Unfortunately, about half of patients still require PAH therapy post-transplant, and some patients can even get worse, particularly in the first six months following transplant. Thus, it's important to continue PAH therapy in the initial post-transplant period and to monitor patients very closely with clinical visits, lab tests, echocardiograms, and right heart catheterization. Since liver transplant is a major surgery and only half of patients get better, predicting which patients will improve following transplant is an important area of ongoing and future research.

Interestingly, although portal hypertension is required for the development of portopulmonary hypertension, PH severity is not directly related to the liver disease severity, and portopulmonary hypertension can occur in patients with even mild severity of liver disease or portal hypertension. Because patients with portopulmonary hypertension don't always have severe enough liver disease to qualify for a transplant and because portopulmonary hypertension can sometimes improve with liver transplant, patients with portopulmonary hypertension who respond to PAH therapy are eligible to receive something called a MELD exception.

So, what do I mean by that?

Well, the MELD score is used to prioritize liver transplant, and is calculated from lab tests, such as a bilirubin, sodium, creatinine, and the INR. Higher numbers indicate worse survival without liver transplant, and that's higher priority for liver transplant. The MELD exception for portopulmonary hypertension provides bonus points in order to prioritize liver transplant for patients with diseases like portopulmonary hypertension where their outcomes may not be reflected by that MELD score alone.

In the United States, patients with portopulmonary hypertension who are treated with PAH therapy and achieve improvement in their portopulmonary hypertension - so that their pulmonary artery pressure is less than 35 and the pulmonary vascular resistance is less than 5 Wood units, or their mean PA pressure is between 35 and 45 with a pulmonary vascular resistance less than 3 Wood units, are eligible to receive this MELD exception to prioritize liver transplant, provided they also have relatively preserved right ventricular function. Once a MELD exception is granted, a right heart catheterization is then required every three months to ensure that patients continue to meet these criteria and haven't developed any worsening of their pulmonary hypertension.

Lastly, another important difference between portopulmonary hypertension and idiopathic pulmonary arterial hypertension is that portopulmonary hypertension is associated with a higher risk of hospitalization and significantly worse survival. According to a multicenter study in the United States called the REVEAL Registry, patients with portopulmonary hypertension had a significantly worse five-year survival of 40% compared to 64% in patients with idiopathic pulmonary arterial hypertension. The reasons for this are not known, but are likely related to these patients having two different problems, both pulmonary arterial hypertension and liver disease. Other factors, such as differences in treatment or socioeconomic status, may also account for differences in outcomes, but we don't really know.

Fortunately, recent studies have found that outcomes can be improved with a combination of both PAH therapy and liver transplant in selected patients. Given the poor survival in portopulmonary hypertension, however, it's really important that we learn more about this disease so we can develop better and targeted treatment.

So, we've reviewed important differences between portopulmonary hypertension and idiopathic pulmonary arterial hypertension regarding treatment, the role of liver transplant, and survival, but why do some patients with portal hypertension get portopulmonary hypertension and others don't?

No one knows for sure, but we do know that there are some risk factors for developing portopulmonary hypertension in addition to the presence of portal hypertension. For example, female sex, similar to other forms of PAH, is associated with an increased risk for developing portopulmonary hypertension, as well as autoimmune liver disease. There have also been recent advances in the field with understanding what causes portopulmonary hypertension. Sex hormones such as estradiol, for example, are thought to play an important role.

In conclusion, portopulmonary hypertension refers to PAH that develops in the setting of portal hypertension. There are important differences between portopulmonary hypertension and idiopathic pulmonary arterial hypertension, such as evidence regarding treatment, the role of liver transplantation, and overall survival. Recent studies suggest that long-term outcomes of portopulmonary hypertension are improved with a combination of PAH therapy and liver transplant. Despite these recent advances in our knowledge, however, portopulmonary hypertension is an important and really understudied type of pulmonary arterial hypertension where many unanswered questions remain.

This has been Dr. Hilary DuBrock, and I'm aware my patients are rare.

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