Hilary M. DuBrock, MD: Patients with portopulmonary hypertension tend to respond quite well to PAH therapy. The main challenge in treating portopulmonary hypertension is to achieve acceptable hemodynamic criteria to enable a safe liver transplantation and to improve a patient’s perioperative risk stratification for liver transplantation. These criteria include a mean PA [pulmonary artery] pressure less than 35 mmHg and a pulmonary vascular resistance less than, ideally, 3 Wood units or 240 dynes. The challenge with this is that in patients with portopulmonary hypertension, when you start PH [pulmonary hypertension]—targeted therapy, pulmonary vascular resistance improves but cardiac output often increases, which can then drive up the mean PA pressure and make it hard to achieve that mean PA pressure of 35 mmHg. Thus, that is sometimes a challenge in treating patients with portopulmonary hypertension as you’re trying to achieve that goal.

Additionally, patients with portopulmonary hypertension—particularly with parenteral prostacyclin therapy—can develop worsening ascites, splenomegaly, and thrombocytopenia, which can make it challenging to treat. Signs and symptoms of right heart failure, such as ascites and lower extremity edema, can often be difficult to differentiate from patients with decompensated cirrhosis as well. You really need to follow both your echocardiogram and your right heart catheterization to identify patients who have progressive pulmonary hypertension and need more aggressive therapy.

Lastly, the evidence for PAH [pulmonary artery hypertension]—targeted therapy in portopulmonary hypertension is less robust since patients with portopulmonary hypertension have been excluded from most clinical trials of PAH–targeted therapies. In addition, hepatic encephalopathy can sometimes be a limiting factor in treating patients with portopulmonary hypertension when it relates to medication adherence or use of parenteral prostacyclin therapy.

Charles D. Burger, MD: When considering treatment for patients with portopulmonary hypertension, we don’t have as many published data as we might in some of the other subgroups, for a couple of reasons. First, it’s an unusual diagnosis. Second, some of the early-generation treatments for pulmonary arterial hypertension showed some risk, in the 10% range, for causing blood test abnormalities that indicated toxicity to the liver. There is some hesitation in including patients with portopulmonary hypertension in some of the larger drug trials because of some of that early experience.

We’ve certainly learned over the years, however, that many of the medications can be safely used. But it’s always more reassuring when you have a randomized clinical trial that confirms that benefit. One such trial is PORTICO, where macitentan was studied for benefit in portopulmonary hypertension. It was a positive trial showing benefit and, of course, safety. It’s very important that the patients be able to tolerate these medications and that they can be safely prescribed and used, obviously showing objective evidence of benefit. That trial reinforces use of macitentan in this population as an option for treatment.

If the patient improves but perhaps doesn’t improve to the point that you would be satisfied, whether that’s eligibility for liver transplant or some other marker of severity of illness, that patient may need additional therapy. We often move to the prostaglandin pathway, the prostanoid pathway. We’ve used agents in the nitric oxide pathway, the PDE5 inhibitors. It requires judgment, so you really want to have an experienced provider individualizing the decision for that patient’s situation so that tolerability, safety, and benefit are optimized in the treatment regimen.

Hilary M. DuBrock, MD: PAH—targeted therapies improve prognosis in patients with portopulmonary hypertension via two ways. First, PAH–targeted therapy improves a patient’s pulmonary hypertension, right ventricular function, and hemodynamics, which can improve their overall survival related to PH. PAH–targeted therapy also can improve pulmonary hemodynamics to the point where a patient who was previously ineligible for a liver transplant is now eligible to have a liver transplant, which may treat their underlying liver disease. In addition to treating the underlying liver disease, liver transplantation can also improve a patient’s portopulmonary hypertension. Patients with portopulmonary hypertension, for example, can come off PAH–targeted therapy after transplant, meaning some patients can even be cured of their portopulmonary hypertension with liver transplant.

Without PAH—targeted therapies, however, the risk of liver transplant would be too high, such that they wouldn’t be able to undergo this potentially life-saving procedure. To summarize, PAH–targeted therapies improve pulmonary hypertension, improve risk stratification, and enable safe liver transplantation in patients who need a transplant, which can treat the underlying liver disease and sometimes even treat the pulmonary hypertension itself.