The pulmonary histopathology of POPH individuals is indistinguishable from other PAH phenotypes [4, 12]. Based upon autopsy and lung explant studies, POPH is characterized by a spectrum of obstructive and remodeling changes in the pulmonary arterial bed. Initially, medial hypertrophy with smooth muscle proliferation and a transition to myofibroblasts has been documented. As this proliferative pathologic process advances, plexogenic arteriopathy eventually develops [4, 12].

The pulmonary vascular pathology occurs within the context of a hyperdynamic state caused by extrahepatic (splanchnic) vasodilation [5]. It is unknown if this persistent high flow state initiates (by shear stress) or exacerbates (in combination with circulating mediators) the pulmonary vascular proliferative process. In addition, it is possible that a genetic predisposition may also play a role, since not all patients with portal hypertension due to cirrhosis develop POPH [23]. Pulmonary endothelial cells lack prostacyclin synthase in patients with POPH (hence a lack of prostacyclin vasodilation) [24]. The pulmonary vascular bed is exposed to increased levels of circulating endothelin 1 in the setting of cirrhosis (a potent vasoconstrictor and facilitator of smooth muscle proliferation) [25, 26] and may be deficient in local nitric oxide effect (for vasodilation) [27]. The role of other circulating and receptor factors that may affect the pulmonary endothelium due to the existence of portal hypertension is speculative. These factors include vasoconstrictive/proliferative mediators such as serotonin, thromboxane, vasoactive intestinal peptide, and vascular endothelial growth factor, as well as the possible imbalance of endothelin receptors (ET_A—mediating vasoconstriction; ET_B—mediating vasodilation) in the pulmonary arterial bed [27]. The mechanistic link between estrogen signaling, serum estradiol levels, circulating endothelial progenitor cells, and the development of POPH is a current research hypothesis of interest [28, 29].

As the pulmonary vasoproliferative process progresses, the increasing resistance to flow restricts the degree of CO flowing through the pulmonary vascular bed. Strain on the right ventricle will be seen with dilation of the right ventricle and reduction in systolic function. Progressive reduction in CO will evolve with right heart failure leading to hepatic venous engorgement and worsening portal hypertension. Death from either right heart failure or portal hypertension complications will inevitably occur without therapeutic intervention [5].

The most common and predominant symptom of POPH is dyspnea on exertion. POPH may be unnoticed as patients with advanced liver disease have multiple reasons for dyspnea including ascites , anemia, fluid retention, and muscle wasting. Chest pain and syncope are symptoms suggestive of severe POPH [5]. Physical findings in POPH may be absent or subtle and nonspecific; however, the presence of a hyperdynamic precordium, an accentuated second heart sound (best heard at the apex), and a systolic murmur due to tricuspid valve regurgitation may be noted. With severe POPH, there may be marked distension of the jugular veins, peripheral edema, ascites, and a right ventricular third heart sound (S3). The lung examination is usually normal and it is uncommon to have clubbing or cyanosis (as seen in HPS). Mild hypoxemia is common and often associated with abnormal overnight pulse oximetry . The chest radiograph usually demonstrates cardiomegaly and enlargement of the central pulmonary arteries as the duration and severity of POPH progresses [5]. The electrocardiogram may show rightward electrical axis, right bundle branch block pattern and when POPH is severe, the presence of inverted T-waves in the precordial V1–V4 leads can be seen, which suggests a severe effect on the right ventricle. Although rare, it is important to rule out chronic pulmonary emboli as a cause of PAH even in the context of liver disease, especially in the setting of portal vein and hepatic vein thromboses. Pulmonary function tests are usually not helpful in the diagnosis or management of POPH because reduced single breath diffusing capacity (a common abnormality seen in PAH) is frequently seen in most patients with advanced liver disease.

Screening for POPH via transthoracic echocardiography (TTE) has been the most practical method to detect POPH [30–32]. By assessing the tricuspid regurgitant peak velocity (TR), estimating the right atrial pressure by inferior vena cava changes with inspiration and using the modified Bernoulli equation, an estimate of right ventricle systolic pressure (RVSP) can be determined in approximately 80 % of patients with portal hypertension [30]. This quantitative approach allows one to decide which patients should precede to RHC for the definitive characterization of pulmonary hemodynamics. RVSP > 50 mmHg has been the cutoff criteria used in the current Mayo Clinic algorithm to perform RHC [3]; rarely, immeasurable TR with abnormal qualitative right ventricular size or function results in RHC. TTE was noted to have a 97 % sensitivity and 77 % specificity to detect moderate-to-severe PAH prior to LT [30].

Deciding who needs pulmonary artery PAH-specific therapy and determining the risks for potential LT are critical in the management of patients with POPH (Fig. 19.1). POPH patients with MPAP > 35 mmHg are particularly vulnerable to poor outcomes with attempted LT, especially if there is no attempt to treat the POPH with current PAH-specific medications. The immediate goal in the treatment of POPH is to improve pulmonary hemodynamics by reducing the obstruction to pulmonary arterial flow (↓MPAP, ↓PVR, and ↑CO), ultimately improving and/or normalizing RV function. This can be accomplished by medications that result in vasodilation, antiplatelet aggregation and have antiproliferative effects[5]. Drug therapy may augment the lack of pulmonary endothelial prostacyclin synthase deficiency (prostacyclin infusion), block circulating endothelin-1 effects (endothelin receptor antagonists), and enhance local nitric oxide vasodilatation effects (phosphodiesterase inhibitors and soluble guanylate cyclase stimulator) [5, 33].

Aside from one study evaluating the effect of riociguat (a soluble guanylate cyclase stimulator) in PAH [33], controlled randomized studies evaluating PAH-specific therapies have excluded POPH patients. Evidence regarding therapy in POPH has originated from uncontrolled studies, where PAH-specific therapies used for other types of PAH proved to be beneficial for patients with POPH [34–51] (Table 19.2). Improvements in both MPAP and PVR are the ideal goals in treating POPH. However, MPAP may not decrease as much as desired, as increases in CO associated with reduced obstruction to flow (measured by decreased PVR) will result in higher flow (and increased pressure).