Portopulmonary hypertension (PPH) is the well-recognized relationship of pulmonary arterial hypertension (PAH) that evolves as a consequence of portal hypertension [1]. PPH is included within Group I of the 5th World symposium on pulmonary hypertension [2]. The first clinical and pathologic report of what we now know as PPH was provided by Mantz and Craige in 1951 [3]. These authors described necropsy results of a 53-year-old female with spontaneous portocaval shunt (due to a probable congenital portal vein narrowing) that originated at the confluence of the portal, splenic, and mesenteric veins, coursed through to mediastinum and was lined by varying amounts of thrombus thought to have embolized via the innominate vein into the right heart and pulmonary arteries. In addition to embolized small pulmonary arteries, an extreme endothelial proliferation and recanalization process was documented [3]. Since the 1980s, enhanced recognition and renewed importance of PPH has evolved with the evolution of liver transplantation (LT) and potential outcomes associated with PPH. Specific screening recommendations and diagnostic criteria are now clearly defined for this syndrome. Despite the lack of randomized controlled trials for its medical treatment, extrapolation of the therapeutic advances in treating pulmonary artery hypertension with specific effects in PPH has stimulated ongoing interest and importance in this syndrome. This chapter summarizes the most recent advances in the comprehensive management of patients with PPH.

Transthoracic echocardiography (TTE) has been the most practical screening method to detect PPH [8–10]. 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 ∼80% of patients with portal hypertension [8]. This quantitative approach allows one to decide which patients should proceed to RHC for the definitive characterization of pulmonary hemodynamics. The presence of RVSP >50 mmHg has been the cutoff criterion to proceed to RHC in the current Mayo Clinic algorithm followed since 1996 [5]; 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 [8].

It is unclear as to who coined the term “portopulmonary hypertension”, but Yoshida et al. [12] appear to be the first authors to use the term in 1993 as they described the first successful case of PPH to undergo successful LT (39-year-old male with long-standing chronic active hepatitis). Subsequently, several small series and case reports with autopsy results have described pulmonary arterial obstruction and pulmonary plexogenic arteriopathy with and without thromboemboli [7,13–16]. Two distinct pulmonary vascular obstructive patterns causing PAH in association with portal hypertension are well described:

1. Chronic pulmonary emboli from spontaneous or surgical portocaval shunts and/or in situ thrombus; and
   
2. A vasoconstrictive, proliferative endothelial/smooth muscle process due to circulating mediators that bypassed normal hepatic metabolism due to flow patterns of portal hypertension.

Large series have confirmed the coexistence of these portal and pulmonary vascular abnormalities and have shown that they are not coincidental. An unselected series of 17 901 patients documented PAH associated with cirrhosis more than five times more frequently than PAH without cirrhosis [17]. Within the 1981–1987 NIH national registry of “primary” pulmonary hypertension from 32 centers reported by Rich et al. [18], additional analyses by Groves et al. [19] concluded that 8.3% likely had PPH (17/204; 187 had primary pulmonary hypertension). Hadengue et al. [20] reported the largest prospective study of patients with portal hypertension (n = 507) in which portopulmonary hemodynamic measurements concluded that 2% had PPH.

With the era of PAH-specific therapy and LT, prospective studies have focused on the frequency of PPH in clinical settings, national registries, and individual transplant center experiences. Humbert et al. [21] reported a 10.4% frequency of PPH (70/674) from 17 French university hospitals pulmonary hypertension registry clinic experiences over a 12-month period (2002–2003). The US-based REVEAL Registry documented a 5.3% PPH frequency (174/3; 525) in which there were 68% prevalent and 32% incident cases satisfying the criteria that MPAP >25 mmHg and PVR >240 dyn/s/cm⁻⁵ with PAWP <15 mmHg [22]. Of interest were the additional 29 patients that satisfied MPAP and PVR criteria, but in whom the PAWP was >15 mmHg; each of those patients had a transpulmonary gradient >12 mmHg (abnormal). Following slightly different PVR diagnostic criteria as part of outpatient RHC diagnostic assessments, the largest PPH-liver transplant center experiences reported to date are as follows: 8.5% (Baylor 102/1205; PVR >120 dyn/s/cm⁻⁵), 6.1% (Clichy, France 10/165; PVR >120 dyn/s/cm⁻⁵), and 5.3% (Mayo Clinic 66/1235; PVR >240 dyn/s/cm⁻⁵) [5,23,24].

The natural history of PPH has been difficult to characterize and has also been confounded by small series from eras in which none of the current PAH-specific therapies were available versus the current era with the evolving PAH-specific therapies and LT experiences. Robalino and Moodie [25] reported a dismal 5-year survival rate of 4% (n = 78) in an era prior to the availability of continuous IV prostacyclin infusion. Swanson et al. [26] reported a 14% 5-year survival rate in PPH patients (n = 19) denied LT and not treated with any of the current PAH-specific therapies. From the French National Center for PAH (n = 154 over a 20-year span until 2004), Le Pavec et al. [27] described 1, 3, and 5-year survival rates of 88%, 75%, and 68%, respectively, PPH patients (but mainly Child A and alcoholic cirrhotics). Only one-third had been treated with PAH-specific therapies with severity of cirrhosis and reduced CO poor prognostic factors. Causes of death in all series mentioned herein were equally distributed between right heart failure due to PPH and direct complications of liver disease (bleeding, sepsis, hepatocellular carcinoma).

It is not clear why only 6–8% of patients with portal hypertension develop PPH, which is indistinguishable from the histopathology of other PAH phenotypes [6,7]. Based upon autopsy and lung explant studies, PPH 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. Intuitively, this vasoconstrictive process could be responsive to pulmonary arterial vasodilator therapy. As this proliferative pathologic process advances, platelet aggregates, in situ thrombosis, intimal fibrosis, and finally, taking a sporadic, web-like shape involving the entire pulmonary arterial wall with recanalization for the passage of pulmonary arterial blood [6,7]. This web-like pathology is termed plexogenic arteriopathy and it is unknown whether such structures are irreversible [7].

The factors leading to such pulmonary vascular obstruction in the setting of liver disease are complex, but originate from the development of portal hypertension. The pulmonary vascular pathology occurs within the context of a hyperdynamic state caused by extrahepatic (splanchnic) vasodilatation [31]. 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. Genetic predisposition may also have a role because not all patients with portal hypertension due to cirrhosis develop PPH [32]. It has been demonstrated that the pulmonary endothelial cells lack prostacyclin synthase in PPH patients (hence a lack of prostacyclin vasodilatation) [33], the pulmonary vascular bed is exposed to increased levels of circulating endothlin-1 in the setting of cirrhosis (a potent vasoconstrictor and facilitator of smooth muscle proliferation) [34,35], and may be deficient in local nitric oxide effect (for vasodilatation) [36]. The role of other circulating and receptor factors that may affect the pulmonary endothelium is speculative. These factors include vasoconstrictive/proliferative mediators such as serotonin, thromboxane, vasoactive intestinal peptide, and vascular endothelial growth factor (VEGF); as well as the possible imbalance of endothelin receptors (ET_A – mediating vasoconstriction; ET_B (mediating vasodilatation) in the pulmonary arterial bed [36]. The mechanistic link between estrogen signaling, serum estradiol levels, circulating endothelial progenitor cells, and the development of PPH is a current research hypothesis of interest [37,38].

It is also hypothesized that, initially, the intrahepatic injury leads to an intrahepatic increased resistance to flow. Such injury evokes mediators that cause splanchnic vasodilatation via enhanced local nitric oxide effect and presumed angiogenesis effect [31,39]. The splanchnic bed becomes hyporesponsive to vasoconstrictors; excess volume occurs due to renal retention and a hyperdynamic state is generated. This high flow exacerbates the existing portal hypertension due to increased intrahepatic resistance to flow, leading to the creation of alternative flow pathways: portocaval shunts and esophagogastric varices. Presumably, such aberrant pathways allow other mediators to reach the pulmonary arterial bed and, in the setting of high flow, “trigger” the pulmonary arterial proliferative process.