Portopulmonary Hypertension
Section snippets
Diagnostic criteria
POPH is likely best defined as pulmonary artery hypertension (PAH) associated with portal hypertension, whether or not that portal hypertension is secondary to underlying liver disease [2]. The diagnosis of POPH is traditionally based on hemodynamic data from right heart catheterization (RHC). Diagnostic hemodynamic criteria include increased mean pulmonary artery pressure (mPAP) higher than 25 mmHg at rest, normal pulmonary artery occlusion pressure (PAOP) less than 15 mmHg, and an increased
Epidemiology and prevalence
The prevalence of POPH in patients with liver disease is not well defined. The first retrospective autopsy studies showed that the prevalence of PAH ranged from 0.25% to 0.73% in populations with portal hypertension or cirrhosis, as compared with 0.13% of those without either abnormality [14], [15], [16]. More recent work using hemodynamic studies have estimated the prevalence of POPH to be between 2% and 5% [6]. In addition, the prevalence in patients undergoing LT is likely higher, with one
Pathology and histology
Histopathologically, the pulmonary vasculature of POPH is indistinguishable from that of other forms of PAH. POPH is characterized by vasoconstrictive, proliferative, and obliterative changes in the pulmonary vascular bed. Plexiform arteriopathy, medial hypertrophy, intimal fibrosis, adventitial proliferation, and fibrinoid necrosis of small arteries may be seen [14], [15], [21]. Thrombus with recanalization may be present, which likely are not the result of emboli, as no systemic sources of
Pathophysiology and pathogenesis
At the present time, the pathogenesis of POPH is not fully understood. Two things known at the present time are that the development of POPH appears to be independent of the cause of the portal hypertension [24], and the severity of the underlying portal hypertension or liver disease does not appear to correlate with the severity of the PAH [19].
It appears that three vascular abnormalities combine to cause the vascular obstruction that leads to the increase in PVR seen in POPH: an imbalance of
Clinical features
In the early stages of POPH, patients may be asymptomatic or only have symptoms of their underlying portal hypertension. This then requires that the health care providers treating these patients must have a high clinical suspicion for pulmonary hypertension, especially in patients undergoing evaluation for LT.
The most common initial symptom in those patients who are symptomatic is dyspnea on exertion. However, dyspnea in a patient with underlying liver disease can stem from a myriad of
Evaluation
Identification of POPH in patients with underlying portal hypertension or liver disease is critical not only to guide medical therapy, but also to assess appropriate candidacy for LT. All patients undergoing evaluation for LT should be screened for POPH because mortality in patients with moderate to severe POPH is increased during the perioperative period [2], [41]. Therefore, the advisability and timing of transplantation may be influenced by POPH, and it is unacceptable to make the diagnosis
Medical management
At the present time, there are no major long-term studies or guidelines on the use of pharmacotherapy in POPH [4], [6]. No randomized, controlled clinical trial (RCT) has been conducted for the purpose of POPH management. Likely secondary to the rarity of POPH, treatment of this disease has been empirical. Therefore, the usual approach in treating PAH from any cause has been to initiate therapy when the patient is both symptomatic and has an elevated mPAP (>35 mmHg) as well as an increased PVR
Liver transplantation
Traditional thinking has held that POPH is a contraindication for LT. This is opposite of HPS, which is an indication for LT. However, in a highly selected subset of patients with POPH, LT may be beneficial.
The presence of POPH increases the risk for perioperative, as well as long-term, morbidity and mortality associated with LT [71]. As mPAP and PVR increase, so does the mortality associated with LT [72]. Many, if not all, LT centers consider mPAP higher than 50 mmHg to be an absolute
Prognosis
Survival from time of diagnosis is difficult to predict. As compared with idiopathic PAH, patients with POPH appear to have a substantially shorter survival rate [14]. This was demonstrated in a survival analysis by Kawut and colleagues [83] in 2005, which showed a higher risk for death in patients with POPH as compared with patients with idiopathic PAH, after adjustment for age and ethnicity (Fig. 7). Preliminary data from the Mayo Clinic demonstrate survival after 1, 2, and 5 years in
Follow-up
Patients with POPH should be followed with clinical assessments, as well as echocardiography, on a regular basis to screen for progression of disease. The 6-minute walk test, a useful prognostic tool in patients with idiopathic PAH, may not be as useful in patients with POPH, owing to complications of their underlying liver disease, including ascites and lower extremity edema [6]. However, serial RHC may be necessary for accurate assessment of pulmonary hemodynamics in patients with POPH.
Unique cases
POPH and HPS are two distinct diseases, with completely different mechanisms of action. However, case reports can be found that describe the spontaneous resolution of HPS, followed by the development of PAH over many months [88], [89], [90], [91]. This transition has mainly occurred in the setting of cirrhosis with cessation of alcohol use. Case reports also exist that demonstrate the development of POPH after LT in patients with preexisting HPS [92]. Only one published case has suggested the
Pediatric considerations
POPH is not a disease unique to adults, but affects the pediatric population as well. A recent report in The Journal of Pediatrics summarizes the clinical course of seven patients with POPH [94]. Causes of underlying portal hypertension included biliary atresia, cavernous transformation of the portal vein, primary sclerosing cholangitis, and cryptogenic cirrhosis. The median interval between diagnosis of portal hypertension and POPH was 12.1 years. The symptoms that prompted evaluation for POPH
Summary
POPH is characterized by the obstruction of pulmonary arterial blood flow as a consequence of portal hypertension. This obstruction is more than simple vasoconstriction of the pulmonary vasculature, as pathologic changes such as plexogenic arteriopathy can be demonstrated. As this vasculopathy progresses, pulmonary vascular resistance increases to the point of right-sided heart failure, and eventually death [4].
The absence of a good animal model coupled with the rarity of POPH has not allowed
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