Fig. 11.9  Maximal intensity projection reconstructions showing dilated pulmonary veins and arteriovenous communications (black arrow), consistent with underlying Type-II HPS

ation in HPS patients, with concomitant decreases in portal vein pressure, but this beneft must be balanced against the increased rate of hepatic encephalopathy in these patients [107]. In select patients with Type-II HPS and large intrapulmonary shunts, embolization therapy has been reported to improve hypoxemia and dyspnea, but this remains an investigational approach [108] (Fig. 11.9). In summary, in HPS, supplemental oxygen is the only therapeutic modality with proven clinical beneft short of liver transplantation, which remains a limited resource.

Conclusion

PoPH and HPS are uncommon pulmonary vascular complications of chronic liver disease. Signs and symptoms are nonspecifc and are easily confused with the manifestations of chronic liver disease. Both conditions confer markedly increased morbidity and mortality in liver disease patients. Mechanisms of disease pathogenesis are unclear but likely involve vasoactive mediators affecting the pulmonary circulation and are likely mechanistically interrelated.

Although the exact circulating factors responsible for PoPH and HPS pathogenesis have yet to be identifed, current evidence suggests that abnormalities in the bone morphogenic protein system and dysregulation of ET-1, in the setting of hepatic dysfunction and portal hypertension, favor a state of excess angiogenesis, ECM breakdown, and vascular remodeling. Further hinting at the complex relationship between PoPH and HPS, both conditions can occur independently of one another, occur simultaneously in the same patient, or can transition from one to the other in an individual patient. With respect to the latter, two scenarios have

been proposed: (1) low resistance intrapulmonary vascular dilations’ characteristic of HPS effectively decreases the pulmonary vascular resistance, masking underlying PoPH until liver transplantation closes these vascular lesions, and (2) elevated pulmonary vascular resistance specifc to PoPH limits blood ow through intrapulmonary vascular dilations, hiding HPS until targeted pulmonary vasodilator augments cardiac output and worsens intrapulmonary shunting. Exciting research into the mechanistic relationship between PoPH and HPS is ongoing, including employing state-of-­ the-art techniques such as single-cell RNA sequencing that promise to resolve the common and divergent molecular pathways driving disease pathogenesis in these two disorders.

Given the signifcant impact PoPH and HPS have on prognosis, treatment, and candidacy and outcomes of liver transplantation, screening of all chronic liver disease and liver transplant candidates for these disorders is recommended by international guidelines. Pulmonary vasodilator therapy is the mainstay of therapy for PoPH, and although liver transplantation can be helpful in some cases, identifying the patients who are most likely to beneft is challenging. Liver transplant is generally curative in HPS; and the only other therapy demonstrated to have beneft is supplemental oxygen. Given the high morbidity and mortality of both conditions, maintaining a high index of suspicion to promote early diagnosis and management is imperative. As liver transplantation as a therapeutic option is limited and ­mechanisms of disease pathogenesis remain unclear, additional investigation of targeted therapeutics is crucial to promoting optimal patient outcomes in this high-risk population.

Clinical Vignette

A 50-year-old woman presented with increasing dyspnea on exertion and increased abdominal ascites for the past year. She had a history of hepatitis C virus and alcohol-induced liver cirrhosis and was currently undergoing liver transplant evaluation. She had never had an episode of variceal bleeding but had known esophageal varices that required banding. A contrast echocardiogram on admission (Fig. 11.10) reveals an elevated right ventricular systolic pressure as well as right ventricular dilation and impaired systolic function, suggestive of underlying pulmonary hypertension. There are also a few bubbles appearing in the left atrium after 4 cardiac cycles, but the patient does not demonstrate hypoxemia at rest, and has a normal arterial blood gas analysis. She subsequently undergoes a right heart catheterization, notable for a mean pulmo-

nary arterial pressure of 38 mmHg, a pulmonary capillary wedge pressure of 8 mmHg, and a calculated pulmonary vascular resistance of 6.4 Wood Units. A diagnosis of PoPH is made, and the patient is started on dual oral therapy with sildenafl three times a day, and macitentan once daily. Despite these interventions, the patient’s dyspnea progresses, and she is subsequently found to be hypoxemic at rest and placed on supplemental oxygen. A repeat right heart catheterization shows improved pulmonary vascular hemodynamics, with a mean pulmonary arterial pressure of 22 mmHg, and a pulmonary vascular resistance of 2.3 Wood Units. Contrast-enhanced echocardiogram testing is repeated, showing numerous bubbles appearing in the left atrium after 3 cardiac cycles, and resting room air arterial blood gas demonstrates an elevated alveolar-arterial gradient of 30 mmHg. The patient is subsequently diagnosed with HPS, undergoes an expedited liver transplant evaluation, and is placed on the transplant waiting list. Two months later, she undergoes a successful liver transplantation, and follow-up echocardiographic, right heart catheterization, and arterial blood gas testing is normal, indicating resolution of both PoPH and HPS.

Fig. 11.10  Representative contrast-enhanced transthoracic echocardiogram showing evidence of PoPH (including dilation of right atrium (thick white arrow) and a dilated and hypertrophied right ventricle (thick yellow arrow)) as well as evidence of HPS (bubbles present in left atrium and left ventricle after three cardiac cycles (thin white arrows))

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