EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Hepatopulmonary syndrome and portopulmonary hypertension are complications of portal hypertension with opposing mechanisms that can coexist. Moderate portopulmonary hypertension, which is a contraindication to a liver transplant, must be managed with pulmonary vasodilators to normalize pulmonary arterial pressures before a transplant listing. Concomitant hepatopulmonary syndrome complicates the management of portopulmonary hypertension, as pulmonary vasodilators can theoretically exacerbate the intrapulmonary dilatation believed to cause hepatopulmonary syndrome. We describe a case of a post-liver transplant patient with concomitant hepatopulmonary syndrome and portopulmonary hypertension safely treated with sildenafil.

Key words : Phosphodiesterase-5 inhibitor, Portal hypertension, Pulmonary arterial hypertension

Hepatopulmonary syndrome and portopulmonary hypertension are 2 distinct pulmonary vascular complications of portal hypertension.¹ Portopulmonary hypertension is defined as elevated pulmonary artery pressure (mean ≥ 25 mm Hg at rest or > 30 mm Hg during exercise) and increased pulmonary vascular resistance (>240 dyne.s-1.cm-5) associated with portal hypertension. Hepatopulmonary syndrome is characterized by hypoxemia and intrapulmonary vascular dilatation thought to result from decreased hepatic clearance of pulmonary vasodilators. Treatment of portopulmonary hypertension consists of pulmonary vasodilators. This is based on small case series and extrapolation from evidence for idiopathic pulmonary arterial hypertension and liver transplant. Liver transplant is the only effective treatment for hepatopulmonary syndrome, with resolution of dyspnea in most patients after transplant.

Hepatopulmonary syndrome and portopulmonary hypertension are both indications for liver transplant; however, half of the patients with moderate portopulmonary hypertension (mean pulmonary pressure ≥ 35 mm Hg) die soon after liver transplant.2 The 2013 American Association for the Study of Liver Diseases guidelines for evaluating liver transplant recommend offering liver transplant to patients with moderate portopulmonary hypertension who respond to pulmonary vasodilators.² It is often believed that hepatopulmonary syndrome and portopulmonary hypertension are mutually exclusive clinical conditions, as the former is associated with pulmonary vasodilatation, and the latter with increased pulmonary vascular resistance. In fact, as many as 71% of patients with portopulmonary hypertension may have intrapulmonary vascular dilatation identified by contrast-enhanced echocardiography,³ and the 2 conditions can coexist. This makes treating these patients problematic, as treating portopulmonary hypertension with pulmonary vasodilators in the setting of coexisting hepatopulmonary syndrome could result in worsening hypoxia. There is a paucity of data regarding response to treating portopulmonary hypertension with coexisting hepatopulmonary syndrome, especially in the post-liver transplant setting. We report a case of a post-liver transplant patient with concomitant hepatopulmonary syndrome and portopulmonary hypertension treated with sildenafil.

A 58-year-old woman with history of suspected hepatopulmonary syndrome and liver transplant was transferred to our tertiary referral hospital 5 years after the transplant to investigate portopulmonary hypertension and hepatopulmonary syndrome and suitability for retransplant after an episode of severe hypoxemic respiratory failure.

Relevant medical history included orthotopic liver transplant for end-stage liver disease secondary to chronic hepatitis C with recurrent hepatitis C genotype 3 infection leading to allograft cirrhosis; esophageal varices; and chronic kidney disease. Medications before admission included tacrolimus (0.5 mg orally twice daily), mycophenolate mofetil (500 mg orally twice daily), gabapentin (600 mg orally twice daily), ramipril (2.5 mg orally once daily), rabeprazole (20 mg orally twice daily), and magnesium (250 mg orally twice daily).

Dyspnea and hypoxemia first occurred before the liver transplant. This was treated with supplemental oxygen initiated 3 days before the liver transplant, and weaned off approximately 1 month later. This led to a suspected diagnosis of hepatopulmonary syndrome before the transplant that improved with the transplant. Over the next 5 years, she required only intermittent supplemental oxygen, mostly at bedtime.

Five years after the transplant, she presented to her local hospital with acute dyspnea and progressively increasing supplemental oxygen requirements. Admission laboratory values were all unremarkable. Hypoxemia progressed despite high-flow oxygen (oxygen saturation 92% with Optiflow at fraction of inspired oxygen of 0.7), appropriate intravenous antibiotic treatment and aggressive diuresis for suspected pneumonia and right ventricular failure secondary to volume overload. She was transferred to our tertiary care center for further investigations and management.

Pulmonary function tests recently performed demonstrating isolated reduction in diffusion capacity (38% predicted), with no obstructive or restrictive features. A chest computed tomography performed at the local hospital showed no pulmonary, pleural, or mediastinal abnormalities, and a follow-up lung ventilation/perfusion nuclear medicine scan identified no perfusion mismatch. Contrast-enhanced echocardiography revealed normal right ventricular size and systolic function, severe pulmonary hypertension, and intrapulmonary shunting.

Right heart catheterization showed mean right atrial pressure 10 mm Hg, pulmonary capillary occlusion pressure 11 mm Hg, pulmonary artery pressure 55/23 mm Hg (mean, 36 mm Hg), cardiac index 3.4 L/min/m2 (measured by thermodilution), pulmonary vascular resistance of 296 dyne.s.cm5, and no intracardiac left-to-right shunt, consistent with moderate pulmonary artery hypertension.

Based on these investigations, the diagnosis of coexisting hepatopulmonary syndrome and moderate portopulmonary hypertension was made. Candidacy for repeat liver transplant was deemed to be dependent upon the ability to normalize pulmonary pressure (mean < 35 mm Hg), and maintain normal right ventricular function. Sildenafil was started at 12.5 mg (orally 3 times daily), and increased to 25 mg (orally 3 times daily) the following day without hypotension or increased oxygen demands.

On a 3-month outpatient follow-up, the patient reported significant improvement in respiratory status and exercise tolerance. Home nasal cannula oxygen use was occasional at rest, 3 litres with exertion, and 2.5 litres nocturnally. She reported some dyspnea on exertion and occasionally with activities of daily living. She reported occasional lightheadedness, but denied syncopal or presyncopal episodes and chest pain. Relevant physical examination findings included office blood pressure of 140/100 mm Hg, resting oxygen saturation of 93% on room air, and no signs of heart failure.

On a 6-minute walking test on room air, the patient walked a total of 269 metres, stopping because of dyspnea and desaturating to 88% on room air. An echocardiogram on April 22, 2015, revealed normal biventricular systolic function and normal right ventricle size. Right heart catheterization performed on May 22, 2015, revealed slightly decreased pulmonary arterial pressure of 48/24 mm Hg (mean 35 mm Hg), pulmonary vascular resistance of 208 dyne.s.cm5 and improved cardiac index of 3.8 L/min/m². She is currently followed and assessed by the liver transplant program.

This case report is the first in the literature to demonstrate safe use of sildenafil to treat portopulmonary hypertension in the presence of coexisting hepatopulmonary syndrome. The hypoxia of hepatopulmonary syndrome results from intrapulmonary shunting and impaired alveolar oxygen diffusion thought to be due to accumulation of endogenous pulmonary vasodilators.¹ Thus, the use of a pulmonary vasodilator (eg, sildenafil) could theoretically worsen the intrapulmonary dilatation, exacerbating hepatopulmonary syndrome.

In 1 case report illustrating this hypothesis, hepatopulmonary syndrome was diagnosed after worsened dyspnea upon initiation of sildenafil to treat portopulmonary hypertension.⁴ Further testing revealed intrapulmonary vascular dilatation on contrast-enhanced echocardiography that worsened after administration of sildenafil, with a concomitant decrease in PaO₂ from 84 mm Hg down to 56 mm Hg. Conversely, other reports that describe patients whose hepatopulmonary syndrome resolved after the development and progression of portopulmonary hypertension did not demonstrate recurrence of hepatopulmonary syndrome after initiating pulmonary vasodilators.^5,6

When considered in the context of the best-available literature, our case report suggests that sildenafil, initiated in a carefully monitored setting, may be safely used for portopulmonary hypertension with coexisting hepatopulmonary syndrome to lower pulmonary pressure to meet liver transplant criteria. Further research should clarify the effect of coexisting hepatopulmonary syndrome on liver transplant outcomes of patients with portopulmonary hypertension treated with pulmonary vasodilators.

Volume: 15 Issue: 6 December 2017

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