Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPHTN) are the two major pulmonary vascular complications of liver disease. While HPS is characterized by low pulmonary vascular resistance, PPHTN is defined by the presence of elevated pulmonary vascular resistance. Given these seemingly opposing pathophysiologic mechanisms, these conditions were traditionally felt to be mutually exclusive. In this series, we present three patients with severe hepatopulmonary syndrome who had spontaneous resolution of their HPS with the subsequent development of PPHTN. To our knowledge, this is the largest case series presented of this phenomenon in nontransplanted patients. One proposed mechanism for the occurrence of this phenomenon involves dysregulation of the same vascular signaling pathway, which may lead to both pulmonary vascular dilatations and pulmonary arterial remodeling in the same patient. Another theory involves the possible differential binding of endothelin-1, a vasoactive signaling peptide that induces vasoconstriction when bound to receptor A and vasodilation when bound to receptor B. Although the mechanisms for this phenomenon remain unclear, it is important to be vigilant of this phenomenon as it may change the patient's overall treatment plan, especially in regard to appropriateness and timing of liver transplant.
Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPHTN) are two of the most common pulmonary complications of liver disease [
A 57-year-old Caucasian female with a history of cirrhosis secondary to nonalcoholic steatohepatitis as well as mild asthma presented with a two-year history of shortness of breath. The patient had been placed on supplemental oxygen for significant hypoxemia approximately 1 year after the onset of her shortness of breath. At the time of her presentation to our center, the patient was requiring 1 liter of supplemental oxygen per minute at rest and 3 liters per minute (L/min) with exertion. Her asthma was not felt to play a role in her dyspnea as it had been well controlled off bronchodilators for a period of greater than 10 years. Physical exam was notable for an oxygen saturation of 91% on 2 L/min of oxygen and mild digital clubbing. Her Model for End-Stage Liver Disease (MELD) score at the time of presentation to our center was 14. The patient’s computed tomography (CT) scan of the chest showed areas of mild ground glass opacities in the right upper lobe with adjacent pleural thickening and no evidence of thromboembolic disease. A wedge lung biopsy had previously been performed and the pathology had returned without evidence of interstitial fibrosis, vascular dilatations, intimal thickening, or arteriovenous malformations but did show nonspecific focal areas of eosinophilic vasculitis. Contrast-enhanced echocardiogram showed an estimated right ventricular systolic pressure (RVSP) of 31 to 36 mmHg and evidence of an intrapulmonary shunt. Pulmonary function tests (PFTs) showed an isolated impairment in diffusing capacity (DLCO) of 31% predicted. The patient also underwent a technetium 99-macroaggregate albumin scan that revealed a 17% right to left shunt. An arterial blood gas (ABG) on room air revealed a pH of 7.46, partial pressure of oxygen in the arterial blood (PO2) of 56 millimeters of mercury (mmHg), partial pressure of carbon dioxide in the arterial blood (PCO2) of 26 mmHg, and an alveolar-arterial (A-a) gradient of 61 mmHg. These findings were consistent with a diagnosis of hepatopulmonary syndrome and the patient was placed on the liver transplant (LT) list with a MELD exception for HPS. Prior to listing, the patient underwent a surveillance right heart catheterization (RHC) showing a mean pulmonary artery pressure (mPAP) of 21 mmHg and a normal pulmonary capillary wedge pressure (PCWP). Over the next three years, the patient’s shortness of breath and hypoxia gradually improved and she was slowly weaned off of oxygen (Figure
Sequence of events for Case
A 63-year-old Caucasian male with hepatitis C cirrhosis presented with a 4-year history of worsening dyspnea on exertion. He reported a history of platypnea and his symptoms had progressed to severe dyspnea with any activity. Approximately 1 year prior to presentation, the patient had been admitted to an outside hospital for hypoxemia and had been placed on supplemental oxygen. At the time of presentation to our center, the patient was using supplemental oxygen at 2 L/min at rest and 5-6 L/min with exertion. On physical exam, the patient’s oxygen saturation was 90% on 3 L/min of oxygen and he had marked digital clubbing and peripheral cyanosis. The patient’s MELD score at the time of presentation was 12. The patient’s CT scan of the chest showed mild peripheral pulmonary fibrosis and enlargement of the distal pulmonary arterioles and nontapering pulmonary vessels, suggestive of hepatopulmonary syndrome. Contrast-enhanced echocardiography revealed an RVSP of 29 mmHg and an intrapulmonary shunt. The patient’s pulmonary function tests demonstrated an isolated severe impairment in DLCO of 31% predicted. An ABG on room air revealed a pH of 7.45, PO2 of 58 mmHg, PCO2 of 28 mmHg, and A-a gradient of 57 mmHg. An oxygen shunt study with 100% oxygen given via face mask also revealed an elevated shunt fraction of 8.7%. Given these findings, the patient was diagnosed with severe HPS and listed for LT with a MELD exception. One year after his initial evaluation, the patient’s shortness of breath had improved and he no longer required supplemental oxygen (Figure
Sequence of events for Case
A 56-year-old Hispanic male with hepatitis C cirrhosis and associated hepatocellular carcinoma with a MELD score of 15 was evaluated for liver transplantation. Despite a relative lack of pulmonary symptoms, routine PFTs showed a diffusing capacity of 80% of predicted. An ABG on room air revealed a pH of 7.41, PO2 of 56 mmHg, PCO2 of 37 mmHg, and A-a gradient of 48 mmHg. A 100% oxygen shunt study revealed an elevated shunt fraction of 15.7%. A CT scan of the chest demonstrated no evidence of pulmonary parenchymal disease, and a contrast-enhanced echocardiogram performed revealed a pulmonary shunt consistent with HPS and an RVSP of 38 mmHg. Six months after his initial presentation, the patient presented to our center, again without pulmonary symptoms, and his hypoxemia had resolved with a room air oxygen saturation of 96% (Figure
Sequence of events for Case
Two of the most common pulmonary complications of end-stage liver disease are hepatopulmonary syndrome and portopulmonary hypertension. Hepatopulmonary syndrome is defined as a triad of liver disease, an elevated A-a gradient on room air, and evidence of intrapulmonary vascular dilatation [
Though HPS and PPHTN are clinically distinct entities with seemingly distinct pathophysiologies, they can very rarely occur simultaneously or sequentially in the same patient. The majority of cases of sequential development of PPHTN after HPS have been reported in patients who have undergone liver transplant. In a sense, patients go from being too “vasodilated” to too “vasoconstricted” after their underlying liver disease is resolved. A review of the literature has shown four cases in which pulmonary hypertension developed after liver transplantation in adult patients with preexisting hepatopulmonary syndrome [
The opposite—patients with existing PPHTN and the subsequent development of HPS—has also been reported in two separate case reports, one with a short time interval of days and one with a longer time interval of two years [
Why patients with portal hypertension develop both pulmonary complications of liver disease, whether simultaneously or transitioning from one to the other, remains unclear. Both PPHTN and HPS may be the result of abnormal angiogenesis of the pulmonary microcirculation induced by chronic liver disease. As compared to PPHTN which mostly involves small muscular pulmonary arteries, the vascular remodeling process in HPS involves more distal structures such as precapillary and capillary vessels. The dysregulation of the same vascular signaling pathway may lead to both pulmonary vascular dilatations and pulmonary arterial remodeling leading to PPHTN in the same patient [
In addition, one of our patients was given garlic during his HPS course because of its potential benefit [
To our knowledge, this is the largest case series reported of patients with clinically significant severe HPS with subsequent resolution of their HPS and hypoxemia with conversion to significant PPHTN. In every case, it changed the patients’ eligibility, status, and treatment plan prior to LT. It is extremely important to be aware of this phenomenon so that patients who have HPS are still continuously monitored for signs and symptoms of PPHTN. At our center, we continue routine screening of these patients with transthoracic echocardiograms annually. Ultimately LT has been shown to lead to resolution of both pulmonary vascular complications of liver disease but the timing is extremely crucial in both situations with LT proven to be high risk in patients with HPS and a PaO2 < 50 mmHg and in patients with PPHTN with a mPAP > 35 mmHg [