Acute Respiratory Failure and Pulmonary Complications in End-Stage Liver Disease

Nida Qadir, MD; Tisha Wang, MD; Igor Barjaktarevic, MD, PhD; Steven Y. Chang, MD, PhD


Semin Respir Crit Care Med. 2018;39(5):546-555. 

In This Article

Hepatopulmonary Syndrome

HPS is a pulmonary vascular disorder defined by the combination of liver disease, an increased alveolar–arterial (A–a) gradient with impaired arterial oxygenation, and evidence of intrapulmonary vascular dilatations at the capillary and precapillary levels, as demonstrated by a positive contrast-enhanced bubble echocardiogram.[12] HPS occurs in 4 to 47% of patients with liver disease referred to liver transplantation centers and occurs across the full range of etiologies of liver disease, regardless of the presence or absence of portal hypertension.[1] The severity of underlying liver disease does not predict the presence of HPS or the degree of associated hypoxemia.

Patients with HPS commonly present with dyspnea, platypnea, resting hypoxemia, progressive cyanosis, and orthodeoxia. Platypnea and orthodeoxia refer to dyspnea and arterial oxygen desaturation, respectively, that improve from the sitting to supine position, caused by the gravitational increase in blood flow and shunting through dilated vessels in the lung bases while in the seated position. The presence of orthodeoxia is highly specific for HPS in the context of underlying liver disease.[13] Cutaneous spider angiomas are also commonly seen in patients with HPS. In one study, clubbing had the highest positive predictive value for HPS and the absence of dyspnea had the highest negative predictive value.[14]

The etiology of HPS is unknown, but the hallmark of the condition—microvascular dilatation of the pulmonary arterial circulation—is felt to be at least partially related to nitric oxide (NO)-mediated pulmonary vasodilation.[15] An additional factor is the induction of pulmonary angiogenesis with vascular remodeling via vascular endothelial growth factor -A, which results in an increased absolute number of vessels in the lung, most of which are dilated.[16] Impaired hepatic clearance of intestinal endotoxins in the portal circulation with induction of tumor necrosis factor (TNF) may also play a role.[17] The vasodilatation of pulmonary vessels causes ventilation–perfusion mismatching, anatomical and functional right-to-left shunt physiology, and impaired lung diffusion due to decreased intrapulmonary blood transit time in the setting of an often hyperdynamic circulation, which all leads to hypoxemia.[12]

The diagnosis of HPS is confirmed by the demonstration of pulmonary vascular dilatation with transthoracic contrast-enhanced echocardiography, a highly sensitive imaging tool for detecting an intrapulmonary right-to-left shunt.[18] The severity should be assessed with an arterial blood gas to measure the A–a gradient and arterial oxygen tension. Nuclear scanning with technetium-labeled macroaggregated albumin is an alternative imaging study that can demonstrate right-to-left shunts. Although nuclear scanning cannot differentiate between intracardiac and intrapulmonary shunts, it can quantify shunt fraction by calculating the proportion of radionuclide uptake by the kidneys and the brain.[19] Computed tomography of the chest can be obtained to exclude other causes of hypoxemia, and can rarely show arteriovenous malformations although they are typically too small to be visualized on imaging.

Untreated, HPS carries a high mortality with a 5-year survival rate of 23%.[2] Medical therapies are limited and only OLT is curative.[12] Since 2002, donor liver allocation in the United States has been prioritized based on the Model for End-Stage Liver Disease (MELD) score and to account for the progressive deterioration of oxygenation among HPS patients while awaiting OLT, the United Network for Organ Sharing has granted additional MELD points for cases of significant HPS (room air partial pressure of oxygen [PaO2] < 60 mm Hg) to expedite transplantation.[20] The mainstay of treatment for HPS otherwise remains supplemental oxygen, although oral garlic supplementation has been shown to significantly improve oxygenation in a pilot study[21] and a subsequent small randomized controlled trial.[22] Pentoxifylline, a TNF-α inhibitor that decreases angiogenesis, has also been shown to be effective in improving PaO2 in animal studies and two pilot human studies.[23,24]

Additional medical therapies have a limited role in HPS, and OLT should be pursued in cases with severe and refractory hypoxemia. OLT has demonstrated consistent benefit in improving oxygenation and pulmonary vascular dilatation, with complete resolution of signs and symptoms of HPS observed in more than 80% of transplanted patients.[2] Recent literature has shown that even patients with severe hypoxemia (PaO2 < 50 mm Hg) have favorable survival rates with OLT that are comparable to survival rates in other conditions warranting OLT, although this should only be pursued at experienced centers.[3,25]