Hepatopulmonary Syndrome

Physiologic abnormality

Diagnostic criteria

Impaired gas exchange

Arterial blood gas sampling while breathing ambient air with:

PaO₂ < 80 mm Hg or

Alveolar–arterial oxygen gradient ≥ 15 mmHg if age <65 years, or ≥ 20 mmHg if age ≥ 65 years^a

Intrapulmonary shunting

Transthoracic echocardiogram with agitated saline demonstrating “late passage” (after >3 cardiac cycles) of bubbles into left atrium

Radiolabeled macroaggregated albumin scan with a brain shunt fraction of >6 %

Liver disease

Cirrhosis and/or portal hypertension^b

No specific defined testing required, but other causes of hypoxemia must be ruled out^c

^aAaPO₂ = (FiO₂[P _atm − PH₂O] − [PCO₂/0.8]) − PaO_2, where PaO₂ represents partial pressure of arterial oxygen, FiO₂ fraction of inspired oxygen, P _atm atmospheric pressure, PH₂O partial pressure of water vapor at body temperature, and PaCO₂ partial pressure of arterial carbon dioxide (0.8 corresponds to the standard gas exchange respiratory ratio at rest)

^bPatients may have acute and/or chronic hepatitis in the absence of cirrhosis and/or portal hypertension, although nearly all patients with HPS have cirrhosis

^cTesting may include high-resolution pulmonary CT scanning to assess for parenchymal abnormalities, or pulmonary function testing to evaluate for obstructive or restrictive defects

Epidemiology of Hepatopulmonary Syndrome

The true prevalence of HPS among all patients with cirrhosis is unknown. Published estimates from case series and multicenter studies are that anywhere from 8 to 35 % of patients with cirrhosis have HPS. The upper bound of these estimates derives from a cohort of patients being evaluated for liver transplantation (LT) in the USA [1, 5, 7, 8]. However, an even greater proportion of patients with cirrhosis have evidence of intrapulmonary shunting without hypoxemia, underscoring the need to screen patients for HPS with pulse oximetry [9, 10]. Although HPS is classically described as occurring only among cirrhotics with portal hypertension, it has been described in the setting of acute or chronic hepatitis, or chronic liver disease with advanced fibrosis but not cirrhosis [11–13].

Pathophysiology of Hepatopulmonary Syndrome

Our current understanding of the pathogenesis of HPS draws from experimental studies using animal models (Fig. 18.1). The presence of cirrhosis leads to increased mediators of endothelial injury within the lungs. Animal models of HPS demonstrate that these endothelial cells lead to the production of compounds which result in pre- and post-capillary dilatation of the pulmonary vasculature, and subsequent intrapulmonary shunting of blood that characterizes HPS [14, 15]. Compounding these vascular dilations is decreased capillary tone within the pulmonary vasculature due to mechanistic pathways involving angiogenesis, remodeling, and vasculogenesis [16, 17].

Fig. 18.1

Pathogenesis of hepatopulmonary syndrome. HPS hepatopulmonary syndrome, ET endothelin, TNF tumor necrosis factor, CO carbon monoxide, NO nitric oxide, Pakt phopsho-Akt, p-ERK phosphor-ERK

Clinical Manifestations of Hepatopulmonary Syndrome

A symptomatic patient with HPS may present with a constellation of complaints and physical exam findings described below; conversely, the disease can manifest only as asymptomatic hypoxemia. Nearly 50 % of cirrhotic patients with HPS being evaluated for LT may complain of dyspnea [7]. However, several other potential etiologies for these symptoms commonly exist in this patient population and must be evaluated in order to diagnose HPS. Patients with large-volume ascites may complain of dyspnea due to decreased thoracic compression by abdominal contents. Other cardiopulmonary conditions, including obstructive sleep apnea, chronic obstructive pulmonary disease, and congestive heart failure are common in this population, and may lead to dyspnea [7].

Dyspnea due to HPS may occur with either exertion or at rest, but patients may also note exacerbation of dyspnea while upright. This symptom which can be seen in other disease states is platypnea. It is manifest as worsening dyspnea, while in the upright position compared with the supine position, as distinct from worsening of shortness of breath in the supine position (orthopnea) that is classically ascribed to congestive heart failure [7]. Platypnea is thought to be caused by preferential shunting of blood to the lower lung fields in the upright position, where there are a greater number of intrapulmonary vascular dilations that cause right-to-left shunting of blood within the pulmonary vasculature.

On physical exam, patients may have stigmata of chronic liver disease that include muscle wasting, jaundice, or abdominal distention due to ascites. Spider angiomata, which are dilated blood vessels on the surface of the skin found in a subset of patients with cirrhosis, are more commonly seen in patients with HPS [7]. Distal cyanosis or clubbing may be present; however, either of these findings may also be seen in patients with cirrhosis, irrespective of HPS, and/or in patients with chronic lung disease. The sensitivity of any of these clinical signs for characterizing HPS is low, as they are reported in a limited (10 %) subset of HPS patients [7].

By definition, patients with HPS must have some degree of arterial hypoxemia, which will manifest clinically as hypoxia measured using standard pulse oximetry. Although an arterial blood gas is needed for diagnosing HPS, since pulse oximetry may overestimate arterial oxygenation in this patient population, pulse oximetry remains a key tool for identifying HPS in at-risk patients with chronic liver disease. An oxygen saturation on pulse oximetry (SpO₂) of ≤ 97 % has a 96 % sensitivity and positive likelihood ratio of 3.9 for detecting arterial hypoxemia, with a cutoff value ≤ 94 % identifying all subjects with a PaO₂ < 60 mmHg [9]. The degree of hypoxemia may be exaggerated when a patient with HPS moves from the supine to upright position—this decrease in oxygen saturation being called orthodeoxia, the laboratory correlate to platypnea. Due to preferential shunting of blood to other lung fields in the upright position, there is increased ventilation/perfusion (V/Q) mismatch that causes a decrease in patient’s SpO₂ when moving from the supine to upright position [17].

Diagnosis of Hepatopulmonary Syndrome

Figure 18.2 highlights a proposed diagnostic algorithm to evaluate a patient with cirrhosis for HPS. The first step is the measurement of room air oxygen saturation in order to detect HPS at an early stage, or in an asymptomatic patient. A detailed description of the required diagnostic elements for HPS is described below.

Fig. 18.2

Diagnostic algorithm for hepatopulmonary syndrome. HPS hepatopulmonary syndrome, PaO ₂partial pressure of arterial oxygen, A–a gradient alveolar–arterial gradient, TTE transthoracic echocardiogram, TEE transesophageal echocardiogram, COPD chronic obstructive pulmonary disease

Hypoxemia: The intrapulmonary shunting of blood through the pulmonary vasculature without being exposed to the high oxygen environment leads to arterial hypoxemia. While pulse oximetry is an accurate screening test for HPS, arterial blood gas sampling is required for the diagnosis. Two definitions of hypoxemia are accepted for the diagnosis of HPS: (1) PaO₂ < 80 mmHg or (2) A–a gradient ≥ 15 mmHg in subjects < 65 years of age, or ≥ 20 mmHg in those ≥ 65 years of age [7, 18]. However, the A–a gradient is the optimal measurement and diagnostic test as using a PaO₂ cutoff may lead to the underdiagnosis of HPS. The A–a gradient is a more objective measure of gas exchange, and accounts for the respiratory abnormalities commonly encountered in patients with cirrhosis. Specifically, the calculation of the A–a gradient requires both the PaO₂ and the partial pressure of carbon dioxide (PaCO₂). The hyperventilation commonly seen in cirrhotics may result in exhalation of increased levels of CO₂, which leads to a corresponding increase in PaO₂. For example, a patient with a PaCO₂ of 25 mmHg (normal 35–45 mmHg) and a PaO₂ of 85 mmHg has significant gas-exchange abnormalities as indicated by an A–a gradient of 33 mmHg, yet would not be diagnosed as HPS based on a cutoff of < 80 mmHg. Accordingly, National Institutes of Health-sponsored clinical trials of treatments for HPS rely on the A–a gradient as the oxygenation level inclusion criterion [19].

Intrapulmonary shunting: The second diagnostic criterion for HPS requires demonstration of intrapulmonary shunting of blood (right-to-left shunting) via pulmonary vascular dilations. The most commonly used imaging technique for identifying the right-to-left shunting of blood is a transthoracic echocardiogram (TTE) with agitated saline (also known as a “bubble echo”). This modality requires that a patient undergo a standard TTE with an intravenous injection of agitated saline that contains bubbles, while the heart is visualized in a four-chamber view. These microscopic bubbles are trapped in the pulmonary capillaries of normal subjects after passing from the right atrium through the right ventricle into the pulmonary artery. Yet, they may be shunted directly to the left side in the presence of atrial (i.e., atrial septal defect, patent foramen ovale) or ventricular abnormalities (i.e., ventricular septal defect), or intrapulmonary shunts as seen in HPS [20].

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