Chapter 78 Hepatic and Biliary Disease
The pulmonary consequences of liver disorders can be classified according to whether they predominantly affect the pleural space, the lung parenchyma, or the pulmonary circulation. Unique pulmonary abnormalities occur in patients with severe alpha1-antitrypsin deficiency, primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). The impact of hepatic dysfunction on the respiratory system during sleep has recently been appreciated (Table 78-1).
HCV, hepatitis C virus; NSIP, nonspecific interstitial pneumonia; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; SaO2, arterial oxygen saturation; UIP, usual interstitial pneumonia.
Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH) are the major pulmonary vascular problems that complicate portal hypertension from any cause. HPS, a pulmonary vascular dilation abnormality leading to arterial hypoxemia, occurs in 5% to 15% of patients with portal hypertension. POPH, resulting from pulmonary vascular obstruction or obliteration, has been reported in 4% to 16.5% of patients with advanced liver disease. Pleural effusions related to the formation of ascites develop in 5% to 10% of cirrhotic patients.
Pulmonary function abnormalities can be demonstrated in approximately 50% of patients with advanced liver disease. The most common abnormality is a reduced diffusing capacity for carbon monoxide (DLCO). Abnormal oxygenation measured by increased alveolar-arterial oxygen gradient or reduced arterial oxygen tension (PaO2) is common (40%-50%). Nocturnal oxygenation abnormalities are also common (~50%) and underdiagnosed in patients with advanced liver disease.
Portal hypertension appears to be a prerequisite for the development of either HPS or POPH. Previous portosystemic surgical shunts have been reported in up to 30% of patients with POPH. Conditions leading to abnormal ascites usually precede the development of pleural effusions (“hepatic hydrothorax”). Smoking in the setting of ZZ or SZ α1-antitrypsin deficiency genotypes leads to the greatest risk of emphysema and varying degrees of expiratory airflow obstruction. The Child-Pugh classification for the severity of liver diseases correlates poorly with most pulmonary consequences, with the exception of hepatic hydrothorax. The epidemic of hepatitis C disease does not appear to be related to any unique or common pulmonary abnormality, but the use of interferon-alpha to treat hepatitis C virus (HCV) infection is associated with well-documented drug-induced pulmonary side effects. The clinical presence of ascites or encephalopathy, as well as narcotic and sedative use, appears to predispose to abnormal overnight oximetry and sleep-disordered breathing.
Circulating mediators, associated with the probable genetic predisposition, appear to cause HPS or POPH. Such mediators (causing vasodilation or vasoproliferation, respectively) could arise because of the abnormal metabolism of the dysfunctional liver. However, such specific circulating mediators have yet to be identified in humans.
HPS is characterized by arterial hypoxemia caused by precapillary-capillary dilations or direct arteriovenous communications. Excess perfusion for a given area of ventilation, diffusion limitation, and true anatomic shunting contribute to the degree of abnormal arterial oxygenation (Figure 78-1). Increased concentrations of exhaled nitric oxide have been demonstrated in HPS. Animal models of HPS have found upregulation of endothelin B receptors causing vasodilation and evidence of angiogenesis.
Figure 78-1 Mechanisms of arterial hypoxemia in hepatopulmonary syndrome. A, Normal ventilation and evenly matched perfusion; no anatomic shunts. B, Many capillaries are dilated with blood flow that is not uniform, and ventilation-perfusion excess mismatch occurs. Restricted oxygen diffusion into the center of the dilated capillaries occurs. Anatomic shunts that bypass the alveoli can develop. Hypoxemia evolves from each of these abnormalities.
(From Rodriguez-Roisin R, Krowka MJ: N Engl J Med 358:2378–2387, 2008.)
POPH results from vasoproliferation (endothelium and smooth muscle), along with in situ thrombosis, which causes an increased pulmonary vascular resistance (PVR) to arterial flow. It is important to note the various pulmonary hemodynamic patterns that may exist in the patient with advanced liver disease (Table 78-2).
Hepatic hydrothorax is a transudative pleural effusion caused by the formation of ascitic fluid. A combination of negative pleural pressure and positive abdominal pressure forces ascitic fluid into the pleural spaces through diaphragmatic defects and lymphatics. Rarely, the fluid may be chylous; infected pleural fluid may occur in the presence of spontaneous bacterial peritonitis.
Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis
PBC has systemic manifestations presumably because of autoimmune phenomena. Pulmonary granulomas, lymphocytic infiltrates, and organizing pneumonia can result. Rarely, both PBC and PSC may be associated with airway inflammation, hilar adenopathy, and mediastinal adenopathy (noncaseating granulomas found at biopsy).
Severe deficiency of the circulating alpha-1 protein is caused by single point mutations in the synthesis of this protein within hepatocytes. Accumulation of polymerized protein within the endoplasmic reticulum of hepatocytes leads to clinically significant deficiency in serum α1-antitrypsin (especially in ZZ and SZ genotypes). Such deficiency subsequently leaves neutrophil elastase unopposed within the lung, causing lung damage (panacinar emphysema and bronchiectasis).