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).

Table 78-1 Major Pulmonary Consequences of Portal Hypertension (with or Without Cirrhosis)

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.

Pathophysiology

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.

Hepatopulmonary Syndrome

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.)

Portopulmonary Hypertension

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).

Table 78-2 Pulmonary Hemodynamic Patterns Associated with Advanced Liver Disease

Hepatic Hydrothorax

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).

Alpha_l-Antitrypsin Deficiency

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).

Diagnosis

Hepatopulmonary Syndrome

The HPS diagnosis is established by demonstrating pulmonary vascular dilation as the cause for hypoxemia. Hypoxemia is usually defined as PaO₂ less than 80 mm Hg or alveolar-arterial oxygen gradient greater than 15 to 20 mm Hg. Two noninvasive methods are available to document abnormal pulmonary vascular dilation. Qualitatively, a positive contrast-enhanced transthoracic echocardiogram reflects the passage of microbubbles (usually absorbed during a first pass through normal lungs) through dilated pulmonary vessels, with subsequent detection in the left atrium. Quantitatively, an abnormal brain uptake of technetium-labeled macroaggregated albumin (^99mTc MAA) (uptake > 6%) after lung perfusion reflects the passage of radiolabeled albumin aggregates through the lungs and subsequent uptake in the brain (Figure 78-2). Contrast echocardiography is more sensitive than ^99mTc lung scanning to detect pulmonary vascular dilation. A lung biopsy is not necessary. Figure 78-3 provides a practical clinical algorithm for the evaluation of suspected HPS.

Figure 78-2 Lung perfusion scan with quantified technetium 99 (^99mTc) macroaggregated albumin (MAA) abnormal uptake over the brain. GM, geometric mean; NM, nuclear medicine.

Figure 78-3 Current screening and diagnostic algorithm at the Mayo Clinic for patients with suspected hepatopulmonary syndrome (HPS).

Portopulmonary Hypertension

Screening for pulmonary hypertension is accomplished by transthoracic Doppler echocardiography. Increased right ventricular systolic pressure (RVSP) greater than 50 mm Hg suggests but does not prove clinically significant POPH. A right-sided heart catheterization must be accomplished to establish the diagnosis. Figure 78-4 provides a screening algorithm used at the Mayo Clinic; clinicians may have other criteria to determine candidates for right-sided heart catheterization. Most centers adhere to the triad of mean pulmonary artery pressure (MPAP) greater than 25 mm Hg, normal pulmonary capillary wedge pressure (PCWP) less than 15 mm Hg, and increased pulmonary vascular resistance (PVR) greater than 240 dynes.sec.cm⁻⁵) as definitive criteria for POPH. A lung biopsy is neither necessary nor advised. Chronic pulmonary emboli should be excluded.

Figure 78-4 Screening, diagnostic, and staging algorithm followed at the Mayo Clinic for patients with portopulmonary hypertension (POPH). RVSP, right ventricular systolic pressure; MPAP, mean pulmonary artery pressure; PAOP, pulmonary artery occlusion pressure (pulmonary capillary wedge pressure); CO, cardiac output; PVR, pulmonary vascular resistance; TPG, transpulmonary gradient; PASP, pulmonary artery systolic pressure.

Hepatic Hydrothorax

This is a clinical diagnosis based on the chest radiograph showing a pleural effusion that can be right-sided (70%), left-sided (15%), or bilateral (15%). Thoracentesis is usually performed only when dyspnea is extreme, or atypical symptoms (e.g., pain, fever) exist suggesting another process such as empyema or metastatic hepatocellular carcinoma. Hepatic hydrothorax may occur in the absence of clinical ascites.

Alpha₁-Antitrypsin Deficiency

Pulmonary dysfunction in the setting of severe α₁-antitrypsin deficiency should be established by standard PFTs, to assess degree of expiratory airflow limitation and hyperinflation, and high-resolution CT (HRCT) of the chest, to assess for subclinical emphysema, bullae, and bronchiectasis. A combination of abnormal serum genotypes (usually ZZ or SZ, with MM normal) and decreased α₁-antitrypsin level confirms the diagnosis.

Sleep-Disordered Breathing

Overnight oximetry (OvOx) using finger pulse monitoring to screen for abnormal nocturnal oxygenation is inexpensive and clinically important. Abnormal OvOx abnormalities include frequent and severe hemoglobin desaturation (Figure 78-5). These abnormalities are common in LT candidates despite a lack of daytime somnolence. Abnormal OvOx is associated with massive ascites, encephalopathy, and increased baseline alveolar-arterial oxygen gradients. If OvOx is abnormal, formal polysomnography (PSG; overnight sleep study with multiple variable noninvasive monitoring) should be conducted. PSG is the “gold standard” to diagnose specific sleep-disordered breathing etiologies.

Figure 78-5 Overnight oximetry (OvOx) tracing of hemoglobin saturation by oxygen (SaO₂) via finger tip monitoring. A, Normal. Minimal variations in SaO₂ and no drops in SaO₂ below 90% saturation. B, Desaturator: defined as SaO₂ less than 90% more than 10% of sleep time; and frequent drops in SaO₂ greater than 4%.

Clinical Course

Hepatopulmonary Syndrome

Few data exist to characterize the clinical course in HPS. In the largest series to date, 5-year survival associated with LT was 76% versus 23% in non-LT group (Figure 78-6). Complete resolution of HPS often follows LT; the time to resolution is directly related to the severity of hypoxemia and may take months. Mortality is rarely a direct consequence of hypoxemia.

Figure 78-6 Long-term outcome (5-year and 10-year survival) in patients with hepatopulmonary syndrome, lung transplant (LT) cohort versus no lung transplant (no-LT) cohort.

(From Iyer V et al: Liver Transpl 17:S130, 2011).

Portopulmonary Hypertension

The 5-year survival without pulmonary vasodilator treatment is 4% to 14%. Mortality is equally the result of progressive right-sided heart failure and the complications related to liver disease. Long-term survival benefit has been noted with 24-hour continuous IV epoprostenol therapy in POPH versus no treatment. Despite pulmonary vasomodulating therapy, successful outcome during and after LT remains problematic and unpredictable. Despite aggressive therapy, POPH may resolve, remain stable, or progress following LT.

Alpha₁-Antitrypsin Deficiency

In patients with the ZZ phenotype, long-term survival is significantly reduced in smokers. No data describe the long-term outcomes in patients with ZZ phenotype, cirrhosis, and pulmonary function abnormalities, with or without LT. The risk of liver cancer increases with age in ZZ patients.

Sleep-Disordered Breathing

The effect of arterial hypoxemia (nocturnal or daytime) on hepatic function that may already be impaired is poorly understood. Better nocturnal oxygenation using supplemental oxygen or airway devices may significantly improve quality of life, as well as ameliorate cardiovascular dysfunction (rhythm disturbances, systemic hypertension).