Gastroesophageal Reflux

Gastroesophageal reflux disease (GERD) is “a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications,” which are subclassified as esophageal and extraesophageal. Among the esophageal symptoms are episodes of chest pain, which may vary from recurrent mild retrosternal “heartburn” to acute crushing substernal distress indistinguishable from the pain of angina or even acute myocardial infarction (see also Chapter 31 ). Among the extraesophageal symptoms, chronic cough, chronic laryngitis, and refractory asthma have attracted the most attention, but other respiratory disorders include chronic obstructive pulmonary disease (COPD), chronic bronchitis, pulmonary aspiration complications (aspiration pneumonia, lung abscess, bronchiectasis), and pulmonary fibrosis.

Pathogenesis

Three basic GERD-associated mechanisms lead to respiratory disorders. First, gross aspiration-linked pulmonary syndromes are usually the result of free esophageal reflux with large-volume retrograde flow. Frequently, there is reduced basal lower esophageal tone and both impaired esophageal motility and clearance. Affected patients may have recurrent aspiration pneumonia, bronchiectasis, or pulmonary opacities. Endoscopic examination usually reveals severe anatomic changes, such as visible breaks or Barrett epithelialization of the distal esophagus.

The second pathogenic mechanism is related to the microaspiration of gastric contents from the proximal (upper) esophagus. Small-volume aspirates produce an exudative mucosal reaction in the larynx and in the tracheobronchial tree. Respiratory symptoms are less obvious and range from hoarseness or chronic cough to difficult-to-control asthma. Jack and coworkers, using simultaneous tracheal and esophageal pH measurements in asthmatics with GERD, showed episodes of reflux that were followed by a fall in intratracheal pH; episodes with a fall in intratracheal pH resulted in a marked fall in peak expiratory flow rate that was several times greater than that observed when reflux was not followed by a change in intratracheal pH ( Fig. 93-1 ). Accordingly, microaspiration into the bronchial tree not only takes place but also may induce an important increase in airway resistance.

Graphs showing simultaneous esophageal ( solid blue squares ) and tracheal ( solid beige triangles ) pH measurements in four patients with both gastroesophageal reflux and asthma, along with recordings of peak expiratory flow rate (PEFR, solid pale-green circles ), over a 24-hour period.

In the study, there were 37 significant falls in esophageal pH suggestive of gastroesophageal reflux. Five of these episodes were followed by a fall in tracheal pH (from a mean of 7.1 to 4.1) and were associated with a significant decrease in PEFR (mean change −84 ± 16 L/min), whereas during the remaining 32 episodes of gastroesophageal reflux without tracheal aspiration, the mean change in PEFR was minimal (−8 ± 4 L/min). Gray areas show when the patient is supine. Arrows show episodes of falls in esophageal pH, tracheal pH, and PEFR.

(From Jack CI, Calverley PMA, Donnelly RJ, et al: Simultaneous tracheal and oesophageal pH measurements in asthmatic patients with gastro-oesophageal reflux. Thorax 50:201–204, 1995.)

Lastly, the third pathogenic mechanism linked to GERD is gastroesophageal reflux activation of a vagal reflex acting between the distal (lower) esophagus and the tracheobronchial tree; this reflex mechanism can be reproduced by the infusion of hydrochloric acid into the esophagus of some, but not all, patients with asthma.

The relationship between GERD and respiratory disorders is further complicated by the fact that physiologic alterations associated with asthma or cough, or with bronchodilator therapy, may themselves promote gastroesophageal reflux. Episodes of bronchospasm and cough are accompanied by an increase in the negative pressure within the thorax, and hence in the esophagus, which favors reflux; obstructive sleep apnea syndrome may act by the same mechanism to increase nocturnal reflux. In addition, hyperinflation and “gas trapping” may flatten the diaphragm, allowing the lower esophageal sphincter to be drawn up into the thorax and impairing the antireflux barrier. Bronchodilator therapy may also promote gastroesophageal reflux. Theophylline increases gastric acid secretion and decreases lower esophageal sphincter tone. Indeed, asthmatics with gastroesophageal reflux who receive theophylline show an increase in esophageal acid exposure and reflux symptoms. Specific β-adrenergic agents relax smooth muscle tone throughout the body thereby promoting gastroesophageal reflux. A decrease in lower esophageal sphincter pressure has been shown with β-adrenergic drugs administered orally or intravenously, but not when these agents were given by inhalation.

Inflammatory Bowel Disease

Extraintestinal complications of inflammatory bowel disease (IBD) have been described in virtually all organ systems; but, surprisingly, disease in the lungs appears “much less frequently” than manifestations in other organs. We say “surprisingly” because the gut and lungs share a common embryologic origin, and thus might possess similar vulnerability to immunologically mediated comorbidities. Pulmonary complications arise more commonly with ulcerative colitis than with Crohn disease; respiratory involvement may develop at any age, and some conditions (e.g., airway disease) appear more often in women than in men. In most cases, respiratory symptoms develop after the diagnosis of IBD has been made, frequently several years afterward. Nonetheless, respiratory symptoms can antedate or be concomitant with those of the bowel disease. Even in patients without symptoms, there may be impaired pulmonary function, such as a decrease in diffusing capacity for carbon monoxide (D l _CO ) and forced expiratory volume in 1 second, and an increase in residual volume and bronchial hyperresponsiveness. Reviews of published cases have confirmed and extended earlier observations about the noniatrogenic pulmonary complications of IBD, which can be classified as shown in Table 93-1 .

Most intrinsic (non–drug-related) pulmonary complications involve the airways—anywhere from the larynx to the bronchioles—and may take the form of epiglottitis, tracheal stenosis, bronchiectasis, chronic bronchitis, or bronchiolitis. Endoscopic examination shows marked erythema, swelling of the mucosa, and deformation of the airway lumen. Biopsy specimens have revealed mucosal ulceration, thickening of the basement membrane, and marked infiltration by neutrophils and plasma cells. In some cases, the inflammatory process in the subglottic area can take the form of pseudotumoral lesions, with the potential of producing life-threatening acute upper airway obstruction requiring aggressive airway management. This panoply of discrete airway pathology has been enriched by the addition of asthma, which proved to be the most common pulmonary comorbidity of both ulcerative colitis and Crohn disease identified in a large cohort. The association between IBD and asthma supports the belief that patients suffering from one autoimmune condition are more likely than the general population to have a second immune-mediated disorder, which may result from shared susceptibility genes.

Another major category of pulmonary complications of IBD is the group of parenchymal disorders, including interstitial lung diseases, such as cryptogenic organizing pneumonia, sarcoidosis, interstitial fibrosis, and pulmonary infiltration with eosinophilia. Pulmonary function test results in patients with IBD, even when asymptomatic and with normal chest radiographs, may reveal a variety of abnormalities. Probably the most common is an obstructive ventilatory defect, as described earlier, but pulmonary restriction is also well described. A reduction in D l _co during the active phases of IBD has been reported, which also suggests that subclinical pulmonary parenchymal involvement may be more prevalent than previously suspected. Furthermore, bronchoalveolar lavage examination in patients with Crohn disease—who did not have clinical evidence of pulmonary involvement—has revealed the presence of a lymphocytic alveolitis, chiefly owing to an increase of CD4-positive T lymphocytes.

Other pulmonary lesions include necrobiotic nodules, corresponding histologically to aggregates of neutrophils with areas of necrosis, which have been reported in a few patients. Serositis affecting the pleura or the pericardium, or both, has been reported in a small number of cases, especially during periods of increased disease activity. Finally, colobronchial fistulas have been reported in some cases of Crohn disease, the majority of them presenting with left lower lobe pneumonia. Involvement of the esophagus is rare in Crohn disease, but a few cases of bronchoesophageal fistula associated with esophageal Crohn disease have been reported. Although conservative management has been tried, most patients with fistulas require surgical treatment.

Pulmonary thromboembolic events and chronic thromboembolic pulmonary hypertension are more frequent in patients with IBD, even in those who are asymptomatic, than in control subjects. The study by Grainge and colleagues indicates that patients with stable IBD have a higher risk of venous thromboembolism than controls, ( hazard ratio [HR], 3.4); in addition, those patients with an IBD flare have an even higher incidence of thromboembolism (HR, 8.4). Because deep vein thrombosis and pulmonary embolism may be clinically silent, an early diagnosis of thromboembolism can be challenging, and the duration of systemic anticoagulation must take into account the individual risk of intestinal bleeding.

In addition, drugs are a frequent cause of pulmonary manifestations in patients with IBD. Antiinflammatory drugs, often the first step in the treatment of IBD, consist of aminosalicylates (sulfasalazine, mesalamine) and glucocorticosteroids. Immune system suppressors (azathioprine, methotrexate) and tumor necrosis factor- α (anti-TNF-α) inhibitors serve to maintain remission. Because most of these medications induce respiratory side effects, consequences of therapy must be considered in the differential diagnosis of new-onset lung disease; offending medications must be recognized and discontinued to prevent a potentially fatal outcome. The spectrum of medication-induced respiratory manifestations includes eosinophilic and granulomatous pneumonitis, interstitial lung disease, pulmonary fibrosis, and a heightened susceptibility to infections. Azathioprine increases the risk of both infection and disease by viruses, glucocorticosteroids by fungi, and TNF-α inhibitors by intracellular microorganisms (mycobacteria, fungi).

The majority of patients with pulmonary disorders associated with IBD are treated with glucocorticosteroids, either by inhalation or by mouth, which usually results in rapid control of symptoms, especially in those patients who do not have severe structural impairment (e.g., bronchiectasis). Lung transplantation has been performed in some patients with severe respiratory compromise associated with IBD.

Pleural Effusion

Pleural effusion develops in 5% to 10% of patients with cirrhosis of the liver and is traditionally referred to as hepatic hydrothorax in the absence of coexisting cardiopulmonary disease (see Chapter 79 ). Unless the pleural fluid is complicated by infection, hepatic hydrothoraces are transudates and are most commonly located in the right hemithorax. Effusions may also be left-sided or bilateral, and may or may not be associated with concurrent ascites. The effusion is usually mild to moderate in size and asymptomatic, but in some cases it can be massive and provoke shortness of breath. The mechanism is related to the presence of anatomic communications—usually small diaphragmatic defects—and to the prevailing pressure gradient between the abdominal and pleural cavities that facilitates movement of ascitic fluid into the chest. The presence of pleural fluid disturbs lung mechanics, resulting in decreased lung volumes and pulmonary compliance, and pulmonary gas-exchange abnormalities.

The clinical management of pleural effusion associated with liver disease is often difficult. Repeated thoracenteses have only transitory effects, and thoracostomy tube drainage may result in substantial protein loss. Transjugular intrahepatic portosystemic shunting decreases portal hypertension and, in turn, reduces the size of both the ascites and hydrothorax; transjugular intrahepatic portosystemic shunting is often beneficial, at least in the short term, but long-term outcome depends on the severity of the underlying liver dysfunction. If the patient is not a candidate for transjugular intrahepatic portosystemic shunting, other approaches, including video-assisted thoracoscopic surgery to repair diaphragmatic defects and/or induce a pleurodesis, should also be considered.

Pulmonary Function Disturbances

The most common lung function abnormality in patients with end-stage hepatic disease is a decreased D l _CO ; likewise, both obstructive and restrictive ventilatory defects have been observed. The coexistence of massive ascites can decrease lung compliance, increase pleural pressure, and reduce diaphragmatic motility. Together, these pathophysiologic alterations restrict ventilatory capacity and reduce the efficiency of gas exchange, causing increased alveolar-arterial P o ₂ difference values with or without clinically evident hypoxemia.

Hepatopulmonary Syndrome

Severe hypoxemia (arterial P o ₂ < 60 mm Hg) is uncommon in patients with uncomplicated chronic hepatic disease and, when present in patients without coexisting cardiopulmonary disease, should strongly suggest hepatopulmonary syndrome (HPS). Because patients with advanced liver disorders characteristically hyperventilate and are hypocapnic, measurement of the alveolar-arterial P o ₂ difference becomes more sensitive than arterial P o ₂ alone to detect gas-exchange disturbances in HPS.

HPS is rigorously defined as a syndrome characterized by a clinical triad: (1) advanced chronic liver disease; (2) arterial oxygenation defect, which ultimately leads to severe arterial hypoxemia; and (3) widespread pulmonary vascular dilations. The pulmonary gas-exchange disturbance is characterized by arterial oxygen desaturation that may be mild, moderate, severe, or extremely severe ( Table 93-2 ). There is an increased alveolar-arterial P o ₂ difference, commonly associated with hypocapnia and respiratory alkalosis. At sea level, while breathing ambient air, resting alveolar-arterial P o ₂ difference values at or above 15 mm Hg can be considered abnormal for most adults; for those older than 64 years, an alveolar-arterial P o ₂ difference equal to or above 20 mm Hg can be considered abnormal. Although HPS is prevalent in most kinds of common chronic liver diseases, it may also be seen in other unusual liver disorders such as Budd-Chiari syndrome.

The most conspicuous pathologic finding is pronounced vascular dilation of all peripheral branches of the pulmonary vasculature, at both the precapillary and capillary levels of the lung (15 to 150 µm in diameter), near the gas-exchange area in an otherwise intact pulmonary parenchyma.

Diagnosis

Systemic hypotension, a normal or low pulmonary artery pressure (P pa ), an inordinately high cardiac output, and a reduced pulmonary vascular resistance are the hemodynamic hallmarks of HPS. When the constellation of hypoxemia, normal or low P pa , spider nevi, and finger clubbing is observed in a patient with advanced liver disease, the diagnosis of HPS is likely.

The diagnostic criteria for HPS are as follows : presence of liver disease; gas-exchange abnormalities, more specifically an increased alveolar-arterial P o ₂ difference (>15 mm Hg), with or without concomitant arterial hypoxemia (arterial P o ₂ < 80 mm Hg); and a positive contrast-enhanced echocardiogram or an abnormal intravenous radiolabeled perfusion lung scan, or both. Additional features that can be useful for further establishing the diagnosis of HPS include a decreased D l _CO , dyspnea with or without platypnea and orthodeoxia (i.e., arterial hypoxemia that worsens by at least 5% or 4 mm Hg when the patient is upright vs. recumbent), and a hyperkinetic circulatory state with normal or low P pa . Although thoracic computed tomography scanning appears to be nonspecific, it may be used to exclude coexistent respiratory comorbidities.

Two-dimensional contrast-enhanced echocardiography appears to be the most sensitive and accurate noninvasive diagnostic procedure to identify right-to-left shunts by finding microbubbles of air in the left heart cavities within 3 to 6 beats of their visualization in the right-sided chambers ( Fig. 93-2 ) (seeVideo 61-1 ). Normally, echogenicity in the left chambers is not detected because the intravenously injected microbubbles (60 to 90 µm in diameter) are trapped in the pulmonary capillaries (8 to 15 µm in diameter). Contrast-enhanced echocardiography cannot distinguish among the different forms of pulmonary vascular deformities (i.e., precapillary, capillary, and pleural dilations vs. direct arteriovenous communications), but it can clearly differentiate them from intracardiac malformations, such as a patent foramen ovale, in which the microbubbles appear in the left heart almost simultaneously with their appearance in the right. Alternatively, the demonstration of technetium-99m-macroaggregated albumin activity over extrapulmonary organs (e.g., liver, spleen, kidneys, and brain) strongly suggests the presence of right-to-left shunting, because under normal conditions the albumin macroaggregates (20 to 60 µm in diameter) are completely trapped in the pulmonary capillary bed. This test does not distinguish between intrapulmonary and intracardiac shunting but can serve to estimate the severity of the shunt.

Contrast-enhanced echocardiograms in a patient with hepatopulmonary syndrome.

Left, Normal four-chamber view (LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle). Center, Injected microbubbles appear in the RV ( arrow ) . Right, Within five beats, microbubbles appear in the LV ( arrow ). The demonstration of microbubbles in the left cardiac chambers is highly suggestive of the presence of intrapulmonary vascular dilations, or, alternatively, of anatomic arteriovenous malformations. (See alsoVideo 61-1 .)

(Courtesy Dr. C. Paré, Hospital Clinic, Universitat de Barcelona, Barcelona.)

The prevalence of HPS ranges between 5% and 32%. Using contrast-enhanced echocardiography—the “gold standard” for identifying intrapulmonary vascular dilations—the prevalence of a positive echocardiography test in patients with chronic liver disease is approximately 20%. However, patients with a positive contrast-enhanced echocardiogram without coexisting gas-exchange disturbances, are considered to have a forme fruste of HPS whose natural history is not yet known.

Although data describing the natural history of HPS are scant, it appears that patients with HPS not undergoing liver transplantation worsen progressively and have an adverse outcome, with median survival of 41 months following the diagnosis of HPS. In a prospective study, HPS was an independent risk factor for poor prognosis in patients with cirrhosis; those with HPS had a significantly shorter median survival (approximately 11 months) than those without HPS (41 months), even after adjusting for differences in liver disease.

Gas-Exchange Abnormalities

When HPS is mild to moderate, the predominant mechanism of hypoxemia is ventilation-perfusion inequality, essentially due to the presence of areas in which ventilation is preserved but perfusion is profoundly increased. In contrast, when HPS is severe, increased intrapulmonary shunt develops and worsens along with coexisting ventilation-perfusion imbalance, and constitutes the primary abnormality. Collectively, with increasing severity of the liver dysfunction, there is greater systemic and pulmonary dilation, a lower hypoxic pulmonary vascular response, and a greater degree of ventilation-perfusion inequality, including increased intrapulmonary shunt. A “diffusion-perfusion defect” has also been postulated to explain an increased diffusion gradient for oxygen in dilated pulmonary capillaries ( Fig. 93-3 ). The contention is that pulmonary vascular dilation causes inadequate diffusion of oxygen to the center of the enlarged capillary. Moreover, the coexistence of a hyperkinetic state and the resulting shorter transit time of red blood cells would exaggerate this diffusion-induced gas-exchange disturbance.

Mechanisms of arterial hypoxemia in hepatopulmonary syndrome in a two-compartment gas exchange model.

A, In the homogeneous lung of a healthy individual, with uniform alveolar ventilation and pulmonary blood flow, the capillary ranges between 8 and 15 µm in diameter and oxygen diffuses properly into the capillary while ventilation-perfusion is well balanced. B, In hepatopulmonary syndrome, where many capillaries are dilated and blood flow is nonuniform, alveolar ventilation-to-pulmonary perfusion mismatch emerges as the predominant mechanism at any clinical stage, either with or without the presence of intrapulmonary shunt and coexistent with oxygen diffusion limitation into the center of the dilated capillaries in the most advanced stages.

(From Rodriguez-Roisin R, Krowka MJ: Hepatopulmonary syndrome—a liver-induced lung vascular disorder. N Engl J Med 358:2378–2387, 2008.)

Portopulmonary Hypertension

Pulmonary arterial hypertension (PAH) associated with portal hypertension—also known as portopulmonary hypertension (POPH)—is another mysterious pulmonary vascular disorder that appears to be associated with chronic hepatic disease. Because both the diagnosis and the outcome of POPH, particularly in relation to the therapeutic benefits of liver transplantation, appear to be substantially different from those of HPS, it is important to highlight the distinctions between the two disorders. POPH is defined by the following triad of hemodynamic abnormalities in a patient with portal hypertension: (1) mean P pa exceeding 25 mm Hg at rest; (2) mean pulmonary artery wedge pressure less than 15 mm Hg; (3) pulmonary vascular resistance greater than 240 dynes • sec ⁻¹ • cm ^–5 (normal, less than 130 dynes • sec ⁻¹ • cm ⁻⁵ ).

Various studies have estimated the prevalence of portopulmonary hypertension in those evaluated for liver transplantation as between 5% and 6%. Furthermore, findings from a large cooperative trial of 536 patients with portal hypertension established that female gender and associated autoimmune hepatitis conferred increased risk for development of POPH, whereas hepatitis C was associated with decreased risk.

In classic retrospective postmortem studies, the prevalence of histopathologic evidence of PAH in patients with liver cirrhosis or POPH (or both) ranged between 0.25% and 0.73%. In a case-control study conducted by the International Primary Hypertension Study Group, the incidence of primary (or idiopathic) PAH was found in 7.3% of patients with cirrhosis, 3.1% of those with human immunodeficiency virus infection, and none of the controls. According to these and subsequent observations, POPH has been classified as a category of PAH with hemodynamic criteria consistent with the standard classification and definition of PAH, as discussed in Chapter 58 (see Table 58-1 ).

From a histopathologic viewpoint, the vascular lesions in POPH are indistinguishable from those identified in idiopathic (primary) PAH (see Chapter 58 ), namely intimal thickening, smooth muscle proliferation, plexogenic pulmonary arteriopathy, and in situ thrombosis, all of which—plus vasoconstriction—contribute to the greatly increased pulmonary vascular resistance. Chemla and colleagues postulated that the portosystemic shunting of vasoactive agents such as thromboxanes, serotonin, bradykinin, and neuropeptide Y, which are normally metabolized by the healthy liver, may result in pulmonary arterial vasoconstriction; an attractive alternative hypothesis is that pulmonary endothelial dysfunction leads to a decreased production of the endogenous vasodilator NO.

The most common symptom of POPH is shortness of breath on exertion; patients may also experience chest pain, syncope, and hemoptysis. Radiographically, both an enlarged cardiac silhouette and a pulmonary artery prominence are noted in approximately one half to two thirds of patients with POPH. Overall, maximal airflow rates and lung volumes are normal or nearly normal, whereas D l _CO , arterial P o ₂ , and alveolar-arterial P o ₂ difference may be reduced, although less so than in HPS. Compared with patients with idiopathic PAH, patients with POPH have a lower mean P pa and a higher cardiac index and mixed venous oxygen saturation.

Transthoracic echocardiography is now done routinely in patients being considered for liver transplantation because the presence of POPH affects the outcome of surgery. Characteristic echocardiographic findings of idiopathic PAH in the setting of portal hypertension suggest, but do not prove, POPH. Right heart catheterization is needed to confirm the diagnosis. Until recently, it was believed that median survival in POPH was extremely poor; new information, however, indicates overall survival rates at 1 and 3 years of 88% and 75%, similar to that in patients with idiopathic PAH.

Treatment for POPH, however, remains challenging because there are no randomized controlled studies for guidance: available agents include epoprostenol, iloprost, sildenafil, and bosentan. In a retrospective study, the safety and efficacy of inhaled iloprost and bosentan were assessed in 31 patients with POPH for up to 3 years; although both agents were safe with regard to liver function, bosentan proved to be better than iloprost in improving exercise capacity, hemodynamics, and—of note—survival rates. Prospective trials are clearly needed to provide further guidance.

Primary Biliary Cirrhosis

Primary biliary cirrhosis, an autoimmune disease, is characterized by a chronic, cholestatic, granulomatous, and destructive process that involves the intrahepatic bile ducts. When severe, these processes result in cholestasis, cirrhosis, and liver failure. The autoimmunologic basis is reflected in the presence of several immunologic alterations, such as depressed T-suppressor cell function, hypergammaglobulinemia, and the presence of antimitochondrial antibodies. Connective tissue diseases such as the sicca complex, Sjögren syndrome, and scleroderma are frequently associated with primary biliary cirrhosis, which also has an association with POPH. Several respiratory abnormalities have been associated with primary biliary cirrhosis: interstitial lung disorders, such as lymphocytic interstitial pneumonitis and fibrosing alveolitis; subclinical intrapulmonary granulomas that mimic sarcoidosis ; increased numbers of CD4 ⁺ lymphocytes in the bronchoalveolar lavage fluid; and obstructive airway disease, such as bronchiectasis. Occasionally, the pulmonary manifestations precede the liver involvement. In addition, thoracic wall deformities secondary to osteopenic vertebral com­plications induced by abnormal vitamin D metabolism related to poor absorption of fat-soluble vitamins can be also observed. A reduced D l _CO , with or without ventilatory defects, is one of the functional hallmarks of the disease, particularly when a connective tissue disorder coexists.

Chronic Active Hepatitis

Chronic active hepatitis, an increasingly frequent liver disease that is characterized by diffuse parenchymal inflammation and hepatic cell necrosis, may be caused by viral hepatitis (most commonly hepatitis C virus), autoimmune disorders, and drug-related liver injury. Pulmonary fibrosis and lymphoid interstitial pneumonitis have been reported but are rare. After years of smoldering inflammation, which is often asymptomatic, chronic active hepatitis can lead to cirrhosis and liver failure, which has been associated with HPS. Patients with chronic hepatitis C virus infection and coexistent COPD may demonstrate an accelerated annual decline in forced expiratory volume in 1 second.

Sclerosing Cholangitis

Sclerosing cholangitis is an unusual disease that results from chronic inflammation affecting both intrahepatic and extrahepatic bile ducts. It has been linked with inflammatory obstructive airway diseases such as bronchiectasis; however, the relationship remains unproven because ulcerative colitis, a frequent clinical accompaniment, has also been associated with the same respiratory complications.

Alpha ₁ -Antitrypsin Deficiency

The discovery that certain patients with COPD had low levels of circulating alpha1-antitrypsin led to the current protease-antiprotease theory of the pathogenesis of pulmonary emphysema (see Chapter 43 for complete discussion). This hereditary disorder is nearly always associated with the homozygous PiZZ phenotype. Genetically predisposed infants often present with hepatomegaly or hepatosplenomegaly and evidence of cholestasis. Most children with alpha ₁ -antitrypsin-induced liver disease recover, but cirrhosis develops in about 15%, presumably from toxic effects of the mutant antitrypsin protein retained in the endoplasmic reticulum of hepatocytes ; HPS has been reported as a complication of this form of cirrhosis. COPD is the most common pulmonary complication. COPD is unrelated to the presence of liver disease, develops in adults, and is characterized by panacinar emphysema, especially in the lower lung zones, and bronchial abnormalities, including bronchiectasis.