A <92%, arterial oxygen pressure [Pao21 <70

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1 308 MichaelJ. Krowka disease is not reversible after liver transplantation. in Laennec s cirrhosis. J Clin Invest 1953;32:1025- Anesthesiology 1992;77: Nasraway SA, Wein RD, Spanier TB, Rohrer RJ, Free- 13, MS, Duke J, Nitric oxide reduces man RB, Rand WM, et al. Hemodynamic correlates of hypertension during hepatic transplantation. Anesthesioutcome in patients undergoing orthotopic liver trans- OlOgy 1994;81: Dlantation: Evidence for early postoperative myocardial 14. Kowalski HJ, Abelmann WH. The cardiac output at rest depression. Chest 1995;10i:il ~ PATHOPHYSIOLOGY OF ARTERIAL HYPOXEMlA IN ADVANCED LIVER DISEASE Michael J, Krowka rterial hypoxemia (hemoglobin saturation A <92%, arterial oxygen pressure [Pao21 <70 mm Hg or alveolar-arterial gradient >25 mm Hg) occurs with varying frequency (11% to 69%) in series of patients with advanced liver This report discusses the pathophysiology of such hypoxemia and updates the clinician on current thoughts concerning differential diagnosis, etiology, and reversibility of abnormal oxygenation in liver disease. Pathophysiology As with other organ systems, the lung can respond to injury in only a finite number of ways. There appears to be five main pulmonary mechanisms that result in arterial hypoxemia; four of those may occur as a consequence of hepatic dysfunction (Fig 1). Ventilation-Perfusion Mismatch Ideally, the ratio of ventilation (liters per second of airflow) to perfusion (liters per second of venous blood flow) is approximately 1 (V/Q = 1). Abnormal V/Q ratios in various regions of the lung are the most common reason for hypoxemia in any type of patient.6 Those with liver disease may have decreased ventilation due to smoking effects (bronchitis and emphysema), ainvay/emphysematous change due to al-antitrypsin (AAT) deficiency, or organizing pneumonitis complicating primary biliary cirrhosis (PBC). Decreased ventilation due to premature small airway From the Division of Thoracic Diseases and Internal Medicine, Mayo ClinicJacksonville, Jacksonville, FL. Address reprint requests to Michael J. Krauka, MD, 4500 San Pablo Rd, Muyo ClinicJacksonville,Jacksonville, FL Copynght & the American Association for the Study of Liver Diseases /96/ $3.00/0 closure has been documented in the lungs of cirrhotic patients (caused by dilated vessels or interstitial edema).s Impaired hypoxic vasoconstriction (an inability to constrict pulmonary arterioles while breathing a low inspired fraction of oxygen) occurs in varylng degrees in cirrhotic patients; excessive perfusion to areas of normal, or worse, abnormal, areas of ventilation may cause an imbalance in V/Q ratios9 Such impairment in association with low pulmonary vascular tone may herald the earliest presentation of what is termed hepatopulmonary syndrome (HPS).9 The most dramatic manifestation of HPS results from anatomic vascular dilatation and arteriovenous communications causing severe hypoxemia due to diffusion-perfusion defects and shunt, respectively. Abnormal perfusion patterns can also exist when pulmonary artery hypertension (high pulmonary vascular tone associated with vasoconstriction) complicates liver disease (portal hypertension), Interestingly, the resultant V/Q mismatch is minimal,i0 (except if pulmonary emboli are the inciting factors). Treatment with vasodilators can cause deterioration in V/Q in these patients, even when hemodynamics improve, suggesting that high pulmonary vascular tone may enhance gas exchange. The pulmonary arterial changes are pathologically indistinguishable from those seen in primary pulmonary hypertension. Finally, the effects of ascites and pleural effusions ( hepatic hydrothorax ) may compress normal lung tissue and alter V/Q relationships; interestingly, the changes in Pao2 may be minimal although symptoms of dyspnea can be substantial.12 A key point to remember about abnormal V/Q is that hypoxemia caused by such a mechanism responds significantly to supplemental oxygen given either by nasal prongs or face mask. A poor response

2 Arterial Hypoxemia in Advanced Liver Disease 309 Figure 1. Pathophysiology of hypoxemia in patients with liver disease and associated differential diagnoses. to supplemental oxygen suggests the existence of a shunt or severe diffusion-perfusion abnormality (see below). Diffusion Limitation Oxygen diffuses from the alveoli into the pulmonary capillaries in a passive manner. Such diffusion can be limited by processes that impair the movement of oxygen through the interstitium, ie, inflammation that results in an accumulation of lymphocytes, neutrophils, and edema between the alveoli and capillaries. Collagen deposition ( fibrosis ) and development of granulomas also occur; the end result is an inflammatory process (nicely demonstrated by high-resolution computed tomography of the chest and confirmed by lung biopsy) that causes a reduction in Pao,. PBC provides the most frequent example of hepatic dysfunction associated with such pulmonary pathology (an autoimmune process possibly involving common epithelial antigens).7 Hypoxemia due to diffusion limitation also improves with an increased fraction of inspired oxygen; such limitation can be quantified by the classic DLCO (diffusing capacity of the lung for carbon monoxide) pulmonary function test. Alveolar Hypoventilation This process does not occur as a direct consequence of liver disease. Instead, many patients with hepatic dysfuncnon hyperventilate with a resulting reduction in Paco,--less than 35 mm Hg-and slight increase in Pao,. Only if such patients are substandly sedated will hypovennlation play a role in causing hypoxemia. Shunt Essentially, shunt represents an extreme V/Q mismatch-relatively no ventilation going to regions of perfused lung (V/Q = 0). l3 Severe hypoxemia associ- ated with advanced liver disease can result from physiologic or anatomic intrapulmonary shunts and extrapulmonary shunts. Intrapulmonary shunt resulting from a physiologic cause-complete lack of ventilation to a region of normal perfusion-is well described in adult respiratory distress syndrome (ARDS) and in the respiratory insufficiency that complicates acute liver failure.14 The anatomic cause for intrapulmonary shunt results from direct arteriovenous communications in which an abnormal path of perfusion totally bypasses normal ventilation at the capillary level; such pathology occurs in some patients with hepatopulmonary syndrome. l5,i6 Extrapulmonary shunts in liver disease can be caused by intracardiac abnormalities or portal vein-pulmonary vein communications. htracardiac shunt associated with hypoxemia implies an abnormal right-toleft flow of blood between cardiac chambers (usually at the atrial level) in which mixed venous blood never reaches the lungs for oxygenation. Cirrhotic patients with pulmonary hypertension and receiving propano- 101 have been described with such shunts, presumably caused by high pulmonary artery/right heart pressures, which open patent foramen ovale and cause a shunt physiology. Although severe hypoxemia can result, it may be reversed by eliminating the P-blocker medication. Direct portal vein-pulmonary vein communications via the mediastinum are well described in cirrhotic patients; the degree of blood flow through such extrapulmonary shunts has been documented to be minimal and does not contribute significantly to hypoxemia. lfl Importantly, increasing the fraction of inspired oxygen (even to 100% 0,) has very little effect on improving the abnormal Pao, caused by shunting at the intrapulmonary, intracardiac, or extrapulmonary levels. l9 Diff usion-perfusion Abnormality This cause for hypoxemia characterizes the most frequent physiology associated with hepatopulmonary syndrome: diffusion limitation through dilated precapillary and capillary vessels (plasma limitation?/ proliferation of vessels?) with rapid perfusion of venous blood through such abnormal vasculature, which directly abuts gas exchange units Interestingly, although severe hypoxemia (Pao, <50 mm Hg) can result f?om breathing room air, 100% inspired oxygen can dramatically improve Pao, to well over 500 mm Hg in some patients. Others may have a poor response to 100% oxygen due to advanced stages of dilatations (or pure shunt pathways). The oxygen problem can worsen as one moves

3 310 MichaelJ. Krowku from the supine to standing position (orthodeoxia), because increased gravitational blood flow through dilated vessels in the lung bases. That both a diffusion and perfusion defect exists has been suggested by the multiple inert gas elimination technique (MIGET) in selected patient^.^^-^^ To date, there appears to be no true gold standard upon which to define this complex physiology because of possible limitations of interpretation of MIGET studies in the setting of dilated vasculature and hyperdynamic cir~ulation.~~-~~ It should come as no surprise that the exact reason for hypoxemia in a given patient may be multifactorial. It is important, however, to identify the predominant and reversible processes so that appropriate therapeutics may be considered. Finally, the roles of cardiac output and oxygen consumption as extrapulmonary factors affecting arterial oxygenation in patients with liver disease should not be underestimated. Differential Diagnoses From a practical perspective, the predominant cause of hypoxemia in patients with liver disease frequently can be determined from the patients history and physical examination; the confirmation of clinical suspicions should include the quantification of hypoxemia severity. Hypoxemia may be caused by pathophysiology affecting the pleural space, pulmonary parenchyma (airways, alveoli, and interstitiurn), or the pulmonary circulation as categorized in Table 1. With the exception of PBC, all of these disorders can affect both children and adults, although it is quite unusual to have significant emphysema in children. History Many patients with liver disease complain of fatigue. It must be kept in mind that hypoxemia may be responsible for such presentation, as opposed to the classic complaint of dyspnea (at rest or with exer- Table 1. Differential Diagnosis of Hypoxernia in Advanced Liver Disease Pulmonary Process Pleural space Pleural effusion with or without ascites with infected pleural fluid Screen Diaanosis Chest CT Thoracentesis Confirmation Pulmonary parenchyma Emphysema AAT deficiency / PFTs AAT IeveVphenotype non-aat antitrypsin / PFTs HRCT Expiratory airflow obstruction bronchitis/ PFTs (FEV1/FVC ratio) bronchospasm Interstitial lung disease lymphocytic alveolitis/granulomas /HRCT fibrosing alveolitis /HRCT airspace disease/ards Pulmonary circulation Hepatopulmonary syndrome Positional ABGs, CE echo, Pulmonary angiogram/autopsy 99mT~MAA scan Pulmonary artery hypertension DTE Right heart catheterization Pulmonary embolism V/Q scan US for DVT Pulmonary angiogram Abbreviations:, chest radiograph: CE echo, contrast-enhanced transthoracic echocardiography; DTE, Doppler transthoracic echocardiography; V/Q scan, ventilation/perfusion lung scan; US for DVT, compressive duplex ultrasound assessing for deep vein thrombosis; HRCT, high-resolution chest computed tomography of the chest; PFTs, pulmonary function tests; Positional ABGs, Pa02 measured supine and standing; FEVl /FVC, forced expiratory volume in 1 second divided by forced vital capacity; 99mTcMAA scan, technetium-labeled macroaggregated albumin lung and brain scan.

4 Arterial Hypoxmia in Advanced Liver Disease 31 1 cise). Indeed, progressive dyspnea with exertion may be the first clue of a significant oxygenation problem. The time frame of gradually worsening dyspnea symptoms is usually over weeks or months. Worsening dyspnea when moving from the supine to standing position (platypnea) suggests hepatopulmonary syndrome and significant hypoxemia. Chest pain and syncope suggest pulmonary hypertension of a significant hemodynamic degree (which may be associated with minimal abnormality in Pao,). Acute dyspnea (and hypoxemia) suggests a pulmonary infection or thromboembolic disease. Physical Examination The existence of icterus may minimize the suspicion for hypoxemia (and usual findings of cyanosis). Dusky nail beds and lips suggest significant hypoxemia (> 5 g of unoxygenated hemoglobin); clubbing of digits is frequently associated with severe hypoxemia and suggests hepatopulmonary syndrome. Auscultation of the chest with tidal breathing may hear the fine inspiratory crackles of interstitial lung processes (especially in PBC); the distinction between lymphocytic (reversible?) and fibrotic changes (irreversible) cannot be made by examination alone. Asymmetric reduction in breath sounds and abnormal percussion should suggest moderate to large pleural effusions (especially in the setting of clinical ascites). Bilateral reduction of breath sounds and hyperinflation of the chest should suggest emphysema and the possibility of severe AAT deficiency. Wheezing and congestion (sometimes best heard during cough or forced expiration) indicates probable bronchcspasm, which can accompany any type of airway inflammation. F dy, an abnormally loud P2 (heard especdly at the cardiac apex) is strongly suggestive of significant pulmonary artery hypertension.26 Appropriate Testing and Screening Clinical experience and available resources at specific institutions will guide the degree of investigation. Table 1 summarizes the major causes of hypoxemia with suggested diagnostic screening and confirmatory approaches. Hemoglobin saturation via finger pulse oximetry, while breathing room air in the standing position, provides an inexpensive and reasonable screening for significant hypoxemia. Saturation less than 92% (which correlates to a Pao, of approximately 65 to 70 mm Hg) should be followed by arterial blood gas measurement of Pao2 to quantify the true severity of hypoxemia. Etiology Unfortunately, the specific reasons for hypoxemia are best known only to the level as shown in Fig 1, with the exception of emphysema caused by severe AAT deficiency (lack of neutrophil elastase inhibition due to dysfunctional and deficient AAT protein primarily synthesized in hepatocytes; abnormal accumulation and degradation of the protein also play major roles in the pathophysiology).27 Biochemical reasons for pulmonary vascular dilatation/ proliferation (hepatopulmonary syndrome), pulmonary vasoconstriction/ obliteration (pulmonary hypertension), and the interstitial lung disease of PBC (lymphocytic alveolitis and fibrosing alveolitis), to name a few, are speculative. Genetic susceptibility, nitric oxide, inflammation, and growth factors (platelet-derived growth factor, transforming growth factor, and vascular endothelial growth factor) may play various roles in such vascular pathology (and remodeling) that complicates liver disea~e.~~,~~ Additional animal studies and the identification of specific inciting factors in the portal and hepatic circulations should be of potential clinical interest.30 Reversibility The resolution of hypoxemia complicating liver disease varies with time and pathophysiology. Hypoxemia associated with pleural effusions, ascites, and pneumonitis may improve acutely (days) after appropriate interventions. Abnormal oxygenation due to ARDS, HPS, and pulmonary hypertension is of great interest due to potential and complete resolution over weeks or months in selected patients following liver tran~plantation.~l-~~ Identification of key prognostic indicators that characterize the natural history in these entities continues to evolve; defining the boundaries of reversibility remains an important clinical research effort. A multicenter hepatopulmonary spdrome/pulmonary hypertension database for liver transplantation candidates/recipients has been initiated (MJ Krowka, MS Mandell, principal investigators). References 1. Rodman T, Sobel M, Close HP. Arterial oxygenation unsaturation and ventilation-perfusion defect of Laennec's cirrhosis. N Engl J Med 1960;263: Naeiji R, Melot C, Hallermans R. Pulmonary hemodynamics in liver cirrhosis. Semin Respir Med 1985;7: Krowka MJ, Cortese DA. Pulmonary aspects of liver

5 312 MichaelJ. Krowka disease and liver transplantation. Clin Chest Med 1989; 10: Hourani JM, Bellamy PE, Tashkin DP, Batra P, Simmons MS. Pulmonary dysfunction in advanced liver disease: frequent occurrence of an abnormal diffusing capacity. Am J Med 1991 ; Fahey JV, Keer KM, Lake JR, Gold WM. Pulmonary function before and after liver transplantation. Am Rev Respir Dis 1992;145:A West JB. Ventilationlblood flow and gas exchange. 4th ed. London: Blackwell Scientific Publications, Ruff F, Hughes JMB, Stanley N, McCarthy D, Greene R, Aronoff A, et al. Regional lung function in patients with hepatic cirrhosis. J Clin Invest 1971 ;50: Domino KB, Eisenstein BL, Tran T, Hlastala MJ. Increased pulmonary perfusion worsens ventilationperfusion matching. Anesthesiology 1993;79: Agusti AGN, Roca J, Bosch J, Rodriguez-Roisin R. The lung in cirrhosis. J Hepatol 1990;10: Agusti AGN, Rodriguez-Roisin R. Effect of pulmonary hypertension on gas exchange. Eur Respir J 1993;6: Mandell MS, Groves BM. Pulmonary hypertension in chronic liver disease. Clin Chest Med 1996;17: Alberts WM, Salem AJ, Solomon DA. Hepatic hydrothorax: cause and management. Arch Intern Med 1991 ;151: Nunn JF. Applied respiratory physiology 2nd ed. London: Butterworths, Matuschak GM. Lung-liver interactions in sepsis and multiple organ failure syndrom. Clin Chest Med 1996;17: Rydell R, Hoffbauer FW. Multiple pulmonary arteriovenous fistulas in juvenile cirrhosis. Am J Med 1956;21: Schraufnagel DE, Kay JM. Structural and pathologic changes in the lung vasculature in chronic liver disease. Clin Chest Med 1996;17: Raffy 0, Sleiman C, Vachiery F, Mah H, Rove C, Hadenque A, et al. Severe hypoxemia of liver disease: hepatopulmonary syndrome or primary pulmonary hypertension? Am J Respir Crit Care Med 1996;153: Nakamura T, Nakamura S, Tazawa S, et al. Measurement of blood flow through portopulmonary anastomosis in portal hypertension. J Lab Clin Med 1965;65: Edell ES, Cortese DA, Krowka MJ, Rehder K. Severe hypoxemia and liver disease. Am Rev Respir Dis 1989; 140: Genovesi MG, Tierney DF, Taplin GV, Eisenberg H. An intravenous radionuclide method to evaluate hypoxemia caused by abnormal alveolar vessels: limitations of conventional techniques. Am Rev Respir Dis 1976; 114: Krowka MJ, Cortese DA. Severe hypoxemia associated with liver disease: Mayo Clinic experience and experimental use of almitrine bismesylate. Mayo Clin Proc 1987;62: Thorens JB, Junod AF. Hypoxemia and liver cirrhosis: a new argument in favor of a diffusion-perfusion defect. Eur Respir J 1992;5: Agusti AGN, Rodriguez-Roisin R, Roca J. Gas exchange abnormality in patients with cirrhosis. Clin Chest Med 1996;17: Wagner PD. Impairment of gas exchange in cirrhosis [editorial]. Eur Respir J 1995;8: Crawford ABH, Regins J, Laks L, Donnelly P, Engel LA, Young IH. Pulmonary-vascular dilatation and diffusion dependent impairment of gas exchange in liver cirrhosis. Eur Respir J 1995;8: Hurst JW. Cardiovascular diagnosis: The initial examination. St. Louis: Mosby, Krowka MJ. Recent observations in a-1-antitrypsin deficiency, primary biliary cirrhosis, chronic hepatitis C and other hepatic disorders. Clin Chest Med 1996;17: Voelkel NF, Tuder RM. Cellular and molecular mechanisms in the pathogenesis of severe pulmonary hypertension. Eur Respir J 1995;8: Panos R. Growth factors and cytokine mediators in liver-lung interaction. Clin Chest Med 1996;17: Chang SW, Ohara N. Pulmonary circulatory dysfunction in rats with primary biliary cirrhosis: an animal model of the hepatopulmonary syndrome. Am Rev Respir Dis Doyle HR, Marino IR, Miro A, Scott V, Martin M, Fung J, et al. Adult respiratory distress syndrome secondary to endstage liver disease-successful outcome following liver transplantation. Transplantation 1993;55: Lange PM, Stoller JK. Hepatopulmonary syndrome: effect of liver transplantation. Clin Chest Med 1996;17: Krowka MJ, Porayko MK, Plevak DJ, Pappas SC, Steers JL, Wiesner RH. Hepatopulmonary syndrome with progressive hypoxemia as an indication for liver transplantation. Mayo Clin Proc 1996; (submittedfor publication). 34. Plevak D, Krowka M, Rettke S, Dunn W, Southhorn P. Successful liver transplantation in patients with mild to moderate pulmonary hypertension. Transplant Proc 1993;25: Scott V, DeWolf A, Kang Y, et al. Reversibility of pulmonary hypertension after liver transplantation: a case report. Transplant Proc 1993;25: Koneru 6, Ahmed S, Weisse AB, Grant GP, McKim KA. Resolution of pulmonary hypertension of cirrhosis after liver transplantation. Transplantation :