Portopulmonary Hypertension and Hepatopulmonary Syndrome, and Liver Transplantation Michael A. Ramsay, MD, FRCA At present, liver transplantation is the only effective treatment to improve the outcome in patients with hepatopulmonary syndrome, a life-threatening condition whose prevalence can be close to 20% in patients with end-stage liver disease who are awaiting liver transplantation. Pulmonary arterial hypertension occurring in the setting of portal hypertension, namely portopulmonary hypertension, another major pulmonary-hepatic-vascular condition, has prevalence on the order of 5% in patients awaiting liver transplantation. Unlike hepatopulmonary syndrome in moderate-to-severe stages of portopulmonary hypertension, liver transplantation may not reverse the condition and because of the increase in perioperative morbidity and mortality, this is being regarded by many authorities as a contraindication to liver transplant. As a result, a therapeutic regimen of vasodilator therapy strategy becomes necessary to ameliorate the portopulmonary hypertension and allow time for conditioning of the right ventricle, before proceeding to transplantation. Careful assessment of right ventricular function by echocardiography is essential before undertaking liver transplantation in patients with portopulmonary hypertension. Transplantation should be delayed until both the pulmonary pressures reduce to the mild to moderate range and the right ventricle becomes conditioned to the extra work load and can safely sustain the patient through the rigors of transplantation.

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Portopulmonary Hypertension

The pulmonary circulation is a low-pressure and low-resistance vascular circuit when compared with the systemic circulation. Typically, patients with advanced liver disease have a hyperdynamic circulatory state with an increased cardiac output (CO) and decreased systemic vascular resistance.1 This high-flow state may be confounded by cardiac failure, cardiomyopathy, volume overload, and rarely, by a pathologic increase in pulmonary vascular resistance (PVR) which could be a result 69

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of arteriolar medial hyperplasia, thrombosis, or fibrosis. All these states can be causes of raised pulmonary artery pressures. The key to understanding the risk for an unfavorable outcome is to accurately define the etiology of the pulmonary hypertension. A degree of cardiomyopathy has been reported to occur in all cirrhotic patients, if only for a down-regulation of b receptors.2 The diagnosis of true portopulmonary hypertension (POPH) is based upon pulmonary hemodynamic criteria obtained via right-heart catheterization. It is essential to accurately characterize the pulmonary hemodynamics in these patients as there can be many different etiologies of pulmonary hypertension in liver transplant candidates. The calculation of the PVR is essential in distinguishing POPH from the increased strain on the right heart caused by the increased afterload from the other reasons for pulmonary hypertension. These include volume overload, cardiac failure, and cardiomyopathy, as a result of direct muscle damage from the disease state, or the result of an extremely high CO flowing through the pulmonary circulation. This characterization is crucial to further management of the patient. POPH is defined as pulmonary arterial hypertension associated with portal hypertension, with or without hepatic disease. Diagnostic criteria for POPH include a mean pulmonary artery pressure (mPAP) >25 mm Hg (at rest) or >30 mm Hg (during exercise), with mean pulmonary artery occlusion pressure (mPAOP) <15 mm Hg and a PVR of >240 dynes s cm – 5.3 The PVR is calculated as the (mPAP – mPAOP)/CO. This may be expressed in Wood units (normal 1 to 1.4), or multiplied by 80 to give dynes s cm – 5 (normal 80 to 120 dynes s cm – 5). The mPAP is calculated from the pulmonary artery systolic pressure minus the pulmonary artery diastolic pressure divided by 3. The PVR is an important measurement as it represents the afterload to the right ventricle (RV). The RV function is vital to the success of the liver transplant procedure, as RV dysfunction or failure will result in an increase in central venous pressure, which is transmitted to the hepatic veins causing graft congestion that may lead to graft failure, and potential loss of graft and patient. POPH may be further divided into mild (mPAP, 25 to 35 mm Hg), moderate (mPAP>35 and <45 mm Hg), and severe pulmonary hypertension (mPAP>45 mm Hg). A moderate increase in mPAP is found in up to 20% of patients with cirrhosis and portal hypertension.4 This increase in mPAP is most commonly caused either by the large increases in CO (and there may be a normal or low PVR), or because of volume overload with an increased mPAOP.5 In these incidences, as there are no pathologic changes occurring in the pulmonary arterioles, these are not classified as POPH and require very different management. True POPH is found in 3.1% to 4.7% patients with cirrhosis and, if untreated, carries a high mortality.6–10 The risk of mortality in this

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patient group is higher than in those patients with idiopathic pulmonary hypertension (ie, not associated with portal hypertension), despite there being a higher cardiac index and lower PVR.11 In true POPH, the development of moderate to severe pulmonary hypertension, with extensive pulmonary vascular medial hyperplasia causing an increased PVR, results in a median survival time, reported to be as short as 6 months.12 Mild to moderate POPH may reverse after liver transplantation, but the patients should be carefully monitored postoperatively and vasodilator therapy continued, if necessary.13,14 Liver transplantation alone may not reverse the pathologic changes seen in the pulmonary vasculature of patients with moderate to severe POPH, and the pulmonary hypertension may continue to progress after transplantation. This carries a significant mortality, both intraoperatively and postoperatively, if vasodilators and cardiac function, especially RV function, are not managed very carefully.9,10,15 Therefore, vasodilator therapy may have to be continued for many months or years postoperatively to allow vascular remodeling to take place.16,17 If liver transplantation is undertaken, the perioperative mortality in patients with mild POPH is not increased, but patients with moderate to severe POPH have a high perioperative mortality rate.9,16 When the PVR is increased, it may cause the potential shunting of blood flow through anatomic intracardiac defects, and this may affect oxygenation and also increase the risk of cerebral and other systemic emboli. Pathophysiology

The histopathologic appearance of POPH is of intimal proliferation, medial smooth muscle hypertrophy, and fibrosis in the small pulmonary arteries.18,19 Thrombosis with recanalization may be present, and this in situ thrombosis has been attributed to abnormal local endothelial thrombolytic activity and a hypercoagulable state, together with platelet activation.20 A characteristic histologic feature of pulmonary hypertension, including POPH, is the plexiform lesion, which is a dilated pulmonary artery with the normal structure replaced by an intraluminal plexus of endothelial cells and slitlike vascular channels. Portal hypertension induces systemic inflammatory changes and increased vascular wall shear stress, which may trigger a cascade of intracellular signals that activate various genes in the vascular endothelium. This may lead to pulmonary vascular remodeling in genetically susceptible patients.21 Plasma levels of vasoconstrictors, that is, norepinephrine, renin-angiotensin-aldosterone, arginine vasopressin, and vasodilators [nitric oxide (NO), glucagon, vasoactive peptide, and substance P], have been documented in the setting of portal hypertension.22,23 An imbalance of vasoactive substances reaches the pulmonary circulation

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in abnormally high concentrations as a result of portosystemic shunts and defective hepatic metabolism, causing the pathologic pulmonary vascular lesions. In cirrhosis, the development of portosystemic shunts and a dramatic decrease in the phagocytic capacity of the liver allow circulating bacteria or bacterial endotoxins from the gastrointestinal tract to enter the pulmonary circulation.24,25 An increase in pulmonary phagocytic activity is ascribable to the extensive accumulation of pulmonary intravascular macrophages that adhere to the pulmonary endothelium. Activated macrophages release numerous cytokines including tumor necrosis factor-b, growth factors, and NO, that might contribute to the development of pulmonary vascular disease seen in these patients. Both serotonin and endothelin-1 may cause vasoconstriction and mitogenesis in pulmonary arteries. The lung is normally protected from high levels of free plasma serotonin by the normal hepatic metabolism and the storage of serotonin in platelets. Portal hypertension is associated with decreased platelet levels, reduced platelet uptake, and increased levels of serotonin. Endothelin-1 is produced by the pulmonary endothelium and also by the liver, and is a powerful vasoconstrictor. Genetic factors may play a role in the development of the hyperplastic vasculopathy. Mutations in the bone morphogenetic protein receptor type 2 has been linked to familial pulmonary hypertension.26 The pathologic changes in the microvasculature of the lungs of patients with POPH eventually become fibrotic and at this stage they are irreversible. However, concomitant with these changes, vascular dilations and shunt formation may occur, such as that seen in patients with hepatopulmonary syndrome (HPS).18 This observation suggests that these changes may balance each other until one predominates.27 The pulmonary vascular abnormalities may progress, even after orthotopic liver transplantation, unless long-term pulmonary vasodilator therapy is instituted.17 The shunt formations do resolve after transplantation, and this may reveal the underlying pulmonary hypertension. Therefore, transplantation may be considered an effective therapy for HPS, in contrast to POPH. The resistive changes may progress, even after liver transplantation, unless pulmonary vasodilator therapy is continued until vascular remodeling has taken place. Clinical Features

Patients with portal hypertension, who report dyspnea at rest or during exercise, should be assessed for the presence of POPH. It can be argued that, because this is such a common symptom of the end-stage liver disease patient who is severely debilitated and with severe ascites, a cardiac assessment that includes echocardiography should be

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performed as a routine on all liver-transplant candidates. Chest discomfort and syncope are features of advanced POPH. Physical examination may include an elevated jugular venous pressure, an accentuated P2 component, a tricuspid regurgitation murmur, rightventricular heave, and increasing signs of right-heart failure. Chest radiography may show increased main pulmonary artery size or cardiomegaly, and pulmonary function tests may show a reduced diffusion capacity of carbon monoxide at the lung (DLCO). Arterial blood gases may show mild to moderate hypoxemia, an increased alveolararterial oxygen partial pressure difference AaPO2 gradient, and decreased PaCO2.28 Electrocardiography suggests right-atrial enlargement, right-ventricular hypertrophy, or-right-axis deviation.29 Transthoracic echocardiographic findings include the presence of a tricuspid jet velocity, pulmonic valve insufficiency, paradoxical septal motion, right-ventricular hypertrophy and/or dilatation, and an increased right-ventricular systolic pressure estimate (RVsys) by the Bernouilli equation. These signs in the setting of portal hypertension suggest POPH. Pulmonary hemodynamic measurements by rightheart catheterization must be done to confirm the diagnosis. A retrospective analysis showed that the screening Doppler echocardiography (RVsys>50 mm Hg) essentially identifies all patients that should proceed to right-heart catheterization.30 A prospective study of liver transplant candidates who underwent Doppler echocardiography (RVsys>30 mm Hg) and catheterization measurements documented the sensitivity, specificity, and positive predictive and negative values for a diagnosis of POPH as 100%, 96%, 59%, and 100%, respectively.31 Patients who are listed for orthotopic liver transplantation should have echocardiography performed annually; and those with POPH may need to be followed more frequently, at least 2 or 3 times every year. Clinical Management

The clinical management of the pretransplant patient with POPH is to precisely evaluate and document the diagnostic hemodynamic data and cardiac function, so that a risk-benefit assessment can be made about the optimal timing of liver transplantation. An mPAP>25 mm Hg and a calculated PVR>240 dynes s cm – 5 are considered pathologic. POPH is further graded hemodynamically into mild (mPAP = 25 to 35 mm Hg), moderate (mPAP>35 to 45 mm Hg), and severe (mPAP>45 mm Hg). Management of the patient with POPH<35 mm Hg does not present any additional risk to the patient so long as consideration is given to preventing an increase in central venous pressure after reperfusion of the graft and the resulting graft congestion that would take place. This relies on accurate volume replacement and

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also on good RV function that should be assessed by transthoracic or transesophageal echocardiography. If a dilated right heart is noticed on echocardiography, it is possible that the RV may not handle the increased afterload caused by the increase in CO, and this should be tested preoperatively with the administration of a liter-fluid challenge and a dobutamine stress test infusion. Careful assessment of how the RV handles this should weigh the decision whether the liver transplantation should be deferred for further evaluation and vasodilator therapy. Moderate and severe pulmonary hypertension places the liver transplantation patient at increased risk of perioperative morbidity and mortality. The data available to date would indicate a perioperative mortality of greater than 70% if liver transplantation was carried out with a mPAP>45 mm Hg.9,16 These patients require that transplantation be deferred and an aggressive treatment with vasodilator therapy be instituted. Frequent monitoring of right-heart function should be instituted to assess the effectiveness of the therapy, and for signs of conditioning of the RV and reduction in mPAP. When liver transplant is considered appropriate, then the RV should be tested with a fluid load and a dobutamine stress test under close echocardiographic surveillance. Transplantation should only be scheduled when the RV performance has improved. In selected patients with severe POPH, combined heart-lung-liver or lung-liver transplant may be considered.32 The management of the moderate POPH patient with mPAP>35 <45 mm Hg requires careful assessment. Preoperative treatment with pulmonary vasodilators, such as epoprostenol, may reduce the mPAP to 35 mm Hg. These patients with moderate POPH may benefit from a ‘‘test of reversal’’ using up to 40 ppm of inhaled NO or an inhaled prostacyclin PGI2.17,33 A cardiac functional assessment by echocardiogram of right and left ventricular function is essential to rule out concomitant cardiomyopathy and to closely follow right heart function. Transplantation should only proceed when the RV is considered conditioned to sustain the hemodynamic rigors of the procedure. It may take many months of treatment with vasodilators, such as epoprostenol, to reverse or stabilize the pulmonary artery pressures.34,35 Reassessment of the patient at frequent intervals by echocardiography can provide information not only on the progress of therapy but also on the condition of the RV. If the RV develops into a good contracting ventricle, the patient may tolerate liver transplantation with a higher mPAP.16,35 However, if only the mPAP declines and the RV function does not improve, the patient is still at risk.36 The goal of pretransplant therapy for the transplant candidate with POPH is 2-fold: to reduce the mPAP to <35 mm Hg, a level well tolerated during liver transplantation, and also to allow conditioning of the RV so that patients with higher levels of mPAP may be safely transplanted.

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Other measures to reduce POPH may include diuretics that can reduce both intravascular volume and hepatic congestion that occur in patients with right-sided heart failure by decreasing RV preload. The administration of b-receptor blockers can reduce the effects of circulating catecholamines. Pulmonary artery vasodilators reverse vasoconstriction,. but will have little or no effect if fibrotic changes predominate. Prostacyclin PGI2 (epoprostenol) is a potent systemic and pulmonary vasodilator, and is also a powerful inhibitor of platelet aggregation. However, epoprostenol can only be administered by continuous intravenous infusion, and this requires chronic central venous access with the concomitant risk of infection and thrombosis. Long-term continuous infusion of epoprostenol has resulted in significant and favorable changes in mPAP and PVR.38 Common adverse effects attributable to epoprostenol include jaw pain, headache, diarrhea, flushing, leg pain, and nausea or vomiting. Oral sildenafil has been used in managing POPH, but no clinical trials have been reported studying its efficacy in this condition.39 Inhaled aerosolized prostocyclin (iloprost) has also been used successfully to lower mPAP in patients with POPH.40 The dual endothelin-receptor antagonist (A and B) bosentan is an orally available therapy that has shown efficacy in treating pulmonary hypertension. However, caution has been raised in its use in treating POPH as it may cause a transient increase in hepatic enzymes.41 Operative Management

If the diagnosis of pulmonary hypertension is made on the operating room table just beforethe start of surgery, a decision has to made as to the risks associated with proceeding with the operation with those on deferring the surgery, and further evaluating and treating the patient. This decision needs to be made rapidly as another recipient may need to be admitted or the organ passed on to another center. The decision to proceed should be based on the severity of the mPAP, the reversibility of the mPAP, and the condition of the RV evaluated by transesophageal echocardiogram. A careful rechecking of the hemodynamic data to ensure its accuracy must be undertaken. The elimination of other diagnoses or confounding factors, such as fluid overload, cardiomyopathy, respiratory acidosis, and excessive catecholamine production, should be carried out. The reversibility of mPAP can be rapidly tested by the administration of inhaled NO. Those patients with POPH, who undergo liver transplantation successfully, have a varied survival rate and resolution of pulmonary hemodynamics. One study reported a mortality of 71% at 36 months after transplantation in patients with POPH who did not receive postoperative epoprostenol.10 The same group reported a 100% survival in a group of liver-transplant patients with POPH treated acutely with inhaled NO followed by

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epoprostenol to bring the mPAP to <40 mm Hg at the time of transplant. Normalization of pulmonary pressures occurred in all patients, but took between 2 days and 18 months of postoperative epoprostenol therapy.17 The function of the RV may be tested with TEE surveillance while a 1 L fluid bolus and a dobutamine infusion are administered. If at the time of surgery, the mPAP is reduced to <40 mm Hg, the PVR is <240 dynes s cm – 5, and the right-ventricular function is not impaired, then there can be a reasonable expectation that surgery can proceed safely. Inhaled NO may assist in the management of transient acute rises in pulmonary artery pressures associated with reperfusion of the new graft.42 Decision Tree

Management of pulmonary hypertension diagnosed at induction of anesthesia for liver transplantation is shown in Figure 1. 1. If mPAP is <35 mm Hg and PVR<240 dynes s cm – 5, and good cardiac function: continue with liver transplant. 2. If mPAP is 35 to 40 mm Hg and PVR<240 dynes s cm – 5, and good cardiac function determined by TEE: an attempt to reduce mPAP to <35 mm Hg and PVR<240 dynes s cm – 5, and proceed with liver transplant. If irreversible, but right-ventricular function good (dobutamine and fluid challenge), then proceed with liver transplant. If RV function is poor, then surgery defers. 3. If mPAP>40 mm Hg and PVR>240 dynes s cm – 5, then liver transplant is deferred for this patient and vasodilator therapy is initiated. An increase in CO is frequently seen (5% to 18% of patients) after reperfusion of the new graft (Fig. 2). This can cause a significant increase in pulmonary artery pressures in the patient with POPH and lead to right-ventricular failure. The increase in right-heart filling pressures causes graft congestion and failure or even the demise of the patient. Postoperatively, the epoprostenol infusion therapy may need to be continued for as long as 18 months before complete reversal of the pretransplant pulmonary hypertension occurs.17 If the epoprostenol is not continued, the pathologic changes in the pulmonary vasculature may continue with eventual demise caused by right-ventricular failure. Conditioning of the RV has now been seen in 4 of our liver-transplant patients who presented with severe POPH and underwent prolonged vasodilator therapy. The mPAP stabilized but did not decline significantly, whereas the RV became hypertrophied and contracted well and this has allowed successful OLT to be performed despite severe POPH.

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Figure 1. Decision tree: the management of POPH diagnosed at the time of transplantation. (From Ramsay M. Liver transplantation considerations and outcomes for the POPH patient. Adv Pulmon Hypertens. 2004;2:9–18. Reprinted by permission of Advances in Pulmonary Hypertension, the official journal of the Pulmonary Hypertension Association.)37

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HPS

HPS is a clinical triad of an arterial oxygen defect, caused by intrapulmonary vascular dilatations in a patient with liver disease, most commonly cirrhosis. The diagnostic criteria include an arterial partial pressure (PaO2) <70 mm Hg with an increased alveolar-arterial oxygen partial pressure difference (AaPO2) without arterial carbon-dioxide retention. An AaPO2 >20 mm Hg caused by intrapulmonary shunting in a patient breathing room air is diagnostic in cirrhotic patients.3,43–46 The incidence of HPS reported in patients with liver disease ranges between 4% and 29%.47 The difference in reporting is the result of varying diagnostic benchmarks. However, the key to the development of hypoxia is the development of pulmonary vasodilatation, which causes intrapulmonary shunts that result in excess perfusion of the lungs. The rapid flow of blood through the dilated circulation results in the failure of all the red cells to be oxygenated. This can be corrected by the inhalation of supplementary oxygen. Rarely, discrete shunts develop that bypass the alveoli, and additional oxygen will not improve oxygenation (Fig. 3).

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There are numerous other etiologies of hypoxia in patients with liver disease. These etiologies include atelectasis caused by pleural effusions or massive ascites, pneumonia, decreased hypoxic pulmonary vasoconstrictive response, adult respiratory distress syndrome, alveolar hypoventilation, and diffusion abnormalities. The resulting ventilation-perfusion mismatch causes hypoxia. The pulmonary vascular dilatation in HPS may be inferred by delayed (3 to 6 cardiac cycles) positive contrast-enhanced echocardiography or a >5% extrapulmonary uptake of technetium-labeled macro-aggregated albumen after a perfusion scan. Pathophysiology

The vasodilatations may take the form of dilated precapillary and capillary vessels, or direct arterio-venous communications. The former occur diffusely throughout the lung, and the latter seem as discreet vascular shunts. Both pathologies may occur together. If the capillary changes predominate, it is classified as type-1 HPS, and if the discreet shunts are the major influence, it is termed type 2. In patients who develop type-1 HPS, the hypoxia will respond to increased concentrations of inspired oxygen, as the physiologic problem caused by the capillary dilatations is a reduced transit time for the red cells passing the alveoli. An increase in the alveolar PaO2 will increase the passage of oxygen across the alveolar membrane to the red cells. Type-2 HPS, however, is a pure anatomic shunting of blood away from the alveoli, and therefore, increasing the inspired oxygen will not correct the hypoxia (Fig. 3). Coil embolization by interventional radiology may improve oxygenation in type-2 HPS. There is evidence that an increase in NOproduction in the lung is pivotal for the development of HPS.48 HPS occurs most commonly in patients with cirrhotic liver disease, associated with

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Figure 2. Reperfusion of liver graft in patient with pulmonary hypertension. (From Ramsay M. Liver transplantation considerations and outcomes for the POPH patient. Adv Pulmon Hypertens. 2004;2:9–18. Reprinted by permission of Advances in Pulmonary Hypertension, the official journal of the Pulmonary Hypertension Association.)37

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Figure 3. Pathophysiology of HPS. Type-1 HPS exhibits a dilated pulmonary vasculature. The transit time for the red cells is decreased creating a shunt that is remedied by supplemental O2. Type-2 HPS exhibits the development of anatomic vascular shunts. These shunts are not remedied by supplemental O2.

portal hypertension and excessive concentrations of exhaled NO have been detected.49 Clinical Features

The symptoms and signs of HPS include cyanosis, digital clubbing, cutaneous telangiectasias, orthodeoxia, platypnea, shortness of breath, and hypoxemia. The natural history of the disease results in a mortality of 18% at 1 year after diagnosis and 41% at 2.5 years.50 In patients presenting for liver transplantation with an abnormal PaO2<70 mm Hg, a contrastenhanced transthoracic echocardiogram is performed as a screening tool looking for a delayed (3 to 6 beats) appearance of contrast in the left heart. Arterial blood gas analysis is then performed with the patient breathing room air in the supine and standing positions. The amount of right-to-left shunting can be assessed by repeating the arterial blood gas analysis with the patient breathing 100% oxygen. Finally, to quantify the degree of intrapulmonary shunting, a technetium-99m-labeled macroaggregated lung and brain perfusion scans are performed.

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Clinical Management

Liver transplantation can cause a complete resolution of type-1 HPS within 15 months of the procedure.51,52 Type-2 HPS may require further intervention, such as the placement of intrashunt coils to occlude the anatomic shunt. The mortality associated with liver transplantation and HPS is associated with the PaO2 at the time of surgery. A rate of 29% mortality is reported within 90 days postoperatively in patients with a PaO2<50 mm Hg.53 If transplantation is performed with a PaO2>50 mm Hg, the mortality is <4%. The intraoperative risks include the passage of air and other emboli across from the right-side circulation to the systemic side, with the potential for cerebral insult.54 The development of HPS is considered an indication for liver transplantation, as HPS will reverse after transplantation. POPH is not an indication for transplantation as the reversal after transplantation is not established. The resolution of HPS can unmask POPH.27 ’

References

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