Pulmonary Hypertension in Sickle Cell Disease
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《新英格兰医药杂志》
Sickle cell disease was first described in 1910 by Herrick and Irons. The irregularly shaped blood cells observed by Irons were those of Walter Clement Noel, a dental student with symptoms that included joint pain and shortness of breath. After graduation, Dr. Noel returned to his native Grenada, where he died suddenly at 32 years of age. Although the cause of death was recorded as pneumonia, his death was most likely the result of sudden, undetected pulmonary hypertension.
Today, we know that pulmonary hypertension and chronic lung disease are two of the most common causes of death among patients with sickle cell disease. Autopsy studies reveal clinically unsuspected obliterative pulmonary vasculopathy with signs of pulmonary hypertension in a third of all patients with sickle cell disease (see Figure), although the true frequency of pulmonary hypertension is unknown. Retrospective studies have shown that as many as 60 percent of patients with sickle cell disease are affected by pulmonary hypertension, and similar frequencies are now being observed among patients with many other hemolytic anemias, including congenital spherocytosis, thalassemia, and paroxysmal nocturnal hemoglobinuria. Chronic hemolysis and asplenia are the pathologic links between hemolytic anemia and pulmonary hypertension.
Figure. Histologic Appearance of Pulmonary Vessels from a Patient with Sickle Cell Disease and Previously Undetected Pulmonary Hypertension.
Changes on light microscopy demonstrate obliterative vasculopathy, with severe intimal hyperplasia, fibrosis, and thrombosis (hematoxylin and eosin, x40). Courtesy of Dr. Elizabeth Manci, University of South Alabama.
Hemolysis results in the release of free hemoglobin, which scavenges nitric oxide and catalyzes the formation of reactive oxygen species. Cell breakdown also releases red-cell arginase, which limits the availability of arginine to nitric oxide synthetase, resulting in a deficiency of nitric oxide. Asplenia increases the circulation of platelet-derived mediators, which promotes pulmonary microthrombosis and the adhesion of red cells to endothelium.
More is known about the pathophysiology of pulmonary hypertension in sickle cell disease than about that of pulmonary hypertension complicating any other hemolytic anemia. The catalysts of lung injury in patients with sickle cell disease include infection, bronchoreactive lung disease, and fat embolism. However, mild, undetected episodes of regional pulmonary hypoxia may be more important in the development of pulmonary hypertension and sudden death syndrome. These subclinical hypoxic events would explain the high rate of pulmonary hypertension in patients who do not have repeated episodes of acute chest syndrome.
Episodes of regional pulmonary hypoxia result in sickling, increased vascular adhesion, and the production of vasoactive substances. Repeated episodes of these hypoxic events, followed by reoxygenation, cause ischemia (i.e., reperfusion injury) with progressive tissue damage, altered pulmonary vascular tone, and vascular proliferation in the muscle wall. An associated hypercoagulable state causes pulmonary thrombosis of the constricted vessels, resulting in progressive loss of the vascular bed. Eventually, obliterative pulmonary vasculopathy with pulmonary hypertension develops. Normally, the vasodilatative and cytoprotective effects of nitric oxide counteract the process induced by the effects of hypoxia before irreversible damage occurs. However, the levels of both arginine (the substrate for nitric oxide) and nitric oxide metabolites are low, owing to increased production of arginase and the nitric oxide–scavenger effect of plasma hemoglobin. Therefore, the pulmonary vascular dilatation and inhibition of endothelial damage caused by nitric oxide are absent, and the process proceeds unchecked.
It is common to find undetected pulmonary hypertension at autopsy in patients with sickle cell disease, because routine clinical and laboratory findings are insensitive. Clinical symptoms are absent until irreversible damage results in shortness of breath. Chest radiographs are usually unchanged, even when high-resolution computed tomographic scanning demonstrates microvascular occlusion and hypoperfusion of the lung. Reactive airway disease has been noted in up to half of all patients with sickle cell disease and is a risk factor for acute chest syndrome and pulmonary hypertension. However, audible wheezing is frequently absent in patients, even when obstructive abnormalities of pulmonary function are noted. Measurements on pulse oximetry do not reflect the degree of lung damage until later stages. The study by Gladwin et al. in this issue of the Journal (pages 886 –895) gives us a reliable, noninvasive tool for the identification of pulmonary hypertension before end-stage progression occurs.
This well-designed, prospective study should have profound effects on the morbidity associated with sickle cell disease. A total of 195 consecutive patients were screened for pulmonary hypertension with the use of the tricuspid regurgitant jet velocity. Pulmonary hypertension was defined by a velocity of at least 2.5 m per second. The reliability of this technique was confirmed by means of selective cardiac catheterization. Thirty-two percent of the patients had pulmonary hypertension, which was strongly associated with early death. Two of the risk factors for pulmonary hypertension were hemolysis and elevated systolic systemic arterial pressure. Anecdotal data suggest that transfusion or pulmonary vasodilator therapy may be beneficial in such patients, but further study is required.
The study by Gladwin et al. suggests that there are three requirements for the management of pulmonary hypertension. The first is the use of echocardiography as a reliable, noninvasive screening test. The second is the confirmation of a critical pulmonary-pressure value. In comparison with patients who have primary pulmonary hypertension, patients with sickle cell disease have a higher risk of death with mild elevations in pulmonary pressure. Several reports support the use of a tricuspid regurgitant jet velocity of 2.5 m per second as a good threshold for intervention. The third requirement is the identification of risk factors, which could lead to the prevention of pulmonary hypertension. Relative systolic hypertension, a known predictor of stroke and death, is also a risk factor for pulmonary hypertension. More detailed studies of other epigenetic factors and genetic polymorphisms are needed.
For pulmonary hypertension that is not related to hemolytic anemia, new treatments have resulted in clinical responses and improved survival. Prostacyclin analogues, endothelin-1–receptor antagonists, phosphodiesterase inhibitors, and thromboxane inhibitors, along with anticoagulants and calcium-channel blockers, are currently available or are the subjects of ongoing clinical trials. Encouraging pilot studies have shown that infusions of prostacyclin analogues reduce pulmonary-artery pressures during cardiac catheterization in patients with sickle cell disease. These therapeutic agents most likely have a role in the treatment of pulmonary arterial hypertension associated with hemolysis. Therapy focused on the unique pathophysiology of pulmonary hypertension associated with hemolytic anemia is needed. Nitric oxide, L-arginine, hydroxyurea, dipyridamole, and transfusion therapy may become important options.
Increasing nitric oxide activity causes pulmonary vascular dilatation, inhibits endothelial damage, and prevents the proliferation of vascular smooth muscle. Although the inhalation of nitric oxide by patients with sickle cell disease decreases intrapulmonary shunting and improves oxygenation, it is difficult to continue such inhalation for long periods. Two inexpensive oral agents that are available, arginine and hydroxyurea, have antisickling properties and can both enhance the availability of nitric oxide and prevent rebound symptoms. Morris et al.1 reported that in patients with sickle cell disease and pulmonary hypertension, treatment with L-arginine improved nitric oxide synthesis, resulting in a 15 percent decrease in pulmonary-artery pressure. Arginine also reduces the density of sickled red cells by inhibiting the loss of cations, which may improve red-cell survival. Hydroxyurea, in addition to increasing fetal hemoglobin levels, causes an arginine-dependent elevation of nitric oxide levels. Arginine and hydroxyurea are synergistic and may therefore be a beneficial combination for many patients.
Long-term transfusion therapy in patients with sickle cell disease reduces the synthesis of sickle cells and its pathologic effects, including phosphatidylserine-exposed red cells, inflammatory mediators, thrombogenic factors, and endothelial damage. The risks of most complications of the disease are reduced, including the risks of pulmonary events and central nervous system vasculopathy. Data from pilot studies suggest that transfusion therapy may also reverse early pulmonary hypertension. Although transfusion is potentially effective, its use has been limited by its toxicity. Recent advances, including red-cell pheresis, improved cross-matching of red cells, and new iron-chelator therapies, minimize these risks. Since transfusion prevents stroke in asymptomatic patients with abnormal velocity in the intracranial vessels, it may be effective in preventing severe pulmonary hypertension in patients in whom mild elevations in pulmonary pressure have been detected on echocardiography.
It is now possible to identify patients in need of treatment before pulmonary hypertension becomes an end-stage condition and to intervene with potentially beneficial therapy. The most serious obstacle to improving outcomes is the lack of access to specialized services for patients with sickle cell disease, which are pivotal in the implementation of new therapy. It is estimated that only 10 percent of patients outside of comprehensive centers are monitored for pulmonary disease according to the guidelines of the National Institutes of Health — a fact that reflects a growing disparity between the standard of care and the delivery of care. This problem must be addressed if we are to improve outcomes for patients with sickle cell disease who have pulmonary hypertension.
Source Information
From the Department of Hematology–Oncology, Northern California Sickle Cell Center, Children's Hospital and Research Center at Oakland.
References
Morris CR, Morris SM Jr, Hagar W, et al. Arginine therapy: a new treatment for pulmonary hypertension in sickle cell disease? Am J Respir Crit Care Med 2003;168:63-69.(Elliott P. Vichinsky, M.D)
Today, we know that pulmonary hypertension and chronic lung disease are two of the most common causes of death among patients with sickle cell disease. Autopsy studies reveal clinically unsuspected obliterative pulmonary vasculopathy with signs of pulmonary hypertension in a third of all patients with sickle cell disease (see Figure), although the true frequency of pulmonary hypertension is unknown. Retrospective studies have shown that as many as 60 percent of patients with sickle cell disease are affected by pulmonary hypertension, and similar frequencies are now being observed among patients with many other hemolytic anemias, including congenital spherocytosis, thalassemia, and paroxysmal nocturnal hemoglobinuria. Chronic hemolysis and asplenia are the pathologic links between hemolytic anemia and pulmonary hypertension.
Figure. Histologic Appearance of Pulmonary Vessels from a Patient with Sickle Cell Disease and Previously Undetected Pulmonary Hypertension.
Changes on light microscopy demonstrate obliterative vasculopathy, with severe intimal hyperplasia, fibrosis, and thrombosis (hematoxylin and eosin, x40). Courtesy of Dr. Elizabeth Manci, University of South Alabama.
Hemolysis results in the release of free hemoglobin, which scavenges nitric oxide and catalyzes the formation of reactive oxygen species. Cell breakdown also releases red-cell arginase, which limits the availability of arginine to nitric oxide synthetase, resulting in a deficiency of nitric oxide. Asplenia increases the circulation of platelet-derived mediators, which promotes pulmonary microthrombosis and the adhesion of red cells to endothelium.
More is known about the pathophysiology of pulmonary hypertension in sickle cell disease than about that of pulmonary hypertension complicating any other hemolytic anemia. The catalysts of lung injury in patients with sickle cell disease include infection, bronchoreactive lung disease, and fat embolism. However, mild, undetected episodes of regional pulmonary hypoxia may be more important in the development of pulmonary hypertension and sudden death syndrome. These subclinical hypoxic events would explain the high rate of pulmonary hypertension in patients who do not have repeated episodes of acute chest syndrome.
Episodes of regional pulmonary hypoxia result in sickling, increased vascular adhesion, and the production of vasoactive substances. Repeated episodes of these hypoxic events, followed by reoxygenation, cause ischemia (i.e., reperfusion injury) with progressive tissue damage, altered pulmonary vascular tone, and vascular proliferation in the muscle wall. An associated hypercoagulable state causes pulmonary thrombosis of the constricted vessels, resulting in progressive loss of the vascular bed. Eventually, obliterative pulmonary vasculopathy with pulmonary hypertension develops. Normally, the vasodilatative and cytoprotective effects of nitric oxide counteract the process induced by the effects of hypoxia before irreversible damage occurs. However, the levels of both arginine (the substrate for nitric oxide) and nitric oxide metabolites are low, owing to increased production of arginase and the nitric oxide–scavenger effect of plasma hemoglobin. Therefore, the pulmonary vascular dilatation and inhibition of endothelial damage caused by nitric oxide are absent, and the process proceeds unchecked.
It is common to find undetected pulmonary hypertension at autopsy in patients with sickle cell disease, because routine clinical and laboratory findings are insensitive. Clinical symptoms are absent until irreversible damage results in shortness of breath. Chest radiographs are usually unchanged, even when high-resolution computed tomographic scanning demonstrates microvascular occlusion and hypoperfusion of the lung. Reactive airway disease has been noted in up to half of all patients with sickle cell disease and is a risk factor for acute chest syndrome and pulmonary hypertension. However, audible wheezing is frequently absent in patients, even when obstructive abnormalities of pulmonary function are noted. Measurements on pulse oximetry do not reflect the degree of lung damage until later stages. The study by Gladwin et al. in this issue of the Journal (pages 886 –895) gives us a reliable, noninvasive tool for the identification of pulmonary hypertension before end-stage progression occurs.
This well-designed, prospective study should have profound effects on the morbidity associated with sickle cell disease. A total of 195 consecutive patients were screened for pulmonary hypertension with the use of the tricuspid regurgitant jet velocity. Pulmonary hypertension was defined by a velocity of at least 2.5 m per second. The reliability of this technique was confirmed by means of selective cardiac catheterization. Thirty-two percent of the patients had pulmonary hypertension, which was strongly associated with early death. Two of the risk factors for pulmonary hypertension were hemolysis and elevated systolic systemic arterial pressure. Anecdotal data suggest that transfusion or pulmonary vasodilator therapy may be beneficial in such patients, but further study is required.
The study by Gladwin et al. suggests that there are three requirements for the management of pulmonary hypertension. The first is the use of echocardiography as a reliable, noninvasive screening test. The second is the confirmation of a critical pulmonary-pressure value. In comparison with patients who have primary pulmonary hypertension, patients with sickle cell disease have a higher risk of death with mild elevations in pulmonary pressure. Several reports support the use of a tricuspid regurgitant jet velocity of 2.5 m per second as a good threshold for intervention. The third requirement is the identification of risk factors, which could lead to the prevention of pulmonary hypertension. Relative systolic hypertension, a known predictor of stroke and death, is also a risk factor for pulmonary hypertension. More detailed studies of other epigenetic factors and genetic polymorphisms are needed.
For pulmonary hypertension that is not related to hemolytic anemia, new treatments have resulted in clinical responses and improved survival. Prostacyclin analogues, endothelin-1–receptor antagonists, phosphodiesterase inhibitors, and thromboxane inhibitors, along with anticoagulants and calcium-channel blockers, are currently available or are the subjects of ongoing clinical trials. Encouraging pilot studies have shown that infusions of prostacyclin analogues reduce pulmonary-artery pressures during cardiac catheterization in patients with sickle cell disease. These therapeutic agents most likely have a role in the treatment of pulmonary arterial hypertension associated with hemolysis. Therapy focused on the unique pathophysiology of pulmonary hypertension associated with hemolytic anemia is needed. Nitric oxide, L-arginine, hydroxyurea, dipyridamole, and transfusion therapy may become important options.
Increasing nitric oxide activity causes pulmonary vascular dilatation, inhibits endothelial damage, and prevents the proliferation of vascular smooth muscle. Although the inhalation of nitric oxide by patients with sickle cell disease decreases intrapulmonary shunting and improves oxygenation, it is difficult to continue such inhalation for long periods. Two inexpensive oral agents that are available, arginine and hydroxyurea, have antisickling properties and can both enhance the availability of nitric oxide and prevent rebound symptoms. Morris et al.1 reported that in patients with sickle cell disease and pulmonary hypertension, treatment with L-arginine improved nitric oxide synthesis, resulting in a 15 percent decrease in pulmonary-artery pressure. Arginine also reduces the density of sickled red cells by inhibiting the loss of cations, which may improve red-cell survival. Hydroxyurea, in addition to increasing fetal hemoglobin levels, causes an arginine-dependent elevation of nitric oxide levels. Arginine and hydroxyurea are synergistic and may therefore be a beneficial combination for many patients.
Long-term transfusion therapy in patients with sickle cell disease reduces the synthesis of sickle cells and its pathologic effects, including phosphatidylserine-exposed red cells, inflammatory mediators, thrombogenic factors, and endothelial damage. The risks of most complications of the disease are reduced, including the risks of pulmonary events and central nervous system vasculopathy. Data from pilot studies suggest that transfusion therapy may also reverse early pulmonary hypertension. Although transfusion is potentially effective, its use has been limited by its toxicity. Recent advances, including red-cell pheresis, improved cross-matching of red cells, and new iron-chelator therapies, minimize these risks. Since transfusion prevents stroke in asymptomatic patients with abnormal velocity in the intracranial vessels, it may be effective in preventing severe pulmonary hypertension in patients in whom mild elevations in pulmonary pressure have been detected on echocardiography.
It is now possible to identify patients in need of treatment before pulmonary hypertension becomes an end-stage condition and to intervene with potentially beneficial therapy. The most serious obstacle to improving outcomes is the lack of access to specialized services for patients with sickle cell disease, which are pivotal in the implementation of new therapy. It is estimated that only 10 percent of patients outside of comprehensive centers are monitored for pulmonary disease according to the guidelines of the National Institutes of Health — a fact that reflects a growing disparity between the standard of care and the delivery of care. This problem must be addressed if we are to improve outcomes for patients with sickle cell disease who have pulmonary hypertension.
Source Information
From the Department of Hematology–Oncology, Northern California Sickle Cell Center, Children's Hospital and Research Center at Oakland.
References
Morris CR, Morris SM Jr, Hagar W, et al. Arginine therapy: a new treatment for pulmonary hypertension in sickle cell disease? Am J Respir Crit Care Med 2003;168:63-69.(Elliott P. Vichinsky, M.D)