Case 31-2004 — A Four-Year-Old Boy with Hypoxemia
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《新英格兰医药杂志》
Presentation of Case
A four-year-old boy was transferred to this hospital because of hypoxemia of unknown origin. Five days before admission, he had been taken to the emergency room of another hospital with a fever of eight hours' duration (peak temperature, 40.6°C), associated with a cough and one episode of vomiting. On examination in the emergency room, the temperature was 39.9°C, the pulse 130 beats per minute, and the respiratory rate 32 breaths per minute, with an oxygen saturation of 87 to 90 percent while breathing room air. He weighed 18.6 kg and was 1.1 m tall. Auscultation of the chest revealed wheezing in the left lung. There was a grade 2/6 systolic ejection murmur at the left sternal border. The blood pressure was normal in both arms and legs.
The laboratory values recorded at the first hospital are shown in Table 1 and Table 2. A chest radiograph revealed that the heart was normal in size; there was a possible infiltrate in the right hilar area. Because of the low oxygen saturation and concern about the possible presence of an infiltrate, the patient was admitted to that hospital with a presumptive diagnosis of either viral or mycoplasmal pneumonia. Ceftriaxone was administered intravenously, azithromycin was administered orally, and nebulized albuterol treatments were given every four hours, as was supplemental oxygen.
Table 1. Hematologic Laboratory Values Obtained in the Emergency Room of the First Hospital.
Table 2. Blood Chemical Values.
The child's fever resolved within 24 hours, but he continued to require oxygen by rebreather mask or nasal cannula to maintain adequate oxygen-saturation levels. The calculated levels of oxygen saturation while the patient was breathing room air ranged from 88 to 93 percent but increased to 98 percent while he was breathing 6 liters of oxygen per minute through a rebreather mask and 93 to 95 percent while he was breathing 2 liters of oxygen per minute through a nasal cannula. An electrocardiogram showed sinus tachycardia at a rate of 127 beats per minute and right-axis deviation. A bedside echocardiogram was obtained, which revealed a trace of aortic insufficiency with no evidence of a right-to-left shunt. An attempt was made to obtain a high-resolution computed tomographic (CT) scan of the chest, but the patient became agitated and began crying; the oxygen-saturation level fell to 75 percent. Because of the persistent hypoxemia and the need for sedation to obtain the CT scan, the patient was transferred to this hospital on the fifth hospital day.
The patient had been delivered at 38 weeks of gestation by cesarean section; his birth weight was 5.27 kg. His mother had had gestational diabetes. Respiratory distress and bradycardia were noted at birth, and oxygen was administered for six days. The infant's parents were told that he had a heart problem, which was not further explained. Thereafter, the parents observed that he often had shortness of breath with bottle feeding and increased respiratory effort with exertion. His parents had emigrated from Mexico before his birth; his father traveled there often, but the patient had not traveled outside the United States. He lived with his parents and two older brothers, who were well, and he was functioning well in preschool. An uncle had an undefined vascular abnormality. The patient was allergic to amoxicillin; his vaccinations were up to date.
On physical examination, the boy was tall and thin for his age; he appeared well. He was breathing oxygen by nasal cannula. The temperature was 38.4°C, the pulse 118 beats per minute, the blood pressure 106/59 mm Hg, and the respiratory rate 44 breaths per minute. Examination of the ears, nose, and throat showed no abnormalities. Cardiovascular examination revealed a grade 2/6 systolic murmur, heard best over the lower left portion of the sternum. The intensity of this murmur fluctuated with a change in position. The lungs were clear on percussion and auscultation. Abdominal examination revealed no abnormalities. There was no hepatosplenomegaly. Examination of the skin showed no rash. There was mild clubbing of the fingers and toes. There was no cyanosis or edema of the arms or legs. Arterial blood gas values are shown in Table 3.
Table 3. Blood Gas Values on Second Hospital Day.
An echocardiogram was obtained on the day after admission. The valves appeared normal, and there was no evidence of coarctation of the aorta, patent ductus arteriosus, mitral-valve prolapse, or valvular insufficiency. The estimated ejection fraction was 73 percent.
On the second hospital day, CT scanning of the patient's chest was performed while the patient was under general anesthesia, after the intravenous administration of contrast material. The heart was normal in size, and the aorta and its branches were normal. The pulmonary artery was not enlarged. The left inferior pulmonary vein was prominent but not definitely enlarged. The lung parenchyma showed loss of volume in the left lower lobe, with a consolidation that appeared nodular. There was patchy atelectasis at the base of the right lung. Perfusion images showed no direct arteriovenous communication.
A chest radiograph obtained on the third hospital day showed resolution of the left lower consolidation that had been seen on the chest CT scan. The lungs were clear. The plasma level of D-dimer was 298 ng per milliliter. On the fourth hospital day, a ventilation–perfusion scan was obtained. The ventilation study revealed normal initial distribution of the labeled radioactive material and no regions of abnormal retention on clearance of the labeled material. Perfusion was heterogeneous, but with a normal gradient of the labeled material from the base to the apex. Activity consistent with a right-to-left shunt was noted both in the brain and in the kidneys. The findings suggested a low probability of the presence of pulmonary emboli.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. T. Bernard Kinane: Although the differential diagnosis of hypoxemia is broad, it can be refined by defining the duration of hypoxemia and the underlying physiological mechanism. When I saw this child, he had had hypoxemia for at least seven days and had two findings that suggested chronic hypoxemia: clubbing of the fingers and toes, which is an unusual finding in children, and elevated hemoglobin and hematocrit values. Although several physiological mechanisms can lead to hypoxemia,1 enough data are available in this case to identify the mechanism. The partial pressure of oxygen improved only minimally when the patient was breathing 100 percent oxygen, yet oxygen saturation improved with this therapy. In addition, the alveolar–arterial gradient, measured while the patient was breathing room air, was elevated (24 mm Hg), as was the partial pressure of carbon dioxide in the arterial blood.
The physiological mechanisms that induce hypoxemia include altitude, hypoventilation, diffusion defects, shunts, and ventilation–perfusion defects. Altitude is not a concern in this case, since Boston is at sea level, and the value for the partial pressure of oxygen should improve with oxygen therapy. Hypoventilation is seen occasionally in children and may be due to failure of the central respiratory center or abnormalities of the peripheral nerves and muscles. In hypoventilation, the partial pressure of oxygen is depressed and that of carbon dioxide is elevated. There is a normal alveolar–arterial gradient and a robust response to oxygen, unlike the findings in this case. Diffusion defects arise when the distance that oxygen must travel from the alveolus to the hemoglobin in the pulmonary capillary is altered; such defects result in hypoxemia with exercise at altitude but rarely at rest. This type of hypoxemia responds to inhaled oxygen and is therefore unlikely in this case. The shunting of blood through intracardiac defects or abnormal intrapulmonary vessels is a frequent cause of hypoxemia. The hallmarks of shunting are a poor response to inhaled oxygen therapy and an increased alveolar–arterial gradient. In some cases, there may be a partial response to oxygen therapy. The most frequent cause of hypoxemia is a ventilation–perfusion mismatch, which can lead to clinically significant hypoxemia but is responsive to oxygen therapy.
The predominant clinical feature of this patient's presentation was the poor response of the arterial partial pressure of oxygen to the inhalation of 100 percent oxygen; accordingly, the predominant physiological feature in this case is a shunt (Table 4). Other mechanisms may coexist, since the partial pressure of carbon dioxide was elevated and there was a partial response of the oxygen-saturation levels to oxygen therapy.
Table 4. Differential Diagnosis of Hypoxemia.
Shunts can be divided into two types: intracardiac and intrapulmonary. Intracardiac shunts result from an abnormal connection between the pulmonary and systemic circulations. They occur in approximately 20 percent of patients with congenital heart disease. Conditions that could cause such a shunt in the age group of the patient in this case include tetralogy of Fallot, Eisenmenger's syndrome (with an atrial septal defect, ventricular septal defect, or patent ductus arteriosus), and pulmonary-artery hypertension with a patent foramen ovale.2 However, the variation in the intensity of this patient's cardiac murmur according to his position suggests that the murmur was benign, and two echocardiograms would easily have identified these defects. Thus, an intracardiac shunt is extremely unlikely in this case.
Chronic intrapulmonary shunts are unusual, and the differential diagnosis includes two conditions: pulmonary arteriovenous malformations3 and the hepatopulmonary syndrome.4,5 Pulmonary arteriovenous malformations are characterized by an abnormal communication between the pulmonary arteries and veins.6 Such malformations are rare, detected in only 2 of 15,000 consecutive autopsies.7 They occur twice as often in females as in males and are rarely identified in infancy but are increasingly identified with advancing age. Approximately two thirds of pulmonary arteriovenous malformations occur in the context of hereditary hemorrhagic telangiectasia, also known as the Rendu–Osler–Weber syndrome.8,9,10
Pulmonary arteriovenous malformations occur in approximately one third of patients with hereditary hemorrhagic telangiectasia. These patients present with symptoms that range from very mild to life-threatening. The most common symptoms include epistaxis, dyspnea, and hemoptysis.3 The most common findings on physical examination are telangiectasia, bruits over the chest, and clubbing. This patient had dyspnea, which occurs in approximately 50 percent of patients, and he had clubbing, which occurs in approximately 30 percent. Furthermore, there is a possible family history of a vascular abnormality, in the child's uncle. The diagnosis of pulmonary arteriovenous malformations is established by confirming the presence of a shunt and by obtaining chest films and CT scans that reveal the presence of such malformations.11 Calculation of the shunt fraction (the cardiac output that bypasses the pulmonary capillaries) can be helpful but can be established only after the patient has been breathing 100 percent oxygen through a tightly fitting mask.12 This maneuver is difficult to perform in a young child. The current approach is to use contrast-enhanced echocardiography and injection with technetium-99m–labeled macroaggregated albumin to confirm the presence of pulmonary arteriovenous malformations. In this case, the possibility of a pulmonary arteriovenous malformation needs to be ruled out.
The hepatopulmonary syndrome is characterized by dilatation of the pulmonary vascular bed in the context of chronic liver disease.4,5 This syndrome should be considered in cases of chronic liver disease with an increase in the alveolar–arterial gradient and evidence of intrapulmonary vascular dilatation. The hepatopulmonary syndrome occurs in up to 50 percent of patients with chronic liver disease from any cause.13 There is no consistent relationship between the severity of liver disease and the hypoxia associated with the hepatopulmonary syndrome. The presence of spider nevi has been associated with an increased incidence of the hepatopulmonary syndrome.14 Patients who have this syndrome can present with either hepatic symptoms (80 percent of patients) or pulmonary symptoms (20 percent). The main pulmonary symptom is dyspnea, which may be accompanied by platypnea or orthodeoxia.15 These symptoms are usually accompanied by hypoxemia, which can be severe and progress despite stable liver disease.
Pulmonary capillaries normally range in diameter from 8 to 15 μm, whereas in patients with the hepatopulmonary syndrome, the range is 15 to 100 μm (Figure 1). The hypoxemia that accompanies this condition is due to the failure of the blood in the center of the dilated capillary to oxygenate completely because of the distance from the alveolar gas. For this reason, there is a partial response to oxygen therapy.
Figure 1. Mechanism of Shunting in the Hepatopulmonary Syndrome.
In a normal lung, the capillary diameter is 8 to 15 μm and oxygen diffuses rapidly into the capillary. In a classic shunt, blood bypasses the alveolus, whereas in the hepatopulmonary syndrome, the capillaries are dilated to 15 to 100 μm in diameter, and oxygen fails to diffuse into the center of the dilated capillary.
The findings in this case are consistent with the hepatopulmonary syndrome. The normal liver-function tests argue against this diagnosis but could be a reflection of subclinical dysfunction, since the occurrence of the hepatopulmonary syndrome does not reflect the severity of the liver disease. The boy did not have spider nevi, but he did have a partial response to oxygen therapy. To confirm the diagnosis of the hepatopulmonary syndrome, the presence of an intrapulmonary shunt must be verified, and vascular dilatation can be further identified by pulmonary angiography. The diagnosis of the hepatopulmonary syndrome requires proof of liver disease.
In summary, this child has chronic hypoxemia that is probably due to intrapulmonary shunting. The main diagnostic considerations are a pulmonary arteriovenous malformation and the hepatopulmonary syndrome. Pulmonary arteriovenous malformations are easily identified by CT scanning. May we review the radiologic studies?
Dr. Sjirk J. Westra: The first examination was contrast-enhanced CT scanning of the chest, performed while the patient was under general anesthesia. The heart and the mediastinal vessels were normal in size, with no structural abnormalities. The lung parenchyma was characterized by a nodular-appearing consolidation in the left lower lobe, which was interpreted as anesthesia-related atelectasis. High-resolution images showed an enlarged caliber of the pulmonary vasculature in the dependent lower lung zones (Figure 2). Dynamic scanning during rapid, intravenous injection of a bolus of contrast material showed sequential enhancement of pulmonary arteries and veins, with no evidence of a direct arteriovenous connection or early filling of a pulmonary vein, which would suggest pulmonary arteriovenous fistula or another malformation.
Figure 2. Chest CT Scan.
A high-resolution section through the lung bases shows peripheral pulmonary vascular congestion (arrow) and nodular atelectatic changes in the left lower lobe (asterisk).
A chest radiograph obtained on the following day showed resolution of atelectasis in the left lower lobe, and the lungs were clear. The ventilation–perfusion radionuclide scan showed normal ventilation and slight heterogeneity of the perfusion of the lungs, but no segmental defects — findings that are consistent with a low probability of pulmonary emboli. However, abnormal activity of the radiotracer was seen in the brain and kidneys, a finding considered indicative of a right-to-left shunt.
Dr. Kinane: In the absence of a pulmonary arteriovenous malformation on the chest CT scans, the diagnosis is most likely the hepatopulmonary syndrome. We proceeded with further imaging studies of the liver and made plans for a liver biopsy, depending on the findings.
Dr. T. Bernard Kinane's Diagnosis
Hepatopulmonary syndrome.
Anatomical Discussion
Dr. Westra: On further review of the upper abdominal sectional views of the chest on CT scanning, a direct fistulous connection between the portal vein and the inferior vena cava was demonstrated. Dynamic gadolinium-enhanced magnetic resonance angiography of the chest and upper abdomen was performed to further clarify the cause of the arteriovenous shunting. This examination confirmed the presence of an extrahepatic fistulous connection between the splenomesenteric confluence and the inferior vena cava, with congenital absence of the extrahepatic and intrahepatic portal vein (Figure 3A). A hypertrophied hepatic artery was the only vessel perfusing the liver parenchyma (Figure 3B). The liver showed architectural distortion, as inferred from the anomalous position of the gallbladder, with relative atrophy of the right hepatic lobe and hypertrophy of the left hepatic lobe. This is a common finding in chronic liver disease with cirrhosis. However, the liver parenchyma in this case was homogeneous and not macronodular, and there were no secondary signs of portal hypertension, such as ascites, splenomegaly, or portal venous collateral vessels. Apparently, mesenteric blood flow directly drained into the inferior vena cava, thereby bypassing the diseased liver, so that the typical manifestations of chronic liver disease and portal hypertension did not develop.
Figure 3. Abdominal MRI Studies.
Panel A shows the presence of a portacaval fistula. The arrow indicates the direction of flow between the portal vein (p) and the inferior vena cava (i). The anomalous position of the gallbladder (asterisk) indicates an architectural distortion of the liver, with an atrophic right lobe. Panel B, an axial, contrast-enhanced magnetic resonance angiogram of the arterial phase, shows a hypertrophic hepatic artery, which is the only vessel perfusing the liver.
This congenital anomaly of the splanchnic vasculature, known as the Abernethy malformation,16,17 is relatively common in dogs (particularly in Yorkshire terriers), but it is extremely uncommon in humans. In this boy, the malformation apparently led to subclinical chronic liver disease, manifested as chronic hypoxia, through the pathogenetic pathway of the hepatopulmonary syndrome. This syndrome is characterized by radiographic findings of chronic liver disease combined with dilatation of subpleural pulmonary vessels resembling spider nevi, which are predominantly located in the lower lobes of the lungs.18,19,20
Dr. Kinane: The Abernethy malformation is a surprising cause of the hepatopulmonary syndrome, and I did not consider it before it was identified on the CT scan. Two types of the Abernethy malformation — which arise from defects in vitelline vein formation (Figure 4) — have been described.21,22 In type 1, which this child had, the portal vein is completely diverted into the inferior vena cava, and there is a complete absence of formation of the intrahepatic portal vein. In type 2, the portal venous system is completely formed, and there is an abnormal communication with systemic veins, usually the inferior vena cava.
Figure 4. The Abernethy Malformation.
In the type 1 Abernethy malformation, which the patient in this case had, the portal vein is completely diverted into the inferior vena cava, instead of draining into the liver.
To date, there are 19 cases of type 1 malformation (15 in girls and 4 in boys), and 6 cases of type 2 (5 in boys and 1 in a girl) have been reported.16,21 The type 1 malformation is frequently associated with other abnormalities, including ventricular septal defects and aortic-arch defects.23 The clinical features and the prognosis for the two types are similar. Hepatic encephalopathy and the hepatopulmonary syndrome frequently develop. Brain abscess associated with the Abernethy malformation has been described.21 It is postulated that the pulmonary capillaries are dilated and fail to filter out circulating bacteria. The Abernethy malformation, although rare, should be considered in cases of the hepatopulmonary syndrome in which the liver disease is not initially obvious.
The pathogenesis of the pulmonary vasodilatation in patients with the hepatopulmonary syndrome is not known. However, some insight can be derived from the Abernethy malformation and from experience with the use of vascular shunts to correct congenital heart defects. In some of the latter cases, the superior vena cava is anastomosed to the right pulmonary artery, and the blood from the lower part of the body, including the hepatic vein, is directed to the left pulmonary artery. In patients who undergo this correction, dilatation of the right-sided pulmonary vasculature develops. This progression of events suggests that a factor in the lower part of the body can prevent pulmonary vasodilatation.24,25 To hypothesize further on the basis of the Abernethy malformation, blood from the gut must cross through the liver to prevent pulmonary vasodilatation. We can therefore postulate that the proposed factor is produced in the liver but that blood from the gut is necessary for its production.
Treatment of the Abernethy type 1 malformation is directed at the pulmonary vascular bed, since an anatomical repair is impossible. Strategies include the embolization of dilated blood vessels and the pharmaceutical regulation of vessel tone. Embolization may be followed by an initial improvement in oxygen saturation, but there is a subsequent return to previous levels.26 Inhibitors of vasodilatation, including somatostatin analogues, nitric oxide synthase inhibitors, and indomethacin, have resulted in poor responses and troublesome side effects. Liver transplantation has been attempted in some cases,27 but the early mortality was about 30 percent, as compared with 10 percent among patients without the hepatopulmonary syndrome. For those who survive, liver transplantation is an effective therapy, with intrapulmonary shunting improving over a period of six weeks.4,28
The plan for this child has been to monitor his oxygen-saturation levels, and when they fall to the low end of the 80 percent range, to consider liver transplantation. At the most recent follow-up, when he was five years eight months old, he used supplemental oxygen at the rate of 1 liter per minute, with oxygen saturation levels in the 80 percent range at rest, but dropping to as low as 73 percent with exertion. A radionuclide scan showed a right-to-left shunt of 60 percent (Figure 5). The results of liver-function tests have continued to be normal. We will probably need to consider a liver transplantation for this child soon.
Figure 5. Ventilation–Perfusion Radionuclide Scan.
The scan, obtained when the patient was five years eight months old, shows abnormal activity of the radiotracer in the brain and kidneys, which is indicative of a right-to-left shunt, measured at 60 percent.
Anatomical Diagnosis
Hepatopulmonary syndrome due to the Abernethy malformation, type 1.
Dr. Kinane is a member of the speakers bureaus of AstraZeneca and GlaxoSmithKline.
Source Information
From the Pediatric Service (T.B.K.) and the Department of Radiology (S.J.W.), Massachusetts General Hospital; and the Department of Pediatrics (T.B.K.) and the Department of Radiology (S.J.W.), Harvard Medical School.
References
West JB. Respiratory physiology — the essentials. 5th ed. New York: Williams and Wilkins, 1995:45-61.
Bernstein D. The cardiovascular system. In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson textbook of pediatrics. 16th ed. Philadelphia: W.B. Saunders, 2000:337-409.
Gossage JR, Kanj G. Pulmonary arteriovenous malformations: a state of the art review. Am J Respir Crit Care Med 1998;158:643-661.
Lange PA, Stoller JK. The hepatopulmonary syndrome: effect of liver transplantation. Clin Chest Med 1996;17:115-123.
Krowka MJ, Cortese DA. Hepatopulmonary syndrome: current concepts in diagnostic and therapeutic considerations. Chest 1994;105:1528-1537.
Churton T. Multiple aneurysms of the pulmonary artery. BMJ 1897;1:1223-1225.
Sloan RD, Cooley RN. Congenital pulmonary arteriovenous aneurysm. Am J Roentgenol Radium Ther Nucl Med 1953;70:183-210.
Plauchu H, de Chadarevian JP, Bideau A, Robert JM. Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population. Am J Med Genet 1989;32:291-297.
Haitjema T, Disch F, Overtoom TT, Westermann CJ, Lammers JW. Screening family members of patients with hereditary hemorrhagic telangiectasia. Am J Med 1995;99:519-524.
Vase P, Holm M, Arendrup H. Pulmonary arteriovenous fistulas in hereditary hemorrhagic telangiectasia. Acta Med Scand 1985;218:105-109.
Remy J, Remy-Jardin M, Wattinne L, Deffontaines C. Pulmonary arteriovenous malformations: evaluation with CT of the chest before and after treatment. Radiology 1992;182:809-816.
Whyte MK, Peters AM, Hughes JM, et al. Quantification of right to left shunt at rest and during exercise in patients with pulmonary arteriovenous malformations. Thorax 1992;47:790-796.
Hopkins WE, Waggoner AD, Barzilai B. Frequency and significance of intrapulmonary right-to-left shunting in end-stage hepatic disease. Am J Cardiol 1992;70:516-519.
Rodriguez-Roisin R, Roca J, Agusti AG, Mastai R, Wagner PD, Bosch J. Gas exchange and pulmonary vascular reactivity in patients with liver cirrhosis. Am Rev Respir Dis 1987;135:1085-1092.
Lange PA, Stoller JK. The hepatopulmonary syndrome. Ann Intern Med 1995;122:521-529.
Usuki N, Miyamoto T. A case of congenital absence of the intrahepatic portal vein diagnosed by MR angiography. J Comput Assist Tomogr 1998;22:728-729.
Badler R, Price AP, Moy L, Katz DS. Congenital portocaval shunt: CT demonstration. Pediatr Radiol 2002;32:28-30.
McAdams HP, Erasmus J, Crockett R, Mitchell J, Godwin JD, McDermott VG. The hepatopulmonary syndrome: radiologic findings in 10 patients. AJR Am J Roentgenol 1996;166:1379-1385.
Lee K-N, Lee H-J, Shin WW, Webb WR. Hypoxemia and liver cirrhosis (hepatopulmonary syndrome) in eight patients: comparison of the central and peripheral pulmonary vasculature. Radiology 1999;211:549-553.
Engelke C, Schaefer-Prokop C, Schirg E, Freihorst J, Grubnic S, Prokop M. High-resolution CT and CT angiography of peripheral pulmonary vascular disorders. Radiographics 2002;22:739-764.
Alvarez AE, Ribeiro AF, Hessel G, Baracat J, Ribeiro JD. Abernethy malformation: one of the etiologies of hepatopulmonary syndrome. Pediatr Pulmonol 2002;34:391-394.
Howard ER, Davenport M. Congenital extrahepatic portocaval shunts -- the Abernethy malformation. J Pediatr Surg 1997;32:494-497.
Kohda E, Saeki M, Nakano M, et al. Congenital absence of the portal vein in a boy. Pediatr Radiol 1999;29:235-237.
Srivastava D, Preminger T, Lock JE, et al. Hepatic venous blood and the development of pulmonary arteriovenous malformations in congenital heart disease. Circulation 1995;92:1217-1222.
Lee J, Menkis AH, Rosenberg HC. Reversal of pulmonary arteriovenous malformation after diversion of anomalous hepatic drainage. Ann Thorac Surg 1998;65:848-849.
Ryu JK, Oh JH. Hepatopulmonary syndrome: angiography and therapeutic embolization. Clin Imaging 2003;27:97-100.
Arguedas MR, Abrams GA, Krowka MJ, Fallon MB. Prospective evaluation of outcomes and predictors of mortality in patients with hepatopulmonary syndrome undergoing liver transplantation. Hepatology 2003;37:192-197.
Taille C, Cadranel J, Bellocq A, et al. Liver transplantation for hepatopulmonary syndrome: a ten-year experience in Paris, France. Transplantation 2003;75:1482-1489.
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Case 31-2004: A Four-Year-Old Boy with Hypoxemia
Hoftman N., Kinane T. B., Shannon D. C.(T. Bernard Kinane, M.D., )
A four-year-old boy was transferred to this hospital because of hypoxemia of unknown origin. Five days before admission, he had been taken to the emergency room of another hospital with a fever of eight hours' duration (peak temperature, 40.6°C), associated with a cough and one episode of vomiting. On examination in the emergency room, the temperature was 39.9°C, the pulse 130 beats per minute, and the respiratory rate 32 breaths per minute, with an oxygen saturation of 87 to 90 percent while breathing room air. He weighed 18.6 kg and was 1.1 m tall. Auscultation of the chest revealed wheezing in the left lung. There was a grade 2/6 systolic ejection murmur at the left sternal border. The blood pressure was normal in both arms and legs.
The laboratory values recorded at the first hospital are shown in Table 1 and Table 2. A chest radiograph revealed that the heart was normal in size; there was a possible infiltrate in the right hilar area. Because of the low oxygen saturation and concern about the possible presence of an infiltrate, the patient was admitted to that hospital with a presumptive diagnosis of either viral or mycoplasmal pneumonia. Ceftriaxone was administered intravenously, azithromycin was administered orally, and nebulized albuterol treatments were given every four hours, as was supplemental oxygen.
Table 1. Hematologic Laboratory Values Obtained in the Emergency Room of the First Hospital.
Table 2. Blood Chemical Values.
The child's fever resolved within 24 hours, but he continued to require oxygen by rebreather mask or nasal cannula to maintain adequate oxygen-saturation levels. The calculated levels of oxygen saturation while the patient was breathing room air ranged from 88 to 93 percent but increased to 98 percent while he was breathing 6 liters of oxygen per minute through a rebreather mask and 93 to 95 percent while he was breathing 2 liters of oxygen per minute through a nasal cannula. An electrocardiogram showed sinus tachycardia at a rate of 127 beats per minute and right-axis deviation. A bedside echocardiogram was obtained, which revealed a trace of aortic insufficiency with no evidence of a right-to-left shunt. An attempt was made to obtain a high-resolution computed tomographic (CT) scan of the chest, but the patient became agitated and began crying; the oxygen-saturation level fell to 75 percent. Because of the persistent hypoxemia and the need for sedation to obtain the CT scan, the patient was transferred to this hospital on the fifth hospital day.
The patient had been delivered at 38 weeks of gestation by cesarean section; his birth weight was 5.27 kg. His mother had had gestational diabetes. Respiratory distress and bradycardia were noted at birth, and oxygen was administered for six days. The infant's parents were told that he had a heart problem, which was not further explained. Thereafter, the parents observed that he often had shortness of breath with bottle feeding and increased respiratory effort with exertion. His parents had emigrated from Mexico before his birth; his father traveled there often, but the patient had not traveled outside the United States. He lived with his parents and two older brothers, who were well, and he was functioning well in preschool. An uncle had an undefined vascular abnormality. The patient was allergic to amoxicillin; his vaccinations were up to date.
On physical examination, the boy was tall and thin for his age; he appeared well. He was breathing oxygen by nasal cannula. The temperature was 38.4°C, the pulse 118 beats per minute, the blood pressure 106/59 mm Hg, and the respiratory rate 44 breaths per minute. Examination of the ears, nose, and throat showed no abnormalities. Cardiovascular examination revealed a grade 2/6 systolic murmur, heard best over the lower left portion of the sternum. The intensity of this murmur fluctuated with a change in position. The lungs were clear on percussion and auscultation. Abdominal examination revealed no abnormalities. There was no hepatosplenomegaly. Examination of the skin showed no rash. There was mild clubbing of the fingers and toes. There was no cyanosis or edema of the arms or legs. Arterial blood gas values are shown in Table 3.
Table 3. Blood Gas Values on Second Hospital Day.
An echocardiogram was obtained on the day after admission. The valves appeared normal, and there was no evidence of coarctation of the aorta, patent ductus arteriosus, mitral-valve prolapse, or valvular insufficiency. The estimated ejection fraction was 73 percent.
On the second hospital day, CT scanning of the patient's chest was performed while the patient was under general anesthesia, after the intravenous administration of contrast material. The heart was normal in size, and the aorta and its branches were normal. The pulmonary artery was not enlarged. The left inferior pulmonary vein was prominent but not definitely enlarged. The lung parenchyma showed loss of volume in the left lower lobe, with a consolidation that appeared nodular. There was patchy atelectasis at the base of the right lung. Perfusion images showed no direct arteriovenous communication.
A chest radiograph obtained on the third hospital day showed resolution of the left lower consolidation that had been seen on the chest CT scan. The lungs were clear. The plasma level of D-dimer was 298 ng per milliliter. On the fourth hospital day, a ventilation–perfusion scan was obtained. The ventilation study revealed normal initial distribution of the labeled radioactive material and no regions of abnormal retention on clearance of the labeled material. Perfusion was heterogeneous, but with a normal gradient of the labeled material from the base to the apex. Activity consistent with a right-to-left shunt was noted both in the brain and in the kidneys. The findings suggested a low probability of the presence of pulmonary emboli.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. T. Bernard Kinane: Although the differential diagnosis of hypoxemia is broad, it can be refined by defining the duration of hypoxemia and the underlying physiological mechanism. When I saw this child, he had had hypoxemia for at least seven days and had two findings that suggested chronic hypoxemia: clubbing of the fingers and toes, which is an unusual finding in children, and elevated hemoglobin and hematocrit values. Although several physiological mechanisms can lead to hypoxemia,1 enough data are available in this case to identify the mechanism. The partial pressure of oxygen improved only minimally when the patient was breathing 100 percent oxygen, yet oxygen saturation improved with this therapy. In addition, the alveolar–arterial gradient, measured while the patient was breathing room air, was elevated (24 mm Hg), as was the partial pressure of carbon dioxide in the arterial blood.
The physiological mechanisms that induce hypoxemia include altitude, hypoventilation, diffusion defects, shunts, and ventilation–perfusion defects. Altitude is not a concern in this case, since Boston is at sea level, and the value for the partial pressure of oxygen should improve with oxygen therapy. Hypoventilation is seen occasionally in children and may be due to failure of the central respiratory center or abnormalities of the peripheral nerves and muscles. In hypoventilation, the partial pressure of oxygen is depressed and that of carbon dioxide is elevated. There is a normal alveolar–arterial gradient and a robust response to oxygen, unlike the findings in this case. Diffusion defects arise when the distance that oxygen must travel from the alveolus to the hemoglobin in the pulmonary capillary is altered; such defects result in hypoxemia with exercise at altitude but rarely at rest. This type of hypoxemia responds to inhaled oxygen and is therefore unlikely in this case. The shunting of blood through intracardiac defects or abnormal intrapulmonary vessels is a frequent cause of hypoxemia. The hallmarks of shunting are a poor response to inhaled oxygen therapy and an increased alveolar–arterial gradient. In some cases, there may be a partial response to oxygen therapy. The most frequent cause of hypoxemia is a ventilation–perfusion mismatch, which can lead to clinically significant hypoxemia but is responsive to oxygen therapy.
The predominant clinical feature of this patient's presentation was the poor response of the arterial partial pressure of oxygen to the inhalation of 100 percent oxygen; accordingly, the predominant physiological feature in this case is a shunt (Table 4). Other mechanisms may coexist, since the partial pressure of carbon dioxide was elevated and there was a partial response of the oxygen-saturation levels to oxygen therapy.
Table 4. Differential Diagnosis of Hypoxemia.
Shunts can be divided into two types: intracardiac and intrapulmonary. Intracardiac shunts result from an abnormal connection between the pulmonary and systemic circulations. They occur in approximately 20 percent of patients with congenital heart disease. Conditions that could cause such a shunt in the age group of the patient in this case include tetralogy of Fallot, Eisenmenger's syndrome (with an atrial septal defect, ventricular septal defect, or patent ductus arteriosus), and pulmonary-artery hypertension with a patent foramen ovale.2 However, the variation in the intensity of this patient's cardiac murmur according to his position suggests that the murmur was benign, and two echocardiograms would easily have identified these defects. Thus, an intracardiac shunt is extremely unlikely in this case.
Chronic intrapulmonary shunts are unusual, and the differential diagnosis includes two conditions: pulmonary arteriovenous malformations3 and the hepatopulmonary syndrome.4,5 Pulmonary arteriovenous malformations are characterized by an abnormal communication between the pulmonary arteries and veins.6 Such malformations are rare, detected in only 2 of 15,000 consecutive autopsies.7 They occur twice as often in females as in males and are rarely identified in infancy but are increasingly identified with advancing age. Approximately two thirds of pulmonary arteriovenous malformations occur in the context of hereditary hemorrhagic telangiectasia, also known as the Rendu–Osler–Weber syndrome.8,9,10
Pulmonary arteriovenous malformations occur in approximately one third of patients with hereditary hemorrhagic telangiectasia. These patients present with symptoms that range from very mild to life-threatening. The most common symptoms include epistaxis, dyspnea, and hemoptysis.3 The most common findings on physical examination are telangiectasia, bruits over the chest, and clubbing. This patient had dyspnea, which occurs in approximately 50 percent of patients, and he had clubbing, which occurs in approximately 30 percent. Furthermore, there is a possible family history of a vascular abnormality, in the child's uncle. The diagnosis of pulmonary arteriovenous malformations is established by confirming the presence of a shunt and by obtaining chest films and CT scans that reveal the presence of such malformations.11 Calculation of the shunt fraction (the cardiac output that bypasses the pulmonary capillaries) can be helpful but can be established only after the patient has been breathing 100 percent oxygen through a tightly fitting mask.12 This maneuver is difficult to perform in a young child. The current approach is to use contrast-enhanced echocardiography and injection with technetium-99m–labeled macroaggregated albumin to confirm the presence of pulmonary arteriovenous malformations. In this case, the possibility of a pulmonary arteriovenous malformation needs to be ruled out.
The hepatopulmonary syndrome is characterized by dilatation of the pulmonary vascular bed in the context of chronic liver disease.4,5 This syndrome should be considered in cases of chronic liver disease with an increase in the alveolar–arterial gradient and evidence of intrapulmonary vascular dilatation. The hepatopulmonary syndrome occurs in up to 50 percent of patients with chronic liver disease from any cause.13 There is no consistent relationship between the severity of liver disease and the hypoxia associated with the hepatopulmonary syndrome. The presence of spider nevi has been associated with an increased incidence of the hepatopulmonary syndrome.14 Patients who have this syndrome can present with either hepatic symptoms (80 percent of patients) or pulmonary symptoms (20 percent). The main pulmonary symptom is dyspnea, which may be accompanied by platypnea or orthodeoxia.15 These symptoms are usually accompanied by hypoxemia, which can be severe and progress despite stable liver disease.
Pulmonary capillaries normally range in diameter from 8 to 15 μm, whereas in patients with the hepatopulmonary syndrome, the range is 15 to 100 μm (Figure 1). The hypoxemia that accompanies this condition is due to the failure of the blood in the center of the dilated capillary to oxygenate completely because of the distance from the alveolar gas. For this reason, there is a partial response to oxygen therapy.
Figure 1. Mechanism of Shunting in the Hepatopulmonary Syndrome.
In a normal lung, the capillary diameter is 8 to 15 μm and oxygen diffuses rapidly into the capillary. In a classic shunt, blood bypasses the alveolus, whereas in the hepatopulmonary syndrome, the capillaries are dilated to 15 to 100 μm in diameter, and oxygen fails to diffuse into the center of the dilated capillary.
The findings in this case are consistent with the hepatopulmonary syndrome. The normal liver-function tests argue against this diagnosis but could be a reflection of subclinical dysfunction, since the occurrence of the hepatopulmonary syndrome does not reflect the severity of the liver disease. The boy did not have spider nevi, but he did have a partial response to oxygen therapy. To confirm the diagnosis of the hepatopulmonary syndrome, the presence of an intrapulmonary shunt must be verified, and vascular dilatation can be further identified by pulmonary angiography. The diagnosis of the hepatopulmonary syndrome requires proof of liver disease.
In summary, this child has chronic hypoxemia that is probably due to intrapulmonary shunting. The main diagnostic considerations are a pulmonary arteriovenous malformation and the hepatopulmonary syndrome. Pulmonary arteriovenous malformations are easily identified by CT scanning. May we review the radiologic studies?
Dr. Sjirk J. Westra: The first examination was contrast-enhanced CT scanning of the chest, performed while the patient was under general anesthesia. The heart and the mediastinal vessels were normal in size, with no structural abnormalities. The lung parenchyma was characterized by a nodular-appearing consolidation in the left lower lobe, which was interpreted as anesthesia-related atelectasis. High-resolution images showed an enlarged caliber of the pulmonary vasculature in the dependent lower lung zones (Figure 2). Dynamic scanning during rapid, intravenous injection of a bolus of contrast material showed sequential enhancement of pulmonary arteries and veins, with no evidence of a direct arteriovenous connection or early filling of a pulmonary vein, which would suggest pulmonary arteriovenous fistula or another malformation.
Figure 2. Chest CT Scan.
A high-resolution section through the lung bases shows peripheral pulmonary vascular congestion (arrow) and nodular atelectatic changes in the left lower lobe (asterisk).
A chest radiograph obtained on the following day showed resolution of atelectasis in the left lower lobe, and the lungs were clear. The ventilation–perfusion radionuclide scan showed normal ventilation and slight heterogeneity of the perfusion of the lungs, but no segmental defects — findings that are consistent with a low probability of pulmonary emboli. However, abnormal activity of the radiotracer was seen in the brain and kidneys, a finding considered indicative of a right-to-left shunt.
Dr. Kinane: In the absence of a pulmonary arteriovenous malformation on the chest CT scans, the diagnosis is most likely the hepatopulmonary syndrome. We proceeded with further imaging studies of the liver and made plans for a liver biopsy, depending on the findings.
Dr. T. Bernard Kinane's Diagnosis
Hepatopulmonary syndrome.
Anatomical Discussion
Dr. Westra: On further review of the upper abdominal sectional views of the chest on CT scanning, a direct fistulous connection between the portal vein and the inferior vena cava was demonstrated. Dynamic gadolinium-enhanced magnetic resonance angiography of the chest and upper abdomen was performed to further clarify the cause of the arteriovenous shunting. This examination confirmed the presence of an extrahepatic fistulous connection between the splenomesenteric confluence and the inferior vena cava, with congenital absence of the extrahepatic and intrahepatic portal vein (Figure 3A). A hypertrophied hepatic artery was the only vessel perfusing the liver parenchyma (Figure 3B). The liver showed architectural distortion, as inferred from the anomalous position of the gallbladder, with relative atrophy of the right hepatic lobe and hypertrophy of the left hepatic lobe. This is a common finding in chronic liver disease with cirrhosis. However, the liver parenchyma in this case was homogeneous and not macronodular, and there were no secondary signs of portal hypertension, such as ascites, splenomegaly, or portal venous collateral vessels. Apparently, mesenteric blood flow directly drained into the inferior vena cava, thereby bypassing the diseased liver, so that the typical manifestations of chronic liver disease and portal hypertension did not develop.
Figure 3. Abdominal MRI Studies.
Panel A shows the presence of a portacaval fistula. The arrow indicates the direction of flow between the portal vein (p) and the inferior vena cava (i). The anomalous position of the gallbladder (asterisk) indicates an architectural distortion of the liver, with an atrophic right lobe. Panel B, an axial, contrast-enhanced magnetic resonance angiogram of the arterial phase, shows a hypertrophic hepatic artery, which is the only vessel perfusing the liver.
This congenital anomaly of the splanchnic vasculature, known as the Abernethy malformation,16,17 is relatively common in dogs (particularly in Yorkshire terriers), but it is extremely uncommon in humans. In this boy, the malformation apparently led to subclinical chronic liver disease, manifested as chronic hypoxia, through the pathogenetic pathway of the hepatopulmonary syndrome. This syndrome is characterized by radiographic findings of chronic liver disease combined with dilatation of subpleural pulmonary vessels resembling spider nevi, which are predominantly located in the lower lobes of the lungs.18,19,20
Dr. Kinane: The Abernethy malformation is a surprising cause of the hepatopulmonary syndrome, and I did not consider it before it was identified on the CT scan. Two types of the Abernethy malformation — which arise from defects in vitelline vein formation (Figure 4) — have been described.21,22 In type 1, which this child had, the portal vein is completely diverted into the inferior vena cava, and there is a complete absence of formation of the intrahepatic portal vein. In type 2, the portal venous system is completely formed, and there is an abnormal communication with systemic veins, usually the inferior vena cava.
Figure 4. The Abernethy Malformation.
In the type 1 Abernethy malformation, which the patient in this case had, the portal vein is completely diverted into the inferior vena cava, instead of draining into the liver.
To date, there are 19 cases of type 1 malformation (15 in girls and 4 in boys), and 6 cases of type 2 (5 in boys and 1 in a girl) have been reported.16,21 The type 1 malformation is frequently associated with other abnormalities, including ventricular septal defects and aortic-arch defects.23 The clinical features and the prognosis for the two types are similar. Hepatic encephalopathy and the hepatopulmonary syndrome frequently develop. Brain abscess associated with the Abernethy malformation has been described.21 It is postulated that the pulmonary capillaries are dilated and fail to filter out circulating bacteria. The Abernethy malformation, although rare, should be considered in cases of the hepatopulmonary syndrome in which the liver disease is not initially obvious.
The pathogenesis of the pulmonary vasodilatation in patients with the hepatopulmonary syndrome is not known. However, some insight can be derived from the Abernethy malformation and from experience with the use of vascular shunts to correct congenital heart defects. In some of the latter cases, the superior vena cava is anastomosed to the right pulmonary artery, and the blood from the lower part of the body, including the hepatic vein, is directed to the left pulmonary artery. In patients who undergo this correction, dilatation of the right-sided pulmonary vasculature develops. This progression of events suggests that a factor in the lower part of the body can prevent pulmonary vasodilatation.24,25 To hypothesize further on the basis of the Abernethy malformation, blood from the gut must cross through the liver to prevent pulmonary vasodilatation. We can therefore postulate that the proposed factor is produced in the liver but that blood from the gut is necessary for its production.
Treatment of the Abernethy type 1 malformation is directed at the pulmonary vascular bed, since an anatomical repair is impossible. Strategies include the embolization of dilated blood vessels and the pharmaceutical regulation of vessel tone. Embolization may be followed by an initial improvement in oxygen saturation, but there is a subsequent return to previous levels.26 Inhibitors of vasodilatation, including somatostatin analogues, nitric oxide synthase inhibitors, and indomethacin, have resulted in poor responses and troublesome side effects. Liver transplantation has been attempted in some cases,27 but the early mortality was about 30 percent, as compared with 10 percent among patients without the hepatopulmonary syndrome. For those who survive, liver transplantation is an effective therapy, with intrapulmonary shunting improving over a period of six weeks.4,28
The plan for this child has been to monitor his oxygen-saturation levels, and when they fall to the low end of the 80 percent range, to consider liver transplantation. At the most recent follow-up, when he was five years eight months old, he used supplemental oxygen at the rate of 1 liter per minute, with oxygen saturation levels in the 80 percent range at rest, but dropping to as low as 73 percent with exertion. A radionuclide scan showed a right-to-left shunt of 60 percent (Figure 5). The results of liver-function tests have continued to be normal. We will probably need to consider a liver transplantation for this child soon.
Figure 5. Ventilation–Perfusion Radionuclide Scan.
The scan, obtained when the patient was five years eight months old, shows abnormal activity of the radiotracer in the brain and kidneys, which is indicative of a right-to-left shunt, measured at 60 percent.
Anatomical Diagnosis
Hepatopulmonary syndrome due to the Abernethy malformation, type 1.
Dr. Kinane is a member of the speakers bureaus of AstraZeneca and GlaxoSmithKline.
Source Information
From the Pediatric Service (T.B.K.) and the Department of Radiology (S.J.W.), Massachusetts General Hospital; and the Department of Pediatrics (T.B.K.) and the Department of Radiology (S.J.W.), Harvard Medical School.
References
West JB. Respiratory physiology — the essentials. 5th ed. New York: Williams and Wilkins, 1995:45-61.
Bernstein D. The cardiovascular system. In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson textbook of pediatrics. 16th ed. Philadelphia: W.B. Saunders, 2000:337-409.
Gossage JR, Kanj G. Pulmonary arteriovenous malformations: a state of the art review. Am J Respir Crit Care Med 1998;158:643-661.
Lange PA, Stoller JK. The hepatopulmonary syndrome: effect of liver transplantation. Clin Chest Med 1996;17:115-123.
Krowka MJ, Cortese DA. Hepatopulmonary syndrome: current concepts in diagnostic and therapeutic considerations. Chest 1994;105:1528-1537.
Churton T. Multiple aneurysms of the pulmonary artery. BMJ 1897;1:1223-1225.
Sloan RD, Cooley RN. Congenital pulmonary arteriovenous aneurysm. Am J Roentgenol Radium Ther Nucl Med 1953;70:183-210.
Plauchu H, de Chadarevian JP, Bideau A, Robert JM. Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population. Am J Med Genet 1989;32:291-297.
Haitjema T, Disch F, Overtoom TT, Westermann CJ, Lammers JW. Screening family members of patients with hereditary hemorrhagic telangiectasia. Am J Med 1995;99:519-524.
Vase P, Holm M, Arendrup H. Pulmonary arteriovenous fistulas in hereditary hemorrhagic telangiectasia. Acta Med Scand 1985;218:105-109.
Remy J, Remy-Jardin M, Wattinne L, Deffontaines C. Pulmonary arteriovenous malformations: evaluation with CT of the chest before and after treatment. Radiology 1992;182:809-816.
Whyte MK, Peters AM, Hughes JM, et al. Quantification of right to left shunt at rest and during exercise in patients with pulmonary arteriovenous malformations. Thorax 1992;47:790-796.
Hopkins WE, Waggoner AD, Barzilai B. Frequency and significance of intrapulmonary right-to-left shunting in end-stage hepatic disease. Am J Cardiol 1992;70:516-519.
Rodriguez-Roisin R, Roca J, Agusti AG, Mastai R, Wagner PD, Bosch J. Gas exchange and pulmonary vascular reactivity in patients with liver cirrhosis. Am Rev Respir Dis 1987;135:1085-1092.
Lange PA, Stoller JK. The hepatopulmonary syndrome. Ann Intern Med 1995;122:521-529.
Usuki N, Miyamoto T. A case of congenital absence of the intrahepatic portal vein diagnosed by MR angiography. J Comput Assist Tomogr 1998;22:728-729.
Badler R, Price AP, Moy L, Katz DS. Congenital portocaval shunt: CT demonstration. Pediatr Radiol 2002;32:28-30.
McAdams HP, Erasmus J, Crockett R, Mitchell J, Godwin JD, McDermott VG. The hepatopulmonary syndrome: radiologic findings in 10 patients. AJR Am J Roentgenol 1996;166:1379-1385.
Lee K-N, Lee H-J, Shin WW, Webb WR. Hypoxemia and liver cirrhosis (hepatopulmonary syndrome) in eight patients: comparison of the central and peripheral pulmonary vasculature. Radiology 1999;211:549-553.
Engelke C, Schaefer-Prokop C, Schirg E, Freihorst J, Grubnic S, Prokop M. High-resolution CT and CT angiography of peripheral pulmonary vascular disorders. Radiographics 2002;22:739-764.
Alvarez AE, Ribeiro AF, Hessel G, Baracat J, Ribeiro JD. Abernethy malformation: one of the etiologies of hepatopulmonary syndrome. Pediatr Pulmonol 2002;34:391-394.
Howard ER, Davenport M. Congenital extrahepatic portocaval shunts -- the Abernethy malformation. J Pediatr Surg 1997;32:494-497.
Kohda E, Saeki M, Nakano M, et al. Congenital absence of the portal vein in a boy. Pediatr Radiol 1999;29:235-237.
Srivastava D, Preminger T, Lock JE, et al. Hepatic venous blood and the development of pulmonary arteriovenous malformations in congenital heart disease. Circulation 1995;92:1217-1222.
Lee J, Menkis AH, Rosenberg HC. Reversal of pulmonary arteriovenous malformation after diversion of anomalous hepatic drainage. Ann Thorac Surg 1998;65:848-849.
Ryu JK, Oh JH. Hepatopulmonary syndrome: angiography and therapeutic embolization. Clin Imaging 2003;27:97-100.
Arguedas MR, Abrams GA, Krowka MJ, Fallon MB. Prospective evaluation of outcomes and predictors of mortality in patients with hepatopulmonary syndrome undergoing liver transplantation. Hepatology 2003;37:192-197.
Taille C, Cadranel J, Bellocq A, et al. Liver transplantation for hepatopulmonary syndrome: a ten-year experience in Paris, France. Transplantation 2003;75:1482-1489.
Related Letters:
Case 31-2004: A Four-Year-Old Boy with Hypoxemia
Hoftman N., Kinane T. B., Shannon D. C.(T. Bernard Kinane, M.D., )