Severe Hypoxemia-associated Intrapulmonary Shunt in a Patient with Chronic Liver Disease: Improvement after Medical Treatment 1, 2


Introduction Arterial hypoxemia is a common pulmonary complication of chronic liver disease such as hepatic cirrhosis and non cirrhotic liver disease (1). This hypoxemia has been explained by different mechanisms such as alveolar capillary diffusion limitation, alveolar ventilation-perfusion mismatch, or rightto-left intrapulmonary shunting (2-5). The latter mechanism seems to be predominant in patients with severe hypoxemia (3, 5), and it has been related to dilated alveolar capillaries and small arteriovenous intrapulmonary shunts (6). Finally, improvement of severe hypoxemia in patients with chronic liver disease has been very seldom reported as occurring spontaneously or after liver transplantation (1, 7). Nor are there any convincing reports of beneficial results from medical treatment (1, 7). We report here a case of severe hypoxemia related to a noncirrhotic liver disease that improved after medical treatment. Case Report In October 1987, a 20-yr-old woman was referred to us for dyspnea and severe hypoxemia (see below). She had been suffering from fever, hepatosplenomegaly, and diffuse lymphadenopathy for 3 yr. Two diseases were demonstrated in this patient. The diagnosis of angioimmunoblastic lymphadenopathy (AIL) was established after lymph node biopsy. A liver needle biopsy showed a noncirrhotic liver disease, i.e., a Grade 3 nodular regenerative hyperplasia of the liver (NRH) according to the Wanless classification (8); there was no liver involvement with AIL. A Grade 1 portal hypertension and slight liver impairment were present: prothrombin time was 80070 normal value, levels of alkaline phosphatase and gamma-glutamyl transpeptidase were raised to twice as high as the normal upper limit. Pao2, Paco2' and pH were 46, 23, and 7.46 mm Hg, respectively, with the patient in the supine position breathing room air. Pao2 fell to 33 mm Hg in the sitting position. Chest radiograph and high resolution CT scan were normal. Fiberoptic bronchoscopy, bronchial biopsy, and total and differential cell counts in bronchoalveolar lavage were normal. Results of pulmonary function tests were normal except for a 46070 reduction in TLC. Radionuclide lung perfusion with technetium 99m-Iabeled macroaggregates of albumin showed rapid uptake of radioactivity in liver, kidneys, and brain, suggesting a right-to-Ieft shunt. Contrast-enhanced two-dimensional echocardiography was performed as previously described (9). After a peripheral injection of microbubble bolus (caused by vigorous shaking of saline), the appearance of echoes was observed in the left atrium within five beats after visualization of the right side of the heart; this in-


SUMMARY A 20-yr-old woman with chronic liver disease and angloimmunoblastic lymphadenopathy presented with marked hypoxemia caused by Intrapulmonary shunt. Her respiratory tract showed her to be free of angiolmmunoblastic lymphadenopathy manifestations. After 12 months of treatment with cyclophosphamide and corticosteroid, the immunologic disease disappeared. Unexpectedly, hypoxia-associated intrapulmonary shunt was no longer present either. To the best of our knowledge, this Is the first case of dramatic improvement, with medical therapy, of severe hypoxemia related to noncirrhotic liver disease. However, the mechanism by which this treatment caused AM REV RESPIR DIS 1992; 146:526-527 the regression of intrapulmonary shunt is unknown.

dicated a right-to-Ieft intrapulmonary shunt. The absence of immediate opacification of the left heart chambers after the arrival of microbubbles in the right side excluded possible interatrial shunt. During right-side heart catheterization, this shunt was quantified by means of (1) calculation of the arteriovenous oxygen content difference, with the patient breathing 100070 oxygen, and (2) multiple inert gas elimination technique (MIGET). To calculate the shunt fraction during pure oxygen breathing we used the standard Berggren equation, assuming a capillary oxygen saturation of 100070. Briefly, simultaneous mixed venous and arterial samples were drawn. Blood gas tension and pH (ABL; Radiometer, Copenhagen, Denmark) and hemoglobin concentration and saturation were measured (OSM3 hemoximeter; Radiometer). In addition, the ventilation-perfusion ratio (VA/Q) distribution evaluated by the MIGET, as described by one of us (10), demonstrated a pure shunt with no increase in percentage of blood flow in areas of low VA/Q (table 1). Thus, evaluated by the two methods, shunt percentages were 23 and 20070 of cardiac output, respectively (table 1). The predicted Pao2 was not significantly different from the measured Pao2, and this excluded a major diffusion problem. Rightside heart catheterization showed typically low vascular tone and high cardiac index (table 1). The final diagnosis in this patient was severe hypoxemia as a result of intrapulmonary shunt (IPS) associated with a NRH and an AIL. For 14 months, AIL was treated with prednisone (1 mg/kg/day followed by tapered daily doses) and cyclophosphamide (600mg/m 2/month) (figure 1). After 3 months there was a resolution of respiratory symptoms, but hepatomegaly was unchanged. At the same time, blood gas values remained diminished (figure 1). These values returned to normal at the end of a 12-month treatment (figure 1). This therapy was then stopped, and 3 months later a series of investigations were performed. Abnormalities in liver function tests and hepatic sample pathology remained unchanged. TLC was improved, but it was still 33070 below normal values. By contrast, we no longer found evidence of IPS when using the four methods mentioned above (table 1). In August 1991, the patient was doing well with pulse oximetry of 97.2070 saturation.

Discussion Severe hypoxemia in patients with cirrhotic liver disease has long been known, and it was recently reported in patients with noncirrhotic liver disease (1). Its mechanism has been demonstrated as being a consequence of the presence of intrapulmonary vascular dilatation (6), which until recently was considered to be a contraindication to livertransplantation (7). To the best of our knowledge, this is the first case showing complete resolution of a severe hypoxia-associated IPS in a patient with chronic liver disease and treated with steroids and cyclophosphamide for an immunologic disease. NRH is a noncirrhotic liver disease characterized by a diffuse micronodular transformation of the liver without fibrosis (8). Presumably, severe hypoxemia in our patient was related to IPS-associated NRH. It has been shown that NRH was associated with systemic diseases such as lymphoproliferative disorders (8). On the basis of negative results of pulmonary investigations (see above), our patient was free from AIL respiratory involvement. A major diffusion problem was also excluded by the MIGET (3, 5). The reduction of TLC observed could not explain the severity of the hypoxemia observed, and it (Received in original form August 13, 1991 and in revised form March 1, 1992) 1 From the Service de Pneumologie et de Reanimation Respiratoire, Hopital Tenon, Paris, Service d'Hepato-Gastroenterologie, Hopital du Kremlin Bicetre, Kremlin Bicetre, Service d'Immuno-Hematologie, Hopital St. Louis, Paris, and Departement de Physiologie, Hopital Henri Mondor, Creteil, France. 2 Correspondence and requests for reprints should be addressed to Jacques L. Cadranel, M.D., Service de Pneumologie et de Reanimation Respiratoire, Hopital Tenon, Paris 75020, France.



in analog (13), and cyclooxygenase inhibitors (14). Reports on several hypoxemic cirrhotic patients who underwent liver transplantation have been disappointing. First, shunt closure apparently did not occur; second, postoperBefore After ative morbidity was increased (1, 7). On the 40 100 other hand, reduction of IPS has been obPao2, mm Hg 24 37 Paco2, mm Hg tained in several patients after recovery from 5.4 4.1 CI, L/m 2/min severe liver disease or after liver transplantaPpa, mm Hg 14 20 tion (13-19). Silverman and coworkers (15) obPpw, mm Hg 7 11 served complete reversal of severe hypoxemia PRA, mm Hg 10 6 in a child who experienced spontaneous resoPsa, mm Hg 70 110 lution of hepatitis. Starzl and coworkers (16) 7.3 18 SVR,IU and Stoller and colleagues (17) described dra1.3 2.2 PVR,IU matic improvement of IPS in three children 30 45 Pvo2, mm Hg SF6 shunt, % * 20 1.5 and an adult after livertransplantation. These O2 shunt, % t 23 2.5 observations would imply that IPS could be Low VA/a, %t 0 0 reduced by restoration of liver function and that humoral factor(s) may possibly be inDefinition of abbreviations: CI = cardiac index; SVR = sysvolved in constitution of IPS (1, 7, 13, 14). temic vascular resistances; Psa = systemic artery pressure; Ppa = pulmonary artery pressure; Ppw = pulmonary wedge In addition, abnormal production of various pressure; PRA = right atrial pressure; PVR = pulmonary vascirculating vasoactive substances (prostaglancular resistances; Pvo2 = mixed venous Po 2. dins, atrial natriuretic polypeptide, renin* Percentage of blood flow to unventilated units determined angiotensin system, nitric oxide, etc.), which by the MIGET (see text). t Shunt fraction during 100% O2 breathing determined by " could affect the pulmonary circulation and arteriovenous O2 content difference measurement (see text). gas exchanges, has been demonstrated in pa:t: Percentage of blood flow perfusing lung units with VAIO tients with chronic liver disease (7). On the less than 0.1 determined by the MIGET (see text). other hand, the circulating factor could not be cleared by a modified liver; also, a metabolite could interact inappropriately with the is a frequent abnormality found in patients pulmonary vascular endothelium. However, with IPS (11). However, results of gas ex- it is unknown whether the resolution of IPS change analysis showing a pure shunt with observed in our patient resulted from the renormal VA/Q distribution were very sugges- sponse of the AIL to chemotherapy or was tive of IPS (3, 5). Finally, IPS has been al- caused by a particular type of liver disease ready described in other non cirrhotic liverdis- (NRH). ease reviewed in reference 1. Veryfew data are available about improvement of severe hypoxemia-associated IPS in References adults spontaneously or after medical or sur- 1. Krowka MJ, Cortese DA. Pulmonary aspects gical treatment. Previous attempts to improve of chronic liver disease and liver transplantation. oxygenation with estrogens and beta block- Clin Chest Med 1989; 10:593-616. ers have been unsuccessful (1). Modest im- 2. Rodriguez-Roisin R, Roca J, Agusti A GN, provement, which deserves further study, has Mastai R, Wagner PD, Bosch J. Gas exchange and been reported with almitrine (12),somatostat- pulmonary vascular reactivity in patients with livTABLE 1


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er cirrhosis. Am Rev Respir Dis 1987; 135:1085-92. 3. Castaing Y, Manier G. Hemodynamic disturbances and VA/Q matching in hypoxemic cirrhotic patients. Chest 1989; 96:1064-9. 4. Melot C, Naeije R, Dechamps P, Hallemans R, Lejeune P. Pulmonary and extrapulmonary contributors to hypoxemia in liver cirrhosis. Am Rev Respir Dis 1989; 139:632-46. 5. Edell ES, Cortese DA, Krowka MJ, Rehder K. Severe hypoxemia and liver disease. Am Rev Respir Dis 1989; 140:1631-5. 6. Berthelot P, Walker JG, Sherlock S, Reid L. Arterial changes in the lungs in cirrhosis of the liver. Lung spider nevi. N Engl J Med 1966; 274:291-8. 7. Krowka MJ, Cortese DA. Hepatopulmonary syndrome: an evolving perspective in the era of liver transplantation. Hepatology 1990; 11:138-42. 8. Wanless IR. Micronodular transformation (nodular regenerative hyperplasia) of the liver: a report of 64 cases among 2,500 autopsies and a new classification of benign hepatocellular nodules. Hepatology 1990; 11:787-97. 9. Shub C, Tajik AJ, Seward JB, Dines DE. Detecting intrapulmonary right-to-Ieft shunt with contrast echocardiography. Observations in a patient with diffuse pulmonary arteriovenous fistulas. Mayo Clin Proc 1976; 51:81-4. 10. Adnot S, Radermacher P, Andrivet P, DuboisRande JL, Dupeyrat A, Lemaire F. Effects of sodium-nitroprusside and uradipil on gas exchange and ventilation-perfusion relationships in patients with congestive heart failure. Eur Respir J 1991; 4:69-75. 11. Hourani JM, Bellamy PE, Tashkin DP, Batra P, Simons MS. Pulmonary dysfunction in advanced liver disease: frequent occurrence of an abnormal diffusing capacity. Am J Med 1991; 90:693-700. 12. Krowka MJ, Cortese DA. Severe hypoxemia associated with liver disease: Mayo Clinic experience and the experimental use of almitrine bismesylate. Mayo Clin Proc 1987; 62:164-73. 13. Salem 0, Dindzans V, Freeman J, O'Doriso T, Ruthardt F, Van Theil O. Liver transplantation following preoperative closure of intrapulmonary shunts. Hepatology 1989; 10:659. 14. Shijo H, Sasaki H, Yuh K, Sakaguchi S, Okumura M. Effects of indomethacin on hepatogenic pulmonary angiodysplasia. Chest 1991; 99: 1027-9. 15. Silverman A, Cooper MD, Moller JH, Good RA. Syndrome of cyanosis, digital clubbing and hepatic disease in siblings. J Pediatr 1968; 72:70-80. 16. Starzl TE, Groth CG, Brettschneider L, et at. Extended survival in 3 cases of orthotopic homotransplantation of the human liver. Surgery 1968; 63:549-63. 17. Stoller JK, Moodie D, Schiavone WA, et at. Reduction of intrapulmonary shunt and resolution of digital clubbing associated with primary biliary cirrhosis after liver transplantation. Hepatology 1990; 11:54-8. 18. Chen NS, Barnet CA, Farrer PA. Reversibility of intrapulmonary arteriovenous shunts in liver cirrhosis documented by serial radionuclide perfusion lung scans. Clin Nucl Med 1984; 9:279-82. 19. Shijo H, Nakayama K, Sasaki H, et at. Reversibility of pulmonary telangiectasia in liver cirrhosis evidenced by serial dynamic pulmonary perfusion imaging. Clin Nucl Med 1989; 14:909-11.

Severe hypoxemia-associated intrapulmonary shunt in a patient with chronic liver disease: improvement after medical treatment.

A 20-yr-old woman with chronic liver disease and angioimmunoblastic lymphadenopathy presented with marked hypoxemia caused by intrapulmonary shunt. He...
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