PULMONARY HYPERTENSION WITH COEXISTING PORTAL HYPERTENSION
Solveig 0 . Rossi, MD
Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine, Madison, Wisconsin 53792 0
Fetal Pediatr Pathol Downloaded from informahealthcare.com by University of Newcastle Upon Tyne on 12/19/14 For personal use only.
Enid Gilbert-Barness, MD
0 Department of Pathology and Laboratory Medicine and Pediatrics, University of Wisconsin School of Medicine, Madison, Wisconsin 53792
Thomas Saari, M D and Robert Corliss, M D
0 Department of Pediatrics, University of Wisconsin School of Medicine, Madison, Wisconsin 53792
A 1O-year-old boy who had portal hypertension secondary to portal fibrosishtrahepatic biliary atresia developed syncopal episodes related to strenuous activity. A work-up excluded a metabolic or neurologic etiology and cardiac catheterization demonstrated sknificant pulmonary hypertension. six months later he died and an autopsy revealed pulmonary plexogenic arteriopathy without microemboli. Previous reported cases of this symptom complex are reviewed. In addition, he had a history of nonspecific colitis, ulcerative stomatitis, and conjunctivitis responsive to steroid therapy. The possible relationship of these manifestations to the portal pulmonary pathology is discussed. KEY WORDS: coexisting pulmonary and portal hypertension.
INTRODUCTION The coexistence of pulmonary and portal hypertension is rare and has been reported only over the last four decades (see Table 1). The etiology is still uncertain but the finding of plexogenic pulmonary arterial lesions in many of the cases suggests a background of vasoconstriction, possibly in association with a hypersensitivity. We report a patient in whom the liver disease was diagnosed 7 years before the onset of pulmonary hypertensive symptoms and was associated with ulcerative stomatitis and nonspecific colitis, possibly a hypersensitivity phenomenon.
We thank Doctors Henry Tazelaar, William Edwards, and Jurgen Ludwig of the Mayo Clinic for review of this case and helpful suggestions. Address reprint requests to Solveig 0. Rossi, M.D., Department of Pathology, Clinical Science Center E5/379, University of Wisconsin Hospital and Clinics, 600 Highland Avenue, Madison, Wisconsin 53792. Pediatric Pathology, 12r433-439, I 9 9 2 Copy;Sht @ 1992 by Hemisphere Publishing Corporation
433
P
0
P
Naeye Naeye Naeye Naeye Sallam et al. Levine et al. Levine et al. Saunders et al. Bower et al. Cohen et al. McDonnel et al. McDonnel et al. McDonnel et al. McDonnel et al. McDonnel et al. McDonnel et al. McDonnel et al. McDonnel et al. McDonnel et al. Flernale et al. Edwards et al. Edwards et al. Edwards et al. Edwards et al. Edwards et al. Edwards et al. Edwards et al. Edwards et al. Edwards et al. Edwards et al. Edwards et al. Edwards et al. Yutani et al. Yutani et al.
4 5 6
(1) (12) (3) (3) (13) (14) (8) (9) (9) (9) (9) (9) (9) (9) (9) (9) (15) (7) (7) (7) (7) (7) (7) (7) (7) (7) (7) (7) (7) (10) (10)
(1)
(1) (1)
(11) (1) (1)
Reference
1960 1960 1960 1960 1970 1973 1973 1979 1980 1983 1983 1983 1983 1983 1983 1983 1983 1983 1983 1985 1987 1987 1987 1987 1987 1987 1987 1987 1987 1987 1987 1987 1988 1988
1951 1960 1960
Year
34M 76F 76M 13F 15F 11M 15M 24M 16F 17M 34F 50F 34M 27F 21F 52M 28F 30F 37M 21M 68M 56M 25M 74F 45F 42M 58M 40M 38F 51F 28F 65M 26M 25M
53F 42M 28F
Age (Y9 and sex Stenotic portal vein Portal cirrhosis and portal vein thrombosis Postnecrotic hepatic cirrhosis and portal vein thrombosis Hepatic portal cirrhosis Idiopathic portal cirrhosis Portal cirrhosis Portal vein thrombosis Portocaval shunt Portal vein stenosis Congenial extrahepatic biliary atresia Portal vein thrombosis Portal vein thrombosis Congenial malformation of portal vein Alcoholic cirrhosis Alcoholic cirrhosis Postnecrotic cirrhosis Chronic active hepatitis with cirrhosis Postnecrotic cirrhosis Alcoholic cirrhosis Postnecrotic cirrhosis Chronic active hepatitis with cirrhosis Postnecrotic cirrhosis Portal thrombosis Alcoholic cirrhosis Cryptogenic cirrhosis Hepatoportal sclerosis Cryptogenic sclerosis Alcoholic cirrhosis Alcoholic cirrhosis Alcoholic cirrhosis Alcoholic cirrhosis Alcoholic cirrhosis and hepatoma Cryptogenic cirrhosis Cryptogenic cirrhosis Alcoholic cirrhosis and hepatoma Nodular regenerative hyperplasia Nodular regenerative hyperplasia
Liver disease
“Plex, Plexiform pulmonary arteriopathy; T.E., thromboembolic pulmonic vascular disease; N.A., not available.
8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37
7
Mantz et al. Naeye Naeye
Authors
1 2 3
Case
TABLE 1. Association of Pulmonary Hypertension with Portal Hypertension
Fetal Pediatr Pathol Downloaded from informahealthcare.com by University of Newcastle Upon Tyne on 12/19/14 For personal use only.
T.E. T.E. and Plex T.E. Plex and necrotizing arteritis N.A. Plex Plex Plex Plex Plex Plex Plex Plex Necrotizing arteritis Plex Necrotizing arteritis Plex Plex Plex No necropsy performed Medial hypertrophy Plex Plex Plex Plex and T.E. Plex and T.E. Plex and T.E. Plex and T.E. Plex and T.E. Plex and T.E. Plex and T.E. T.E. Plex Plex and T.E.
T.E. T.E. and Plex T.E. and Plex
Microscopic pulmonary pathology‘
PULMONARY AND PORTAL HYPERTENSION
435
Fetal Pediatr Pathol Downloaded from informahealthcare.com by University of Newcastle Upon Tyne on 12/19/14 For personal use only.
CASE REPORT This 10-year-old boy had a long, complicated past medical history. At the age of 2 l I 2 years he was diagnosed with nonspecific eosinophilic colitis, which was responsive to sulfasalazine. Hepatosplenomegaly was noted with abnormalities in liver enzymes. A liver biopsy revealed portal fibrosis. In addition, he had multiple allergies and transient eczema, which began at 6 months of age. Ulcerative stomatitis and conjunctivitis lesions were biopsied and revealed an increased number of eosinophils but were otherwise nonspecific. The lesions resolved with prednisone. He was followed clinically and the portal fibrosis was thought to be stable. At 10 years of age, he developed syncopal episodes associated with strenuous activity. Cardiac catheterization revealed a pulmonary artery pressure between 70 and 80 mm Hg, unresponsive to oxygen and with no gradient across any valve. A selective subpulmonary angiogram did not show evidence of emboli. An immunologic work-up for a possible underlying immune disorder or autoimmune disease was not contributory. Six months after the onset of pulmonary hypertension, the patient died, at the age of 10 years.
AUTOPSY FINDINGS At autopsy, the patient was mildly icteric but without spider nevi or a dilated abdominal vein pattern. There was 200 ml of yellow, clear ascites. The heart was enlarged and the combined weight of the heart and lungs was 850 g. The hypertrophied right ventricle measured 0.8 cm in thickness. The right atrium and ventricle were mildly dilated. No congenital abnormalities were identified. The lungs were grossly normal without any recognizable parenchymal disease. There were no gross arterial emboli or infarcts. A mild dilatation of the pulmonary artery was noted at its origin; however, no gross pulmonary vascular disease was identified. The liver weighed 750 g (expected 850 g) and revealed marked fibrosis, particularly in the hilar area. Microscopic sections showed broad portal fibrotic bands and intrahepatic biliary atresia. Comparison with the original biopsy 8 years previous showed similar changes. The portal vein was free of old or recent thrombi. The spleen showed congestive changes and weighed 720 g (normal, 80-90 9). Esophageal venous varices were prominent. Prior to dissection, the lungs were perfused with 10% buffered formalin. Blocks were taken from central and peripheral representative areas of each lung lobe, and sections were stained with hematoxylin-eosin, elastic van Gieson, and trichrome stains. Microscopy of the lungs did not show any parenchymal disease; however, pulmonary arterial changes were extensive in all lobes and included grade I-IV
436
S. 0 . ROSS1 ET AL.
Fetal Pediatr Pathol Downloaded from informahealthcare.com by University of Newcastle Upon Tyne on 12/19/14 For personal use only.
(Heath and Edwards) pulmonary hypertensive lesions. Arterioles and arteries showed medial hypertrophy with concentric-laminar intimal fibrosis extending into medium-sized arteries (Fig. 1). Larger branches had duplication of the elastic membranes. Multiple plexiform lesions were seen ranging from very early to fully developed lesions (Fig. 2). There were no organizing thrombi or eccentric intimal fibrosis. Acute fibrinoid necrosis and arteritis were not seen.
DISCUSSION This is a case of “idiopathic” pulmonary hypertension with welldocumented liver disease and portal hypertension. Clinically, the liver pathology antedated the onset of pulmonary hypertension by 7 years, and a single combined etiology of the liver-lung disease (such as alpha,-antitrypsin deficiency) could not be identified. Evidence of pulmonary hypertension was clearly suggested by autopsy findings of isolated right-sided cardiac hypertrophy with no other acquired or congenital cardiac anomalies present to explain this finding. Portal hypertension was evident by marked splenomegaly and well-developed portosystemic collaterals. There was evidence of hypersplenism with thrombocytopenia. These findings suggest a syndrome of coexistent portal and pulmonary arterial hypertension similar to previously reported cases (1- 15). Among suggested
FIGURE 1. Microscopic section of lung showing medial hypertrophy of medium-sized pulmonary artery, x 45
Fetal Pediatr Pathol Downloaded from informahealthcare.com by University of Newcastle Upon Tyne on 12/19/14 For personal use only.
PULMONARY AND PORTAL HYPERTENSION
FIGURE 2. Microscopic section of lung showing plexiform vascular lesion,
X
437
10.
etiologies of the pulmonary vascular changes were multiple emboli arising from the portal vein (1). In our case, however, the pulmonary changes were not consistent with organization of recurrent emboli; concentric-laminar intimal fibrosis was found rather than eccentric intimal fibrosis. Also, postmortem examination failed to show the presence of thrombi in the portal vein or emboli in the pulmonary vessels. This is in keeping with findings reported by other authors (2, 3). These authors described plexogenic pulmonary arteriopathy with concentric laminar intimal fibrosis, strongly suggestive of a vasoconstrictive etiology (4).It is postulated that humoral agents-possibly of intestinal originbypass the liver in the presence of well-developed portosystemic shunts. Thus, escaping liver metabolism, they gain direct access to the pulmonary circulation, where they induce vasoconstriction. Possible humoral agents include thromboxanes, serotonin, and histamine. In our case, plexiform lesions were readily identifiable, supporting a vasoconstrictive origin. There was no coexisting thrombosis. Plexogenic arteriopathy in coexistence with thrombi has been documented by Edwards et al. (7), who reported thrombotic lesions in 7 of 10 patients with plexogenic pulmonary arteriopathy. Possible thrombogenic mechanisms include local endothelial injury predisposing to thrombosis rather than embolization from the portal vein. Other authors support the theory that pulmonary hypertension is a complication of portal hypertension alone and does not require the presence of intrin-
Fetal Pediatr Pathol Downloaded from informahealthcare.com by University of Newcastle Upon Tyne on 12/19/14 For personal use only.
438
S. 0 . ROSS1 ET AL.
sic liver disease. In our case, there was marked portal fibrosis without cirrhosis. This is consistent with other observations of “noncirrhotic” liver disease leading to pulmonary hypertension (8) with plexiform lesions. The rarity of this syndrome has been explained through individual hyperactivity of the pulmonary vessels. This patient had a history of allergies and eczema. Immunologic defects, however, were not identified. A possible relation between the apparent hypersensitivity manifestations and the hepatopulmonary pathology is obscure. Lastly, pulmonary hypertension has been reported in patients with portal hypertension due to schistosomiasis (16). In the presence of hepatoportal disease with collateral circulation, the schistosoma eggs may bypass the liver and be carried to the pulmonary vasculature, where their presence elicits a granulomatous reaction with vascular inflammation, eventually resulting in pulmonary hypertension. This was not considered a likely etiology of the pulmonary pathology in this patient.
REFERENCES 1. Naeye RL. “Primary” pulmonary hypertension with coexisting portal hypertension. A retrospective
study of six cases. Circulation 1960;22:376-4. 2. Segel N, Kay J M , Bayley TJ, Paton A. Pulmonary hypertension with hepatic cirrhosis. Br Heart J 1968;30:575-8. 3. Levine O R , Harris R C , Blanc WA, Mellins RB. Progressive pulmonary hypertension in children with portal hypertension. J Pediatr 1973;83:964-72. 4. Wagenvoort CA. Lung biopsies and pulmonary vascular disease. In: Weir EK, Reeves JT, eds. Pulmonary Hypertension. Mount Kisco: Futura, 1984;393-437. 5. McGoon M D , Vanhoutte P M . Aggregating platelets contract isolated canine pulmonary arteries by releasing 5-hydroxytryptamine. J Clin Invest 1984;74:828-33. 6. Vanhoutte P M . Serotonin and the vascular wall. Int J Cardiol 1987;14:189-203, 7. Edwards BS, Weir EK, Edwards WD, Ludwig J , Dykoski R K , Edwards JE. Coexistent pulmonary and portal hypertension: Morphologic and clinical features. J Am Call Cardiol 1987; 10: 1233-8. 8. Cohen MD, Rubin LJ, Taylor WE, Cuthbert JA. Primary pulmonary hypertension: An unusual case associated with extrahepatic portal hypertension. Hepatology 1983;3:588-92. 9. McDonnell PJ, Toye PA, Hutchins G M . Primary pulmonary hypertension and cirrhosis: Are they related? Am Rev Respir Dis 1983;127:437-41. 10. Yutani C , Imakita M , Ishibashi-Ueda H , Okubo S, Naito M , Kunieda T. Nodular regenerative hyperplasia of the liver associated with primary pulmonary hypertension. Hum Pathol 1988;19:72631. 11. Mantz FA, Craige E. Portal axis thrombosis with spontaneous portacaval shunt and resultant car pulmonale. Arch Pathol 1951;52:91-7. 12. Sallam M , Watson WC. Pulmonary hypertension due to micro-thromboembolism from splenic and portal veins after portocaval anastomosis. Br Heart J 1970;32:269-71, 13. Saunders JB, Constable TJ, Heath D , Smith P, Paton A. Pulmonary hypertension complicating portal vein thrombosis. Thorax 1979;34:281-3. 14. Bower JS, Dantzker D R , Naylor B. Idiopathic pulmonary hypertension associated with nodular pulmonary infiltrates and portal venous thrombosis. Chest 1980;78: l 11-3. 15. Flemale A, Sabot JP, Popijn M, et al. Pulmonary hypertension associated with portal thrombosis. Eur J Respir Dis 1985;66:224-8. 16. Watt G, Long GW, Calubaquib C, Ranoa CP. Cardiopulmonary involvement rare in severe SchZsLosoma japonicum infection. Trop Geogr Med 1986:223-9.
PULMONARY AND PORTAL HYPERTENSION
439
ADDITIONAL READING Yamaguchi M, Kurnada K, Okarnoto R , Ozawa K, Morikawa S, Yamamoto R. Pulmonary hypertension associated with portal hypertension in a child. Pediatr Surg Int 1991;6:47-90.
Fetal Pediatr Pathol Downloaded from informahealthcare.com by University of Newcastle Upon Tyne on 12/19/14 For personal use only.
Received April 8, I991 Revision accepted September 20, 1991
Solveig 0 . Rossi, MD
Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine, Madison, Wisconsin 53792 0
Fetal Pediatr Pathol Downloaded from informahealthcare.com by University of Newcastle Upon Tyne on 12/19/14 For personal use only.
Enid Gilbert-Barness, MD
0 Department of Pathology and Laboratory Medicine and Pediatrics, University of Wisconsin School of Medicine, Madison, Wisconsin 53792
Thomas Saari, M D and Robert Corliss, M D
0 Department of Pediatrics, University of Wisconsin School of Medicine, Madison, Wisconsin 53792
A 1O-year-old boy who had portal hypertension secondary to portal fibrosishtrahepatic biliary atresia developed syncopal episodes related to strenuous activity. A work-up excluded a metabolic or neurologic etiology and cardiac catheterization demonstrated sknificant pulmonary hypertension. six months later he died and an autopsy revealed pulmonary plexogenic arteriopathy without microemboli. Previous reported cases of this symptom complex are reviewed. In addition, he had a history of nonspecific colitis, ulcerative stomatitis, and conjunctivitis responsive to steroid therapy. The possible relationship of these manifestations to the portal pulmonary pathology is discussed. KEY WORDS: coexisting pulmonary and portal hypertension.
INTRODUCTION The coexistence of pulmonary and portal hypertension is rare and has been reported only over the last four decades (see Table 1). The etiology is still uncertain but the finding of plexogenic pulmonary arterial lesions in many of the cases suggests a background of vasoconstriction, possibly in association with a hypersensitivity. We report a patient in whom the liver disease was diagnosed 7 years before the onset of pulmonary hypertensive symptoms and was associated with ulcerative stomatitis and nonspecific colitis, possibly a hypersensitivity phenomenon.
We thank Doctors Henry Tazelaar, William Edwards, and Jurgen Ludwig of the Mayo Clinic for review of this case and helpful suggestions. Address reprint requests to Solveig 0. Rossi, M.D., Department of Pathology, Clinical Science Center E5/379, University of Wisconsin Hospital and Clinics, 600 Highland Avenue, Madison, Wisconsin 53792. Pediatric Pathology, 12r433-439, I 9 9 2 Copy;Sht @ 1992 by Hemisphere Publishing Corporation
433
P
0
P
Naeye Naeye Naeye Naeye Sallam et al. Levine et al. Levine et al. Saunders et al. Bower et al. Cohen et al. McDonnel et al. McDonnel et al. McDonnel et al. McDonnel et al. McDonnel et al. McDonnel et al. McDonnel et al. McDonnel et al. McDonnel et al. Flernale et al. Edwards et al. Edwards et al. Edwards et al. Edwards et al. Edwards et al. Edwards et al. Edwards et al. Edwards et al. Edwards et al. Edwards et al. Edwards et al. Edwards et al. Yutani et al. Yutani et al.
4 5 6
(1) (12) (3) (3) (13) (14) (8) (9) (9) (9) (9) (9) (9) (9) (9) (9) (15) (7) (7) (7) (7) (7) (7) (7) (7) (7) (7) (7) (7) (10) (10)
(1)
(1) (1)
(11) (1) (1)
Reference
1960 1960 1960 1960 1970 1973 1973 1979 1980 1983 1983 1983 1983 1983 1983 1983 1983 1983 1983 1985 1987 1987 1987 1987 1987 1987 1987 1987 1987 1987 1987 1987 1988 1988
1951 1960 1960
Year
34M 76F 76M 13F 15F 11M 15M 24M 16F 17M 34F 50F 34M 27F 21F 52M 28F 30F 37M 21M 68M 56M 25M 74F 45F 42M 58M 40M 38F 51F 28F 65M 26M 25M
53F 42M 28F
Age (Y9 and sex Stenotic portal vein Portal cirrhosis and portal vein thrombosis Postnecrotic hepatic cirrhosis and portal vein thrombosis Hepatic portal cirrhosis Idiopathic portal cirrhosis Portal cirrhosis Portal vein thrombosis Portocaval shunt Portal vein stenosis Congenial extrahepatic biliary atresia Portal vein thrombosis Portal vein thrombosis Congenial malformation of portal vein Alcoholic cirrhosis Alcoholic cirrhosis Postnecrotic cirrhosis Chronic active hepatitis with cirrhosis Postnecrotic cirrhosis Alcoholic cirrhosis Postnecrotic cirrhosis Chronic active hepatitis with cirrhosis Postnecrotic cirrhosis Portal thrombosis Alcoholic cirrhosis Cryptogenic cirrhosis Hepatoportal sclerosis Cryptogenic sclerosis Alcoholic cirrhosis Alcoholic cirrhosis Alcoholic cirrhosis Alcoholic cirrhosis Alcoholic cirrhosis and hepatoma Cryptogenic cirrhosis Cryptogenic cirrhosis Alcoholic cirrhosis and hepatoma Nodular regenerative hyperplasia Nodular regenerative hyperplasia
Liver disease
“Plex, Plexiform pulmonary arteriopathy; T.E., thromboembolic pulmonic vascular disease; N.A., not available.
8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37
7
Mantz et al. Naeye Naeye
Authors
1 2 3
Case
TABLE 1. Association of Pulmonary Hypertension with Portal Hypertension
Fetal Pediatr Pathol Downloaded from informahealthcare.com by University of Newcastle Upon Tyne on 12/19/14 For personal use only.
T.E. T.E. and Plex T.E. Plex and necrotizing arteritis N.A. Plex Plex Plex Plex Plex Plex Plex Plex Necrotizing arteritis Plex Necrotizing arteritis Plex Plex Plex No necropsy performed Medial hypertrophy Plex Plex Plex Plex and T.E. Plex and T.E. Plex and T.E. Plex and T.E. Plex and T.E. Plex and T.E. Plex and T.E. T.E. Plex Plex and T.E.
T.E. T.E. and Plex T.E. and Plex
Microscopic pulmonary pathology‘
PULMONARY AND PORTAL HYPERTENSION
435
Fetal Pediatr Pathol Downloaded from informahealthcare.com by University of Newcastle Upon Tyne on 12/19/14 For personal use only.
CASE REPORT This 10-year-old boy had a long, complicated past medical history. At the age of 2 l I 2 years he was diagnosed with nonspecific eosinophilic colitis, which was responsive to sulfasalazine. Hepatosplenomegaly was noted with abnormalities in liver enzymes. A liver biopsy revealed portal fibrosis. In addition, he had multiple allergies and transient eczema, which began at 6 months of age. Ulcerative stomatitis and conjunctivitis lesions were biopsied and revealed an increased number of eosinophils but were otherwise nonspecific. The lesions resolved with prednisone. He was followed clinically and the portal fibrosis was thought to be stable. At 10 years of age, he developed syncopal episodes associated with strenuous activity. Cardiac catheterization revealed a pulmonary artery pressure between 70 and 80 mm Hg, unresponsive to oxygen and with no gradient across any valve. A selective subpulmonary angiogram did not show evidence of emboli. An immunologic work-up for a possible underlying immune disorder or autoimmune disease was not contributory. Six months after the onset of pulmonary hypertension, the patient died, at the age of 10 years.
AUTOPSY FINDINGS At autopsy, the patient was mildly icteric but without spider nevi or a dilated abdominal vein pattern. There was 200 ml of yellow, clear ascites. The heart was enlarged and the combined weight of the heart and lungs was 850 g. The hypertrophied right ventricle measured 0.8 cm in thickness. The right atrium and ventricle were mildly dilated. No congenital abnormalities were identified. The lungs were grossly normal without any recognizable parenchymal disease. There were no gross arterial emboli or infarcts. A mild dilatation of the pulmonary artery was noted at its origin; however, no gross pulmonary vascular disease was identified. The liver weighed 750 g (expected 850 g) and revealed marked fibrosis, particularly in the hilar area. Microscopic sections showed broad portal fibrotic bands and intrahepatic biliary atresia. Comparison with the original biopsy 8 years previous showed similar changes. The portal vein was free of old or recent thrombi. The spleen showed congestive changes and weighed 720 g (normal, 80-90 9). Esophageal venous varices were prominent. Prior to dissection, the lungs were perfused with 10% buffered formalin. Blocks were taken from central and peripheral representative areas of each lung lobe, and sections were stained with hematoxylin-eosin, elastic van Gieson, and trichrome stains. Microscopy of the lungs did not show any parenchymal disease; however, pulmonary arterial changes were extensive in all lobes and included grade I-IV
436
S. 0 . ROSS1 ET AL.
Fetal Pediatr Pathol Downloaded from informahealthcare.com by University of Newcastle Upon Tyne on 12/19/14 For personal use only.
(Heath and Edwards) pulmonary hypertensive lesions. Arterioles and arteries showed medial hypertrophy with concentric-laminar intimal fibrosis extending into medium-sized arteries (Fig. 1). Larger branches had duplication of the elastic membranes. Multiple plexiform lesions were seen ranging from very early to fully developed lesions (Fig. 2). There were no organizing thrombi or eccentric intimal fibrosis. Acute fibrinoid necrosis and arteritis were not seen.
DISCUSSION This is a case of “idiopathic” pulmonary hypertension with welldocumented liver disease and portal hypertension. Clinically, the liver pathology antedated the onset of pulmonary hypertension by 7 years, and a single combined etiology of the liver-lung disease (such as alpha,-antitrypsin deficiency) could not be identified. Evidence of pulmonary hypertension was clearly suggested by autopsy findings of isolated right-sided cardiac hypertrophy with no other acquired or congenital cardiac anomalies present to explain this finding. Portal hypertension was evident by marked splenomegaly and well-developed portosystemic collaterals. There was evidence of hypersplenism with thrombocytopenia. These findings suggest a syndrome of coexistent portal and pulmonary arterial hypertension similar to previously reported cases (1- 15). Among suggested
FIGURE 1. Microscopic section of lung showing medial hypertrophy of medium-sized pulmonary artery, x 45
Fetal Pediatr Pathol Downloaded from informahealthcare.com by University of Newcastle Upon Tyne on 12/19/14 For personal use only.
PULMONARY AND PORTAL HYPERTENSION
FIGURE 2. Microscopic section of lung showing plexiform vascular lesion,
X
437
10.
etiologies of the pulmonary vascular changes were multiple emboli arising from the portal vein (1). In our case, however, the pulmonary changes were not consistent with organization of recurrent emboli; concentric-laminar intimal fibrosis was found rather than eccentric intimal fibrosis. Also, postmortem examination failed to show the presence of thrombi in the portal vein or emboli in the pulmonary vessels. This is in keeping with findings reported by other authors (2, 3). These authors described plexogenic pulmonary arteriopathy with concentric laminar intimal fibrosis, strongly suggestive of a vasoconstrictive etiology (4).It is postulated that humoral agents-possibly of intestinal originbypass the liver in the presence of well-developed portosystemic shunts. Thus, escaping liver metabolism, they gain direct access to the pulmonary circulation, where they induce vasoconstriction. Possible humoral agents include thromboxanes, serotonin, and histamine. In our case, plexiform lesions were readily identifiable, supporting a vasoconstrictive origin. There was no coexisting thrombosis. Plexogenic arteriopathy in coexistence with thrombi has been documented by Edwards et al. (7), who reported thrombotic lesions in 7 of 10 patients with plexogenic pulmonary arteriopathy. Possible thrombogenic mechanisms include local endothelial injury predisposing to thrombosis rather than embolization from the portal vein. Other authors support the theory that pulmonary hypertension is a complication of portal hypertension alone and does not require the presence of intrin-
Fetal Pediatr Pathol Downloaded from informahealthcare.com by University of Newcastle Upon Tyne on 12/19/14 For personal use only.
438
S. 0 . ROSS1 ET AL.
sic liver disease. In our case, there was marked portal fibrosis without cirrhosis. This is consistent with other observations of “noncirrhotic” liver disease leading to pulmonary hypertension (8) with plexiform lesions. The rarity of this syndrome has been explained through individual hyperactivity of the pulmonary vessels. This patient had a history of allergies and eczema. Immunologic defects, however, were not identified. A possible relation between the apparent hypersensitivity manifestations and the hepatopulmonary pathology is obscure. Lastly, pulmonary hypertension has been reported in patients with portal hypertension due to schistosomiasis (16). In the presence of hepatoportal disease with collateral circulation, the schistosoma eggs may bypass the liver and be carried to the pulmonary vasculature, where their presence elicits a granulomatous reaction with vascular inflammation, eventually resulting in pulmonary hypertension. This was not considered a likely etiology of the pulmonary pathology in this patient.
REFERENCES 1. Naeye RL. “Primary” pulmonary hypertension with coexisting portal hypertension. A retrospective
study of six cases. Circulation 1960;22:376-4. 2. Segel N, Kay J M , Bayley TJ, Paton A. Pulmonary hypertension with hepatic cirrhosis. Br Heart J 1968;30:575-8. 3. Levine O R , Harris R C , Blanc WA, Mellins RB. Progressive pulmonary hypertension in children with portal hypertension. J Pediatr 1973;83:964-72. 4. Wagenvoort CA. Lung biopsies and pulmonary vascular disease. In: Weir EK, Reeves JT, eds. Pulmonary Hypertension. Mount Kisco: Futura, 1984;393-437. 5. McGoon M D , Vanhoutte P M . Aggregating platelets contract isolated canine pulmonary arteries by releasing 5-hydroxytryptamine. J Clin Invest 1984;74:828-33. 6. Vanhoutte P M . Serotonin and the vascular wall. Int J Cardiol 1987;14:189-203, 7. Edwards BS, Weir EK, Edwards WD, Ludwig J , Dykoski R K , Edwards JE. Coexistent pulmonary and portal hypertension: Morphologic and clinical features. J Am Call Cardiol 1987; 10: 1233-8. 8. Cohen MD, Rubin LJ, Taylor WE, Cuthbert JA. Primary pulmonary hypertension: An unusual case associated with extrahepatic portal hypertension. Hepatology 1983;3:588-92. 9. McDonnell PJ, Toye PA, Hutchins G M . Primary pulmonary hypertension and cirrhosis: Are they related? Am Rev Respir Dis 1983;127:437-41. 10. Yutani C , Imakita M , Ishibashi-Ueda H , Okubo S, Naito M , Kunieda T. Nodular regenerative hyperplasia of the liver associated with primary pulmonary hypertension. Hum Pathol 1988;19:72631. 11. Mantz FA, Craige E. Portal axis thrombosis with spontaneous portacaval shunt and resultant car pulmonale. Arch Pathol 1951;52:91-7. 12. Sallam M , Watson WC. Pulmonary hypertension due to micro-thromboembolism from splenic and portal veins after portocaval anastomosis. Br Heart J 1970;32:269-71, 13. Saunders JB, Constable TJ, Heath D , Smith P, Paton A. Pulmonary hypertension complicating portal vein thrombosis. Thorax 1979;34:281-3. 14. Bower JS, Dantzker D R , Naylor B. Idiopathic pulmonary hypertension associated with nodular pulmonary infiltrates and portal venous thrombosis. Chest 1980;78: l 11-3. 15. Flemale A, Sabot JP, Popijn M, et al. Pulmonary hypertension associated with portal thrombosis. Eur J Respir Dis 1985;66:224-8. 16. Watt G, Long GW, Calubaquib C, Ranoa CP. Cardiopulmonary involvement rare in severe SchZsLosoma japonicum infection. Trop Geogr Med 1986:223-9.
PULMONARY AND PORTAL HYPERTENSION
439
ADDITIONAL READING Yamaguchi M, Kurnada K, Okarnoto R , Ozawa K, Morikawa S, Yamamoto R. Pulmonary hypertension associated with portal hypertension in a child. Pediatr Surg Int 1991;6:47-90.
Fetal Pediatr Pathol Downloaded from informahealthcare.com by University of Newcastle Upon Tyne on 12/19/14 For personal use only.
Received April 8, I991 Revision accepted September 20, 1991
