Pulmonary Hypertension Complicating Portal Hypertension2 DIDIER LEBREC, JEAN-PIERRE CAPRON, DANIEL DHUMEAUX, and JEAN-PIERRE BENHAMOU
SUMMARY We report 9 patients with pulmonary hypertension complicating portal hypertension. The cause of portal hypertension was cirrhosis in 7 patients, nodular regenerative hyperplasia of the liver in 1, and portal vein obstruction in 1. Six patients had been treated by portal-systemic shunting before the clinical onset of pulmonary hypertension. The interval between the first manifestation of portal hypertension and the recognition of pulmonary hypertension ranged from 2 to 15 years. Histologic examination in 1 of these patients revealed medial hypertrophy, concentric intimal proliferation, and plexiform lesions affecting the small pulmonary arteries. Pulmonary hypertension might result from the effect of a vasoconstrictive agent on the small pulmonary arteries or of a substance toxic to the walls of these vessels that is produced in the splanchnic territory, destroyed by the liver in normal subjects, and reaches the pulmonary arteries through portal-systemic shunts in these patients.
Introduction Pulmonary hypertension is a recognized, but uncommon, complication of portal hypertension. Only a small number of cases have been reported (1-11). The report of our experience, based on 9 cases, is warranted because (1) this complication of portal hypertension is not well known to internists, lung specialists, cardiologists, or hepatologists; (2) the prevalence of pulmonary hypertension among patients with portal hypertension has been approximately assessed; (3) pulmonary hypertension in these patients can be easily recognized by clinical examination, chest roentgenogram, and electrocar(Received in original form April 3, 1979 and in revised form May 25,1979) 1 From the Unit£ de Recherches de Physiopathologie He>atique (INSERM), Hdpital Beaujon, Clichy; the Clinique M&licale A, Centre Hospitalier Universitaire, Amiens; and the Unit£ 99 (INSERM), H6pital Henri Mondor, Creteil, France. 2 Requests for reprints should be addressed to Dr. Didier Lebrec, Hopital Beaujon, 92118 Clichy, France.
diogram; (4) we offer a hypothesis for the mechanism of pulmonary hypertension complicating portal hypertension. Case Reports This work is based on the study of 9 patients with portal hypertension in whom pulmonary hypertension was proved by right heart catheterization. Five of these patients belonged to a population of approximately 2,000 adults with portal hypertension of various causes, mainly cirrhosis, who were admitted to Hopital Beaujon between 1958 and 1977. The other 4 patients included in this study were referred to Hopital Beaujon because pulmonary hypertension was suspected. Case 1. A 36-year-old man was admitted on October 14, 1967 for exertional dyspnea. In January 1962, the patient had been hospitalized for jaundice and ascites; alcoholic cirrhosis was then proved by liver biopsy. Three episodes of gastrointestinal bleeding due to ruptured esophageal varices had occurred in June, July, and November 1963; end-to-side portacaval shunt was performed on November 13, 1963. In December 1963, the patient had recurrent gastrointestinal bleeding related to thrombosis of the portacaval shunt. On January 3, 1964, mesocaval shunt was performed. On admission, examination revealed
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LEBREC, CAPRON, DHUMEAUX, AND BENHAMOU
accentuation of the second pulmonic sound, prominence of the main pulmonary arteries on the chest roentgenogram, and right axis deviation and right ventricular hypertrophy on the electrocardiogram. In January 1975, a chest roentgenogram revealed prominence of the main pulmonary arteries, decreased peripheral pulmonary vasculature, and cardiac enlargement involving predominantly the right ventricle. On January 24, 1975, right heart catheterization was performed (table 1). In November 1975, a systolic murmur was audible over the left lower sternal border. In November 1978, the patient was alive. Case 2. A 34-year-old woman was admitted on April 9, 1970 for exertional dyspnea and precordial pain. In October 1968, the patient had been hospitalized for bleeding esophageal varices. Cirrhosis was proved by liver biopsy, but the cause of cirrhosis was unknown. On admission, examination revealed accentuation of the second pulmonic sound. The chest roentgenogram revealed prominence of the main pulmonary arteries and cardiac enlargement,
and the electrocardiogram showed right axis deviation and right ventricular hypertrophy. The lung scan was normal. On April 13, 1970, right heart catheterization was performed (table 1). On June 15, 1971, the patient became extremely dyspneic and died. Necropsy was not permitted. Case 3. A 21-year-old man was admitted on March 6, 1971 for exertional dyspnea. In June 1955, the patient had been hospitalized for jaundice, ascites, and splenomegaly; cirrhosis of unknown origin was diagnosed. In January and March 1962, the patient experienced 2 episodes of gastrointestinal bleeding due to ruptured esophageal varices. Splenorenal shunt was performed on March 12, 1962; cirrhosis was then confirmed by intraoperative biopsy. Since July 1962, the patient had complained of exertional dyspnea. From June 1964 to March 1971, the patient experienced several syncopes. On admission, examination showed systolic murmur audible over the left lower sternal border and accentuation of the second pulmonic sound: the chest roentgenogram showed prominence of the main pulmonary arteries, and the
TABLE 1 CAUSE OF PORTAL HYPERTENSION AND PULMONARY ARTERIAL PRESSURES IN PATIENTS WITH PULMONARY HYPERTENSION COMPLICATING PORTAL HYPERTENSION
Case Present series 1 2 3 4 5 6 7 8 9 Previously reported Kerbel (3) Cohen and Mendelow (4) Lal and Fletcher (5) Segel et al. (6) Senior et at (7) 1 2 3 4 5 6 Sal lam and Watson (9) Levine et al. (10) 1 2 Clinicopathologic conference (11) * + = Present; - = absent, t NM = not measured.
Surgical PortalSystemic Shunt*
Systolic
Diastolic
Mean
Wedge
Cirrhosis Cirrhosis Cirrhosis Portal vein obstruction Nodular regenerative hyperplasia of the liver Cirrhosis Cirrhosis Cirrhosis Cirrhosis
+ + +
82 NMt 90 80
28 NM 40 40
50 83 60 59
7 NM 9 8
+ + +
NM 65 50 96 86
NM 25 30 50 50
100 40 40 65 61
NM 5 7 6 13
Cirrhosis Cirrhosis Cirrhosis Cirrhosis
-
NM 112 135 88
NM 60 84 37
60 85 88 56
NM 10 1 15
Cirrhosis Cirrhosis Cirrhosis Cirrhosis Cirrhosis Cirrhosis Portal vein thrombosis
+ + + + + + +
75 80 86 63 60 39 70
29 28 42 34 22 17 32
51 51 60 43 35 26 48
8 NM 12 10 8 NM NM
Portal vein thrombosis Cirrhosis
+ +
132 93
65 42
85 63
15 8
Cirrhosis
-
100
45
63
NM
Cause of Portal Hypertension
Pulmonary Arterial Pressures, mm Hg
PORTAL AND PULMONARY HYPERTENSION
electrocardiogram showed right axis deviation and right ventricular hypertrophy. T h e lung scan was normal. On June 13, 1971, right heart catheterization was performed (table 1). Pulmonary angiography showed dilatation of the main pulmonary arteries and no vascular obliteration (figure 1). In November 1978, the patient was alive. Case 4. A 21-year-old woman was admitted on April 7, 1972 for exertional dyspnea. On March 2, 1959, the patient had been hospitalized for massive gastrointestinal bleeding due to ruptured esophageal varices related to obstruction of the portal vein, probably caused by thrombosis. On March 11, 1959, mesocaval shunt was performed. On admission, a systolic murmur was audible over the left lower sternal border, and there was accentuation of the second pulmonic sound. A chest roentgenogram and an electrocardiogram were normal. On November 10, 1976, the patient was hospitalized for an episode of syncope. A chest roentgenogram revealed prominence of the main pulmonary arteries and cardiac enlargement. An electrocardiogram showed right axis deviation and right ventricular hypertrophy. T h e lung scan was normal. On November 14, 1976, right heart catheterization was performed (table 1); pulmonary angiography showed dilatation of the main pulmonary arteries and no vascular oblitera-
851
tion. In November 1977, hepatojugular reflux was noted; an electrocardiogram showed right bundle branch block. On November 5, 1977, the patient died of acute circulatory failure. Necropsy was not permitted. Case 5. A 36-year-old woman was admitted on January 23, 1975 for exertional dyspnea and an episode of effort syncope. On February 12, 1971, splenectomy was performed for splenomegaly, neutropenia, and hyperglobulinemia. Intraoperative liver biopsy revealed nodular regenerative hyperplasia of the liver. From March 1971 to the patient's death, large esophageal varices were repeatedly demonstrated radiographically. On admission, the patient had hepatomegaly, ascites, hepatojugular reflux, and a systolic murmur audible over the left lower sternal border. A chest roentgenogram revealed prominence of the main pulmonary arteries, and an electrocardiogram showed right ventricular hypertrophy and incomplete right bundle branch block. During hospitalization, the patient became severely short of breath and cyadyspnea, and precordial pain. On February 4, 1975, the patient became severely short of berath and cyanotic. Right heart catheterization was performed (table 1), and the patient died during this investigation. Necropsy was not permitted. Case 6. A 37-year-old woman was admitted on
Fig. 1. Case 3. Pulmonary angiogram showing dilatation of the main pulmonary arteries and absence of vascular obstruction.
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LEBREC, CAPRON, DHUMEAUX, AND BENHAMOU
January 28, 1976 for syncope and fever. In November 1973, the patient had been hospitalized for bleeding esophageal varices; alcoholic cirrhosis was then proved by liver biopsy. From December 1973 to March 1974, 3 other episodes of gastrointestinal bleeding occurred. On April 9, 1974, the patient underwent end-to-side portacaval shunt. On admission, examination revealed tachycardia at 120 beats/min, gallop sound, and crepitant rales in the right lower chest. A chest roentgenogram revealed an opacity in the right lower chest. An electrocardiogram showed right axis deviation and deep S 1 with prominent Q 3 . T h e lung scan was normal. On February 27, 1976, right heart catheterization was performed (table 1). On April 10, 1976, the patient was admitted for recurrent gastrointestinal bleeding related to thrombosis of the portacaval shunt. An electrocardiogram revealed right ventricular hypertrophy and right bundle branch block. On April 15, 1976, splenorenal shunt was performed. Two days after surgery, the patient died of acute circulatory failure. At necropsy, there was cardiac enlargement due to right ventricular and atrial dilatation and hypertrophy of the right ventricular wall; the main pulmonary arteries were dilated; macroscopic thrombi were not found in the lumina of the pulmonary arteries. Histologic examination of the pulmonary tissue showed medial hypertrophy, concentric intimal fibrosis, and plexiform lesions affecting small pulmonary arteries (figure 2). Thrombi obstructed the lumina of few small pulmonary arteries. Case 7. A 61-year-old man was admitted on January 8, 1977 for hemoptysis and exertional dyspnea. T h e patient had experienced 2 episodes of gastrointestinal bleeding due to ruptured esophageal varices in March and May 1962; alcoholic cirrhosis was diagnosed. End-to-side portacaval shunt was performed on June 12, 1962; intraoperative biopsy confirmed the diagnosis of alcoholic cirrhosis. On admission, examination revealed accentuation of the second pulmonic sound and crepitant rales. A chest roentgenogram revealed prominence of the main pulmonary arteries and enlargement of the heart. An electrocardiogram showed right axis deviation and right ventricular hypertrophy. T h e lung scan was normal. On May 23, 1977, right heart catheterization was performed (table 1). In November 1978, the patient was alive. Case 8. A 45-year-old man was admitted on May 28, 1978 for an episode of syncope, precordial pain, and severe dyspnea. In February 1972, the patient had been hospitalized for bleeding esophageal varices; alcoholic cirrhosis was then proved by liver biopsy. In June 1976, the patient had been hospitalized for jaundice and ascites. On admission, there was accentuation of the second pulmonic sound and systolic murmur audible over the left lower sternal border. A chest roentgenogram showed prominence of the main pulmonary arteries and enlargement of the heart. An electrocardiogram showed
Fig. 2. Case 6. Lung tissue. A. Medial hypertrophy and concentric laminar intimal fibrosis in a muscular pulmonary artery (original magnification: X 140). B. Plexiform lesions (arrows) formed of plexus of small channels developed in the lumina of 2 damaged small pulmonary arteries (original magnification: X 140). right axis deviation, right ventricular hypertrophy, and incomplete right bundle branch block. On June 27, 1978, right heart catheterization was performed (table 1); pulmonary angiogram showed dilatation of the main pulmonary arteries and no obliteration of vessels. During hospitalization, the patient complained of several syncopes and severe dyspnea. In November 1978, the patient was alive. Case 9. A 67-year-old man was admitted on October 28, 1978 for a transient episode of hepatic encephalopathy and exertional dyspnea. T h e patient had experienced 2 episodes of gastrointestinal bleeding due to ruptured esophageal varices in April and June 1963; alcoholic cirrhosis was diagnosed. Endto-side portacaval shunt was performed on July 26, 1963; intraoperative biopsy confirmed the diagnosis
PORTAL AND PULMONARY HYPERTENSION
of alcoholic cirrhosis. On admission, there was accentuation of the second pulmonic sound; a chest roentgenogram revealed prominence of the main pulmonary arteries and enlargement of the heart; and an electrocardiogram showed right axis deviation and right ventricular hypertrophy. On November 2, 1978, right heart catheterization was performed (table 1). In November 1978, the patient was alive. Discussion
In our experience, the prevalence of pulmonary hypertension among patients with portal hypertension was 0.25 per cent. This percentage is only a rough approximation, because (1) pulmonary hypertension might have been unrecognized in a number of our patients with portal hypertension, and (2) some of our patients with portal hypertension are still alive and, conceivably, might one day be affected by pulmonary hypertension. The order of magnitude of this prevalence makes unlikely a fortuitous association of primary pulmonary hypertension with portal hypertension; the prevalence of primary pulmonary hypertension is certainly much lower among the general population. The features of pulmonary hypertension complicating portal hypertension can be outlined from the analysis of our 9 cases and the 14 welldocumented cases previously reported (3-7, 911) in which pulmonary arterial pressure was measured (tables 1 and 2). Eight other previously reported patients (1, 2, 8) in whom pulmonary hypertension was probable, but was not documented by right heart catheterization, were not included in this analysis. Pulmonary hypertension can affect patients with portal hypertension of any cause (table 1). Cirrhosis was the most common cause of portal hypertension in our patients as well as the previously reported patients. The high prevalence of cirrhosis probably simply reflects the predominance of this cause among all causes of portal hypertension in general. In our Case 5, portal hypertension was a consequence of nodular regenerative hyperplasia of the liver, an uncommon disease of obscure origin that is known to induce alterations in intrahepatic circulation (12). The relatively large number of patients treated by surgical portal-systemic shunting, 15 of 23 (table 1), indicates that this procedure favors the development of pulmonary hypertension. In most cases, liver disease and/or portal hypertension were recognized before the first manifestation of pulmonary hypertension; however,
853
in 2 reported cases (3, 11), symptoms of portal hypertension and pulmonary hypertension developed simultaneously. In 2 reported cases (7) and in our Case 9, pulmonary hypertension was clinically latent and was recognized by chest roentgenogram or right heart catheterization 2, 9, and 15 yr, respectively, after the first symptom of portal hypertension. In most patients, the interval between the first manifestation of portal hypertension and the first manifestation or recognition of pulmonary hypertension ranged from 2 to 15 yr (table 2). Subclinical pulmonary hypertension probably precedes the onset of symptoms by months or years. Symptoms of pulmonary hypertension may develop progressively or abruptly. Most patients (18 of 23) (table 2), complained of exertional dyspnea. The other symptoms were present in fewer than one third of the 23 cases on whom this analysis is based: syncope in 6 (the 2 cases of Levine and associates (10), our Cases 3, 4, 5, and 8); precordial pain in 4 (Cohen and Mendelow's case (4), our Cases 2, 5, and 8); hemoptysis in 3 (Kerbel's case (3), Lai and Fletcher's case (5), and our Case 7). The main clinical signs have been accentuation of the second pulmonic sound and systolic murmur audible in the second or third left interspace or over the left lower sternal border; these were found in approximately 75 and 50 %, respectively, of the patients (table 2). A chest roentgenogram revealed prominence of the main pulmonary arteries and enlargement of the heart in approximately 85 and 70 %, respectively, of the patients (table 2). An electrocardiogram demonstrated right ventricular hypertrophy in approximately 70 % of the patients (table 2). The individual values for mean pulmonary arterial pressure ranged from 26 to 100 mm Hg; pulmonary arterial wedge pressure was normal (table 1). In the 9 patients in whom the whole of the clinical course was well documented (Cohen and Mendelow's case (4), the case of Segel and coworkers (6), one case of Senior and associates (7), 1 of the "2 cases of Levine and co-workers (10), the Clinicopathologic Conference case (11), and our Cases 2, 4, 5, and 6), death occurred within 5 years after the first manifestation of pulmonary hypertension. In our Cases 5 and 6, the clinical course was remarkably short, because the interval between the first manifestation of pulmonary hypertension and death was 2 weeks and 3 months, respectively. In all of these patients except one (6), death was due to heart
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LEBREC, CAPRON, DHUMEAUX, AND BENHAMOU
TABLE 2 CLINICAL, RADIOGRAPHIC, AND ELECTROCARDIOGRAPHIC DATA FOR PATIENTS WITH PULMONARY HYPERTENSION COMPLICATING PORTAL HYPERTENSION Chest Roentgenogram
Clinical Data
Case Present series 1 2 3 4 5 6 7 8 9 Previously reported Kerbel (3) Cohen and Mendelow (4) Lai and Fletcher (5) Segel et al. (6) Senior et al. (7) 1 2 3 4 5 6 Sallam and Watson (9) Levine et al. (10) 1 2 Clinicopathologic conference (11)
Accentuation of Second Pulmonic Dyspnea Sound
Systolic Murmur
Prominence of Main Pulmonary Arteries
Electrocardiogram
Right Cardiac Ventricular HyperEnlargetrophy ment
Interval Between Onset of Portal Hypertension and Onset of Pulmonary Hypertension (yr)*
+t + + + + + + +
+ + + + + + +
+ + + + -
+ + + + + + + +
+ + + + + +
+ + + + + + + + +
6 2 7 13 4 2 15 6 15
+ + + +
+ + +
+ + + +
+ + + +
+ + +
+ + +
0 Unknown 12 10
+ + + +
+ + + +
—
+ + + +
+ + + +
+ + -
+
+
+
+
+
+
10 6 11 8 9 2 9
-
+
+ -
+ +
+ -
+ +
8 10
+
+
+
+
+
-
0
:
* Onset was defined as the first clinical manifestation, or the recognition, of portal hypertension or pulmonary hypertension. absent. + = present;
failure and therefore was directly related to pulmonary hypertension, and not to the liver disease or portal hypertension. However, it is worth noting that our Cases 1 and 3 are still alive 11 and 16 years, respectively, after the first clinical manifestation of pulmonary hypertension. These observations indicate that, in some patients, pulmonary hypertension may be relatively well tolerated for a long period. Necropsy was performed in our Case 6 and in 8 previously reported cases (3, 4, 6, 7, 10, 11). Dilatation of the main pulmonary arteries and right ventricular hypertrophy were found in all of them, as were medial hypertrophy and concentric intimal proliferation affecting small pulmonary arteries. Plexiform lesions were demonstrated in our Case 6 and in 5 previously reported cases (4, 6, 10, 11). Massive or multiple
thrombosis of pulmonary arteries was found in 2 cases (7). A single or few thrombi in small pulmonary arteries were noted in our Case 6 and in 2 previously reported cases (3, 11). The mechanism of pulmonary hypertension complicating portal hypertension is not fully understood. However, it is clear that diversion of the portal venous blood into the inferior or superior vena cava plays a major role in the development of pulmonary hypertension. This assertion is based on the following arguments: (i) the diseases affecting these patients were varied, but had a common denominator, portal hypertension; (2) the existence of portal-systemic shunt was proved by the presence of esophageal varices in all of our patients; (3) surgical portal-systemic shunting, which results in total diversion of the portal venous blood into in-
PORTAL AND PULMONARY HYPERTENSION
ferior vena cava, markedly increases the risk of pulmonary hypertension. Pulmonary hypertension has been attributed to microemboli originating from the portal venous territory, passing through portal-systemic shunts, and reaching the pulmonary circulation (5, 7, 9). However, a number of features are poorly explained by this mechanism. (1) Thrombosis in the portal venous territory has been demonstrated at necropsy only in few cases (5, 9) and has not been found in most patients. (2) T h e prevalence of pulmonary hypertension is apparently not higher in the patients with than the patients without thrombosis of the portal vein, which would be expected if pulmonary hypertension were the consequence of microemboli. (3) T h e very low prevalence of chronic pulmonary hypertension complicating pulmonary embolism in general implies that pulmonary embolism without chronic pulmonary hypertension should be common among patients with portal hypertension; this implication is not supported by any pathologic or clinical observations. (4) Pulmonary angiography, available in 7 patients, revealed filling defects in pulmonary arteries in only 1 of them, Cohen and Mendelow's case (4); in the other 6 patients there was no obliteration of these vessels (Sallam and Watson's case (9), the 2 cases of Levine and co-workers (10), and our Cases 1, 4, and 8). (5) Lung scans, which were performed in 4 of our patients and in a previously reported case (11), revealed no defects suggestive of pulmonary embolism in any of them. (6) As mentioned previously, massive or multiple thrombosis of pulmonary arteries was absent in most of the cases in which necropsy was performed. (7) Medial hypertrophy, concentric intimal proliferation, and plexiform lesions affecting small pulmonary arteries, which were demonstrated in most of the necropsied cases (see previous discussion), have been described in primary pulmonary hypertension and are regarded as incompatible with chronic pulmonary embolism (13, 14). Alternatively, pulmonary hypertension might result from the effect of a vasoconstrictive agent on the small pulmonary arteries or of a substance toxic to the walls of these vessels. Thrombosis of pulmonary arteries, which is present in few cases, would then be the consequence of vasoconstriction or alteration of the arterial walls, and not of embolism. T h e assumed vasoconstrictive agent or toxic substance would be produced in the splanchnic territory, would be
855
destroyed by the liver in normal subjects, and would gain access to the pulmonary arteries in the patients with portal-systemic shunts. This mechanism is in part comparable to those invoked in the pathogenesis of dietary pulmonary hypertension and of right heart lesions determined by the carcinoid tumors. In the former, it has been speculated that ingested toxic compounds, such as the appetite depressant agent, Aminorex (5-amino-5-phenyloxazoline), are released from the gut, pass through the liver, and finally reach and injure the pulmonary arteries (15). In the latter, it has been established that serotonin, when produced by intestinal carcinoids, is destroyed by the liver, and when produced by liver metastases, is directly delivered into the hepatic veins, reaches the right heart, and induces endothelial lesions (16). Acknowledgment The writers are grateful to Prof. C. A. Wagenvoort for expert advice on the interpretation of the histologic pulmonary lesions and to Prof. P. Even for constructive criticism and encouragement. They thank Dr. P. Vernant, Dr. S. Gaudeau, Dr. P. Cassan, and Dr. M. Vantelon for referring Patients 1, 3, 4 and 8. References 1. Mantz FA, Craige E. Portal axis thrombosis with spontaneous portacaval shunt and resultant cor pulmonale. Arch Pathol 1951; 52:91-7. 2. Naeye RL. "Primary" pulmonary hypertension with coexisting portal hypertension: a retrospective study of six cases. Circulation 1960; 22:37684. 3. Kerbel NC. Pulmonary hypertension and portal hypertension. Can Med Assoc J 1962; 87:1022-6. 4. Cohen N, Mendelow H. Concurrent "active juvenile cirrhosis" and "primary pulmonary hypertension." Am J Med 1965; 39:127-33. 5. Lai S, Fletcher E. Pulmonary hypertension and portal venous system thrombosis. Br Heart J 1968; 30:723-5. 6. Segel N, Kay JM, Bayley TJ, Paton A. Pulmonary hypertension with hepatic cirrhosis. Br Heart J 1968; 30:575-8. 7. Senior RM, Britton RC, Turino GM, Wood JA, Langer GA, Fishman AP. Pulmonary hypertension associated with cirrhosis of the liver and with portacaval shunts. Circulation 1968; 37:8896. 8. Clinicopathologic conference. A fifty-six year old woman with jaundice and pulmonary hypertension. Am J Med 1969; 47:287-98. 9. Sallam M, Watson WC. Pulmonary hypertension due to micro-thromboembolism from splenic and portal veins after portacaval anastomo-
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LEBREC, CAPRON, DHUMEAUX, AND BENHAMOU
sis. Br Heart J 1970; 32:269-71. 10. Levine OR, Harris RC, Blanc WA, Mellins RB. Progressive pulmonary hypertension in children with portal hypertension. J Pediatr 1973; 83: 964-72. 11. Clinicopathologic conference. Chronic active hepatitis and pulmonary hypertension. Am J Med 1977; 63:604-13. 12. Rougier P, Degott C, Rueff B, Benhamou JP. Nodular regenerative hyperplasia of the liver: Report of six cases and review of the litera-
ture. Gastroenterology 1978; 75:169-72. 13. Wagenvoort CA, Wagenvoort N. Primary pulmonary hypertension: a pathologic study of the lung vessels in 156 clinically diagnosed cases. Circulation 1970; 42:1163-84. 14. Wagenvoort CA. Classifying pulmonary vascular disease. Chest 1973; 64:503-4. 15. Fishman AP. Dietary pulmonary hypertension. Circ Res 1974; 35:657-60. 16. Grahame-Smith DG. The carcinoid syndrome. Am J Cardiol 1968; 21:376-87.
SUMMARY We report 9 patients with pulmonary hypertension complicating portal hypertension. The cause of portal hypertension was cirrhosis in 7 patients, nodular regenerative hyperplasia of the liver in 1, and portal vein obstruction in 1. Six patients had been treated by portal-systemic shunting before the clinical onset of pulmonary hypertension. The interval between the first manifestation of portal hypertension and the recognition of pulmonary hypertension ranged from 2 to 15 years. Histologic examination in 1 of these patients revealed medial hypertrophy, concentric intimal proliferation, and plexiform lesions affecting the small pulmonary arteries. Pulmonary hypertension might result from the effect of a vasoconstrictive agent on the small pulmonary arteries or of a substance toxic to the walls of these vessels that is produced in the splanchnic territory, destroyed by the liver in normal subjects, and reaches the pulmonary arteries through portal-systemic shunts in these patients.
Introduction Pulmonary hypertension is a recognized, but uncommon, complication of portal hypertension. Only a small number of cases have been reported (1-11). The report of our experience, based on 9 cases, is warranted because (1) this complication of portal hypertension is not well known to internists, lung specialists, cardiologists, or hepatologists; (2) the prevalence of pulmonary hypertension among patients with portal hypertension has been approximately assessed; (3) pulmonary hypertension in these patients can be easily recognized by clinical examination, chest roentgenogram, and electrocar(Received in original form April 3, 1979 and in revised form May 25,1979) 1 From the Unit£ de Recherches de Physiopathologie He>atique (INSERM), Hdpital Beaujon, Clichy; the Clinique M&licale A, Centre Hospitalier Universitaire, Amiens; and the Unit£ 99 (INSERM), H6pital Henri Mondor, Creteil, France. 2 Requests for reprints should be addressed to Dr. Didier Lebrec, Hopital Beaujon, 92118 Clichy, France.
diogram; (4) we offer a hypothesis for the mechanism of pulmonary hypertension complicating portal hypertension. Case Reports This work is based on the study of 9 patients with portal hypertension in whom pulmonary hypertension was proved by right heart catheterization. Five of these patients belonged to a population of approximately 2,000 adults with portal hypertension of various causes, mainly cirrhosis, who were admitted to Hopital Beaujon between 1958 and 1977. The other 4 patients included in this study were referred to Hopital Beaujon because pulmonary hypertension was suspected. Case 1. A 36-year-old man was admitted on October 14, 1967 for exertional dyspnea. In January 1962, the patient had been hospitalized for jaundice and ascites; alcoholic cirrhosis was then proved by liver biopsy. Three episodes of gastrointestinal bleeding due to ruptured esophageal varices had occurred in June, July, and November 1963; end-to-side portacaval shunt was performed on November 13, 1963. In December 1963, the patient had recurrent gastrointestinal bleeding related to thrombosis of the portacaval shunt. On January 3, 1964, mesocaval shunt was performed. On admission, examination revealed
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LEBREC, CAPRON, DHUMEAUX, AND BENHAMOU
accentuation of the second pulmonic sound, prominence of the main pulmonary arteries on the chest roentgenogram, and right axis deviation and right ventricular hypertrophy on the electrocardiogram. In January 1975, a chest roentgenogram revealed prominence of the main pulmonary arteries, decreased peripheral pulmonary vasculature, and cardiac enlargement involving predominantly the right ventricle. On January 24, 1975, right heart catheterization was performed (table 1). In November 1975, a systolic murmur was audible over the left lower sternal border. In November 1978, the patient was alive. Case 2. A 34-year-old woman was admitted on April 9, 1970 for exertional dyspnea and precordial pain. In October 1968, the patient had been hospitalized for bleeding esophageal varices. Cirrhosis was proved by liver biopsy, but the cause of cirrhosis was unknown. On admission, examination revealed accentuation of the second pulmonic sound. The chest roentgenogram revealed prominence of the main pulmonary arteries and cardiac enlargement,
and the electrocardiogram showed right axis deviation and right ventricular hypertrophy. The lung scan was normal. On April 13, 1970, right heart catheterization was performed (table 1). On June 15, 1971, the patient became extremely dyspneic and died. Necropsy was not permitted. Case 3. A 21-year-old man was admitted on March 6, 1971 for exertional dyspnea. In June 1955, the patient had been hospitalized for jaundice, ascites, and splenomegaly; cirrhosis of unknown origin was diagnosed. In January and March 1962, the patient experienced 2 episodes of gastrointestinal bleeding due to ruptured esophageal varices. Splenorenal shunt was performed on March 12, 1962; cirrhosis was then confirmed by intraoperative biopsy. Since July 1962, the patient had complained of exertional dyspnea. From June 1964 to March 1971, the patient experienced several syncopes. On admission, examination showed systolic murmur audible over the left lower sternal border and accentuation of the second pulmonic sound: the chest roentgenogram showed prominence of the main pulmonary arteries, and the
TABLE 1 CAUSE OF PORTAL HYPERTENSION AND PULMONARY ARTERIAL PRESSURES IN PATIENTS WITH PULMONARY HYPERTENSION COMPLICATING PORTAL HYPERTENSION
Case Present series 1 2 3 4 5 6 7 8 9 Previously reported Kerbel (3) Cohen and Mendelow (4) Lal and Fletcher (5) Segel et al. (6) Senior et at (7) 1 2 3 4 5 6 Sal lam and Watson (9) Levine et al. (10) 1 2 Clinicopathologic conference (11) * + = Present; - = absent, t NM = not measured.
Surgical PortalSystemic Shunt*
Systolic
Diastolic
Mean
Wedge
Cirrhosis Cirrhosis Cirrhosis Portal vein obstruction Nodular regenerative hyperplasia of the liver Cirrhosis Cirrhosis Cirrhosis Cirrhosis
+ + +
82 NMt 90 80
28 NM 40 40
50 83 60 59
7 NM 9 8
+ + +
NM 65 50 96 86
NM 25 30 50 50
100 40 40 65 61
NM 5 7 6 13
Cirrhosis Cirrhosis Cirrhosis Cirrhosis
-
NM 112 135 88
NM 60 84 37
60 85 88 56
NM 10 1 15
Cirrhosis Cirrhosis Cirrhosis Cirrhosis Cirrhosis Cirrhosis Portal vein thrombosis
+ + + + + + +
75 80 86 63 60 39 70
29 28 42 34 22 17 32
51 51 60 43 35 26 48
8 NM 12 10 8 NM NM
Portal vein thrombosis Cirrhosis
+ +
132 93
65 42
85 63
15 8
Cirrhosis
-
100
45
63
NM
Cause of Portal Hypertension
Pulmonary Arterial Pressures, mm Hg
PORTAL AND PULMONARY HYPERTENSION
electrocardiogram showed right axis deviation and right ventricular hypertrophy. T h e lung scan was normal. On June 13, 1971, right heart catheterization was performed (table 1). Pulmonary angiography showed dilatation of the main pulmonary arteries and no vascular obliteration (figure 1). In November 1978, the patient was alive. Case 4. A 21-year-old woman was admitted on April 7, 1972 for exertional dyspnea. On March 2, 1959, the patient had been hospitalized for massive gastrointestinal bleeding due to ruptured esophageal varices related to obstruction of the portal vein, probably caused by thrombosis. On March 11, 1959, mesocaval shunt was performed. On admission, a systolic murmur was audible over the left lower sternal border, and there was accentuation of the second pulmonic sound. A chest roentgenogram and an electrocardiogram were normal. On November 10, 1976, the patient was hospitalized for an episode of syncope. A chest roentgenogram revealed prominence of the main pulmonary arteries and cardiac enlargement. An electrocardiogram showed right axis deviation and right ventricular hypertrophy. T h e lung scan was normal. On November 14, 1976, right heart catheterization was performed (table 1); pulmonary angiography showed dilatation of the main pulmonary arteries and no vascular oblitera-
851
tion. In November 1977, hepatojugular reflux was noted; an electrocardiogram showed right bundle branch block. On November 5, 1977, the patient died of acute circulatory failure. Necropsy was not permitted. Case 5. A 36-year-old woman was admitted on January 23, 1975 for exertional dyspnea and an episode of effort syncope. On February 12, 1971, splenectomy was performed for splenomegaly, neutropenia, and hyperglobulinemia. Intraoperative liver biopsy revealed nodular regenerative hyperplasia of the liver. From March 1971 to the patient's death, large esophageal varices were repeatedly demonstrated radiographically. On admission, the patient had hepatomegaly, ascites, hepatojugular reflux, and a systolic murmur audible over the left lower sternal border. A chest roentgenogram revealed prominence of the main pulmonary arteries, and an electrocardiogram showed right ventricular hypertrophy and incomplete right bundle branch block. During hospitalization, the patient became severely short of breath and cyadyspnea, and precordial pain. On February 4, 1975, the patient became severely short of berath and cyanotic. Right heart catheterization was performed (table 1), and the patient died during this investigation. Necropsy was not permitted. Case 6. A 37-year-old woman was admitted on
Fig. 1. Case 3. Pulmonary angiogram showing dilatation of the main pulmonary arteries and absence of vascular obstruction.
852
LEBREC, CAPRON, DHUMEAUX, AND BENHAMOU
January 28, 1976 for syncope and fever. In November 1973, the patient had been hospitalized for bleeding esophageal varices; alcoholic cirrhosis was then proved by liver biopsy. From December 1973 to March 1974, 3 other episodes of gastrointestinal bleeding occurred. On April 9, 1974, the patient underwent end-to-side portacaval shunt. On admission, examination revealed tachycardia at 120 beats/min, gallop sound, and crepitant rales in the right lower chest. A chest roentgenogram revealed an opacity in the right lower chest. An electrocardiogram showed right axis deviation and deep S 1 with prominent Q 3 . T h e lung scan was normal. On February 27, 1976, right heart catheterization was performed (table 1). On April 10, 1976, the patient was admitted for recurrent gastrointestinal bleeding related to thrombosis of the portacaval shunt. An electrocardiogram revealed right ventricular hypertrophy and right bundle branch block. On April 15, 1976, splenorenal shunt was performed. Two days after surgery, the patient died of acute circulatory failure. At necropsy, there was cardiac enlargement due to right ventricular and atrial dilatation and hypertrophy of the right ventricular wall; the main pulmonary arteries were dilated; macroscopic thrombi were not found in the lumina of the pulmonary arteries. Histologic examination of the pulmonary tissue showed medial hypertrophy, concentric intimal fibrosis, and plexiform lesions affecting small pulmonary arteries (figure 2). Thrombi obstructed the lumina of few small pulmonary arteries. Case 7. A 61-year-old man was admitted on January 8, 1977 for hemoptysis and exertional dyspnea. T h e patient had experienced 2 episodes of gastrointestinal bleeding due to ruptured esophageal varices in March and May 1962; alcoholic cirrhosis was diagnosed. End-to-side portacaval shunt was performed on June 12, 1962; intraoperative biopsy confirmed the diagnosis of alcoholic cirrhosis. On admission, examination revealed accentuation of the second pulmonic sound and crepitant rales. A chest roentgenogram revealed prominence of the main pulmonary arteries and enlargement of the heart. An electrocardiogram showed right axis deviation and right ventricular hypertrophy. T h e lung scan was normal. On May 23, 1977, right heart catheterization was performed (table 1). In November 1978, the patient was alive. Case 8. A 45-year-old man was admitted on May 28, 1978 for an episode of syncope, precordial pain, and severe dyspnea. In February 1972, the patient had been hospitalized for bleeding esophageal varices; alcoholic cirrhosis was then proved by liver biopsy. In June 1976, the patient had been hospitalized for jaundice and ascites. On admission, there was accentuation of the second pulmonic sound and systolic murmur audible over the left lower sternal border. A chest roentgenogram showed prominence of the main pulmonary arteries and enlargement of the heart. An electrocardiogram showed
Fig. 2. Case 6. Lung tissue. A. Medial hypertrophy and concentric laminar intimal fibrosis in a muscular pulmonary artery (original magnification: X 140). B. Plexiform lesions (arrows) formed of plexus of small channels developed in the lumina of 2 damaged small pulmonary arteries (original magnification: X 140). right axis deviation, right ventricular hypertrophy, and incomplete right bundle branch block. On June 27, 1978, right heart catheterization was performed (table 1); pulmonary angiogram showed dilatation of the main pulmonary arteries and no obliteration of vessels. During hospitalization, the patient complained of several syncopes and severe dyspnea. In November 1978, the patient was alive. Case 9. A 67-year-old man was admitted on October 28, 1978 for a transient episode of hepatic encephalopathy and exertional dyspnea. T h e patient had experienced 2 episodes of gastrointestinal bleeding due to ruptured esophageal varices in April and June 1963; alcoholic cirrhosis was diagnosed. Endto-side portacaval shunt was performed on July 26, 1963; intraoperative biopsy confirmed the diagnosis
PORTAL AND PULMONARY HYPERTENSION
of alcoholic cirrhosis. On admission, there was accentuation of the second pulmonic sound; a chest roentgenogram revealed prominence of the main pulmonary arteries and enlargement of the heart; and an electrocardiogram showed right axis deviation and right ventricular hypertrophy. On November 2, 1978, right heart catheterization was performed (table 1). In November 1978, the patient was alive. Discussion
In our experience, the prevalence of pulmonary hypertension among patients with portal hypertension was 0.25 per cent. This percentage is only a rough approximation, because (1) pulmonary hypertension might have been unrecognized in a number of our patients with portal hypertension, and (2) some of our patients with portal hypertension are still alive and, conceivably, might one day be affected by pulmonary hypertension. The order of magnitude of this prevalence makes unlikely a fortuitous association of primary pulmonary hypertension with portal hypertension; the prevalence of primary pulmonary hypertension is certainly much lower among the general population. The features of pulmonary hypertension complicating portal hypertension can be outlined from the analysis of our 9 cases and the 14 welldocumented cases previously reported (3-7, 911) in which pulmonary arterial pressure was measured (tables 1 and 2). Eight other previously reported patients (1, 2, 8) in whom pulmonary hypertension was probable, but was not documented by right heart catheterization, were not included in this analysis. Pulmonary hypertension can affect patients with portal hypertension of any cause (table 1). Cirrhosis was the most common cause of portal hypertension in our patients as well as the previously reported patients. The high prevalence of cirrhosis probably simply reflects the predominance of this cause among all causes of portal hypertension in general. In our Case 5, portal hypertension was a consequence of nodular regenerative hyperplasia of the liver, an uncommon disease of obscure origin that is known to induce alterations in intrahepatic circulation (12). The relatively large number of patients treated by surgical portal-systemic shunting, 15 of 23 (table 1), indicates that this procedure favors the development of pulmonary hypertension. In most cases, liver disease and/or portal hypertension were recognized before the first manifestation of pulmonary hypertension; however,
853
in 2 reported cases (3, 11), symptoms of portal hypertension and pulmonary hypertension developed simultaneously. In 2 reported cases (7) and in our Case 9, pulmonary hypertension was clinically latent and was recognized by chest roentgenogram or right heart catheterization 2, 9, and 15 yr, respectively, after the first symptom of portal hypertension. In most patients, the interval between the first manifestation of portal hypertension and the first manifestation or recognition of pulmonary hypertension ranged from 2 to 15 yr (table 2). Subclinical pulmonary hypertension probably precedes the onset of symptoms by months or years. Symptoms of pulmonary hypertension may develop progressively or abruptly. Most patients (18 of 23) (table 2), complained of exertional dyspnea. The other symptoms were present in fewer than one third of the 23 cases on whom this analysis is based: syncope in 6 (the 2 cases of Levine and associates (10), our Cases 3, 4, 5, and 8); precordial pain in 4 (Cohen and Mendelow's case (4), our Cases 2, 5, and 8); hemoptysis in 3 (Kerbel's case (3), Lai and Fletcher's case (5), and our Case 7). The main clinical signs have been accentuation of the second pulmonic sound and systolic murmur audible in the second or third left interspace or over the left lower sternal border; these were found in approximately 75 and 50 %, respectively, of the patients (table 2). A chest roentgenogram revealed prominence of the main pulmonary arteries and enlargement of the heart in approximately 85 and 70 %, respectively, of the patients (table 2). An electrocardiogram demonstrated right ventricular hypertrophy in approximately 70 % of the patients (table 2). The individual values for mean pulmonary arterial pressure ranged from 26 to 100 mm Hg; pulmonary arterial wedge pressure was normal (table 1). In the 9 patients in whom the whole of the clinical course was well documented (Cohen and Mendelow's case (4), the case of Segel and coworkers (6), one case of Senior and associates (7), 1 of the "2 cases of Levine and co-workers (10), the Clinicopathologic Conference case (11), and our Cases 2, 4, 5, and 6), death occurred within 5 years after the first manifestation of pulmonary hypertension. In our Cases 5 and 6, the clinical course was remarkably short, because the interval between the first manifestation of pulmonary hypertension and death was 2 weeks and 3 months, respectively. In all of these patients except one (6), death was due to heart
854
LEBREC, CAPRON, DHUMEAUX, AND BENHAMOU
TABLE 2 CLINICAL, RADIOGRAPHIC, AND ELECTROCARDIOGRAPHIC DATA FOR PATIENTS WITH PULMONARY HYPERTENSION COMPLICATING PORTAL HYPERTENSION Chest Roentgenogram
Clinical Data
Case Present series 1 2 3 4 5 6 7 8 9 Previously reported Kerbel (3) Cohen and Mendelow (4) Lai and Fletcher (5) Segel et al. (6) Senior et al. (7) 1 2 3 4 5 6 Sallam and Watson (9) Levine et al. (10) 1 2 Clinicopathologic conference (11)
Accentuation of Second Pulmonic Dyspnea Sound
Systolic Murmur
Prominence of Main Pulmonary Arteries
Electrocardiogram
Right Cardiac Ventricular HyperEnlargetrophy ment
Interval Between Onset of Portal Hypertension and Onset of Pulmonary Hypertension (yr)*
+t + + + + + + +
+ + + + + + +
+ + + + -
+ + + + + + + +
+ + + + + +
+ + + + + + + + +
6 2 7 13 4 2 15 6 15
+ + + +
+ + +
+ + + +
+ + + +
+ + +
+ + +
0 Unknown 12 10
+ + + +
+ + + +
—
+ + + +
+ + + +
+ + -
+
+
+
+
+
+
10 6 11 8 9 2 9
-
+
+ -
+ +
+ -
+ +
8 10
+
+
+
+
+
-
0
:
* Onset was defined as the first clinical manifestation, or the recognition, of portal hypertension or pulmonary hypertension. absent. + = present;
failure and therefore was directly related to pulmonary hypertension, and not to the liver disease or portal hypertension. However, it is worth noting that our Cases 1 and 3 are still alive 11 and 16 years, respectively, after the first clinical manifestation of pulmonary hypertension. These observations indicate that, in some patients, pulmonary hypertension may be relatively well tolerated for a long period. Necropsy was performed in our Case 6 and in 8 previously reported cases (3, 4, 6, 7, 10, 11). Dilatation of the main pulmonary arteries and right ventricular hypertrophy were found in all of them, as were medial hypertrophy and concentric intimal proliferation affecting small pulmonary arteries. Plexiform lesions were demonstrated in our Case 6 and in 5 previously reported cases (4, 6, 10, 11). Massive or multiple
thrombosis of pulmonary arteries was found in 2 cases (7). A single or few thrombi in small pulmonary arteries were noted in our Case 6 and in 2 previously reported cases (3, 11). The mechanism of pulmonary hypertension complicating portal hypertension is not fully understood. However, it is clear that diversion of the portal venous blood into the inferior or superior vena cava plays a major role in the development of pulmonary hypertension. This assertion is based on the following arguments: (i) the diseases affecting these patients were varied, but had a common denominator, portal hypertension; (2) the existence of portal-systemic shunt was proved by the presence of esophageal varices in all of our patients; (3) surgical portal-systemic shunting, which results in total diversion of the portal venous blood into in-
PORTAL AND PULMONARY HYPERTENSION
ferior vena cava, markedly increases the risk of pulmonary hypertension. Pulmonary hypertension has been attributed to microemboli originating from the portal venous territory, passing through portal-systemic shunts, and reaching the pulmonary circulation (5, 7, 9). However, a number of features are poorly explained by this mechanism. (1) Thrombosis in the portal venous territory has been demonstrated at necropsy only in few cases (5, 9) and has not been found in most patients. (2) T h e prevalence of pulmonary hypertension is apparently not higher in the patients with than the patients without thrombosis of the portal vein, which would be expected if pulmonary hypertension were the consequence of microemboli. (3) T h e very low prevalence of chronic pulmonary hypertension complicating pulmonary embolism in general implies that pulmonary embolism without chronic pulmonary hypertension should be common among patients with portal hypertension; this implication is not supported by any pathologic or clinical observations. (4) Pulmonary angiography, available in 7 patients, revealed filling defects in pulmonary arteries in only 1 of them, Cohen and Mendelow's case (4); in the other 6 patients there was no obliteration of these vessels (Sallam and Watson's case (9), the 2 cases of Levine and co-workers (10), and our Cases 1, 4, and 8). (5) Lung scans, which were performed in 4 of our patients and in a previously reported case (11), revealed no defects suggestive of pulmonary embolism in any of them. (6) As mentioned previously, massive or multiple thrombosis of pulmonary arteries was absent in most of the cases in which necropsy was performed. (7) Medial hypertrophy, concentric intimal proliferation, and plexiform lesions affecting small pulmonary arteries, which were demonstrated in most of the necropsied cases (see previous discussion), have been described in primary pulmonary hypertension and are regarded as incompatible with chronic pulmonary embolism (13, 14). Alternatively, pulmonary hypertension might result from the effect of a vasoconstrictive agent on the small pulmonary arteries or of a substance toxic to the walls of these vessels. Thrombosis of pulmonary arteries, which is present in few cases, would then be the consequence of vasoconstriction or alteration of the arterial walls, and not of embolism. T h e assumed vasoconstrictive agent or toxic substance would be produced in the splanchnic territory, would be
855
destroyed by the liver in normal subjects, and would gain access to the pulmonary arteries in the patients with portal-systemic shunts. This mechanism is in part comparable to those invoked in the pathogenesis of dietary pulmonary hypertension and of right heart lesions determined by the carcinoid tumors. In the former, it has been speculated that ingested toxic compounds, such as the appetite depressant agent, Aminorex (5-amino-5-phenyloxazoline), are released from the gut, pass through the liver, and finally reach and injure the pulmonary arteries (15). In the latter, it has been established that serotonin, when produced by intestinal carcinoids, is destroyed by the liver, and when produced by liver metastases, is directly delivered into the hepatic veins, reaches the right heart, and induces endothelial lesions (16). Acknowledgment The writers are grateful to Prof. C. A. Wagenvoort for expert advice on the interpretation of the histologic pulmonary lesions and to Prof. P. Even for constructive criticism and encouragement. They thank Dr. P. Vernant, Dr. S. Gaudeau, Dr. P. Cassan, and Dr. M. Vantelon for referring Patients 1, 3, 4 and 8. References 1. Mantz FA, Craige E. Portal axis thrombosis with spontaneous portacaval shunt and resultant cor pulmonale. Arch Pathol 1951; 52:91-7. 2. Naeye RL. "Primary" pulmonary hypertension with coexisting portal hypertension: a retrospective study of six cases. Circulation 1960; 22:37684. 3. Kerbel NC. Pulmonary hypertension and portal hypertension. Can Med Assoc J 1962; 87:1022-6. 4. Cohen N, Mendelow H. Concurrent "active juvenile cirrhosis" and "primary pulmonary hypertension." Am J Med 1965; 39:127-33. 5. Lai S, Fletcher E. Pulmonary hypertension and portal venous system thrombosis. Br Heart J 1968; 30:723-5. 6. Segel N, Kay JM, Bayley TJ, Paton A. Pulmonary hypertension with hepatic cirrhosis. Br Heart J 1968; 30:575-8. 7. Senior RM, Britton RC, Turino GM, Wood JA, Langer GA, Fishman AP. Pulmonary hypertension associated with cirrhosis of the liver and with portacaval shunts. Circulation 1968; 37:8896. 8. Clinicopathologic conference. A fifty-six year old woman with jaundice and pulmonary hypertension. Am J Med 1969; 47:287-98. 9. Sallam M, Watson WC. Pulmonary hypertension due to micro-thromboembolism from splenic and portal veins after portacaval anastomo-
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LEBREC, CAPRON, DHUMEAUX, AND BENHAMOU
sis. Br Heart J 1970; 32:269-71. 10. Levine OR, Harris RC, Blanc WA, Mellins RB. Progressive pulmonary hypertension in children with portal hypertension. J Pediatr 1973; 83: 964-72. 11. Clinicopathologic conference. Chronic active hepatitis and pulmonary hypertension. Am J Med 1977; 63:604-13. 12. Rougier P, Degott C, Rueff B, Benhamou JP. Nodular regenerative hyperplasia of the liver: Report of six cases and review of the litera-
ture. Gastroenterology 1978; 75:169-72. 13. Wagenvoort CA, Wagenvoort N. Primary pulmonary hypertension: a pathologic study of the lung vessels in 156 clinically diagnosed cases. Circulation 1970; 42:1163-84. 14. Wagenvoort CA. Classifying pulmonary vascular disease. Chest 1973; 64:503-4. 15. Fishman AP. Dietary pulmonary hypertension. Circ Res 1974; 35:657-60. 16. Grahame-Smith DG. The carcinoid syndrome. Am J Cardiol 1968; 21:376-87.
