Published online March 24, 2008
PEDIATRICS Vol. 121 No. 4 April 2008, pp. e892-e899 (doi:10.1542/peds.2006-3411)
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ARTICLE

Pulmonary Hypertension in Patients With Congenital Portosystemic Venous Shunt: A Previously Unrecognized Association

Takuro Ohno, MD, PhDa, Jun Muneuchi, MDa, Kenji Ihara, MD, PhDa, Tetsuji Yuge, MDb, Yoshiaki Kanaya, MDa, Shigeo Yamaki, MD, PhDc and Toshiro Hara, MD, PhDa

a Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
b Department of Pediatrics, Kyushu Kouseinenkin Hospital, Fukuoka, Japan
c Japanese Research Institute of Pulmonary Vasculature, Miyagi, Japan


   ABSTRACT
TOP
 ABSTRACT
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
BACKGROUND. Pulmonary arterial hypertension has been reported to be observed in association with acquired portal hypertension. However, the contribution of congenital anomalies occurring in the portal system to the development of pulmonary arterial hypertension remains to be elucidated.

METHODS. Nine patients with congenital portosystemic venous shunt were studied from January 1990 through September 2005.

RESULTS. Patent ductus venosus was detected in 5 patients, including 3 patients with an absence of the portal vein. The presence of either a gastrorenal or splenorenal shunt was evident in another 4 patients. Six patients had a history of hypergalactosemia with normal enzyme activities, as seen during neonatal screening. Six (66.7%) of the 9 patients were identified to have clinically significant pulmonary arterial hypertension (mean pulmonary artery pressure: 34–79 mm Hg; pulmonary vascular resistances: 5.12–38.07 U). The median age at the onset of pulmonary arterial hypertension was 12 years and 3 months. Histologic studies of lung specimens, which were available in 4 of the 9 patients with congenital portosystemic venous shunt, showed small arterial microthrombotic lesions in 3 patients. This characteristic finding was recognized even in the congenital portosystemic venous shunt patients without PAH.

CONCLUSIONS. This study demonstrated thromboembolic pulmonary arterial hypertension to be a crucial complication in congenital portosystemic venous shunt, and this pathologic state may be latently present in patients with pulmonary arterial hypertension of unknown etiology.

Key Words: congenital portosystemic venous shunt • hypergalactosemia • microthrombosis • pulmonary arterial hypertension

Abbreviations: CPSVS—congenital portosystemic venous shunt • PAH—pulmonary arterial hypertension • IPAH—idiopathic pulmonary arterial hypertension • PA—pulmonary artery • MPAP—mean pulmonary artery pressure • NO—nitric oxide • VSD—ventricular septal defect • 5-HT—5-hydroxytryptamine

Congenital portosystemic venous shunt (CPSVS) is a rare disorder with a variety of connections. A diagnosis can be made at the time of neonate screening, based on the presence of hypergalactosemia without enzyme deficiency,1 although some patients may present with hepatic encephalopathy during their infant to teenage years.2,3 A spontaneous closure may be expected to occur up to ~2 years of age.4

Idiopathic pulmonary arterial hypertension (PAH; IPAH), formerly called primary pulmonary hypertension, is a life-threatening disease that is characterized by progressive PAH, eventually resulting in right heart failure and death. It is a rare disease (1–2 cases per million people) that occurs most commonly in the third decade of life in women and in the fourth decade of life in men, with a mean age at diagnosis of 36.4 years.5 The current management of this condition (including calcium channel blockers, bosentan, prostacyclin analogs, and lung transplantation) is so far limited.6–11

PAH occurs in from 0.3% to 2.3% of patients with acquired portal hypertension because of hepatic cirrhosis12,13 and in those with either a pathologic or surgical portal systemic shunt to the lungs.14,15 However, it remains to be determined whether CPSVS is a risk factor for the future development of PAH. To the best of our knowledge, only a few patients with CPSVS have so far been reported to be associated with PAH,3,16–21 and 4 of them developed PAH during childhood.3,17,19,21

We herein describe a follow-up evaluation of 9 patients with CPSVS. We determined that PAH is 1 of the major complications of CPSVS.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Nine patients with CPSVS had thorough workups, including clinical histories, physical examinations, laboratory tests, chest roentgenography, electrocardiography, pulmonary function test when feasible, echocardiography, radionuclide perfusion lung scan, and cardiac catheterization. Informed consent was obtained from each patient or his or her parents before every examination. These patients were transferred to our hospital from January 1990 through September 2005 for evaluation and therapeutic management, including patients with hypergalactosemia (5 patients), syncopal episodes (2 patients), consciousness disturbance (1 patient), and a strong positive tuberculin skin test result (1 patient), and they were all enrolled in this study. CPSVS is defined as occurring in the absence of primary liver disease and in the presence of either a large shunt vessel or hemangioma that is related to vascular developmental anomalies. We evaluated the following patients’ information and data: clinical features, laboratory or hemodynamic data, imagings, shunt ratio, complications, therapies, and outcomes. The shunt ratio was determined by Tl-201 per-rectal portal scintigraphy. The isotope, administrated rectally into the sigmoid colon, was promptly absorbed into the inferior mesenteric vein, and it reached the liver via the portal vein. When a portosystemic venous shunt was present, the isotope could be detected in both the liver and heart at the same time. The portal/systemic shunt ratio was given as the counts obtained in the heart divided by the total counts obtained in the liver and heart (normal: <5%).22

We serially evaluated the cardiovascular condition of the CPSVS patients by chest radiograph, electrocardiography, and echocardiography. The presence of PAH was speculated based on the following findings: the marked dilatation of the right ventricle and/or main pulmonary artery (PA) on chest radiograph; the characteristic findings suggesting right ventricular hypertrophy on electrocardiography; or the decompression of left ventricle or the increased estimated right ventricular systolic pressure on echocardiogram. When a stenosing of right ventricular outflow tract was not detected by echocardiography, PA systolic pressure was estimated from the peak tricuspid regurgitation jet velocities according to the following equation: PA systolic pressure = 4(V)2 mm Hg, where V is the peak velocity (in meters per second) of a tricuspid valve regurgitant jet.23 When some suggestive findings of PAH were detected, cardiac catheterization was conducted. A diagnosis of PAH was made definite with mean PA pressure (MPAP) of >25 mm Hg based on the findings of cardiac catheterization.24 When PAH was detected, a radionuclide perfusion lung scan was conducted for the differential diagnosis of the PAH etiology.

For the evaluation of the responsiveness of pulmonary arteries to vasodilators, we performed nitric oxide (NO), O2, and an epoprostenol administration test according to the following the protocol: oxygen (7 L/min) was administrated via a facial mask, and the pressure measurements and blood samplings were performed in the right heart at 1, 3, 5, and 10 minutes after starting oxygen administration. Thereafter, NO (20 ppm) was synergistically administered from the side hole of the mask. Pressure measurements and blood samplings were performed 10 minutes after NO administration. The levels of the NO flow ratio were monitored by calculating the oxygen and NO flow ratio. Finally, epoprostenol infusion was started at a rate of 2 ng/kg per minute, and the dose was thereafter increased every 10 minutes until reaching a maximal dose of 10 ng/kg per minute. The hemodynamic data were serially obtained during the time course of epoprostenol infusion. The cardiac index was estimated by the Fick method.25

If we considered a liver transplantation for the CPSVS patients who were expected to progress the PAH, then we performed a lung biopsy in those patients to evaluate the clinical and histologic stages of PAH. Fully informed written consent was obtained from the patients and their parents before we performed the lung biopsy. The obtained lung tissue specimens were fixed by 10% formalin and stained with Elastica-Goldner stain.

To measure the portal venous pressure and to evaluate whether the shunt vessel could be closed, angiocather examination was conducted. The portal venous pressure was measured both through a balloon catheter at the site of the shunt and by measuring hepatic venous wedge pressure via femoral vein approach. The hepatic venous wedge pressure and direct portal venous pressure before and after balloon occlusion were determined, and then we found that some of the CPSVS patients were suitable for a shunt closure.

Before performing the interventional catheterization, we obtained informed written consent from each patient. Under general anesthesia, a catheter with a latex balloon was inserted from the right femoral vein into the shunt vein. A temporary balloon occlusion was then inflated into the shunt vein, and we then confirmed that the shunt occlusion did not affect the portal venous circulation. Thereafter, an embolization was performed by injecting monoethanolamine oleate (Oldamin, Fuji Chemical Industry Co, Toyama, Japan) from the end hole of the placed balloon catheter under temporary balloon occlusion to control the shunt venous flow. No apparent complication occurred either during or after this procedure.


   RESULTS
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Demographics and Vascular Anomaly
Table 1 shows the clinical characteristics of 9 patients (5 boys and 4 girls) with CPSVS. The ages at diagnosis of CPSVS ranged from 1 month to 18 years (median: 7 months). Patent ductus venosus was detected in 5 patients, including 2 patients with an absence of the portal vein (Fig 1A), and gastrorenal or splenorenal shunt was evident in another 4 patients (Fig 1B). There were no patients either with an intrahepatic portosystemic venous shunt or a spontaneous closure of the venous shunt vessel. In addition, no patients demonstrated portal hypertension (6.8–12.9 cm H2O). Cardiac anomalies were present in 5 patients (patients 1, 2, 5, 6, and 7). Six patients had a history of hypergalactosemia with normal enzyme activities, as detected during neonatal screening. Elevated levels of serum total bile acid, blood ammonia, and whole-blood manganese were considered to be a critical finding in patients with congenital portosystemic venous shunt.26


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  		TABLE 1 Demographics of 9 Study Patients

 

Figure 1
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  		FIGURE 1 A selective retrograde venous angiogram. A, An angiogram from the ductus venosus in patient 4. The black arrow indicates ductus venosus, and the white arrow indicates the portal vein. B, An angiogram of a gastrorenal shunt in patient 9. The black arrow indicates a shunt vessel, and the white arrow indicates the inferior vena cava.

 
Neurologic Findings
Central nervous system disorders occurred in 3 patients, 1 with hepatic encephalopathy (patient 4) and 2 with extrapyramidal signs at adolescence (patients 8 and 9). Hepatic encephalopathy was defined at the presence of vomiting, nausea, psychiatric disabilities, and symptoms. In all of the patients with CPSVS, brain MRI demonstrated abnormally high signals in the anterior lobe of hypophysis and/or globus pallidus using T1-weighed but not T2-weighed images, and these were considered to be characteristic findings of CPSVS.26 Based on electroencephalographic evaluations, the 2 patients with extrapyramidal signs were shown to have abnormal findings, such as diffuse low voltage with a disappearance of {alpha}-waves, thus indicating the presence of hepatic encephalopathy.

Hepatic Findings
No liver dysfunction was found in any of these patients. Five (patient 1, 2, 3, 5, and 9) of these patients underwent a liver biopsy, and a histologic analysis of the samples revealed no evidence of liver cirrhosis.

Hemodynamic Findings
Right-sided cardiac catheterization was performed in all of the patients (Fig 1 and Table 2). Six (66.7%) of the 9 patients were identified to have clinically significant PAH (MPAP: 34–79 mm Hg; pulmonary vascular resistances: 5.12–38.07 U). The median age at the onset of PAH was 10 years and 3 months (range: 9 months to 12 years and 9 months). Congenital heart disease (2 patients with atrial septal defect and 1 with ventricular septal defect [VSD]) was identified in 3 PAH patients who were not identified to have any signs of PAH according to an echocardiographic study in early infancy, although they also had no histories of systemic desaturation.


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  		TABLE 2 Laboratory Data in Patients With CPSVS

 
All of the 9 patients received pulmonary angiography. Based on the findings of angiography and echocardiography, they did not have any significant left-to-right shunts; therefore, the closure of the shunts in these patients was not considered. Patient 2, who had a small VSD, was observed for several years without an operation, and thereafter the VSD was observed to close spontaneously. Patient 7 also had an atrial septal defect, but his general condition was so severe with the associations of thrombotic thrombocytopenic purpura (TTP) and acute pancreatitis that cardiac operation could not be performed. In the patients with progressive PAH, pulmonary angiograms showed that the proximal side of pulmonary arteries was considerably dilated and the distal side tapered abruptly, which were consistent with IPAH. In the other patients without PAH, pulmonary angiography showed no apparent abnormality.

Echocardiogram Data
Echocardiography was performed at the diagnosis of CPSVS, and 3 of the 9 patients had PAH at that time. Regular tests with echocardiography identified the PAH development in 2 additional patients with CPSVS during the follow-up period. The Doppler pressure estimations closely correlated with the catheterization findings in all of the patients with tricuspid insufficiency (Table 3). Retrospectively, the electrocardiogram and chest-radiograph findings were less sensitive for detecting PAH at an early phase than echocardiograms, and even with echocardiograms, the grade of PAH could not be sufficiently evaluated in the patients with PAH without tricuspid insufficiency.


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  		TABLE 3 Hemodynamic Assessment

 
Lung Tissue Histology
A histopathologic examination of lung specimens was performed in 4 patients (patients 1, 2, 3, and 5) at the age of 2 years 1 month, 8 years and 9 months, 8 years and 10 months, and 11 years and 2 months, respectively. Microthrombotic lesions were observed in patients 2, 3, and 5. In particular, this characteristic finding was remarkable in patients 2 and 5 (Fig 2).


Figure 2
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  		FIGURE 2 The pathologic findings of lung sections obtained from patient 2. The small-sized muscular artery shows intimal fibrosis by which the lumen is separated into 2 spaces. The picture is considered to represent the recanalization of an organized thrombus based on the findings obtained by using Elastica-Goldner stain.>

 
Per-Rectal Portal Scintigraphy
Tl-201 per-rectal portal scintigraphy was conducted for 8 patients (5 patients with PAH and 3 patients without PAH). The mean portal/systemic shunt ratio was 76.8% ± 15.0%. There was no significant difference in the shunt ratios between those with and without PAH (range: 55%–89%; median: 74% vs range: 74%–99%; median: 79.0%; P > .1, Mann-Whitney U test) or between types of portosystemic venous shunt (patent ductus venosus: range: 55%–79%; median: 66% vs others: range: 74%–99%; median: 87.5%; P > .05, Mann-Whitney U test).

Responsiveness of Pulmonary Arteries to Vasodilators
An NO, O2, and epoprostenol administering examination was performed in 4 patients after a conventional catheterization analysis in the right heart. As a result, the resistance of PA dramatically decreased in 3 of 4 patients after the administration of epoprostenol and NO in association with an increase pulmonary-systemic flow ratio and unchanged MPAP (Table 3). It was, thus, speculated that the decrease of PA resistance and thereby increased pulmonary-systemic flow ratio might cause unchanged PA pressure. Another explanation includes that prostacyclin and NO increased cardiac output and reduced pulmonary arterial pressure and resistance; consequently, these did not remarkably change PA pressure. These 2 patients did not undergo this test, because they enrolled in this study at a relatively early phase, and at that time the therapeutic evaluation of PAH by vasodilators had not yet been introduced at our institute.

Other Findings and Complications
Two of the 9 patients had other complications, including chronic pancreatitis (patient 8) and microangiopathic hemolytic anemia (patient 7). A magnetic radiologic cholangiogram was performed in 1 patient with chronic pancreatitis, and his pancreatic duct had no anomalies, such as pancreatico-biliary maljunction. In patient 7, microangiopathic hemolytic anemia developed 6 months after the onset of PAH. Immunologic abnormalities were detected, including an elevation of the serum anti-double-strand DNA and anticardiolipin antibody levels and of the platelet-associated immunoglobulin G level or the decrease in the serum complement levels.

Outcomes
Catheter embolization of the shunt vessel was conducted in 2 patients (patients 4 and 6). After embolization, the blood ammonia, total bile acid, and manganese levels had dropped to the reference range. An echogram revealed a normal portal venous flow without an abnormal shunt flow. Thereafter, PAH did not develop or progress. Three of 6 patients with PAH died because of refractory right heart failure. The disease duration from the onset of PAH to death varied from 1 year 1 month to 12 years 4 months (Fig 3).


Figure 3
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  		FIGURE 3 Clinical courses of 9 patients with CPSVS. The horizontal lines indicate the follow-up periods; the bold horizontal lines indicate the periods of PAH; the black arrows indicate the ages at cardiac catheterization, and the open triangles indicate the ages at embolization of the shunt vessel. a The age at diagnosis of CPSVS; b age at onset of PAH; c ages at the time of embolization of the shunt vessel (also indicated by open triangles); d age at death.

 

   DISCUSSION
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
We herein report that PAH is a major complication of CPSVS. Our study demonstrated several critical points. First, it is important not to overlook patients with CPSVS during the newborn period when galactosemia of unknown etiology was pointed out by the neonatal mass screening. When a CPSVS is detected, the cardiac catheter test should be considered to determine whether the shunt can be cured by a shunt closure. If the CPSVS cannot be closed, then the patients should be carefully followed-up by serial evaluation of the cardiovascular condition with chest radiograph, electrocardiography, and echocardiography. The chest radiographs and electrocardiograms were useful to some extent as screening tools to detect PAH. However, these modalities are not sensitive enough to detect the early phase of PAH; accordingly, other examinations, including echocardiography, would be helpful, and cardiac catheterization is essential for making a definite diagnosis of PAH.

The pathologic evaluation demonstrated that the findings of lung species from CPSVS patients were particularly distinct from the findings of pulmonary tissue specimens from adult PAH patients. The histology of lung tissue from idiopathic PAH patients was classified based on the report by Hatano and Strasser28 on a World Health Organization meeting. The classification of PAH from pathogenic entities includes plexogenic pulmonary arteriopathy, recurrent pulmonary thromboembolism, and pulmonary veno-occlusive disease. The plexogenic type is characterized initially by pulmonary arterial vasoconstriction with medial hypertrophy, whereas the recurrent pulmonary thromboembolism is characterized by the presence of arterial thrombi of varying ages involving the microscopic-sized pulmonary arteries. The plexogenic arteriopathy is pathognomonic to the advanced stage in the adult idiopathic PAH patients,5 whereas the histopathology obtained from 3 of the CPSVS patients demonstrated characteristic findings for the thromboembolism with localized intimal fibrosis in small-sized muscular arteries. This finding was also recognized in a CPSVS patient without PAH (patient 3), whereas the plexogenic arteriopathy was not remarkable in all of the samples from the patients even in the clinically advanced stage of PAH. One probable explanation for these pathologic findings for the CPSVS patients includes that PAH might come from recurrent microemboli originating in the mesenteric circulation and passing via portal systemic shunts to the lungs. In the previous report, a high prevalence of pathologic or surgical portal systemic shunt has been reported in the patients with unexplained PAH,14 and thrombotic lesions were detected in pulmonary tissue specimens from the patients with both pulmonary and portal hypertension.29 Accordingly, we speculate that the pathologic changes in the pulmonary arteries in the early phase of PAH may be microembolic arteriopathy, and plexogenic arteriopathy might appear with the advancement of PAH. In this study, however, a longitudinal evaluation regarding the lung pathology was not performed; consequently, a further long-time follow-up of lung histopathology is considered to be essential to verify our speculation about the pathologic changes of pulmonary arteries in CPSVS patients and to elucidate the pathogenesis of PAH by CPSVS.

In the patients with CPSVS, a long-standing pulmonary vasoconstriction may occur because of humoral substances, such as serotonin (5-hydroxytryptamine [5-HT]), histamine, estrogen, glucagon, and endotoxin, which are normally metabolized in the liver.30–33 In particular, the 5-HT transporter expression increased in lung tissue specimens, and the pulmonary arteries from patients with IPAH and 5-HT markedly enhanced the growth of cultured pulmonary arterial smooth muscle cells.34,35 As a result, these vasocontracting substances, especially 5-HT, may, therefore, play an important role in the advancement of PAH, and additional affirmative studies are needed.

In this study, 2 CPSVS patients were associated with unusual complications, 1 with chronic pancreatitis and the other with microangiopathic hemolytic anemia. Regarding pancreatitis, it is possible that the high manganese level in the blood because of portal-systemic shunt leads to its accumulation in the pancreas, thus eventually causing pancreatic tissue damage. Indeed, acute pancreatitis occurred in patients with chronic renal failure as a result of hemodialysis with a solution that was contaminated with manganese.36 Moreover, significant pathologic changes in the pancreas, characterized by a pancreatitis-like reaction consisting of infiltration of inflammatory cells and destruction of acinar cells, were observed in manganese-exposed rats.37 In patient 7, who had microangiopathic hemolytic anemia, the PAH occurred much earlier than that in patients without hemolysis. In a histologic study on patients with microangiopathic hemolytic anemia, portal, and PAH, Paré et al38 showed severely dilated plexiform lesions in the pulmonary vasculature, with depositions of fibrin in the vasculature channel. In addition, PAH is known to be associated with autoimmune phenomena in certain patients,39 and patient 7 had various kinds of autoantibodies. We, therefore, speculated that the pulmonary vasculature injury in patient 7 rapidly progressed because of microangiopathic hemolytic anemia and the underlying autoimmunity.

This pathologic state of portosystemic venous shunt may be cured if the shunt vessel is able to be closed. In fact, PAH has also been reported to be complicated by patent ductus venosus, which regressed after stent implantation within the shunt vessel to reduce the diameter and to decrease the shunt flow.17 If a congenital absence of the portal vein coexists, however, then correctional therapies are contraindicated. In such patients, a liver transplantation is the only therapeutic option to prevent a regression of PAH. Losay et al40 suggested that an early liver transplantation is crucial in children with liver disease and PAH. In 2 of the children, the pulmonary arterial pressure and resistance returned to almost normal values within 1 and 6 years after liver transplantation.40 From a pathologic point of view, the pulmonary tissue did not have irreversible plexogenic pulmonary arteriopathy and maintained its function even in the clinically advanced stage of PAH; therefore, liver transplantation might be considered even for the patients with clinically advanced PAH. Newer and more effective pharmacotherapies for PAH are now available, and clinical trials are now underway to determine the safety and efficacy of the new therapies that include oral and inhaled prostacyclin analogues, phosphodiesterase-5 inhibitors, and endothelin receptor antagonists.41 It is possible that an early intervention protocol for PAH using these new drugs may improve the prognosis of PAH; therefore, the early detection and intervention may be essential to adequately treat children with PAH in the future.


   CONCLUSIONS
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
We herein presented our experience in 9 patients with CPSVS, including 6 patients with PAH. These data indicate that PAH is a crucial complication in CPSVS, although, in addition, this pathologic state of CPSVS may be latently present in patients with PAH of unknown etiology.


   ACKNOWLEDGMENTS
 
We thank Dr R.E. Richard for his critical review of this article, Ryoko Hayashi for her valuable technical assistance, and Prof B.T. Quinn for medical advice in English.


   FOOTNOTES
 
Accepted Sep 18, 2007.

Address correspondence to Kenji Ihara, MD, PhD, Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: k-ihara{at}pediatr.med.kyushu-u.ac.jp

The authors have indicated they have no financial relationships relevant to this article to disclose.


What's Known On This Subject

Pulmonary arterial hypertension has been reported to be observed in association with acquired portal hypertension. However, the contribution of congenital anomalies occurring in the portal system to the development of pulmonary arterial hypertension remains to be elucidated.

 

What This Study Adds

This study demonstrated thromboembolic pulmonary arterial hypertension to be a crucial complication in congenital portosystemic venous shunt, and this pathologic state may be latently present in patients with pulmonary arterial hypertension of unknown etiology.

 


   REFERENCES
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics




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