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* From the Departments of Pulmonary Medicine (Drs. Bogaard, Postmus, and Vonk-Nordegraaf), Hepatology (Drs. Tjwa and van Nieuwkerk), and Radiology (Dr. van den Berg), VU Medical Center, Amsterdam, the Netherlands; and the Department of Pulmonary Medicine (Dr. Grotjohan), Isala Klinieken, Zwolle, the Netherlands.
Correspondence to: Harm J. Bogaard, MD, PhD, Department of Pulmonary Medicine, VU Medical Centre, PO Box 7057, 1007 MB, Amsterdam, the Netherlands; e-mail: hj.bogaard{at}vumc.nl
A 31-year-old man visits the pulmonologist after an episode of hemoptysis and dyspnea during an Alpine hiking trip. During the first few days of this trip, he had experienced difficulty keeping up with his traveling companions. When the group ascended to 2,700 m on the fifth day, he started to feel unwell and extremely fatigued. He noticed shortness of breath and a cough, first with white sputum and later with a fair amount of bloody sputum. That night, staying at the same altitude, he had difficulty sleeping and developed a headache. After descent to sea level he had no further complaints. He is a healthy nonsmoker who regularly exercises in a gym, although, from childhood on, his exercise capacity has been somewhat limited in comparison with his peers. He never used drugs or alcohol and takes no medication.
Physical Examination
Vital signs were normal; there was no jugular vein distension, clubbing, or peripheral edema. Chest examination findings were normal. A cardiac examination revealed a hyperkinetic cardiac impulse just outside the midclavicular line, and a loud second heart sound.
Laboratory Findings
The results of a hemogram were normal. The findings of liver biochemistry testing were mildly abnormal, as follows: alkaline phosphatase level, 161 U/L; gammaglutamyl transpeptidase level, 148 U/L; alanine aminotransferase level, 37 U/L; aspartate aminotransferase level, 43 U/L; and total bilirubin concentration, 37 µmol/L. For chest radiography findings, see Figure 1 . A chest CT scan performed with contrast enhancement showed no signs of pulmonary embolism, no arteriovenous malformations, and no parenchymal abnormalities. The findings of perfusion scintigraphy were normal. An ECG showed a right axis deviation. Cardiac ultrasound revealed right ventricular hypertrophy without valvular abnormalities. There was no tricuspid regurgitant jet, and systolic pulmonary artery pressure could not be estimated. For right heart catheterization results, see Table 1 . An upper abdominal ultrasound showed a normal liver and spleen, and an abnormal flow signal in the vicinity of the portal vein. For MRI angiography results, see Figure 2
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Diagnosis: Pulmonary arterial hypertension due to an Abernethy malformation
Pulmonary arterial hypertension and hepatopulmonary syndrome are well-recognized complications of chronic liver disease. Pulmonary arterial hypertension associated with chronic liver disease and hepatopulmonary syndrome are also known as pulmonary-hepatic vascular disorders. Pulmonary arterial hypertension associated with chronic liver disease shares histologic features with many other forms of pulmonary arterial hypertension (eg, intima proliferation, medial smooth muscle hypertrophy, plexiform lesions, and in situ thrombosis), but it is different since it exists within the context of a hyperdynamic circulatory state with increased cardiac output and a decreased systemic vascular resistance. However, when the disease progresses right ventricular failure and decreased cardiac output will follow. The diagnostic criteria are liver disease, a mean pulmonary artery pressure of > 25 mm Hg at rest and/or > 30 mm Hg during exercise, a pulmonary capillary wedge pressure of < 15 mm Hg and a pulmonary vascular resistance > 240 dyne · s · cm–5. The latter criterion is not routinely used in other forms of pulmonary arterial hypertension but is important when a hyperdynamic circulation is found. The pathophysiology is complex and involves alterations in nitric oxide, endothelin-1, and serotonin signaling, possibly due to bacterial translocation, decreased hepatic clearance, inflammation, and increased shear stress. As a consequence, vascular tone increases and vascular remodeling is initiated.
The pathophysiology of hepatopulmonary syndrome is closely related. In this disorder, intrapulmonary vascular dilatations associated with hepatic disease lead to an arterial oxygenation defect.
Pulmonary-hepatic vascular disorders are usually associated with intrinsic liver disease but have also been reported in patients with portosystemic shunts. Congenital anomalies of the splanchnic vasculature are known as Abernethy malformations and are extremely uncommon in humans. In a fetus, blood returning from the placenta by the umbilical vein drains into the left portal vein. From there, approximately half of fetal blood bypasses the liver through the ductus venosus into the inferior vena cava (either directly or after merging with the left hepatic vein). After birth, umbilical vein blood clots and, after a few days, the umbilical vein is completely occluded. With the cessation of umbilical blood flow, portal venous pressure drops, and in the course of 2 or 3 weeks the ductus venosus closes.
Different varieties of persistent portosystemic shunts have been described. The first report of such a malformation was by John Abernethy in 1793; therefore use of the eponym Abernethy malformation has been suggested. Two types of Abernethy malformations are recognized. In the type 1 malformation, a complete absence of the portal vein results in the direct flow of splanchnic blood into the vena cava, completely bypassing the liver. In the type 2 malformation, the portal vein is intact, but, because of a persistent ductus venosus, a variable part of portal blood drains into the vena cava. In this type of malformation, intrahepatic portal veins are hypoplastic. Cause and effect are not clear; hypoplasia of portal veins could result in the persistence of the ductus venosus or, vice versa, a patent ductus venosus could prevent the normal development of the intrahepatic portal circulation. The type 1 malformation is more common in girls, is frequently accompanied by other vascular anomalies, and is not amenable to surgical repair. The type 2 malformation is more frequent in boys, has been described in families, and successful surgical and endovascular procedures to correct this abnormality have been reported. In type 2 malformations, acquired obstruction of hepatic flow (eg, after trauma or with liver cirrhosis) can result in recanalization of a previously closed ductus venosus. Improved imaging techniques have led to increased recognition of these abnormalities.
The clinical presentation of patients with a patent ductus venosus varies from asymptomatic to frank liver failure and hepatic encephalopathy. Pulmonary-hepatic vascular complications have only been reported sporadically, and there is no consensus on how they should be treated. In the few case reports available in the literature, different approaches have been used depending on local expertise and patient characteristics (ie, age, hemodynamic features of the shunt, and liver architecture). Three cases of Abernethy malformations associated with the hepatopulmonary syndrome have been described. Another three patients (two children and one adult) have been described presenting with portopulmonary hypertension. In two of these latter cases, intrahepatic portal structures were intact, and the patent ductus venosus was closed with an endovascular procedure.
In the present patient, pulmonary hypertension was suspected from the chest radiograph (Fig 1), which showed clear lung fields, an enlarged heart (in particular, the right ventricle), and large pulmonary arteries. Right heart catheterization (Table 1) and confirmed pulmonary hypertension classified the condition as pulmonary arterial hypertension, and also revealed a hyperdynamic circulatory state and a substantial difference in oxygen saturation between the inferior vena cava and the superior vena cava. These findings, in combination with mild liver test result abnormalities, led us to suspect a pulmonary-hepatic vascular disorder. MRI angiography (Fig 2) showed a direct connection between the left portal vein (arrow) and the inferior vena cava (arrowhead) [ie, a persistent ductus venosus]. The right portal vein was small, and several collateral vessels were seen surrounding the spleen (Fig 2, top left, asterisk). A liver biopsy was subsequently performed to assess possible parenchymal damage and to ascertain whether a vascular reconstructive procedure should be considered. Liver biopsy (Fig 3 ), however, showed abnormal portal fields with abundant hepatic arterial structures (CD31 stains endothelial cells) and a complete absence of portal venous structures. There were no signs of fibrosis or cirrhosis. Therefore, closure of the ductus in order to redirect portal flow toward the liver was not an option. Our patient was in New York Heart Association functional class I (with a 6-min walking distance of 660 m), which is generally not considered to be an indication for pulmonary vascular treatment. However, since pulmonary arterial hypertension in patients with liver disease can be rapidly progressive, we decided to treat the patient with the endothelin-1 receptor blocker bosentan under close surveillance of liver function. After 6 months of treatment, the hemodynamic profile (Table 1) and 6-min walking distance were identical. No clinical signs of liver failure have developed, and the patient remains in New York Heart Association functional class I. The development of hemoptysis and dyspnea after traveling to high altitude was probably related to a further increase in pulmonary artery pressure due to hypoxic pulmonary vasoconstriction.
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Footnotes
The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
Received for publication January 10, 2007. Accepted for publication February 8, 2007.
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