Hepatopulmonary Syndrome in a Child with Cystic Fibrosis

Hepatobiliary manifestations in cystic fibrosis occur later than respiratory and pancreatic manifestations of the disease. They will often occur when there is a clear respiratory attack (1,2). We report a case history in which pulmonary lesions were preceded by cirrhosis with portal hypertension, the latter resulting, via intrapulmonary vascular shunting, in a clinical picture of hypoxemia without respiratory insufficiency, altogether unusual in this area. CASE REPORT Pierre Alain is the second child in a family of three children. His elder brother and he suffered from cystic fibrosis. They were homozygous for the mutation Delta F 508. The child did not experience any problems during the neonatal period. No episode of hepatitis was noted during early childhood. The diagnosis of Pierre Alain's disease was made at the age of 3 years. The disease manifested itself clinically with chronic diarrhea, hepato-splenomegaly, and two to three infectious bronchial episodes in winter. Biologically, there was evidence of steatorrhea (12 g/day), an increase in serum levels of alanine aminotransferase to 60, aspartate aminotransferase to 55 U/L (<25 normally) and γ-glutamyltranspeptidase to 45 U/L (<20 normally). Prothrombin activity was 87%, and albuminemia, 39 g/L. Serology for cytomegalovirus (CMV) infection was negative. Lung radiography and arterial blood gases were normal. Echography revealed a nodular appearance, liver hyperechogenicity, and an increased lesser omentum-to-aorta ratio, evidencing portal hypertension. At 3.5 years of age, the child had alimentary bleeding resulting from rupture of esophageal varices with loss of erythrocytes, necessitating a transfusion. Hepatic biological examinations revealed no change. Blood gases and thoracic radiography remained normal. A fiberoptic endoscopy showed varices to be spread along the whole length of the esophagus and the esophagogastric junction. Mesenteric caval shunting by means of a jugular graft was achieved at the age of 4 years. Between 4 and 9 years of age, there were no new alimentary manifestations of the disease. Respiratory symptomatology remained limited to two or three infectious bronchial episodes per annum, rapidly resolved through oral antibiotic treatment without any other germ being found, except intermittently a staphylococcus. Blood gases systematically examined twice a year were normal. Growth was normal. At the age of 9, during an examination, hypoxemia was found to be present [Pao2, 9.4 kPa (70 mm Hg)] without involvement of hypercapnia [Paco2 between 4 and 5.4 kPa, inclusive (30 to 40 mm Hg)]. The child showed evidence of cyanosis and digital clubbing. This occurred although clinically there had been no other modifications of respiratory symptomatology. Pulmonary radiography revealed only an intensification of the bronchovascular stroma without evidence of either atelectasis or emphysema. There was no dilatation of the bronchi nor were there images of bubbles when computed tomography scans of the thorax were performed. The bronchi were only slightly inflammatory, and there were signs neither of obstruction nor of suppuration when bronchial fiberoptic endoscopy was performed. The results of pulmonary function tests were the following: vital capacity, 75%; forced expiratory volume in 1 s, 86%; residual volume, 117% of values predicted for weight and height. The cardiovascular clinical examination gave normal results, as did an echocardiogram. There was no pulmonary arterial hypertension. Perfusion lung scan enabled the hypoxemia to be linked to intrapulmonary vascular shunting by showing a very rapid and abnormal flow of technetium-labeled macroaggregated albumin in the general circulation (Fig. 1). This occurrence of hypoxemia worsened rapidly. Between the ages of 9 and 10, Pao2 decreased from 9.4 to 5.4 kPa (70 to 40 mm Hg) in room air and from 54 to 34 kPa (400 to 200 mm Hg) when hyperoxia tests with O2 at 100% were performed. The significance of hypoxemia led to the refutation of the indication for isolated hepatic transplantation, which had been contemplated initially in the face of the very limited alterations in pulmonary radiographic and pulmonary function tests results. At the age of 10.5, the child underwent a triple heart, lung, and liver transplantation. The heart and lung combined transplantation was the surgical technique systematically employed at the time. The child's heart, which was healthy, was grafted to another patient by the domino technique. At the end of the operation, blood gases were normal. A histologic examination of the lungs showed bronchitis lesions, the presence of mucopus, and hyperplasia of the seromucous glands. The alveoli were not affected nor were there vascular anomalies. An examination of the liver revealed biliary cirrhosis lesions. Postoperative development was simple. The child had tubes removed at 16 h. His immunosuppressive treatment combined cyclosporine, azathioprine, and methylprednisolone. Three episodes of mild pulmonary rejection were treated with intravenous pulse doses of methylprednisolone. The child was discharged 59 days after the transplantation. The operation took place a year ago. The child's hepatic function and blood gases are normal. Digital clubbing has disappeared. DISCUSSION Hepatic manifestations are found in 10 to 20% of subjects with cystic fibrosis. They appear later than respiratory manifestations or external pancreatic insufficiency, and the present increase in the life expectancy of affected subjects has led to an increase in their frequency (1). Biliary cirrhosis is here involved. The initial lesion seems to be linked to abnormally thick mucus found in the bile ducts (3). In the adolescent or adult, it is mostly to be found in the form of multinodular cirrhosis. A retention syndrome with increased γ-glutamyl-transpeptidase and alkaline phosphatase is the initial biological anomaly, the most frequently encountered. Results of hepatic echography show the liver to be nodular and hyperechogenous, an increase in size of the lesser omentum revealing portal hypertension. The disease can reveal itself through alimentary bleeding caused by rupture of esophageal varices. Cirrhosis in a patient during cystic fibrosis is a factor contributing to a poor prognosis. It may cause death. Ursodeoxycholic acid is probably capable of slowing its development (4). When cirrhosis has reached the stage of terminal hepatocellular insufficiency, transplantation is the only possible therapeutic solution. Cystic fibrosis is not in itself a formal contraindication for this therapy (5), and isolated liver transplantations in patients without serious respiratory manifestations have been successfully achieved (6,7). Chronic hepatopathy-related hypoxemia has been described (8-11). It can correspond to several mechanisms affecting the pulmonary parenchyma or vascularization. The most frequently mentioned factors are intrapulmonary vascular shunting, ventilation-perfusion mismatch, portopulmonary venous anastomoses, pulmonary hypertension, impaired hypoxic vasoconstriction, reduction in gastransfer capacities and ventilation anomalies linked to liver volume increase, and the presence of ascites (12-17). Among these factors, whatever might be the cause of the liver disease, pulmonary vascular shunting, as described in this case, is the main cause of severe hypoxemia (13,18-22). The mechanism leading to the development of these shunts seems to involve abnormal dilatation of existing precapillary and capillary blood vessels (18,19). They are found where portal hypertension is in evidence. They could be linked to the transmission into the general circulation, through medical or surgical portal systemic anastomoses, of vasoactive peptides metabolized or ordinarily purified by the liver (23,24). Clinically, they result in cyanosis, although pulmonary function tests yield normal results or are only slightly affected. Perfusion lung scan allows diagnosis. Usually, the total quantity of technetium-labeled macroaggregated albumin is embolized in the pulmonary arteries. In the case of a right-to-left shunt, part of it is found elsewhere in the organism, particularly at kidney and skull level (25). Because there was a risk of postoperative worsening in severe hypoxemia, shunt-caused hypoxemia was first considered to be a contraindication for liver transplantation (26). In fact, these shunts can be reversible after recovery from the liver disease. It is now known, on the contrary, that a pulmonary vascular shunting during hepatopathy is an indication for liver transplantation even in the absence of hepatocellular insufficiency (27,28). However, the number of liver transplantations successfully performed in patients with liver disease and very severe hypoxemia due to pulmonary arteriovenous shunting is still limited (27,29). Failure of an isolated liver graft resulting in the death of a patient has been reported under such circumstances, especially when Pao2 level in air is <8.1 kPa (60 mm Hg) (30,31). In the case here described, an isolated liver transplantation could have been indicated and was in fact initially contemplated. The indication was refuted, however, because of the severity of the hypoxemia [preoperative level in air at 5.4 kPa (40 mm Hg)], previous abdominal surgery increasing the operative risk of transplantation (31), and the presence of cystic fibrosis, increasing the risk of postoperative pulmonary infection. Pulmonary vascular shunting can be seen during any cirrhosis with portal hypertension. In cystic fibrosis, they should be sought by means of perfusion lung scan every time liver attack occurs, especially when hypoxia cannot be explained by the bronchopulmonary condition. The discovery of these shunts before the occurrence of a major hypoxemia, and when there is no significant alteration to pulmonary function, can then indicate isolated liver transplantation. Cirrhosis with portal hypertension is most frequent at the age at which pulmonary transplantation is usually indicated for patients. The systematic achievement of perfusion lung scan within the framework of a pretransplantation examination could allow verification that respiration-originating hypoxia is not aggravated by a shunt effect. Evidence of such shunting would be the indication in patients for a lung/liver or liver/heart/lung transplantation.FIG. 1.: Perfusion lung scan. There is abnormal uptake of radiotracer at skull level. The skull/lung uptake is 8% (normal, <1).