Case Report

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A 15-year-old male adolescent with cyanosis and a history of Langerhans-cell histiocytosis that was previously proved by bone biopsy was referred to our institution for variceal bleeding and ascites. He had presented at the age of 2 years with diabetes insipidus and primary hypothyroidism. At that time he was treated with vinblastine, radiation, thyroxine, and desmopressin acetate.

At the age of 10 years, he had splenectomy for pancytopenia. A liver biopsy specimen showed cirrhosis Figure 1 A. At the age of 14 years, insidious dyspnea developed, and he had variceal bleeding that required endoscopic sclerotherapy. The patient did not smoke or have a history of smoking. A transbronchial lung biopsy specimen showed mild interstitial fibrosis and a nonspecific mononuclear infiltrate with absent Birbeck granules. Over the next year, the dyspnea worsened. Therapy with thyroxine and desmopressin acetate was continued, and he began to receive portable oxygen.

View larger version (83K): [in this window] [in a new window]   Figure 1. A. Liver biopsy specimen showing heavy portal fibrosis and a regenerating nodule (original magnification, x 50). B. Chest radiograph showing a mild increase in the lower lung field markings, particularly in the right lower lung field. C. Pulmonary angiogram showing the vasculature well visualized without evidence of pulmonary hypertension. The angiogram suggests a "spongy" texture to the vasculature.

A physical examination showed peripheral cyanosis, clubbing, and spider angiomas. He had preserved lung excursion, absent rales, mild ascites, and an enlarged liver. Serum biochemical determinations showed a cholestatic pattern: His alkaline phosphatase level was 14 µkatal/L (normal, 0.5 to 2.0 µkatal/L), his alanine aminotransferase level was 1.78 µkatal/L (normal, 0.0 to 0.58 µkatal/L), his aspartate aminotransferase level was 1.80 µkat/L (normal, 0.0 to 0.58 µkatal/L), his -glutamyltransferase level was 6.68 µkatal/L (normal, 0.0 to 0.5 µkatal/L), his bilirubin level was 27 µmol/L (normal, 2 to 18 µmol/L), and his hemoglobin concentration was 110 g/L. The prothrombin time, electrolyte levels and renal indices were normal. Viral hepatitis test results were negative. He had normal copper studies and iron deficiency. Antinuclear and antimitochondrial antibody tests were negative. An endoscopic retrograde cholangiogram showed intrahepatic biliary sclerosis.

A chest radiograph showed a mild interstitial pattern that was more apparent in the lower lung fields (Figure 1 B.) Examination of arterial blood gas while the patient breathed room air in the sitting position showed a pH of 7.44, a PCO₂ of 33 mm Hg, and a PO₂ of 55 mm Hg. The estimated shunt fraction was 9% while the patient was supine and 16% while the patient was sitting. The diffusion capacity was 15 mL/min per mm Hg (57% predicted) while the patient was supine and 10 mL/min per mm Hg (38% predicted) while the patient was sitting. The forced expiratory volume in 1 second (FEV₁), forced vital capacity (FVC), and FEV₁/FVC ratio were normal. Total lung capacity was 6.8 L (76% predicted).

A contrast echocardiogram showed evidence of intrapulmonary vasodilatation with passage of bubbles from the right ventricle to the left atrium after four cardiac cycles. Catheterization of the right side of the heart showed no intracardiac defects and a pulmonary artery pressure of 24/3 mm Hg. A pulmonary angiogram showed no dominant arteriovenous malformations Figure 1 C, and a computed tomographic scan showed no fibrocystic changes.

Based on a diagnosis of cirrhosis and the hepatopulmonary syndrome, the patient had orthotopic liver transplantation. His surgery was uneventful. He is now being treated with cyclosporine, azathioprine, and prednisone, and he continues to receive thyroxine and desmopressin acetate. Six months after surgery, he has resumed an active lifestyle and no longer uses supplemental oxygen. Examination of arterial blood gases while the patient is sitting and breathing room air show a pH of 7.4, a PCO₂ of 38 mm Hg, and a PO₂ of 71 mm Hg. He has a normal FVC and FEV₁ and total lung capacity. His resting oxygen saturation is 96% when he is both supine and sitting and breathing room air. Although a contrast echocardiogram showed persistent passage of bubbles (showing that intrapulmonary vasodilatation has not completely resolved), he is able to maintain saturation greater than 90% with fast walking. His diffusion capacity is now 16 mL/min per mm Hg (61% predicted) while supine and 14 mL/min per mm Hg (53% predicted) while sitting, which indicates partial recovery of pulmonary vascular tone.

Discussion

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This patient had cirrhosis and severe lung dysfunction in Langerhans-cell histiocytosis, a disease commonly associated with intrinsic lung disease and pulmonary failure. In this case, the presence of portal hypertension, postural changes in lung function, normal pulmonary artery pressure, and intrapulmonary vasodilatation (which was shown by contrast echocardiography) confirmed the diagnosis of the hepatopulmonary syndrome, a condition that is potentially reversible with liver transplantation [9-11]. Our patient did have mild residual lung changes attributable to pulmonary Langerhans-cell histiocytosis. However, his evaluation and the course of his condition have shown that most of his lung dysfunction was caused by the hepatopulmonary syndrome.

Clinical lung disease is seen in 40% of patients with multisystem Langerhans-cell histiocytosis [12]. Presenting findings vary widely [1]. As in the hepatopulmonary syndrome, physical signs of lung disease may be lacking, and chest radiographs may show only bilateral reticular opacities [13]. Unlike in the hepatopulmonary syndrome, "honeycombing" caused by fibrocystic changes may be seen in the upper lung fields of long-standing cases [13]. Pulmonary function test results often show a restrictive pattern, but approximately one third of patients have normal lung volumes [14]. Early histologic findings are characterized by interstitial granulomas with Langerhans-cells. However, late findings may show only nonspecific fibrosis [15].

In one study, 36 of 63 (57%) patients with stage III Langerhans-cell histiocytosis (symptomatic multiorgan disease) had evidence of pulmonary involvement [4]. Twenty-four of these 36 patients had evidence of liver disease [4]. The prevalence of lung dysfunction among those with cirrhosis was not reported. The hepatopulmonary syndrome has an estimated prevalence of 5% of cirrhotic patients [16]. In some, the symptoms of the hepatopulmonary syndrome outweigh those of cirrhosis and dominate the clinical picture [10]. Patients characteristically have cyanosis, clubbing, and stigmata of cirrhosis. A prominent reticular pattern may be seen on chest radiographs. Other findings include normal or mildly abnormal lung mechanics, low diffusion capacity, and low pulmonary artery pressures [7]. Contrast echocardiography shows the passage of bubbles from the right circulation to the left after four to five cardiac cycles [17]. Loss of vascular tone in the lungs is evident by the postural changes seen in pulmonary testing (orthodeoxia) [6, 7].

Pulmonary failure in Langerhans-cell histiocytosis is usually attributed to advanced lung involvement. Our patient actually had the hepatopulmonary syndrome. The potential reversibility of the latter makes necessary the careful distinction between the syndrome and irreversible pulmonary Langerhans-cell histiocytosis in similar patients.

The Hepatopulmonary Syndrome Study Group includes Daniel L. Metzger, MD; William C. Stevenson, MD; Michael Ishitani, MD; Rolland C. Dickson, MD (University of Virginia Health Sciences Center, Charlottesville, Virginia); and Kevin R. Dye, MD (Community Hospital of Roanoke, Roanoke, Virginia).