Chylothorax, Pseudochylothorax, LAM, and Yellow Nail Syndrome. Chylothorax. Further Reading. Abstract

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1 388 PLEURAL EFFUSIONS / Chylothorax, Pseudochylothorax, LAM, and Yellow Nail Syndrome or progressive over a 6-month period should decortication be considered. See also: Fibrinolysis: Plasminogen Activator and Plasmin. Fibroblast Growth Factors. Occupational Diseases: Asbestos-Related Lung Disease. Pleural Effusions: Hemothorax. Pulmonary Fibrosis. Transforming Growth Factor Beta (TGF-b) Family of Molecules. Tumor Necrosis Factor Alpha (TNF-a). Vascular Endothelial Growth Factor. Further Reading Antony V (2003) Pleural inflammation. In: Light RW and Lee YCG (eds.) Textbook of Pleural Diseases, pp New York: Arnold. Copley SJ, Wells AV, Rabus MB, et al. (2001) Functional consequences of pleural disease evaluated with chest radiography and CT. Radiology 220: Doelken P and Sahn SA (2001) Trapped lung. Seminars in Respiratory and Critical Care Medicine 22: Idell S (1995) Coagulation, fibrinolysis and fibrin deposition in lung injury and repair. In: Phan SH and Thrall RS (eds.) Pulmonary Fibrosis, vol. 80, pp New York: Dekker. Lee YCG and Lane KB (2003) Cytokines in pleural diseases. In: Light RW and Lee YCG (eds.) Textbook of Pleural Diseases, pp New York: Arnold. Nishumura SL and Broaddus C (1998) Asbestos-induced pleural disease. Clinical Chest Medicine 19: Sahn SA (1988) State of the art. The pleura. American Review of Respiratory Disease 138: Schwartz DA and Peterson MW (1998) Asbestosis and asbestosinduced pleural fibrosis. In: Schwartz MI and King TE (eds.) Interstitial Lung Disease, pp Hamilton, ON: Decker. Chylothorax, Pseudochylothorax, LAM, and Yellow Nail Syndrome I Kalomenidis, Athens University, Athens, Greece Y C G Lee, University College London, London, UK & 2006 Elsevier Ltd. All rights reserved. Abstract Chylothorax and pseudochylothorax are pleural effusions with high lipid contents. Chylothorax is a triglyceride-rich effusion caused by the disruption of the thoracic duct, most commonly by trauma or mediastinal tumors. Pseudochylothorax is a chronic, cholesterol-rich pleural effusion, usually secondary to tuberculous pleuritis. Pleural fluid lipid analysis is needed to establish the diagnoses. The initial management strategies for chylothorax include nutrition support, reduction of chyle flow, and drainage of the pleural space for symptomatic relief. If the chylothorax persists, thoracic duct embolization, surgical repair, or pleurodesis may be considered, depending on the etiology of the chylothorax. Lymphangioleiomyomatosis is a progressive cystic lung disease often complicated by recurrent chylous effusions and/or pneumothoraces. Yellow nail syndrome is a rare disorder of unknown etiology characterized by yellow nails, lymphoedema, and recurrent lymphocytic pleural effusions, which may require pleurodesis. Chylothorax Chylothorax, the accumulation of chyle in the pleural cavity, usually develops secondary to disruption of the thoracic duct along its intrathoracic route. The thoracic duct drains chyle (lymph-rich in chylomicrons from dietary fat) from the abdomen through the diaphragm and into the posterior mediastinum before terminating in the region of the left jugular and subclavian veins. The thoracic duct drains approximately 2 l lymphs a day, but the flow rate varies with diet and increases significantly after ingestion of fat. Chyle is rich in T lymphocytes and, typically, has an electrolyte profile similar to serum and a protein concentration higher than 3 g dl 1. Loss of chyle can lead to immunodeficiency, dehydration, and nutritional depletion. Chyle in the pleural space seldom elicits pleural inflammation or fibrosis, and secondary infection of chylous effusion is rare. Pathogenesis and Etiology Chylothorax most frequently results from trauma (including surgery) or tumor infiltration of the thoracic duct (Table 1). Occasionally, chylothorax can accumulate when chylous ascites migrate through the diaphragm into the pleural space. Common causes of chylous ascites include traumatic or malignant disruption of intra-abdominal lymphatic vessels and cirrhosis. Malignancy and trauma (including surgery) are by far the leading causes of chylothorax (Table 1). Lymphoma accounts for 75% of the chylothorax cases due to malignancy. As such, lymphoma needs to be excluded in all patients with chylothoraces in whom no other causes can be identified. Cardiothoracic surgery, especially involving the posterior mediastinum, can lead to postoperative chylothorax (up to 4% in an eosophagectomy series). Nonsurgical thoracic trauma (both penetrating and nonpenetrating) is a recognized cause of chylothorax. Lymphatic abnormalities (e.g., lymphangioleiomyomatosis and benign mediastinal disorders; Table 1) are less common etiologies. A chylothorax is termed idiopathic when no cause is found. Chylothorax can affect people of all ages. Fetal chylothorax, although uncommon, is a recognized cause of developmental abnormalities and can be fatal. Chylothorax is also the most common type of

2 PLEURAL EFFUSIONS / Chylothorax, Pseudochylothorax, LAM, and Yellow Nail Syndrome 389 Table 1 Etiologic classification of chylothorax Malignacy Lymphoma, metastatic carcinoma, Kaposi s sarcoma Trauma Iatrogenic Eosophagectomy, esophagoscopy, cardiac surgery, lung resection (lobectomy or pneumonectomy), heart and lung transplantation, aortic surgery, stellate ganglion blockade, thoracic sympathectomy, high traslumbar aortography, urological laparoscopy, spinal surgery, repair of congenital diaphragmatic hernia, central venous catheter placement Nonsurgical trauma Penetrating or closed trauma involving the thorax or the neck, spinal fracture Minor trauma Weight lifting, straining, coughing, vomiting, childbirth, yawning Miscellaneous Lymphangioleiomyomatosis, tuberous sclerosis, intestinal lymphangiectasis or reticular hyperplasia, yellow nail syndrome, superior vena caval or subclavian vein thrombosis/obstruction, constrictive pericarditis, filariasis, sarcoidosis, tuberculosis, benign tumors, retrosternal goiter, mediastinal fibrosis, lymphangitis of the thoracic duct, amyloidosis, Gorham s syndrome Idiopathic neonatal pleural effusion. It may represent a fetal chylothorax that persisted or can result from thoracic duct rupture during delivery, developmental abnormalities of the thoracic duct, or increased venous pressure from congenital heart diseases. Clinical Manifestations and Diagnosis The main symptom of chylothorax is dyspnea on exertion. Pleuritic chest pain and fever, commonly associated with other exudative pleural effusions, are rare because most disease processes causing chylothoraces involve the mediastinum and/or the lymphatics but not the pleura. Neonatal chylothorax usually presents with respiratory distress, most commonly (75%) within the first week of life. Chylothorax may be unilateral or bilateral (Figure 1). The thoracic duct ascends along the right side of the vertebrae and crosses over to the left between the level of the T4 and T6 vertebrae. Although this route is the typical one, anatomic variations are common among individuals. Rupture of the duct when it ascends to the right of the vertebral column tends to produce right-sided chylothoraces, and interruption of the duct after it crosses over the midline tends to result in left-sided chylothoraces. Pleural fluid from chylothoraces has a characteristic milky or turbid appearance due to its high lipid content. Empyema can also appear turbid from Figure 1 (a) A posteroanterior radiograph of a patient who presented with superior vena cava syndrome and bilateral pleural effusions. The patient has had a pacemaker for 16 years. Twelve years ago, a new pacemaker was inserted from the left side. The wire of the old pacemaker is seen on the patient s right side (arrow). A diagnostic thoracentesis revealed a milky pleural fluid with triglyceride 4500 mg dl 1, a pleural fluid:serum triglyceride ratio 41, and a pleural fluid:serum cholesterol ratio o1 at both hemothoraces. (b) Venography revealed thrombotic obstruction of the superior vena cava extending to the proximal part of the subclavian veins (arrows). Diagnosis: bilateral chylothorax due to obstruction of the superior vena cava. suspended cellular debris and bacteria. However, pleural fluid from empyemas will become clear upon centrifugation. If cloudiness of the pleural fluid persists after centrifugation, it indicates a high lipid content, either due to chylomicrons (as in chylothorax) or cholesterol and lecithin globulin complexes (as in pseudochylothorax). It must be remembered that pleural fluid in chylothorax may not always look

3 390 PLEURAL EFFUSIONS / Chylothorax, Pseudochylothorax, LAM, and Yellow Nail Syndrome milky, especially if the patient is fasting, which can significantly reduce the lipid content in the chyle. Likewise, the effusion remains clear in neonatal chylothorax until milk feeding begins. In patients with cirrhosis, the pleura fluid may be a transudate as a result of dilution by transudative cirrhotic ascitic fluid. A high index of suspicion is therefore required for the diagnosis of chylothorax. The clinical presentation is helpful to differentiate chylothorax from pseudochylothorax. The former is usually a relatively acute condition with a normal pleural surface; the latter is a chronic effusion (often of years) commonly associated with a markedly thickened, or even calcified, pleura. The demonstration of chylomicrons in lipoprotein analysis of the pleural fluid provides a definitive diagnosis of chylothorax. Patients with chylothoraces usually have a fluid triglyceride level 4110 mg dl 1 (1.24 mmol l 1 ), a fluid:serum triglyceride ratio 41, and a fluid:serum cholesterol ratio o1. A triglyceride content o50 mg dl 1 usually excludes the diagnosis. However, it should be noted that the fluid triglyceride levels in chylous effusions may be low after fasting, producing false or negative results. An intermediate triglyceride content (between 50 and 110 mg dl 1 ) may require lipoprotein analysis of pleural fluid for chylomicrons. Lipoprotein analysis may also aid the differentiation between a chylothorax and a pseudochylothorax, if the pleural fluid cholesterol and triglyceride levels are both elevated. Every patient with a nontraumatic chylothorax should undergo computed tomography (CT) scanning of the thorax and abdomen to search for lymphadenopathy or pulmonary parenchymal abnormalities. Bipedal lymphangiography or lymphoscintigraphy (e.g., with Tc-99 human serum albumin) can be performed preoperatively to locate the site of chyle leak if surgical repair is to be undertaken. Pleural biopsy or thoracoscopy is not indicated since the pleura is usually normal in patients with a chylothorax. Neonates with chylothoraces often (50%) have symptoms within the first 24 hours and the chylothoraces are either right-sided or bilateral. Ultrasonography is essential in the diagnosis of fetal chylothorax. Treatment The aims of management of patients with chylothorax are (Table 2): 1. To maintain nutrition and reduce the chyle flow: prolonged loss of chyle will rapidly render the patient malnourished and immunocompromised. Parenteral hyperalimentation or a low-fat diet with Table 2 Management of chylothorax Measures to maintain nutrition and reduce the flow of chyle through the thoracic duct Total parental nutrition or diet with medium-chain triglyceride Octreotide Measures to relief dyspnea by inhibiting the reaccumulation of chyle in the pleural space Thoracentesis or tube thoracostomy Pleuroperitoneal shunting Pleurodesis Treatment of the underlying defect Thoracic duct embolization Ligation of the thoracic duct (video-assisted thoracoscopic surgery or thoracotomy) Radiotherapy (in the case of mediastinal lymphoma) Modified from Light RW and Lee YCG (2005) Pneumothorax, chylothorax, hemothorax and fibrothorax. In: Murray J, Nadel J, Mason R and Broaddus VC (eds.) Textbook of Respiratory Diseases, 4th edn., pp Philadelphia: Saunders. most fats in the form of medium-chain triglycerides (which are absorbed directly into the blood) are recommended because they provide nutritional support without stimulating chyle flow. Input from an experienced dietitian is encouraged. Reducing chyle flow not only decreases nutritional loss but also aids in the closure of the thoracic duct leak. Octreotide, a somatostatin analog, has been reported to reduce chyle leak and hasten closure of thoracic duct, possibly by reducing intestinal fat absorption and increasing fecal fat excretion. 2. To remove chylous pleural fluid to relieve dyspnea: thoracentesis or tube thoracostomy can provide symptomatic relief. If the leak persists, pleuroperitoneal shunts can be considered because they allow recycling of the lymph and thus minimize loss of nutrition and lymphocytes. Pleuroperitoneal shunts are contraindicated in the presence of ascites. In patients with ongoing chyle leak, pleurodesis can be considered. 3. Treatment of the underlying thoracic duct defect: in patients with traumatic chylothorax, the defect frequently closes spontaneously with supportive care. If the chyle leak persists, especially those draining in high volumes despite total parental nutrition, a definitive repair option should be considered: Percutaneous thoracic duct embolization: if available, lymphatic embolization should be attempted before more invasive procedures (e.g., surgery) are performed. With this technique, the duct is cannulated transabdominally under fluoroscopic guidance and embolized with devices such as microcoils. If feeding lymphatic vessels are too small, occlusion of the vessels by needle disruption can reduce the chyle flow. A response rate of 74%

4 PLEURAL EFFUSIONS / Chylothorax, Pseudochylothorax, LAM, and Yellow Nail Syndrome 391 and good safety profile have been reported in case series. Surgical repair: video-assisted thoracoscopic surgery or thoracotomy can help locate the site of leakage and the thoracic duct can be ligated. A pleurodesis may also be performed during the same operation. Treating the underlying cause of the chylothorax: in patients with a chylothorax from malignant disruption of the thoracic duct, radiotherapy has been shown to be effective in approximately two-thirds of patients with lymphoma and half of those with metastatic carcinoma. Should radiotherapy fail, other treatment options listed previously should be considered. For chylothorax secondary to central venous thrombosis, fibrinolytic therapy to unblock the venous drainage can improve the chylothorax. Likewise, transjugular intrahepatic portosystemic shunting has been successfully used to treat chylothorax and chyloascites from cirrhosis. Special consideration for fetal or neonatal chylothorax: congenital chylothorax in utero should be drained under ultrasound guidance and maternal dietary fat restriction initiated. If the chylothorax reaccumulates, pleuroamniotic shunting or pleurodesis have been shown to be useful. If the congenital chylothorax is diagnosed after birth, repeated thoracentesis should be performed to prevent respiratory failure. Octreotide may be beneficial. If these measures fail, a pleuroperitoneal shunt or thoracic duct ligation should be considered. Pseudochylothorax Pseudochylothorax or chyloform pleural effusion is rare and is characterized by a high content of cholesterol or lecithin globulin complexes in the pleural fluid. Pathogenesis and Etiology The leading causes of a pseudochylothorax are tuberculous pleuritis (54%) and rheumatoid pleuritis (9%). Other, rare, etiologies include paragonimiasis, trauma, and surgery. Many patients with tuberculosis (TB)-related pseudochylothoraces have been treated with artificial pneumothorax for pulmonary TB and have chronic pleural effusions secondary to the atelectatic lung. Pleural fluid from TB-related pseudochylothoraces is usually culture negative. The exact pathogenesis of pseudochylothorax is poorly understood. The typical patient has a longstanding exudative effusion and a thickened pleura. Cholesterol may accumulate in the pleural cavity from plasma extravasation during the initial inflammatory phase of the underlying pleural disease. Alternatively, it can arise from degeneration of erythrocytes and leukocytes within the pleural space. The grossly thickened pleura may contribute to the retention of cholesterol by blocking its exit from the pleural parietal lymphatics. Clinical Manifestations and Diagnosis The pleural effusion is usually, although not inevitably, chronic (mean duration, 5 years). Most patients are asymptomatic. Exertional dyspnea due to restrictive pulmonary function defect or symptoms associated with the underlying disease may also be present. The pleural fluid is milky or turbid and cannot be differentiated from that of chylothorax or empyema visually. In pseudochylothorax, the pleural fluid remains turbid after centrifugation, and the pleural fluid cholesterol level is usually 4250 mg dl 1 (6.45 mmol l 1 ) and the fluid:serum triglyceride ratio 41. Microscopic examination of the fluid may reveal cholesterol crystals with a rhomboid appearance (Figure 2); if present, it is considered diagnostic of pseudochylothorax. A CT scan of the thorax commonly demonstrates thickened or calcified pleura and often a layering of fat in nondependent sites of the hemithorax. Treatment Since the majority of pseudochylothoraces are due to TB, it is reasonable to initiate antituberculous chemotherapy in patients with a positive Mantoux test and a history compatible with previous tuberculous infection who have not received appropriate therapy. A therapeutic thoracentesis may help alleviate dyspnea but can be difficult because the pleura is exceedingly thick and the intrapleural pressure strongly negative. As such, the effusions often reaccumulate. Decortication should only be considered in severely symptomatic patients in whom the underlying lung is believed to be functional. Lymphangioleiomyomatosis Lymphangioleiomyomatosis (LAM) affects predominantly females of reproductive age and is characterized by progressive cystic lung disease complicated by recurrent pneumothoraces and chylous effusions. Details of its pathophysiology can be found elsewhere in this encyclopedia (see Interstitial Lung Disease: Lymphangioleiomyomatosis). The majority of patients with LAM (60 81%) will develop a pneumothorax during the course of their

5 392 PLEURAL EFFUSIONS / Chylothorax, Pseudochylothorax, LAM, and Yellow Nail Syndrome Figure 2 Pleural fluid from a patient with pseudochylothorax. (a) The milky appearance of the pleural fluid persisted after the centrifugation. (b) The presence of cholesterol crystals in microscopic examination of the pleural fluid established the diagnosis. disease. Chylothorax is also common and affects up to 30% of patients. Chylothorax is thought to be the result of lymphatic obstruction (from perilymphatic smooth muscle proliferation) and of infiltration of the mediastinal lymph nodes by immature smooth muscle cells. Occasionally, chylothorax accumulates secondary to transdiaphragmatic flow of chylous ascites. LAM should be considered in every woman of reproductive age who presents with a pneumothorax or chylothorax. A CT scan is usually diagnostic for LAM (Figure 3). For the chylothoraces, simple thoracentesis for symptomatic relief is adequate in some patients, but most eventually require pleurodesis or thoracic duct ligation. Because up to 19% of patients with LAM may proceed to lung transplantation, the management of their chylothoraces (and pneumothoraces) should be made in conjunction with the transplant team. Increased bleeding during lung transplant, and a higher resultant mortality, has been described in patients with LAM. This is presumed to be from pleural adhesions, which are often highly vascularized, from associated pleural diseases. Yellow Nail Syndrome Yellow nail syndrome (YNS) is a rare entity characterized by yellow nails, lymphedema, and recurrent pleural effusions. The complete triad is seen only in one-third of patients, and each manifestation of the syndrome may appear at a different time. Therefore, the presence of two of the three symptoms is considered sufficient to establish the diagnosis. YNS has been associated with malignancy and autoimmune diseases. A case of spontaneous resolution of yellow nails after cancer treatment has been reported. The clinical onset varies from birth to late adult life. Nail changes are often the earliest and most common symptom: The nails are slow growing, excessively curved, with a yellowish discoloration. Pleural effusions are present in up to 36% of patients, are often bilateral, and tend to recur. The pleural fluid is usually lymphocytic, exudative, and has a relatively low lactate dehydrogenase (LDH) level. Chylothorax and chylous ascites have been reported. Bronchiectasis, rhinosinusitis, and, rarely, pericardial effusion may also occur with YNS. The pathogenesis of YNS is unknown. It is believed that the main defects involve anatomical (congenital hypoplasia) or functional abnormalities of the lymphatic vessels. Pleural effusions are thought to result from impaired drainage of the pleural space by hypoplastic lymphatic vessels. It is assumed that the pathogenesis involves a triggering event, such as an inflammatory pleuritis, that increases pleural fluid production, which overwhelms the draining capacity of marginally effective lymphatics. The optimal treatment for YNS is unknown. Symptomatic effusions should be drained. Since

6 PLEURAL EFFUSIONS / Hemothorax 393 Hillerdal G (1997) Chylothorax and pseudochylothorax. European Respiratory Journal 10: Hillerdal G (2003) Effusions from lymphatic disruptions. In: Light RW and Lee YCG (eds.) Textbook of Pleural Diseases, pp London: Arnold. Light RW (ed.) (2001) Chylothorax and pseudochylothorax. In: Pleural Diseases, 4th edn., pp Philadelphia: Lippincott Williams & Wilkins. Light RW and Lee YCG (2005) Pneumothorax, chylothorax, hemothorax and fibrothorax. In: Murray J, Nadel J, Mason R, and Broaddus VC (eds.) Textbook of Respiratory Diseases, 4th edn., pp Philadelphia: Saunders. Perkett EA (2003) Pediatric pleural diseases. In: Light RW and Lee YCG (eds.) Textbook of Pleural Diseases, pp London: Arnold. Romero S (2000) Nontraumatic chylothorax. Current Opinion in Pulmonary Medicine 6: Ryu JH, Doerr CH, Fisher SD, et al. (2003) Chylothorax in lymphangioleiomyomatosis. Chest 123: Strausser JL and Flye MW (1981) Management of nontraumatic chylothorax. Annals of Thoracic Surgery 31: Sullivan EJ (1998) Lymphangioleiomyomatosis: a review. Chest 114: Hemothorax J John and S Idell, University of Texas Health Center, Tyler, TX, USA & 2006 Elsevier Ltd. All rights reserved. Abstract Figure 3 (a) A posteroanterior radiograph of a woman with LAM demonstrating hyperinflation, diffuse reticular shadows, and small bilateral pleural effusions. (b) CT scan of the right hemithorax with the characteristic cystic lesions of the lung parenchyma and a pleural effusion. Diagnostic thoracentesis revealed a chylothorax. Kindly provided by Dr Gougoulianis, University of Thessaly, Larisa, Greece. pleural effusions typically reaccumulate, the majority of patients will require a pleurodesis. See also: Interstitial Lung Disease: Lymphangioleiomyomatosis. Pleural Effusions: Overview; Pleural Fluid Analysis, Thoracentesis, Biopsy and Chest Tube. Further Reading Al-Zubairy SA and Al-Jazairi AS (2003) Octreotide as a therapeutic option for management of chylothorax. Annals of Pharmacotherapy 37: Browse NL, Allen DR, and Wilson NM (1997) Management of chylothorax. British Journal of Surgery 84: Cope C (2004) Management of chylothorax via percutaneous embolization. Current Opinion in Pulmonary Medicine 10: Hemothorax is a collection of bloody fluid in the pleural space with a hematocrit at least 50% of the peripheral blood. Hemothorax is most commonly caused by trauma and rarely due to malignancy or pulmonary embolism. Hemothoraces are commonly encountered in clinical practice and may need to be drained depending on their size and effect on gas exchange. Diagnosis hinges on the clinical setting and confirmation by pleural fluid analysis. Apposition of the parietal and visceral pleura by drainage may arrest intrapleural bleeding via tamponade. Thoracoscopy and thoracotomy may be required if drainage alone is unsuccessful. The pathogenesis of large hemothoraces can involve progressive organization and fibrosis leading to lung restriction, arguing for the removal of this fibrotic encasement. Intrapleural thrombolytic therapy is an alternative approach to address organizing hemothoraces. The pleural space is a potential compartment that separates the lung from the ribcage, the diaphragm, and mediastinum. It is lined by the parietal and visceral pleura and normally contains a thin layer of fluid measuring approximately 5 15 ml. A hemothorax is typically a bloody exudative effusion. Laennec first described spontaneous hemothorax in A pleural fluid hematocrit representing greater than 50% of the peripheral hematocrit defines the presence of a hemothorax. Blood-tinged pleural fluids containing lesser amounts are termed hemorrhagic effusions.