Etiology, clinical presentation, and diagnosis of chylothorax

INTRODUCTION — Chylothorax refers to the presence of chyle in the pleural space. When untreated, chylothorax is associated with high morbidity and mortality. The diagnosis, which is often elusive, should be prompt so that therapy can be quickly initiated.

The etiology, clinical presentation, and diagnosis of chylothorax will be reviewed here. The management of chylothorax is discussed elsewhere. (See "Management of chylothorax".)

THORACIC DUCT ANATOMY AND PHYSIOLOGY — The thoracic duct carries chyle (which contains triglycerides in the form of chylomicrons, T lymphocytes, electrolytes, proteins, immunoglobulins, and fat-soluble vitamins) from the intestine to the bloodstream. It commences at the cisterna chyli which is the convergence of the intra-abdominal lymphatics (hepatic, mesenteric, etc) with the lower extremity and retroperitoneal lymphatics, located in the retroperitoneum anterior to the second lumbar vertebra (T12 to L1) and ends at the junction of the left subclavian and jugular veins (figure 1 and figure 2). As the thoracic duct passes through the mediastinum, it also receives nonchylous lymph from tributaries that drain regions of the pulmonary parenchyma and parietal pleura [1]. The sum of these sources accounts for a total lymphatic flow through the thoracic duct of 1500 to 2400 mL/day [2]. This flow increases with dietary intake of fat, particularly long-chain triglycerides.

PATHOGENESIS AND ETIOLOGY — Any disruption or dysfunction of the flow of chyle through the thoracic duct can cause chylothorax. Thus, there are several etiologies of chylothorax that can be broadly categorized as nontraumatic or traumatic (iatrogenic or either blunt or penetrating injury) (table 1). The etiology of chylothorax likely varies by the patient population managed in the institution. Nonetheless, malignancy is typically the leading cause of nontraumatic chylothorax while thoracic surgery is the major cause of traumatic chylothorax. Two large single center studies have retrospectively assessed the etiology of chylothorax (table 1) [3,4]. The largest of these studied 203 patients treated over a 21-year period and found an equal incidence of traumatic (50 percent) and nontraumatic (50 percent) etiologies. Six percent in the nontraumatic group were diagnosed with idiopathic chylothorax after exhaustive evaluation [4]. In contrast, the other older case series found that 72 percent of chylothoraces were nontraumatic [3].

The mechanism of chylothorax varies with the underlying etiology (table 1). Abnormalities of the thoracic duct or lymphatics can occur via the following mechanisms [5-9]:

●Compressive obstruction (eg, malignancy)

●Direct involvement (eg, malignant or infectious lymphadenitis, tear or rupture from surgery or either blunt or penetrating trauma)

●Anomalies (eg, Gorham syndrome, generalized lymphatic anomaly, lymphangiomatosis)

●Dysfunction (eg, reverse flow of chyle toward the lung)

●Stimulation of excess amounts of lymphatic fluid (typically from lymphatic masses or malformations) resulting in rupture or seepage of chyle from lymphatic ducts

●Transfer of chyle across the diaphragm from abdominal or retroperitoneal chyle accumulations (see "Chylous, bloody, and pancreatic ascites", section on 'Chylous ascites' and "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation")

Nontraumatic causes — Nontraumatic chylothorax can be caused by malignant and nonmalignant conditions, the details of which are discussed in this section. (See 'Malignant' below and 'Nonmalignant' below.)

Malignant — Malignancy is the leading cause of nontraumatic chylothorax. Most cases of malignancy-associated chylothorax occur in patients with advanced malignancies. Common malignancies that may be complicated by chylothorax include the following [4,10]:

●Lymphomas (account for approximately 11 to 37 percent of chylothoraces (see "Clinical presentation and initial evaluation of non-Hodgkin lymphoma")

●Lung cancer (see "Clinical manifestations of lung cancer")

●Mediastinal cancer (see "Approach to the adult patient with a mediastinal mass" and "Pathology of mediastinal tumors")

●Chronic lymphocytic leukemia (see "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma")

●Kaposi sarcoma (see "Classic Kaposi sarcoma: Clinical features, staging, diagnosis, and treatment")

●Multiple myeloma (see "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis")

●Metastatic cancer

●Superior vena cava syndrome due to an obstructing mediastinal malignancy

●Lymphangioleiomyomatosis (LAM) (see "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation")

Nonmalignant — Case reports suggest several benign etiologies that include the following [4-6,10-23]:

●Castleman's disease (angiocentric or giant lymph node hyperplasia) (see "HHV-8/KSHV-associated multicentric Castleman disease")

●Benign tumors of the mediastinum (see "Approach to the adult patient with a mediastinal mass")

●Superior vena cava syndrome due to benign neoplasms or aortic aneurysm

●Sarcoidosis (see "Clinical manifestations and diagnosis of sarcoidosis")

●Yellow nail syndrome (see "Overview of nail disorders")

●Histoplasmosis (see "Diagnosis and treatment of pulmonary histoplasmosis")

●Tuberculosis (see "Pulmonary tuberculosis: Clinical manifestations and complications")

●Thoracic irradiation (may be delayed as long as 20 years) (see "Approach to the adult survivor of classic Hodgkin lymphoma", section on 'Pulmonary dysfunction')

●Subclavian vein thrombosis (see "Overview of the causes of venous thrombosis")

●Aortic aneurysm (see "Clinical manifestations and diagnosis of thoracic aortic aneurysm")

●Goiter (see "Clinical presentation and evaluation of goiter in adults")

●Abdominal or retroperitoneal chyle (eg, from lymphangioleiomyomatosis)

●Connective tissue disorders (eg, systemic lupus erythematosus) (see "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Clinical manifestations')

●Liver cirrhosis (see "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis")

●Heart failure (see "Clinical manifestations and diagnosis of advanced heart failure")

●Nephrotic syndrome (see "Overview of heavy proteinuria and the nephrotic syndrome")

●Noonan syndrome (see "Noonan syndrome")

●Down syndrome (see "Down syndrome: Clinical features and diagnosis")

●Turner syndrome (see "Clinical manifestations and diagnosis of Turner syndrome")

●Congenital or idiopathic disorders of the lymphatic system (eg, lymphangiectasia, generalized lymphatic anomaly, lymphangiomatosis, Gorham syndrome, Kaposiform lymphangiomatosis) or lymphatic conduction disorders (eg, lymphatic valve dysfunction, heart failure, cirrhosis, plastic bronchitis, pulmonary lymphatic perfusion syndrome) (see "Nonimmune hydrops fetalis", section on 'Thoracic and lymphatic abnormalities' and "Protein-losing gastroenteropathy", section on 'Diseases with lymphatic obstruction/altered lymphatic flow' and "Tufted angioma, kaposiform hemangioendothelioma (KHE), and Kasabach-Merritt phenomenon (KMP)")

●Waldenström macroglobulinemia (see "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia")

●Amyloidosis (see "Overview of amyloidosis")

●Filariasis (see "Lymphatic filariasis: Epidemiology, clinical manifestations, and diagnosis")

●Thoracic duct cysts

●Constrictive pericarditis (see "Chylopericardium and cholesterol pericarditis" and "Constrictive pericarditis: Diagnostic evaluation")

●Behçet syndrome (see "Clinical manifestations and diagnosis of Behçet syndrome")

●POEMS syndrome (see "POEMS syndrome")

●IgG4-related pleural disease (see "Clinical manifestations and diagnosis of IgG4-related disease")

●Regional ileitis (see "Clinical manifestations, diagnosis, and prognosis of Crohn disease in adults")

●Drug-induced due to dasatinib therapy (eg, treatment of chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia) [24,25]

Idiopathic — Approximately 6 to 14 percent of chylothoraces are idiopathic [4,26]. However, the attribution of a chylothorax to an idiopathic etiology requires a comprehensive patient evaluation and careful follow-up to exclude an occult underlying etiology, such as lymphoma.

Traumatic causes (including iatrogenic causes) — Surgical procedures in the area of the thoracic duct or nearby structures account for the majority of cases of traumatic chylothorax. Surgery can inadvertently disrupt the thoracic duct or tear lymphatic tributaries (ie, iatrogenic injury) [27,28]. Penetrating injury with a trajectory in proximity to the thoracic duct has the potential to disrupt flow. Blunt injury may be due to avulsion or crushing injury of the thoracic duct [29].

Esophagectomy [30], pulmonary resection with lymph node dissection [31], and surgery for congenital heart disease (including heart-lung transplantation [32]) appear to carry the greatest risk, but thoracic duct injury has been reported in association with almost every thoracic surgical procedure [33-35], and may also complicate surgery of the spine [36], rib [37], neck, or abdomen [4,38]. Ingestion of milk (or fatty containing substance such as olive oil) before surgery increases the visualization of the thoracic duct and is thought to reduce the incidence of accidental rupture [39]. Injury to the intra-abdominal portion of the thoracic duct can cause chylous ascites that passes through the diaphragm, resulting in a chylothorax. (See "Sequelae and complications of pneumonectomy", section on 'Chylothorax' and "Evaluation and management of pleural effusions following cardiac surgery", section on 'Chylothorax' and "Heart-lung transplantation in adults", section on 'Chylothorax' and "Complications of esophageal resection", section on 'Chylothorax' and "Pleural complications in lung transplantation", section on 'Chylothorax'.)

Chylothorax can complicate chest trauma [4] and central line placement, pacemaker implantation, and embolization of pulmonary arteriovenous malformations if catheters, pacemaker wires, or embolized material injure the thoracic duct or cause intrathoracic arterial thrombosis that obstructs major lymphatic structures. Cases of iatrogenic chylothorax due to extravasation of total parenteral nutrition (TPN) fluid containing a high concentration of triglycerides (ie, intravenous lipids) from a central vein into the pleural space have been reported [40,41]. A milky-appearing chylous effusion can also result when a nasogastric enteral feeding tube enters the pleural space either by esophageal perforation or misplacement into the trachea with perforation of the parietal pleura with infusion of lipid containing enteral nutrition formulations [42]. (See "Initial evaluation and management of chest wall trauma in adults" and "Initial evaluation and management of blunt thoracic trauma in adults".)

CLINICAL PRESENTATION

Signs and symptoms — The majority of patients with chylothorax present with dyspnea induced by the mechanical effects of a pleural effusion. Additional symptoms include a heavy feeling in the chest, fatigue, and weight loss. Fever and chest pain are rare because chyle within the pleural space does not evoke an inflammatory response and rarely becomes infected due to the bacteriostatic effect of immunoglobulins that are contained in chyle [43]. Chyloptysis (expectorating chylous fluid) is an exceedingly rare manifestation of chylothorax [44]. Since chyle contains protein and fat, patients may be malnourished or have fat-soluble vitamin deficiencies but this is more likely to occur in association with removal of large volumes of chyle rather than the accumulation of chyle in the pleural space where constituents may be slowly resorbed. Similarly, since chronic loss of chyle is associated with immune suppression from loss of immunoglobulins, these patients may be prone to infection in organs other than the pleural space. On physical examination, findings of decreased breath sounds and stony dullness to percussion may be present depending on the size and location of the effusion.

The onset is gradual (eg, weeks) in patients with nontraumatic chylothoraces (eg, malignancy) while the onset of a posttraumatic or postsurgical chylothorax may be immediate if the volume is high (>500mL/day) or occur within a few days after the traumatic event (2 to 10 days) for those in whom accumulation is slower. In postsurgical patients who have a slow leak, accumulation may begin soon after resuming oral intake. Rapid loss may be associated with hypovolemia.

In postsurgical patients, the chylothorax may be first detected as a pleural effusion on serial radiographic evaluations or by the persistent drainage of pleural fluid from a preexisting chest tube. Occasionally, rapid postoperative filling of the pneumonectomy space with fluid (typically takes one to four months) with mediastinal shift to the contralateral side ("tension chylothorax") should also raise the suspicion for chylothorax [45].

Chylothorax should be suspected in a patient who presents with a persistent or recurrent pleural effusion of obscure etiology that is milky, turbid, bloody, or serosanguineous as noted during thoracentesis or in chest tube drainage. Because a milky or opalescent appearance of the pleural fluid is noted in only approximately one-half of patients with chylothorax, a high degree of suspicion is needed, particularly in patients who have had chest, neck, or abdominal surgery [46]. In one study of 38 patients with chylothoraces (defined by the presence of chylomicrons) [47], the pleural fluid was described as milky in 47 percent, bloody in 26 percent, yellow turbid in 11 percent, green turbid in 3 percent, and "other" in 13 percent [47]. Patients may convert to a milky-appearing fluid after ingestion of a high-fat meal.

Some patients may rarely present with uncontrolled atrial fibrillation since digoxin and amiodarone are carried through the chyle into the pleural space and may be lost if high volumes of drainage occur [48].

Patients may also have the symptoms and signs of the underlying disorder (table 1). (See 'Identifying the cause' below.)

Laboratory — There are no specific blood laboratory findings associated with chylothorax. Routine laboratory testing is typically obtained to assess for associated disorders and include a complete blood count and white blood cell differential, and also serum glucose, total protein, and lactic dehydrogenase (LDH) for comparison with pleural fluid values. Rarely, when severe, electrolyte loss into the pleural space may result in hyponatremia, hypocalcemia, and metabolic acidosis. Unless the patient is severely malnourished (which is rare), serum triglycerides, total protein, albumin, and immunoglobulin levels are generally normal despite the loss of these molecules into the pleural space. (See "Pleural fluid analysis in adults with a pleural effusion", section on 'Routine pleural fluid biomarkers'.)

Imaging — Plain radiography and computed tomography (CT) of the chest show evidence of a pleural effusion. Findings of a unilateral pleural effusion occur in approximately 78 percent of patients and involve the right hemithorax in 67 percent and left hemithorax in 33 percent [49]. However, bilateral effusion can also occur. Occasionally, signs of the underlying disorder may be evident (eg, lymphatic masses, lung malignancy, lung cysts, abdominal fluid, central line, pacemaker). (See 'Identifying the cause' below.)

While not appreciated on plain radiography, the thoracic duct and its course through the mediastinum may be identified on CT. The anatomy of the thoracic duct (figure 1 and figure 2) influences the location of the effusion seen with duct injury or obstruction. Thoracic duct injury or obstruction below the fifth thoracic vertebra (where it crosses the mediastinum from right to left) generally results in a right–sided pleural effusion. In contrast, thoracic duct injury or obstruction above this level usually leads to a left-sided effusion [11]. Disease at any level of the mediastinum that disrupts the multiple lymphatic anastomoses and tributaries to the thoracic duct may produce pleural effusions on either or both sides of the chest.

EVALUATION — Chylothorax should be suspected when a pleural effusion is noted on a chest radiograph in a patient with a risk factor (table 1). (See 'Clinical presentation' above.)

Pleural fluid analysis — The initial diagnostic test for patients suspected to have chylothorax is analysis of pleural fluid collected by thoracentesis or from a pre-existing chest tube. Samples of fluid are assessed for triglyceride and cholesterol levels in addition to the tests typically sent in all patients undergoing thoracentesis, which includes white blood cell count and differential, glucose, lactic dehydrogenase (LDH), total protein, cytology, and microbiologic smear and culture.

Appearance, cell count, protein level, LDH, glucose, pH

●Appearance – The appearance of fluid from a chylothorax can be milky, sanguineous, or serous. Although highly suggestive, the detection of milky-appearing fluid (due to the high content of triglycerides in the form of chylomicrons) is not specific for chylothorax, since milky fluid can also be seen in a cholesterol pleural effusion or an empyema. In addition, the milky appearance may clear during a fast and rapidly return after ingestion of dietary fat; thus, the appearance may be non-milky especially if the patient is malnourished, fasting, or on a low fat diet [46,50]. Distinguishing a cholesterol effusion and empyema from a chylothorax is discussed below. (See 'Differential diagnosis' below.)

●Cell counts – The white blood cell differential of fluid from chylothoraces typically has a predominance of lymphocytes, usually greater than 70 percent of the total nucleated cell count, reflecting the cellular composition of lymph [51]. Lymphocytes are largely a polyclonal population of T cells and concentrations range from 400 to 6800 cells/microL. The predominance of lymphocytes contributes to the bacteriostatic nature of chyle, explaining why it rarely becomes infected [11].

●Electrolytes and protein – Chyle has an electrolyte and protein content similar to that of plasma. Although the protein concentration of chyle within lymphatic channels is usually between 2 and 3 g/dL (ie, transudative (table 2)), most chylothoraces (up to 85 percent) have a higher protein concentration making them exudates by Light's criteria (table 3) [46,52]. The mechanisms of the transformation of transudative chyle into exudative chylothorax is unknown. (See "Pleural fluid analysis in adults with a pleural effusion", section on 'Our approach'.)

Transudative (table 2) chylothorax has been reported in a small proportion of patients with amyloidosis, cirrhosis, nephrotic syndrome, superior vena cava obstruction, heart failure, and chylous ascites that has crossed the diaphragm into the pleural space (chylothorax due to chylous ascites has biochemical characteristics that match the ascitic fluid from the patient) [19,46,52-55].

●LDH – The concentration of LDH in chyle is low and, consequently, LDH levels in chylous pleural fluid are also low, being in the range of a transudative pleural effusion by Light's criteria [46,52]. In some [52] but not all [46] series, elevation of LDH in chylous pleural fluid was associated with an underlying cause of a chylothorax (eg, malignancy) rather than from simple chyle leakage from ruptured lymphatic channels [46,52]. (See "Pleural fluid analysis in adults with a pleural effusion", section on 'Our approach'.)

●Glucose – The pleural fluid glucose in chylothorax is usually similar to that in plasma. A pleural fluid glucose below 60 mg/dL suggests coexisting empyema or a malignant pleural effusion. A pleural fluid-to-serum glucose ratio >1 in a patient receiving total parenteral nutrition (TPN) with intravenous lipid solutions indicates the presence of central venous catheter erosion into the mediastinum or pleural space [41].

●pH – Chylous fluid usually has a pH that ranges from 7.40 to 7.80 [56]. Pleural fluid pH measurement for suspected chylothorax is indicated only for patients who have intrapleural malignancy or infection in the differential diagnosis with chylothorax. (See 'Differential diagnosis' below.)

Interpreting pleural fluid characteristics is discussed in detail separately. (See "Pleural fluid analysis in adults with a pleural effusion", section on 'Classification as exudative or transudative'.)

Lipid analysis — Measurement of triglyceride and cholesterol levels should be the initial lipid tests performed in patients with suspected chylothorax. In a patient on a regular diet, a chylothorax typically contains a high concentration of triglycerides (>110 mg/dL [>1.24 mmol/L]) and the cholesterol level is generally less than 200 mg/dL (<5.18 mmol/L). However, 15 percent of chylothoraces have pleural fluid triglyceride concentrations less than or equal to 110 mg/dL (≤1.24mmol/L) and 3 percent have values less than 50 mg/dL (<0.56 mmol/L) [46,57]. A cholesterol concentration greater than or equal to 200mg/dL (≥5.18 mmol/L) supports a cholesterol effusion and is not typically seen in chylothorax. (See 'Cholesterol level' below and 'Cholesterol effusion' below.)

While the cutoff value of 110 mg/dL is typically used, pleural fluid triglyceride levels should be interpreted in the clinical context when used to support the diagnosis of chylothorax since cutoff values for triglyceride levels may depend upon the patient population studied and levels vary with ingestion of fat. For instance, a study of 59 patients with chylothorax demonstrated that a pleural fluid triglyceride cutoff value of >240 mg/dL had the best diagnostic performance with a sensitivity >95 percent and specificity >95 percent [58]. This study, however, had a higher proportion of postoperative patients as compared with older studies that established 110 mg/dL as the ideal cutoff point [46,57]. Thus, when suspicion remains (eg, borderline levels), a subset of patients may need to undergo measurement of pleural fluid chylomicrons using lipoprotein electrophoresis to achieve a definitive diagnosis. If lipoprotein electrophoresis is not available, a repeat measurement of pleural fluid after receiving a high fat diet is appropriate; the sensitivity of this approach, however, has not been studied. (See 'Lipoprotein electrophoresis' below.)

Triglyceride level >110 mg/dL — A pleural fluid triglyceride concentration greater than 110 mg/dL (>1.24 mmol/L) strongly supports the diagnosis of chylothorax and in the right clinical context (ie, patient on a regular diet who has an exudative effusion with a predominance of lymphocytes [>70 percent of the total nucleated cell count] and a known risk factor (table 1)), no further testing is typically required. It is rare that the diagnosis needs confirmation or exclusion by the measurement of chylomicrons using lipoprotein electrophoresis. (See 'Lipoprotein electrophoresis' below.)

Triglyceride level <50 mg/dL — A pleural fluid triglyceride concentration <50 mg/dL (<0.56 mmol/L) provides strong support that the patient does not have a chylothorax and in general no further testing is required. In rare circumstances, if suspicion for a chylothorax remains, direct measurement of pleural fluid for chylomicrons by lipoprotein electrophoresis is recommended or, if lipoprotein electrophoresis is not available, repeat testing of pleural fluid triglyceride after a high fat diet is appropriate. (See 'Lipoprotein electrophoresis' below.)

Triglyceride level between 50 and 110 mg/dL — An intermediate pleural fluid triglyceride level between 50 mg/dL and 110 mg/dL (0.56 mmol/L and 1.24 mmol/L) does not exclude the diagnosis of chylothorax and clinicians should perform lipoprotein electrophoresis of the pleural fluid to detect chylomicrons. If lipoprotein electrophoresis is not available, repeat pleural fluid triglyceride measurements after the patient receives a high-fat food challenge is appropriate [59]. (See 'Lipoprotein electrophoresis' below.)

Lipoprotein electrophoresis — The detection of chylomicrons by lipoprotein electrophoresis of pleural fluid is the definitive diagnostic criterion for chylothorax, but is not routinely performed as a first test because it is laborious, not widely available, and costly. We recommend its use to establish or exclude the diagnosis when the pleural fluid triglyceride level measurement is inconclusive; this includes patients with a triglyceride level between 50 mg/dL and 110 mg/dL (0.56 mmol/L to 1.24 mmol/L) or rare cases when suspicion remains in those with pleural fluid triglyceride levels that are below 50 mg/dL (0.56 mmol/L) or when the diagnosis needs to be confirmed or excluded in those with a pleural fluid triglyceride above 110 mg/dL (1.24 mmol/L; eg, patient with hypertriglyceridemia with a bloody tap) [60].

Other — Fat globules may be noted on Sudan III staining, which stains chylomicrons orange, but this test is rarely performed.

Cholesterol level — In patients with milky pleural fluid, measuring the cholesterol level distinguishes a chylothorax from a cholesterol effusion (also known as a pseudochylothorax or chyliform effusion). The cholesterol level in a chylothorax is generally ≤200 mg/dL (5.18 mmol/L) while cholesterol effusions, which are much less common than chylothoraces, contain a high concentration of cholesterol, typically >200mg/dL (5.18 mmol/L). (See 'Differential diagnosis' below and "Clinical presentation, diagnosis, and management of cholesterol pleural effusions".)

DIAGNOSIS — Most experts agree that a clinically confident diagnosis of chylothorax can be made by demonstrating pleural fluid triglyceride concentration >110 mg/dL (1.24 mmol/L) in the correct clinical context (ie, patient who has an exudative effusion with a predominance of lymphocytes [>70 percent of the total nucleated cell count], on a regular [or high fat] diet with a known risk factor (table 1 and algorithm 1)). Conversely, a pleural fluid triglyceride level <50 mg/dL (0.56 mmol/L) strongly excludes the diagnosis in the correct clinical context (eg, no supporting biochemical features of or risk factors for a chylothorax). When in doubt, the diagnosis should be achieved by the detection of chylomicrons on pleural fluid lipoprotein electrophoresis (eg, those with a pleural fluid triglyceride level between 50 mg/dL and 110 mg/dL [0.56mmol/L to 1.24 mmol/L] or those in whom a high suspicion remains when triglyceride levels are below 50 mg/dL [0.56 mmol/L]) or those with pleural fluid triglyceride levels that are above 110 mg/dL [1.24 mmol/L] [46,47,59]. (See 'Lipid analysis' above.)

DIFFERENTIAL DIAGNOSIS

Milky fluid — For patients who present with pleural fluid that is milky in appearance, the major differential for chylothorax includes cholesterol pleural effusion and empyema. Rarely, tube feed leaks due to a misplaced catheter can cause milky-appearing fluid.

Cholesterol effusion — A cholesterol effusion can be easily distinguished from chylothorax by demonstrating an elevated cholesterol level ≥200 mg/dL (≥5.18 mmol/L) and a cholesterol to triglyceride ratio >1 in the pleural fluid, neither of which should be present in patients with a chylothorax. In addition, while in chylothorax the triglyceride level is typically >110 mg/dL (1.24 mmol/L), in a cholesterol effusion, the triglyceride level is typically below 110 mg/dL (1.24 mmol/L); however, high triglyceride levels can be seen in 25 percent of patients with cholesterol effusions. Chylomicrons, which are characteristic of chylothoraces, are absent in those with a cholesterol effusion. (See "Clinical presentation, diagnosis, and management of cholesterol pleural effusions".)

Empyema — An empyema is readily distinguished from chylothorax by the presence of clinical features that support infection (eg fever, chest pain, leukocytosis). In addition, the supernatant of the pleural fluid from a chylothorax typically fails to clear after centrifugation, whereas milky-appearing empyema fluid clears with centrifugation [56]. Pleural fluid in patients with empyema will also have an elevated white cell count that has a predominance of polymorphonucleated cells (as opposed to elevated lymphocyte counts seen in chylothorax), and the pathogenic organism may be identified on culture (which would typically be absent in chylothorax). (See "Epidemiology, clinical presentation, and diagnostic evaluation of parapneumonic effusion and empyema in adults".)

Tube feed or lipid leak — Rarely, tube feed or intravenous lipids administered with total parenteral nutrition (TPN) may leak into the pleural space due to a misplaced catheter resulting in milky-appearing fluid that has a high triglyceride level. Radiologic examination of the tip of the feeding tube or catheter (eg, by computed tomography [CT]) would distinguish this phenomenon from chylothorax due to other causes. In addition, measurement of the pleural fluid to serum glucose ratio assists in differentiating a chylous effusion (ratio <1) from pleural fluid due to the extravasation of glucose-containing parenteral nutrition into the pleural space (ratio >1) [61].

Non-milky fluid

Exudative effusion — For the approximately 50 percent of patients with chylothorax who do not have pleural fluid with a milky appearance, the differential diagnosis is broad considering that chylothoraces are usually exudative (table 3) but may be occasionally transudative (table 2). In most cases, triglyceride and/or chylomicron analysis will distinguish a chylothorax from all other causes. (See "Pleural fluid analysis in adults with a pleural effusion" and "Diagnostic evaluation of the hemodynamically stable adult with a pleural effusion".)

IDENTIFYING THE CAUSE — Once a chylothorax has been diagnosed by pleural fluid analysis, investigations should be undertaken to discover the underlying etiology. Additional testing mostly depends upon the suspected cause. Most patients undergo additional clinical and laboratory testing as well as computed tomography (CT) of the chest, abdomen, and pelvis (if not already performed). However, others require more extensive testing, particularly those in whom a chyle leak needs to be localized (eg, surgical trauma of the thoracic duct that needs repair) or those in whom an anatomical or functional abnormality of lymphatics is suspected (eg, lymphangiectasia, lymphatic conduction disorder).

Initial evaluation and testing

Clinical re-evaluation — Although suspected risk factors for the development of chylothorax may be apparent on initial history and examination, it is prudent that the clinician re-evaluate for potential etiologies that may have been missed (table 1). The clinician should inquire about recent or distant trauma (particularly chest trauma), medical procedures (eg, central venous catheterization, esophageal/variceal embolectomy), radiation, and surgery. Clinicians should also inquire about symptoms suggestive of lymphoma (eg, sweats, weight loss, lymphadenopathy) and metastatic cancer (cough, hemoptysis, change in bowel habits, weight loss, decreased appetite), and look for features of anatomic anomalies of the lymphatic system, (eg, lymphedema) as well as subtle features of tuberous sclerosis complex (eg, facial angiomas, subungual fibromas or history of pneumothorax to suggest lymphangioleiomyomatosis [LAM]), Down syndrome (intellectual disability, frontal bossing, low set ears), or Noonan syndrome (short stature, murmur, deafness, lymphedema, webbed neck). An evaluation of skin and joints for signs of a connective tissue disorder (eg, systemic lupus erythematosus) and an evaluation of the neck for a goiter (potentially obstructing the thoracic duct), or signs of superior vena cava syndrome (venous distention and raised jugular venous pressure) are also appropriate. A travel history should be obtained (eg, suspected filariasis) and, although rare, a history of intermittent diarrhea and edema (suspected protein losing enteropathy) should be sought.

Chest and abdominal imaging — Clinicians should also re-evaluate previous chest imaging [62]. Although conventional chest radiography can identify the side with the effusion, it is usually not helpful in determining the underlying etiology unless obvious malignancy or trauma is evident. If not already performed, noncontrast-enhanced CT of the thorax, abdomen, and pelvis should be performed and may identify the following [59,63]:

●Mediastinal and retroperitoneal lymphadenopathy or masses

●Abdominal or pelvic fluid suggestive of chylous ascites

●Course of the thoracic duct (to identify a potential site for a leak or an obstructing lesion such as mediastinal or retroperitoneal lymphadenopathy)

●Cystic lesions of the thoracic duct suggestive of retroperitoneal or mediastinal lymphangioleiomyoma

●Mediastinal (eg, substernal goiter, vascular thrombosis), cardiac (eg, constrictive pericarditis), or pulmonary abnormalities (eg, pulmonary cysts and renal angiomyolipoma as manifestations of LAM)

●Potential iatrogenic complications responsible for a perforated thoracic duct (eg, misplaced central line placement)

CT can also assist in preoperative planning for interventional or surgical procedures for the treatment of chylothorax. (See 'Lymphatic imaging in select patients' below and "Management of chylothorax".)

Laboratory testing — Additional laboratory tests that should be performed routinely include peripheral eosinophil count (eg, suspected filariasis) and liver function tests (eg, suspected cirrhosis) while etiology-specific laboratory tests are only performed when rare specific etiologies are suspected (eg, vascular endothelial growth factor-D level for LAM). (See 'Other etiology-specific testing' below.)

Lymphatic imaging in select patients — A small proportion of patients additionally need lymphatic imaging when CT is unhelpful or the underlying etiology remains unknown. We typically perform lymphatic imaging in the following circumstances [64]:

●When the diagnosis of a thoracic duct tear is uncertain after pleural fluid analysis and chest CT

●When anomalous thoracic duct anatomy is suspected (eg, lymphangiectasia, generalized lymphatic anomaly, lymphangiomatosis, Gorham syndrome, Kaposiform lymphangiomatosis or lymphatic conduction disorder)

●When the site of chyle leak is unknown and an intervention is planned to resolve lymph leakage

●When chylothorax recurs after thoracic duct ligation

Choosing among the imaging modalities should be individualized and is influenced by available expertise and the suspected underlying etiology. Most patients undergo lymphangiography, which can localize the site of lymph leakage and identify anatomic abnormalities of the lymphatic system (see 'Lymphangiography' below). However, when chylothorax is suspected to be due to surgical or nonsurgical trauma, localizing the site of chyle leak can be challenging since the leakage may be too slow or diffuse to visualize. Lymphoscintigraphy and magnetic resonance (MR) lymphangiography are alternatives to lymphangiography (especially when anatomic or conduction disorders are suspected), while some experts forgo imaging and use fat solutions administered preoperatively or intraoperatively to confirm or identify the site of a chyle leak. (See 'Lymphoscintigraphy' below and 'Magnetic resonance lymphangiography' below.)

Lymphangiography — Lymphangiography is a contrast-enhanced study of the lymphatic system that can delineate thoracic duct anatomy and identify a potential site of chyle leak, although one study suggested that this information does not influence the course of therapy, particularly in those with nontraumatic chylothorax [49].

Lymphangiography is performed using bilateral localization of pedal lymphatics with a subcutaneous injection of methylene blue (preferentially absorbed by lymphatics), followed by a minor surgical procedure to cannulate the lymphatic vessel and inject Lipiodol contrast agent with fluoroscopy to follow the flow of contrast into the thoracic duct [65,66]. Conventional films and CT images (without intravenous contrast) are then obtained. Lymphangiography can identify areas of chyle leakage and lymphangiectasia in the majority of patients. As an example, in a series of 43 patients who underwent lymphangiography, the location of the leak was identified in 79 percent [67]. Lymphangiography, however, is a technically difficult procedure (eg, injections can be challenging in patients with significant lower extremity edema) and presents risks for respiratory complications due to oily pulmonary embolism or pneumonitis [68]. Intranodal lymphography where Lipiodol is injected into accessible nodes (eg, inguinal), as opposed to lymphatics of the foot, can be used as a technically easier alternative when lower extremity lymphatic anatomy is not desired; because the access is easier and less traumatic, it tends to be used more often in children [69].

Lymphangiography may occasionally be therapeutic since the iodinated contrast is thought to have a local tissue-sclerosing effect [67,70,71]. As an example, in a case series of 43 patients, lymphangiography occluded lymphatic leaks in 70 percent of those with a lymphatic drainage volume less than 500 mL/day and in 35 percent of those with leakage higher than 500 mL/day [67]. In contrast, a separate series found cessation of chyle leak in only 11 of 20 patients who underwent lymphangiography for postoperative chylothorax [70]. (See "Management of chylothorax".)

Lymphoscintigraphy — Lymphoscintigraphy is usually performed by injecting technetium99-labelled human serum albumin-diethylenetriaminepentaacetic acid (HSA-DTPA) into the subcutaneous regions of the dorsum pedis bilaterally. Sequential, anterior, and posterior views of the thorax are obtained with a single photon emission CT combined with integrated low-dose CT (SPECT/CT) [72]. Radiolocalization using lymphoscintigraphy has shown good correlation with lymphangiography and with localization of chyle leaks following surgery, superior vena cava thrombosis, and childbirth [72-76]. Lymphoscintigraphy is limited by its availability and, because of its lower resolution, is not ideal for examining anatomic abnormalities of the lymphatic system but is less invasive than lymphangiography and easier to perform, and it is therefore, sometimes used before lymphangiography as a diagnostic tool in centers where it is available.

Magnetic resonance lymphangiography — Non-contrast MR lymphangiography using heavily T2-weighted imaging provides detailed visualization of the entire thoracic duct [50,77]. This imaging technique can demonstrate the relationship of lymphatics to adjacent structures to assist preoperative planning. Non-contrast MR lymphangiography has demonstrated sites of lymphatic leakage and provided high-resolution imaging. Case reports indicate that dynamic contrast-enhanced MR lymphangiography with an intranodal injection of gadolinium-based contrast agents provides good spatial and temporal resolution for visualizing the anatomy and flow characteristics of the central lymphatic system and can therefore readily identify disorders of lymphatic function and flow [78-82].

Other etiology-specific testing — Additional tests may be performed when specific etiologies are being considered (table 1). These include echocardiography (suspected constrictive pericarditis), vascular endothelial growth factor-D or pleural fluid cytology (suspected LAM), angiotensin converting enzyme (ACE) level (suspected sarcoidosis), connective tissue disorder (CTD) screen (suspected CTD; eg, rheumatoid factor, anti-double stranded DNA, anti-Scl-70), tuberculin skin testing, or circulating filarial antigen (CFA) or blood smears (suspected filariasis). (See 'Pathogenesis and etiology' above.)

PATIENTS WITHOUT A DIAGNOSIS — Some patients despite extensive investigations are left without an explanation for their chylothorax. In these cases, options include observation with a low threshold to repeat testing (eg, repeat thoracentesis or imaging) and referral to a lymphatic expert (eg, expert in lymphatic congenital anomalies or lymphatic interventional radiologist). In some cases, the diagnosis becomes apparent over time while others are left without a diagnosis.

SUMMARY AND RECOMMENDATIONS

●Chylothorax refers to the presence of chyle in the pleural space. Malignancy (classically lymphoma) is the leading cause of nontraumatic chylothorax while inadvertent surgical injury to the thoracic duct is the major cause of traumatic chylothorax (table 1). The mechanisms involved include obstruction, direct involvement or tears, anatomic anomaly, or conduction deficit of the thoracic duct as well as excessive lymph production or transfer of chyle across the diaphragm from the abdomen. (See 'Pathogenesis and etiology' above.)

●Patients with a chylothorax usually present with the typical signs and symptoms induced by the mechanical effects of a pleural effusion. Other manifestations include heaviness in the chest, fatigue, weight loss, and rarely chyloptysis, or malnourishment. The onset is gradual in patients with nontraumatic chylothoraces while the onset of a posttraumatic chylothorax may occur within a few days after thoracic surgery, vascular access procedure, or other traumatic event (2 to 10 days). While a milky appearance of pleural fluid is a classic sign of chylothorax, it is only present in 50 percent of cases; thus, chylothorax should also be suspected in a patient who presents with a persistent or recurrent pleural effusion of obscure etiology that is milky, turbid, bloody, or serosanguinous. (See 'Clinical presentation' above.)

●Chylothorax should be suspected when a pleural effusion is noted on a chest radiograph in a patient with a risk factor (table 1). (See 'Evaluation' above.)

●The initial diagnostic test for patients suspected to have chylothorax is analysis of pleural fluid for triglyceride and cholesterol levels (algorithm 1). In addition, white blood cell count and differential, glucose level, lactic dehydrogenase (LDH) level, total protein level, cytology, and microbiologic smear and culture are warranted. Pleural fluid is classically exudative with a high lymphocyte count (>70 percent), a normal glucose level, a low LDH, and a cholesterol level <200 mg/dL (<5.18 mmol/L). (See 'Appearance, cell count, protein level, LDH, glucose, pH' above and 'Cholesterol level' above.)

•For patients with a pleural fluid triglyceride concentration greater than 110 mg/dL (>1.24 mmol/L) who are on a regular diet and who also have typical biochemical supporting features of a chylothorax listed above and a known risk factor (table 1), no further testing is typically required. A clinically confident diagnosis of chylothorax can usually be made using these criteria. (See 'Triglyceride level >110 mg/dL' above and 'Diagnosis' above.)

•For patients with a pleural fluid triglyceride concentration less than 50 mg/dL (<0.56 mmol/L) who are on a regular diet, no further testing is typically required. These patients do not have chylothorax. (See 'Triglyceride level <50 mg/dL' above and 'Diagnosis' above.)

•For patients with a pleural fluid triglyceride level between 50 mg/dL and 110 mg/dL (0.56 to 1.24 mmol/L) or patients with high or low pleural fluid triglyceride levels in whom the diagnosis needs to be confirmed or excluded, we prefer that lipoprotein electrophoresis of the pleural fluid be performed for the detection of chylomicrons; however, if not available, clinicians may repeat pleural fluid triglyceride measurements after the patient receives a high-fat food challenge. The detection of chylomicrons by lipoprotein electrophoresis is the definitive diagnostic test but not routinely performed since it is costly, not widely available, and laborious. (See 'Triglyceride level between 50 and 110 mg/dL' above and 'Lipoprotein electrophoresis' above and 'Diagnosis' above.)

●For patients who present with pleural fluid that is milky in appearance, the major differential for chylothorax includes a cholesterol pleural effusion (elevated pleural fluid cholesterol level ≥200 mg/dL [≥5.13 mmol/L], pleural fluid cholesterol to triglyceride ratio >1, pleural fluid triglyceride level ≤110 mg/dL [1.24 mmol/L]) and empyema (systemic features of infection, low pleural fluid pH and glucose, high polymorphonucleated pleural fluid white cell count, positive culture, milky appearance clears with centrifugation). For patients with suspected chylothorax who do not have pleural fluid with a milky appearance, the differential diagnosis is broad considering that chylothoraces are usually exudative (table 3) but may be occasionally transudative (table 2). (See 'Differential diagnosis' above and "Pleural fluid analysis in adults with a pleural effusion" and "Diagnostic evaluation of the hemodynamically stable adult with a pleural effusion".)

●Patients with an established diagnosis of chylothorax should undergo additional clinical re-evaluation and laboratory testing (eg, eosinophil count and liver function tests) for diagnoses that may have been missed during the initial evaluation. If not already performed, most patients should also undergo computed tomography (CT) of the chest, abdomen, and pelvis to assess for thoracic duct anatomy and source of chyle leak, mediastinal masses or lymphadenopathy, and abdominal accumulation of chyle as well as thoracic duct and lymphatic abnormalities and several other iatrogenic etiologies (eg, central line misplacement). More advanced imaging of the lymphatics such as contrast-enhanced or magnetic resonance (MR) lymphangiography is indicated in a smaller proportion of patients (eg, those in whom the site of chyle leak cannot be determined by CT, those with suspected anatomical abnormalities or conduction disorders of the lymphatic system). Other tests are guided by the suspected etiology. (See 'Identifying the cause' above.)

●Some patients despite extensive investigations are left without an explanation for their chylothorax (ie, idiopathic chylothorax). In these cases, options include observation with a low threshold to repeat testing (eg, repeat thoracentesis or imaging) and referral to a lymphatic expert. (See 'Patients without a diagnosis' above.)