What every physician needs to know:
Chylothorax and cholesterol effusions (also known as chyliform effusions or pseudochylothorax) are lipid-rich pleural effusions. The lipid content consists of chylomicrons/triglycerides (TG) in a chylothorax and cholesterol in cholesterol effusions. In both conditions, pleural fluid often has an opalescent or milky appearance because of its high fat concentration (Figure 1).
Chylothorax implies a chyle leak that is due to the disruption or blockade of the thoracic duct or its tributaries. Cholesterol effusions have no relationship with lymphatic vessels, but rather are connected with long-standing pleural effusions with or without thickened pleural membranes.
Chylothorax represents about 2% to 3% of all pleural effusions, while cholesterol effusions are rare conditions, with fewer than two hundred cases reported.
Causes of chylothorax can be divided into four major categories: (Table I)
|Surgery||~40%||Congenital heart and diaphragmatic hernia repair surgeries in children, esophagectomy, lung or mediastinal mass resection, coronary artery bypass grafting, radical neck dissection and descending thoracic aortic aneurism repair in adults|
|Tumors||~30%||Lymphoma (70%), metastatic carcinoma|
|Miscellaneous||~20%||Cirrhosis, congenital or acquired lymphatic disorders (e.g., LAM, yellow-nail syndrome), superior vena cava syndrome, innominate or left subclavian vein thromboses, penetrating and blunt trauma, drugs (dasatinib), radiation injury|
|Idiopathic||~10%||Includes congenital chylothorax. In adults, rule out an occult neoplasm or trivial trauma (coughing, hiccupping, sneezing, stretching while yawning and childbirth delivery) before considering a chylothorax as idiopathic|
The most common etiology of cholesterol effusions is tuberculosis (42%), particularly in the context of previous collapse therapy and residual effusions following anti-tuberculosis therapy. The second most common cause is chronic rheumatoid pleurisy (32%). Rare causes include paragonimiasis, yellow nail syndrome, and iatrogenic (e.g. coronary-artery bypass surgery). The cause is unknown in about 15% of cases.
Are you sure your patient has chylothorax or cholesterol effusion? What should you expect to find?
Consider chylothorax in patients with pleural effusion under the following circumstances:
Milky-white fluid is aspirated.
There are predisposing factors (e.g., recent cardiothoracic surgery, suspected lymphoma, cirrhosis, and LAM).
There is continuous pleural fluid drainage thorough a chest tube during the postoperative period (> 400 mL/d).
The cause of a persistent or recurrent effusion is uncertain.
Patients with chylothorax may manifest dyspnea (> 50%) and/or nonproductive cough (< 10%), or no respiratory symptoms (37%) when effusions are small or moderate in size. The onset of symptoms may be acute/subacute in postsurgical chylothorax or gradual in nontraumatic chylothorax.
Given the noninflammatory nature of chyle, pleuritic chest pain or fever should not be expected, with lymphoma being an exception (fever is a “B” symptom). The absence of a milky appearance occurs in half the patients, especially if they are fasting (e.g., in the postoperative period) or malnourished.
Anatomical reasons explain the preferential lateralization of chylothoraces depending on the level of thoracic duct injury or obstruction: If the duct is damaged below the fifth or sixth thoracic vertebrae, the effusion will be right-sided, which is the most common situation. An injury above this level results in a left chylothorax, whereas bilateral chylothorax (20%) results from disruption at the level of the fifth thoracic vertebrae or from the transdiaphragmatic movement of chylous ascites. It should be noted, however, that the anatomical course of the thoracic duct is typical in only 40% to 60% of patients, and several variations exist.
Consider cholesterol effusions when the patient is asymptomatic (1/3) or symptomatic with a unilateral (88%), chronic pleural effusion (> 5 years in 90% of the cases) of unknown etiology, or when the patient has lung entrapment or loculated effusions, whether or not the pleural surfaces are thickened or calcified. Indeed, pleural thickening is absent in 20% of cases.
Beware: there are other diseases that can mimic chylothorax or cholesterol effusion:
A milky fluid can be caused by chylothorax, cholesterol effusion, empyema, or extravasation of lipid-containing parenteral nutrition from a central line that has accidentally migrated into the pleural space. In addition, the differential diagnosis of a non-whitish-appearing chylothorax includes other types of postoperative effusions.
Differentiate cholesterol effusions from chronic tuberculosis empyema, the latter of which is characterized by a chronic, active mycobacterial infection of the pleural space; a thick, calcific pleural rind and rib thickening surrounding loculated pleural fluid, and a purulent fluid that is smear positive for acid-fast bacilli.
How and/or why did the patient develop chylothorax or cholesterol effusion?
Thoracic duct injury or obstruction leading to the leakage of chyle into the pleural space may result from:
accidental damage during cardiothoracic surgery
mediastinal lymphadenopathy that impedes lymph drainage from thoracic structures
invasion of the thoracic duct by lymphomatous or carcinomatous cells
major or minor trauma
spontaneous (Behçet disease) or catheter-related thrombosis, or the external compression (substernal goiter) of great veins
the proliferation of abnormal smooth-muscle cells around the lymph vessels (LAM)
a drug-induced disorder of the lymphatic network. The anti-leukemic agent dasatinib inhibits the platelet-derived growth factor beta receptor, which is involved in lymphangiogenesis. About 30% of dasatinib-treated patients develop drug-related pleural effusions, though they are uncommonly chylous.
In cirrhosis cases, chylothorax appears to be produced by the transdiaphragmatic movement of chylous ascites to the pleural cavity. The origin of the lipids in cholesterol effusions is thought to result from degenerating red and white blood cells in the pleural fluid and trapped cholesterol that changes its lipoprotein-binding characteristics because of local metabolism.
Which individuals are at greatest risk of developing chylothorax or cholesterol effusion?
The prevalence of chylothorax differs based on attendant conditions:
Congenital heart surgery: 9%
Congenital diaphragmatic-hernia repair: 6%
Esophagectomy: less than 4%
Lung resection with thoracic mediastinal lymph node dissection: 1.4%
Descending thoracic aortic-aneurism repair: 0.4%
Lymphoproliferative disorders: 2.5%
Superior vena cava syndrome: 5%
LAM: 15% (tuberous sclerosis complex form) or 20% (sporadic form)
Congenital (i.e. non-traumatic chylous effusion detected antenatally or within 28 days after birth): 1 in 10,000 to 24,000 live births
Predisposing factors for developing cholesterol effusions include residual tuberculosis pleuritis, chronic rheumatoid pleurisy, and lung entrapment.
What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?
A yellowish or serosanguineous appearance of the fluid is even more common than the typical milky appearance. Moreover, cholesterol effusions are milky only in 40% of the cases and often have a satin-sheen or brown appearance.
Aspirate pleural fluid in order to measure:
cell count and differential
glucose and/or pH
Obtain serum simultaneously for protein, LDH, glucose, cholesterol and TG levels.
Pleural fluid characteristics in chylothorax are as follows:
Exudate in 85% of the cases. In two-thirds of these cases, the effusion is classified as an exudate by the protein but not by the LDH-concentration criterion (protein-discordant exudate).
Transudate in 15% of the cases, which should raise suspicions for cirrhosis and, less frequently, heart failure or nephrotic syndrome.
Lymphocytes are predominant in 80% of the cases, although neutrophilic fluids are not rare in the postoperative period.
TG concentration greater than 110 mg/dL in more than 85% of cases; a level less than 50 mg/dL strongly argues against this diagnosis, as this level occurs in less than 3% of cases.
The presence of chylomicrons establishes a definite diagnosis. They should be measured only if there are intermediate TG values (50-110 mg/dL).
If a lipoprotein analysis is not available and if there is doubt about the diagnosis, the administration of a high-fat meal will result in a dramatic change in the appearance and TG content of the pleural fluid.
Pleural fluids in cholesterol effusions are exudates, often lymphocyte-predominant (60%), that are characterized by:cholesterol/TG ratio greater than 1 (97%)
cholesterol crystals on polarized microscopy (pathognomonic, but not a prerequisite) (90%)
cholesterol levels greater than 200 mg/dL (75%)
the absence of chylomicrons
In cholesterol effusions, send the fluid for adenosine deaminase measurement and mycobacterial cultures, the latter being positive only in one-third of tuberculosis cases when classical solid media are employed.
What imaging studies will be helpful in making or excluding the diagnosis of chylothorax or cholesterol effusion?
A chest X-ray confirms the presence of pleural effusion. In chylothorax of uncertain origin, a thoracic and abdominal CT scan may reveal lymphadenopathy, thrombosis or compression of the great veins, and/or cystic parenchymal changes suggestive of LAM.
In cholesterol effusions, a chest CT may demonstrate thickened or calcified pleural surfaces, a loculated fluid collection, and/or the presence of a fat-fluid or fat-calcium level.
In patients where thoracic-duct repair or ligation is planned, localizing the leakage site may require non-contrast-enhanced MRI lymphoductography or intranodal lymphangiography (in which an inguinal lymph node is accessed under ultrasound guidance and, subsequently, an oil-based contrast agent is injected), as the preferred imaging techniques. Less commonly used modalities include lymphoscintigraphy after oral ingestion of 123I-labeled beta-methyl-iodophenyl pentadecanoic acid, or intradermal injection of 99mTc-labeled albumin or colloidal sulfur into the dorsum of the foot or hand; or pedal lymphangiography using lipiodol.
What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of chylothorax or cholesterol effusion?
See imaging studies.
What diagnostic procedures will be helpful in making or excluding the diagnosis of chylothorax or cholesterol effusion?
The diagnosis of chylothorax and cholesterol effusion relies on the pleural fluid analysis (See above.)
After the centrifugation of the pleural fluid, the supernatant is opaque in chylothorax and cholesterol effusions, and clear in empyema (the milkiness is caused by suspended leukocytes and debris). Adding 2mL of ethyl ether will clear the milkiness in chylothorax, but not in a cholesterol effusion.
A pleural fluid-to-serum glucose ratio may assist in differentiating chylothorax (ratio < 1) from the extravascular migration of a central venous catheter in patients receiving total parenteral nutrition (ratio > 1).
CT-guided pleural biopsy or pleuroscopy may be necessary for diagnosing malignancy-related chylothorax if pleural fluid cytological and/or flow cytometrical analyses are inconclusive.
What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of chylothorax or cholesterol effusion?
No pathology/cytology/genetic studies are helpful in making or excluding the diagnosis of chylothorax or cholesterol effusion.
If you decide the patient has chylothorax or cholesterol effusion, how should the patient be managed?
Management decisions for chylothorax depend on the underlying cause, the effusion’s size and the severity of the symptoms, the rate of fluid formation or reaccumulation, and the local expertise. When managing a chylothorax, proceed from conservative measures to more invasive treatments.
Treatment strategies are divided into three categories:
Treatment of the underlying condition – chemotherapy, with or without radiation therapy for lymphomas and metastatic tumors; diuretics, or large-volume paracentesis and/or TIPS for cirrhotic ascites; and temporary discontinuation or dose reduction of dasatinib along with therapeutic thoracentesis when moderate or large effusions result from it (corticosteroids and/or diuretics may be necessary). The mTOR inhibitor silorimus (1 to 5 mg/d) may reduce the size of intractable chylous effusions in patients with LAM, though a response may take several months and effusions can recur after treatment cessation.
Conservative management – therapeutic thoracentesis or chest-tube drainage for symptomatic relief (Figure 2), a period of total parenteral nutrition or a low-fat diet supplemented with oral medium-chain TG to reduce chyle flow in the thoracic duct, and octreotide (sandostatin), 50-100 mcg/8 h SC to reduce intestinal chyle production. According to some reports, etilefrine (a sympathomimetic drug causing smooth muscle contraction of the thoracic duct), either in isolation or combined with octeotride, may facilitate chylothorax resolution.
Therapeutic thoracentesis in a patient with chylothorax
Surgical and/or palliative options should be considered if conservative measures for a two-week period have been unsuccessful, there are severe nutritional or metabolic complications, or the average daily chyle loss exceeds 1 to 1.5 L for a 5- to 7-day period.
In high-output chylothoraces (>1 L/d), the treatment modalities include visualization of the thoracic duct under fluoroscopy by intranodal lymphangiography or percutaneous CT-guided access to the cisterna chyli and injection of a water-soluble iodine contrast, followed by catheterization and embolization of the thoracic duct with multiple radio-opaque micro coils and/or liquid embolic agents (eg., N-butyl cyanoacrylate glue). Conventional lymphangiography itself might reduce or heal chyle leaks in some patients.
Treatment for high-output chylotoraces can also include video-assisted thoracic surgery (VATS, or thoracotomy) for the surgical repair of the lymphatic disruption and/or ligation of the thoracic duct. Oral cream is administered 24 hours prior to the procedure to facilitate the identification of the point of leakage. If the leak is not identifiable, a mass ligation of all the tissues anterior to the esophagus and between the aorta and the azygos vein should be performed. VATS allows for simultaneous pleurodesis with talc poudrage.
In low-output, persistent chylothoraces or those caused by malignancy, controlling pleural effusion may require bedside pleurodesis with doxycycline or talc slurry, or an indwelling catheter (PleurX) or pleuroperitoneal shunting if there has been failed pleurodesis or a trapped lung. A PleurX can also be considered a first choice therapy in place of chemical pleurodesis.
Management of cholesterol effusions includes treatment of the underlying disease, therapeutic thoracentesis for symptomatic relief (the patient may experience substernal chest pain after large-volume aspiration because of the increase in negative pleural pressure (lung entrapment)), and pleurodesis and/or decortication for recurrent symptomatic effusions. Medical treatment solves nearly 80% of the cases.
What is the prognosis for patients managed in the recommended ways?
In chylothorax, conservative treatments have a success rate of about 40%. The remainder of the cases need a surgical or palliative intervention.
Nontraumatic chylothorax appears to respond less well to conservative and surgical measures than does traumatic chylothorax. Its prognosis is dictated by the underlying etiology.
Thoracic duct ligation for high-output or recurrent chylothoraces of traumatic origin is successful in up to 95% of the cases.
The mortality rate of a high output, post-esophagectomy chylothorax is 10% to 15% with early reoperation and greater than 50% with conservative measures.
In most cases, cholesterol effusions follow a benign course.
What other considerations exist for patients with chylothorax or cholesterol effusion?
Lipoprotein analysis of the pleural fluid to demonstrate chylomicrons is rarely performed.
Some chylothoraces are likely undiagnosed because of their non-milky appearance.
In fasting or malnourished patients, reliance on the TG criteria may overlook the diagnosis of chylothorax.
Exclude lymphoma before adopting the diagnosis of idiopathic chylothorax.
Prolonged drainage of a chylothorax may lead to malnutrition, immunosuppression and severe electrolyte abnormalities (hyponatremia and hypocalcemia).
Prophylactic thoracic duct ligation during esophagectomy for cancer is an effective preventive measure for reducing the incidence of postoperative chylothorax. It is best performed by precisely identifying the duct, as opposed to mass ligation.
Persistent, high-output chylothorax requires some form of intervention, thoracic duct embolization being a well-tolerated and efficacious treatment. The standard procedure consists of lymphangiography and transabdominal access to the thoracic duct, followed by embolization.
Intranodal lymphangiography is a feasible technique for opacifying the lymphatic system in order to perform a thoracic duct embolization.
Active tuberculosis should be ruled out in all patients with cholesterol effusions.
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- What every physician needs to know:
- Are you sure your patient has chylothorax or cholesterol effusion? What should you expect to find?
- Beware: there are other diseases that can mimic chylothorax or cholesterol effusion:
- How and/or why did the patient develop chylothorax or cholesterol effusion?
- Which individuals are at greatest risk of developing chylothorax or cholesterol effusion?
- What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?
- What imaging studies will be helpful in making or excluding the diagnosis of chylothorax or cholesterol effusion?
- What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of chylothorax or cholesterol effusion?
- What diagnostic procedures will be helpful in making or excluding the diagnosis of chylothorax or cholesterol effusion?
- What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of chylothorax or cholesterol effusion?
- If you decide the patient has chylothorax or cholesterol effusion, how should the patient be managed?
- What is the prognosis for patients managed in the recommended ways?
- What other considerations exist for patients with chylothorax or cholesterol effusion?