Dynamic Contrast-Enhanced Magnetic Resonance Lymphangiography and Percutaneous Lymphatic Embolization for the Diagnosis and Treatment of Recurrent Chyloptysis.

Chyloptysis, or the expectoration of triglyceride-rich sputum, is rare and typically treated with diet modification and thoracic duct ligation. This article describes 2 patients with prolonged histories of chyloptysis who failed conservative treatment and thoracic duct ligation. Dynamic contrast-enhanced magnetic resonance imaging delineated the lymphatic anatomy and identified the abnormal pulmonary lymphatic perfusion pathways in both patients. This imaging provided guidance for successful percutaneous lymphatic embolization which resulted in resolution of symptoms in both patients.

Defective lymphatic valve development and chylothorax in mice with a lymphatic-specific deletion of Connexin43.

Lymphatic valves (LVs) are cusped luminal structures that permit the movement of lymph in only one direction and are therefore critical for proper lymphatic vessel function. Congenital valve aplasia or agenesis can, in some cases, be a direct cause of lymphatic disease. Knowledge about the molecular mechanisms operating during the development and maintenance of LVs may thus aid in the establishment of novel therapeutic approaches to treat lymphatic disorders. In this study, we examined the role of Connexin43 (Cx43), a gap junction protein expressed in lymphatic endothelial cells (LECs), during valve development. Mouse embryos with a null mutation in Cx43 (Gja1) were previously shown to completely lack mesenteric LVs at embryonic day 18. However, interpreting the phenotype of Cx43-/- mice was complicated by the fact that global deletion of Cx43 causes perinatal death due to heart defects during embryogenesis. We have now generated a mouse model (Cx43∆LEC) with a lymphatic-specific ablation of Cx43 and show that the absence of Cx43 in LECs causes a delay (rather than a complete block) in LV initiation, an increase in immature valves with incomplete leaflet elongation, a reduction in the total number of valves, and altered lymphatic capillary patterning. The physiological consequences of these lymphatic changes were leaky valves, insufficient lymph transport and reflux, and a high incidence of lethal chylothorax. These results demonstrate that the expression of Cx43 is specifically required in LECs for normal development of LVs.

Lymphovenous hemostasis and the role of platelets in regulating lymphatic flow and lymphatic vessel maturation.

Aside from the established role for platelets in regulating hemostasis and thrombosis, recent research has revealed a discrete role for platelets in the separation of the blood and lymphatic vascular systems. Platelets are activated by interaction with lymphatic endothelial cells at the lymphovenous junction, the site in the body where the lymphatic system drains into the blood vascular system, resulting in a platelet plug that, with the lymphovenous valve, prevents blood from entering the lymphatic circulation. This process, known as "lymphovenous hemostasis," is mediated by activation of platelet CLEC-2 receptors by the transmembrane ligand podoplanin expressed by lymphatic endothelial cells. Lymphovenous hemostasis is required for normal lymph flow, and mice deficient in lymphovenous hemostasis exhibit lymphedema and sometimes chylothorax phenotypes indicative of lymphatic insufficiency. Unexpectedly, the loss of lymph flow in these mice causes defects in maturation of collecting lymphatic vessels and lymphatic valve formation, uncovering an important role for fluid flow in driving endothelial cell signaling during development of collecting lymphatics. This article summarizes the current understanding of lymphovenous hemostasis and its effect on lymphatic vessel maturation and synthesizes the outstanding questions in the field, with relationship to human disease.

Pathogenic variants in MDFIC cause recessive central conducting lymphatic anomaly with lymphedema.

Central conducting lymphatic anomaly (CCLA), characterized by the dysfunction of core collecting lymphatic vessels including the thoracic duct and cisterna chyli, and presenting as chylothorax, pleural effusions, chylous ascites, and lymphedema, is a severe disorder often resulting in fetal or perinatal demise. Although pathogenic variants in RAS/mitogen activated protein kinase (MAPK) signaling pathway components have been documented in some patients with CCLA, the genetic etiology of the disorder remains uncharacterized in most cases. Here, we identified biallelic pathogenic variants in MDFIC, encoding the MyoD family inhibitor domain containing protein, in seven individuals with CCLA from six independent families. Clinical manifestations of affected fetuses and children included nonimmune hydrops fetalis (NIHF), pleural and pericardial effusions, and lymphedema. Generation of a mouse model of human MDFIC truncation variants revealed that homozygous mutant mice died perinatally exhibiting chylothorax. The lymphatic vasculature of homozygous Mdfic mutant mice was profoundly mispatterned and exhibited major defects in lymphatic vessel valve development. Mechanistically, we determined that MDFIC controls collective cell migration, an important early event during the formation of lymphatic vessel valves, by regulating integrin ß1 activation and the interaction between lymphatic endothelial cells and their surrounding extracellular matrix. Our work identifies MDFIC variants underlying human lymphatic disease and reveals a crucial, previously unrecognized role for MDFIC in the lymphatic vasculature. Ultimately, understanding the genetic and mechanistic basis of CCLA will facilitate the development and implementation of new therapeutic approaches to effectively treat this complex disease.

Chylothorax: diagnostic approach.

PURPOSE OF REVIEW: This review evaluates recent research findings and proposes an up-to-date diagnostic approach for patients with suspected chylothorax. RECENT FINDINGS: Typically, chylothorax is a milky exudate with high triglyceride content (>110 mg/dl). However, milky appearance is not always the case and triglyceride levels can be less than 110 mg/dl, especially in fasting or malnourished patients. Transudative chylothoraces have been reported when cirrhosis, nephrosis or heart failure co-exist. In addition, although the vast majority of the white blood cells in chyle are lymphocytes, chylothoraces can be neutrophilic, especially the postsurgical ones. SUMMARY: Chylothorax is the accumulation of chyle into the pleural cavity usually due to thoracic duct leak and should be suspected not only in patients with milky effusions but also in the presence of certain co-morbidities or history of chest/neck trauma. Fluid triglycerides more than 110 mg/dl or less than 50 mg/dl virtually establish or exclude the diagnosis, respectively; ambiguous cases with values 50-110 mg/dl require lipoprotein analysis for the demonstration of chylomicrons. In fasting or malnourished patients lipoprotein analysis is suggested even with triglycerides less than 50 mg/dl. Typical pleural fluid in chylothorax is a lymphocytic exudate with low lactate dehydrogenase; atypical fluid characteristics (i.e. transudative nature, neutrophil-predominance or high lactate dehydrogenase) may be a sign of additional causes of pleural fluid accumulation.

Usefulness of triglyceride levels in pleural fluid.

The determination of pleural fluid triglycerides (PF-TRIG) is useful in the diagnosis of chylothorax, but its diagnostic value for other causes of pleural effusions is unknown. The aim of this study was to evaluate the usefulness of PF-TRIG in the diagnosis of other pleural effusions and investigate the origin of their increase in these fluids. We studied 390 pleural effusions (75 tuberculous, 107 neoplastic, 39 parapneumonic, 30 miscellaneous, 42 idiopathic, and 97 transudates). The correlation was analyzed with the PF-TRIG values as the dependent variable and serum triglycerides (S-TRIG) and the pleural fluid/serum protein ratio (PF/S PROT ratio) as independent variables. The PF-TRIG was significantly higher in exudates. The sensitivity of PF-TRIG for identifying exudates was 84.3%, specificity 61.9%. The correlation between PF-TRIG and S-TRIG was significant in the exudates and in the total pleural effusions. There was a significant correlation between PF-TRIG and S-TRIG and capillary permeability, which worsened when looking at the transudates and exudates separately. No correlations were found between the PF-TRIG and the number of red cells and white cells in any of the groups. Except for diagnosing a chylothorax, the determination of triglycerides in pleural fluid does not appear to be justified. The cause of the increase in PF-TRIG in exudates could not be established because the correlations obtained were insufficient to be able to predict PF-TRIG values from their serum values and the measurement of capillary permeability.

Chylothorax in a patient with HIV-related Kaposi's sarcoma.

We present a case of a 33-year-old man with a background of HIV and Kaposi's sarcoma (KS), who presented with a right sided chylothorax. He was managed with percutaneous chest drainage and talc pleurodesis, in addition to his chemotherapy and antiretroviral therapy for KS and HIV, respectively. Good clinical control of the chylothorax remained 4 months post drainage. This case report summarises the approach to investigating and managing pleural effusion, and in particular chylothorax, in HIV patients.

Pleural fluid analysis in chylous pleural effusion.

OBJECTIVES: Chyle is a noninflammatory, lymphocyte-predominant fluid that may cause a pleural effusion as a consequence of thoracic duct leakage into the pleural space. Although chyle is reported to have protein concentrations in the transudative range, chylous effusions are typically exudative, as defined by the standard criteria. We hypothesized that chylous effusions from a thoracic duct leak alone have low lactate dehydrogenase (LDH) concentrations due to the absence of inflammation and are lymphocyte-predominant, protein-discordant exudates. Consequently, pleural effusions that do not meet these criteria but with triglyceride concentrations of > 110 mg/dL or are positive for chylomicrons should be associated with other diagnoses contributing to pleural fluid formation. STUDY DESIGN: Retrospective. METHODS: The pleural fluid analyses of 876 consecutive thoracenteses were reviewed. All cases with a triglyceride concentration of > 110 mg/dL or the presence of chylomicrons were retrieved. The effusions were then classified as transudates, concordant exudates, protein-discordant exudates, and LDH-discordant exudates, and according to lymphocyte predominance (> 50%). The causes of these pleural effusions were determined after the review of the medical record. RESULTS: Twenty-two pleural effusions had elevated triglyceride concentrations and/or were positive for chylomicrons. Eleven effusions were lymphocyte-predominant, protein-discordant exudates, and two of these were associated with chylous ascites. The remaining effusions were transudates (n = 7) or concordant exudates (n = 4); all were associated with conditions known to cause pleural effusion apart from chyle leakage. CONCLUSION: Chylous effusions caused solely by conditions known to cause chylothorax were lymphocyte-predominant, protein-discordant exudates. Protein concentrations in the transudative range or elevated LDH concentrations were associated with a coexisting condition that may impact the management of these chylous effusions.

Antithrombin activity in children with chylothorax.

OBJECTIVE: To determine whether increased antithrombin loss is present in children with chylothorax after cardiac surgery. METHODS: Plasma and pleural effusion samples of children with chylous and non-chylous pleural effusion were assayed for antithrombin activity. RESULTS: Ten children with chylothorax and five children with non-chylous pleural effusion were investigated. There was statistically significant increase in mean antithrombin activity in chylous samples (32.2+/-11.4%) compared to non-chylous samples (14.4+/-13.9%), and significant decrease in plasma of children with chylothorax (44.6+/-15.4%) compared to children with non-chylous pleural effusion (69.9+/-22.4%). Seven of 10 children with chylous and none of the children without chylous developed thrombosis (p<0.007). CONCLUSIONS: Increased loss of antithrombin is present in children with chylothorax, potentially predisposing these children to an increased risk of thrombosis. Repeated antithrombin substitution should be considered in critically ill children with chylothorax.

Chylothorax as a possible diagnostic pitfall: a report of 2 cases with cytologic findings.

BACKGROUND: Chyothorax is an uncommon medical condition. To the best of our knowledge, there have been no detailed English-language report dealing with its cytopathologic findings and diagnostic pitfalls CASES: A 12-year-old boy, hemodialysis dependent, with congenital nephrotic syndrome due to focal segmental glomerular sclerosis and a failed renal transplant, developed shortness of breath. Physical and radiologic examinations revealed a left pleural effusion. A 7-year-old boy developed shortness of breath, with a subsequent finding of a left pleural effusion. Multiple osteolytic skeletal lesions were found in this patient. Both patients underwent thoracocentesis. Cytologically, both fluids contained many relatively uniform, large lymphoid cells with high nuclear/cytoplasmic (N/C) ratio, condensed chromatin and occasional nucleoli, resembling blasts. Some nuclei were convoluted. Mitotic figures were present. Foamy macrophages were present in both cases. The differential diagnosis of these populations of cells included a lymphoproliferative disorder. However, the mature T-lymphocytic nature of the cells was confirmed by immunohistochemistry performed on cell block preparations, confirming the clinical impression of chylothorax in both cases. The first patient had chylothorax as a result of trauma due to therapeutic interventions (subclavian vein cannulation), in the second patient the chylothorax was a part of Gorham-Stout syndrome. CONCLUSION: The large T-lymphocytes that are the major cellular component of chylothorax may arouse suspicion of a lymphoproliferative disorder. Attention to the clinical history and immunophenotyping confirm the benign nature of the pleural space fluid. Also, abundant foamy macrophages can be considered a low-power clue to this diagnosis.

Chylothorax diagnosis: can the clinical chemistry laboratory do more?

BACKGROUND: Chylothorax is a rare anatomical disruption of the thoracic duct associated with a significant degree of morbidity and mortality. Diagnosis usually relies upon lipid analysis and visual inspection of the pleural fluid. However, this may be subject to incorrect interpretation. The aim of this study was to compare pleural fluid lipid analysis and visual inspection against lipoprotein electrophoresis. METHODS: Nine pleural effusion samples suspected of being chylothorax were analysed. A combination of fluid lipid analysis and visual inspection was compared with lipoprotein electrophoresis for the detection of chylothorax. RESULTS: There was 89% concordance between the two methods. Using lipoprotein electrophoresis as gold standard, calculated sensitivity, specificity, negative predictive value and positive predictive value for lipid analysis/visual inspection were 83%, 100%, 100% and 75%, respectively. CONCLUSION: Examination of pleural effusion samples by lipoprotein electrophoresis may provide important additional information in the diagnosis of chylothorax.

The lipoprotein profile of chylous and nonchylous pleural effusions.

The lipoprotein electrophoregrams and the cholesterol and triglyceride levels of the pleural fluid were evaluated for patients with chylous pleural effusions, as defined by the presence of a distinctive band of chylomicrons on the lipoprotein electrophoregram, and in patients with nonchylous effusions of various causes. One hundred forty-one patients were studied during a 3-year period. The chylous effusions had strikingly higher triglyceride levels (median 249, range 49 to 2,270 mg/dl) than the nonchylous group (median 33, range 13 to 107 mg/dl); there were no significant differences in cholesterol or protein between the two groups. The gross description of the fluid was a poor indicator of its origin, being described as consistent with chyle in less than 50% of cases of chylous effusions. The triglyceride values distinguished chylous effusion from nonchylous effusion; values greater than 110 mg/dl are highly suggestive of a chylous effusion. Equivocal cases--triglyceride values between 50 and 110 mg/dl--required lipoprotein analysis. Pleural effusions of undetermined cause, regardless of gross appearance of the fluid, require that a screening triglyceride value be obtained to rule out a chylous effusion.

Chylous transport of amiodarone.

A patient receiving amiodarone for longstanding ventricular dysrhythmias presented with idiopathic chylothorax. During drainage of chylothorax for pleurodesis, serial plasma amiodarone concentrations declined while pleural fluid concentrations remained stable. Chylous transport of amiodarone and other lipid-bound drugs should be recognized to avert complications during chylothorax drainage.

Therapeutic digoxin level in chylous drainage with no detectable plasma digoxin level.

A patient receiving digoxin for long-standing congestive heart failure developed a chylothorax following removal of an infected aortic graft. Drainage of the chylothorax resulted in plasma digoxin concentrations which were near zero while the digoxin levels in the chylous drainage fluid were therapeutic. The sequestration of even low lipid-soluble drugs, such as digoxin, in chyle should be recognized to prevent subtherapeutic plasma levels in patients undergoing chylothorax drainage.

Chylothorax in cirrhosis of the liver: analysis of its frequency and clinical characteristics.

OBJECTIVES: To ascertain the frequency and to describe the clinical and biochemical features of cirrhotic chylothorax. DESIGN: A descriptive clinical study. SETTING: A community teaching hospital. PATIENTS AND METHODS: Since November 1989 to October 1995, 809 patients with pleural effusions were studied by thoracentesis. Pleural effusions with a concentration of triglycerides higher than 110 mg/dL, a pleural fluid to serum triglyceride ratio higher than 1, and a pleural fluid to serum cholesterol ratio lower than 1 were considered chylothorax. RESULTS: Twenty-four patients had pleural effusions that complied with all three aforementioned biochemical conditions. Five of these 24 patients (20%), were found to have liver cirrhosis as the main cause of chylothorax and in 3 of them, an abdominal source of the effusion could be demonstrated by intraperitoneal injection of a radioisotope (99mTc-sulfur colloid). The cirrhotic chylous effusions had significantly lower (p<0.005) protein (median, 1.7; range, 1.4 to 2.7 g/dL), lactate dehydrogenase (LDH) (median, 96; range, 77 to 138 IU/L), and cholesterol (median, 25; range, 22 to 64 mg/dL) levels than chylous effusions resulting from other causes (protein: median, 4.1; range, 1.7 to 6.8 g/dL; LDH: median, 351; range, 140 to 8,600 IU/L; and cholesterol: median, 87; range, 38 to 160 mg/dL). Cirrhotic chylothorax was always a transudate according to Light's criteria. CONCLUSIONS: Chylothorax is a rare and apparently underappreciated manifestation of cirrhosis resulting from transdiaphragmatic passage of chylous ascites. Its uniform biochemical characteristics can facilitate its separation from chylous effusions of different etiology, therefore avoiding potentially harmful diagnostic and therapeutic procedures.

Talc pleurodesis mimics pleural metastases: differentiation with positron emission tomography/computed tomography.

Talc pleurodesis is a technique used in the treatment of patients with persistent pleural effusions or pneumothorax not amenable to other treatment. These are commonly seen in patients with malignant thoracic neoplasms. Radiographic abnormalities resulting from prior talc pleurodesis could be confused with progression of the underlying neoplastic process. Positron emission tomography with F-18 fluorodeoxyglucose (FDG-PET) might be unable to distinguish between malignant and benign inflammatory processes. This report demonstrates the use of combined positron emission tomography/computed tomography (PET/CT) in a patient with a history of both malignant neoplasm and a prior talc pleurodesis. Fusion of PET and CT studies could add information that CT and PET alone cannot. This could alter the diagnostic and therapeutic course for patients with a history of both thoracic neoplasm and talc pleurodesis.

Congenital chylothorax.

Congenital chylothorax is a rare condition in which chyle accumulates in the pleural space because of an intrauterine obstruction or anomalies of the thoracic duct. This paper presents a case of congenital chylothorax diagnosed antepartum echographically. The patient's history revealed a previous sibling with a similar diagnosis. The baby developed respiratory distress after delivery and the diagnosis was established by thoracentesis. Computed tomography of the chest and nuclear lymphangiography were obtained to evaluate the origin of the pleural effusion, but a congenital fistula or other pathology of the thoracic duct could not be demonstrated. Management of the baby consisted of ventilatory support in the delivery room, repeated thoracentesis and thoracostomy tube drainage, total parenteral nutrition and formula containing medium-chain triglycerides. The infant was discharged six weeks after birth in good condition.