Chylothorax in Cirrhosis of the Liver

Chylothorax in Cirrhosis of the Liver* Analysis of Its Frequency and Clinical Characteristics Santiago Romero, MD; Concepcion Martin, MD; Luis Hernandez, MD; Jose Verdu , MD; Celia Trigo, MD; Miguel Perez-Mateo, MD; and Loreto Alemany, MD

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 mgldL, 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 (99 mTc-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 lUlL), and cholesterol (median, 25; range, 22 to 64 mgldL) levels than chylous effusions resulting from other causes (protein: median, 4.1; range, 1.7 to 6.8 gldL; LDH: median, 351; range, 140 to 8,600 lUlL; 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. (CHEST 1998; 114:154-159) Key words: abdominal scintigraphy; ascites; chylothorax; cirrhosis of the liver Abbreviations: LD H =lactate dehydrogenase

E xtensive reviews of unselected patients with chy-

lothorax have included examples with no apparent cause or associated condition other than cirrhosis of the liver.l·2 Clinical details of this rare complication of chronic liver disease have been published only through sporadic case reports, where the biochemical features of the pleural fluid and its relationship with previous chylous ascites were not always elucidated.3-5 Because gross appearance of a pleural fluid can be misleading in the diagnosis of chylous effusions, 6 ·7 *From the Servicios de Neumologia y Analisis Clinicos, Hospital General Universitario de Alicante, and the Servicio de Medicina Nuclear, Hospital Universitario de San Juan, Alicante, Spain. Manuscript received June 10, 1997; revision accepted November 21, 1997. 154

since 1989, we have determined the concentration of triglycerides in pleural effusions in a systematic way to exclude the presence of chylothorax. Until October 1995, 5 of the 24 patients diagnosed as having chylous effusion by biochemical criteria were found to have liver cirrhosis as the main cause of the effusion. The main objectives of the present study were to emphasize the relative high frequency of this kind of chylothorax and to describe its apparently uniform clinical and biochemical features that can facilitate its segregation from chylothorax of different etiology. MATERIALS AND METHODS

From Novembe r 1989 to October 1995, in all patients studied by thoracentesis at our se rvice, the following studies w ere Clinical Investigations

performed on pleural fluid samples: glucose; protein; lactate dehydrogenase (LDH); cholesterol; triglycerides; pH; cell count and differential; bacterial and fungal culture; acid-fast bacilli smear and culture; and cytology. A sample of serum, simultaneously obtained with thoracentesis, was used to measure glucose, total protein, cholesterol, triglycerides, and LDH levels. In patients with coexisting ascites, paracentesis and studies performed on ascitic fluid were done at the discretion of the primary physician. Biochemical parameters were determined using a selective discrete multichannel analyzer (Hitachi 737; Tokyo, Japan ). Total protein concentrations (gldL) were measured using the biuret method. LDH level (IU/L) was measured using a kinetic UV optimized standard method conforming to th e recommendations of th e Deutsche Cesellschaft for Kinische Chemie; the upper normal limit (serum) is defined at 460 IU/L. Cholesterol level (mgldL) was measured using the enzymatic colorimetric method (cholesterol oxidase-phenol-4 aminophenazone, high performance) and triglycerides level using an e nzymatic colorimetric test (GPO-PAP; Boehringer Mannheim; Manheim, Germany). Lipoproteins were analyzed by means of electrophoresis according to the method of Atom, a modification of that outlined by Coifs and Verheyden 8 Electrophoretic separation of pleural fluid lipoproteins was carried out on cellulose acetate (Cellogel; Atom; No. 19003; 5.7X14 em; Biosyste ms; Barcelona, Spain) at 200 V for 40 min at room temperature. Ten microliters of plasma or serum was applied to the cathodic end of each string which was later stained overnight with Sudan black and quantified using a densitometer (Cellosystem; Sebia; Issy-Les- Moulineaux, France). To determine whether communication existed behveen the peritoneal and pleural cavities, an external scanning of the thorax in supine position, after 90 min of an intraperitoneal injection of 37 mBq of 99 ""Tc-sulfur colloid diluted in 20 mL of saline

solution, was performed. An abdominal image was obtained to ensure a homogeneous mixture of the radiotracer with the ascitic fluid. Anterior, poste rior, and optionally lateral planar views of the thorax, at 120 min and 24 h, were repeated. Each view lasted 10 min, and a 128 X 128 matrix was used. The presence of activity in the thorax was inte rpreted as pathologic, indicating free pass of abdominal fluid through a peritoneal-pleural communication. Pleural effusions with a concentration of triglycerides higher than 110 mgldL, a pleural fluid to serum triglyceride ratio higher than 1, and a pleural fluid to serum cholesterol ratio lower than 1 were considered chylothorax. 7 ·9 To compare the concentrations of pleural biochemical parameters behveen cirrhotic and noncirrhotic chylothorax, the Mann Whitney U test was used. Results are expressed as median and range, and were considered significant at p<0.05. RESULTS

During the period of study, 809 patients with pleural effusions were studied by thoracentesis. Twenty-four patients (13 men and 11 women) with a mean age of 59.2±15.6 years had, at least once, pleural effusions that complied with all three aforementioned biochemical conditions and were considered to have chylothorax. Among them, in all 15 patients tested, the finding of a chylomicron band in pleural fluid confirmed their chylous character. The etiology and the appearance of the effusion as well as the age, sex, follow-up, and outcome of the 24 patients with chylothorax are shown in Table 1. One

Table !-Clinical Characteristics of 24 Patients With Chylothorax* Appearance Case/Sex/Age, yr

Ascites

PF

A

Etiology

Outcome

Follow-up, mo

l/M/64 2/F/70 3/F/73 4/F/54 5/M/69 6/M/58 7/F/58 8/F/46 9/F/49 10/M/69 ll/M/87 12/M/23 13/M/67 14/F/73 15/F/69 16/M/4.5 17/M/51 18/F/41 19/M/54 20/M/78 21 /F/63 22/M/25 23/F/62 24/M/73

+ + + + + + + +

M B M M M M M M M M M M

nr nr M M M np M M

Cirrhosis Cirrhosis Cirrhosis Cirrhosis Cirrhosis NH lymphoma NH lymphoma NH lymphoma NH lymphoma NH lymphoma NH lymphoma H lymphoma Gastric carcinoma Vulva carcinoma Ovarian carcinoma Nasal carcinoma Retroperitoneal sarcoma Postoperative Postoperative Lymphocytic leukemia Encapsulated empyema AIDS, tuberculosis Amyloidosis Idiopathic

Dead Dead Dead Dead Dead Dead Dead CR Dead Unavailable Dead CR Dead Dead PR Dead Dead PR Cured Dead Cured Dead Dead Cured

36 4 5

nd

+

y y

np

+

M B M B B B T T M T

nr

+ + +

np np M

7 67 45 30 16

? 4 60 1 15 1 28 23 54 1 68 15 7 5.5

*PF =pleural fluid; A=ascites; nr=not referred; np=no paracentesis; M=milky; T=turbid yellow; Y=straw yellow; B=bloody; PR=partial response; CR =complete response; NH = non-Hodgkin's; H =Hodgkin's. CHEST/114/1 /JULY, 1998

155

Table 2-Additional Clinical Features of Patients With Cirrhosis of the Liver* Etiology

Ch-P Index

Esophageal Varices

B

+ +

Alcoholic Alcoholic Alcoholi c Postnecrotic ' Postnecrotic

c

Cr, mgldL l.l

1.2 0.6 0.7

B

c

+ +

B

*Ch-P= Child-Pugh

26

;

Associated Diseases Hepatocarcinoma AF

l.l

Time from dx to ChT, mo

Cause of Death

7 252 12 48 12

Hepato-renal Sd Hepato-renal Sd HF/encephalopathy Upper GI bleeding HF/encephalopathy

Cr=serum creatinine; dx = diagnosis; ChT =chylothorax; HF=hepatic failure; AF =atrial fibriliation; Sd=syndrome.

patient with postoperative chylothorax had coexisting disseminated carcinoma, and surgical trauma as the cause of the chylothorax could not be ruled out in a patient with lymphoma. The five patients with cirrhotic chylothorax had been previously diagnosed as having liver cirrhosis based on the following clinical and laboratory findings: signs of chronic liver disease, prolonged prothrombin time, hypoalbuminemia, hypergammaglobulinemia, and esophageal varices seen on endoscopy or collateral circulation seen on echography. Additional clinical information of these five patients is given in Table 2. One woman (case 2) was diagnosed as having liver carcinoma by CT-guided fine-needle aspiration puncture 2 months before dying. Biochemical features of pleural and ascitic effusions in patients with cirrhosis are shown in Table 3.

Chylous ascites without radiologic evidence of pleural effusion was demonstrated in one patient (case 1) and the alternative character, chylous-nonchylouschylous, of the pleural effusion could be observed in another (case 5). In the four patients in whom simultaneous comparisons of ascitic and pleural fluids could be made, the chylous pleural effusions had protein and LDH concentrations that were approximately twofold those of the ascites. No uniform differences between other chemical values of the pleural chyle relative to the ascitic chyle were found. Analysis of laboratory values in patients with cirrhotic chylothorax showed that pleural fluid protein, LDH, and cholesterol concentrations as well as leukocyte counts were significantly lower compared with those in chylous effusions resulting from other causes (Table 4). Pleural effusions from all five cirrhotic patients were transudates according to the

Table 3-Pleural Fluid and Ascites Characteristics of Cirrhotic Patients* Protein, gldL Date Case 1 Oc-91 1 Ap-92 My-92 J-93 Case 2 Ap-93 Case 3 Sp-93 Case4 Sp-93 Case 5 Mr-95 Sp-95 Oc-95

Sample

Appearance

A PF PF PF

I

LDH, IUIL

Trig!, mgl dL

Cholesterol , mgldL

PF

PF/S

PF

PF/S

PF

PF/S

PF

PF/S

Chylomicrons

PMN

pH

Culture

nr M M M

2.3 2.7 3.7 1.7

0.28 0.41 0.47 0.23

nd 108 112 91

nd 0.44 0.42 0.28

271 555 830 636

nd 12.1 15.4 nd

48 64 84 30

nd 0.45 0.56 nd

nd nd

380 20 70 nd

nd 7.42 nd nd

(-) (- ) (-)

PF A

B nr

2.0 1.5

0.32 0.24

96 43

0.35 0.15

143 152

3.6 nd

29 nd

0.34 nd

+

10 20

7.36 nd

(-) (-)

PF A

M M

1.4 0.7

0.18 0.09

84 85

0.21 0.21

245 518

2.5 nd

22 25

0.12 nd

+ +

38 24

7.44 nd

(-) (-)

PF A

M M

1.7 0.9

0.27 0.14

138 65

0.29 0.14

328 291

4.1 nd

25 13

0.23 nd

nd nd

70 50

7.46 nd

(-)

PF PF A PF A

M

1.6 3.3 1.0 1.4 0.6

0.22 0.5 0.15 0.22 0.1

77 119 37 70 32

0.19 0.53 0.16 0.31 0.14

187 68 63 170 188

2.7 nd nd nd nd

23 49 nd 24 nd

0.18 nd nd nd nd

+ nd nd nd nd

81 60 18 120 0

7.48 7.48 nd nd nd

y

nr M M

+ nd

nd

(- )

(- )

(- )

nd (-) (-) (-)

*A=ascites; PF = pleural fluid ; PF/S=pleural fluid serum ratio; nr =not referred; nd = not done; T1igl=triglyce rides; M=milky; B=bloody; Y=straw yellow; Oc = October; Ap =April; My= May; JI = July; Sp=September; Mr = March; PMN=polymorphonuclear leukocytes. 1 No radiographic evidence of pleural effu sion at that moment.

156

Clinical Investigations

Table 4-Separate Biochemical Pleural Characteristics of Cirrhotic and Noncirrhotic Patients* Other Etiologies (n= 19) Median (Range)

p Value

1.7 (1.4-2.7) 4.1 (1.7-6.8) 96 (77-138) 351 (140-8,600) 0.27 (0.18-0.41 ) 0.6 (0.46-0.97) 0.29 (0 19-043) 0.87 (038-10) 25 (22-64) 87 (38-160) 245 (143-555) 284 (115-1,652) 129 (100-209) 120 (33-204) 150 (3-630) 1160 (29-9,200) 200 (30-700 ) 1700 (140-12,000) 90 (65-99) 70 (4-100)

< 0.005 < 0001 < 0.001 < 0.001 < 0.005 0.59 0.21 < 001 < 0.01 0.26

Cirrhosis (n=5) Median (Range) PF protein PF LDH PF/S protein PF/S LDI-I PF cholesterol PF triglycerides PF glucose PF lymphocytes PF leukocytes PF lymphocytes, %

ABDDM£N ANT 3D Min

*PF=ple ural fluid ; S=serum.

°

criteria of Light et al. 1 Chylous effusions in the 19 remaining patients were always exudates. Scintigraphy showed the presence of thoracic activity 90 min after the intraperitoneal injection of the radioisotope in the three cirrhotic patients tested (Figs 1 and 2).

THDRAH ANT 24 Hours

FIGURE 2. Case l. Peritoneal scintigraphy of a 65-year-old patient with cirrhosis and chylothorax. The day that 99 "'Tc-sulfur colloid was injected, ascites was barely evident and radiolabeling in th e peritoneal space (top left) is seen mainly in areas where fluid gravitates . As in the previous case, abnormal activity in th e right ple ural space was already evident after 90 min.

DISCUSSION

Light 11 divided the etiology of chylothorax into four major categories: tumor, trauma, idiopathic, and

ABDOMEN RNT 30 Min

FIGURE l. Case 3. Supine posterior views of nuclear scan of abdomen (top left) and upper abdomen and chest after 99 "'Tcsulfur colloid was injected into th e peritoneal cavity. The abdominal view shows widespread activity within th e peritoneal cavity. Abnormal activity is seen in th e right pleural space after 90 min, presumably after movement into the thorax through a right hemidiaphragmatic defect.

miscellaneous. The last category, where cirrhosis was included together with other rare etiologies, accounts for <10% of the cases. 11 So, at first, the high proportion (20%) of cirrhotic chylothorax found in the present series must be considered interesting. In our own previous experience, all pleural fluids that contain chylomicrons had values of triglycerides > llO mgldL, 7 but the positive predictive value of this criterion for chylothorax was low (58%). Because in the present study the pleural concentration of chylomicrons was not always determined, two more conditions were added to the former criterion to increase its specificity: a triglycerides ratio between pleural fluid and serum higher than 1 to avoid false-positive effusions in patients with hypertriglyceridemia, and a pleural fluid to serum cholesterol ratio lower than 1 to exclude pseudochylothorax. 9 These reshictive criteria may contribute to lower the number of chylothoraces included in this series and so enhance the proportion of those secondary to cirrhosis. However, when applying all three criteria, the clinical and biochemical criteria concur better. We believe that cirrhotic chylothorax has been underreported in the past. Pleural effusions in patients with chylous ascites are not always drained or biochemically evaluated, and this fact may contribute to lower its actual frequency. 12- l5 In fact, not only have reported cases of cirrhotic chylothorax been scarce, but its secondary character CHEST / 114 / 1 /JULY, 1998

157

to chylous ascites has not always been emphasized. Six percent of all patients with cirrhosis of the liver and clinical ascites also had hydrothorax and, as Lieberman et aP 6 · 17 demonstrated in most cases, the source of the pleural fluid was in the abdomen. Although an overactive and overdistended thoracic duct, as that of cirrhotic patients, may render it vulnerable to small trauma, there is no reason to think that the aforementioned pathogenic mechanism for hydrothorax does not apply to cirrhotic chylothorax. Cases of chylothorax without clinical or necropsic evidence of ascites have been reported, 3 which may cast some doubts as to the uniform validity of the former pathogenic mechanism . However, as in the case of hepatic hydrothorax,18·19 the existence of chylothorax without clinical evidence of ascites does not rule out the possible abdominal origin of the effusion. In the presence of a free communication between thoracic and peritoneal cavities, a preferential accumulation of fluid at the former will result because of its lower pressure. When the flow of ascitic chylous fluid into the pleural space equals the rate of ascites production, clinical absence of detectable ascites will occur. In the present series, coexisting chylous ascites was demonstrated in the five patients studied and an abdominal source of the chylothorax was demonstrated, by intrape1itoneal injection of a radioisotope, in three of them, including one patient in whom chylous ascites was at that moment barely evident. In some cirrhotic patients, exceptionally high pressure together with degenerative changes 20 ·21 in the splanchnic lymph vessels may lead to rupture of small lymphatics and leakage of whole intestinal lymph into the ascitic fluid . As a result of dilution in coexisting portal hypertension ascites, the chylous ascites in cirrhotics has a lower triglyceride and lymphocyte concentration than chylous ascites secondary to malignancy or trauma and distinctive characteristics of a transudative effusion. In fact, their transudative character was the rule in the present study and may help to identify this kind of chylothorax. Instances of other chylothoraces with biochemical characteristics of transudate, as those secondary to cardiac failure 22 or nephrotic syndrome23 ·24 that were absent in the present series, seem to be extremely rare but they must be excluded. However, the presence of an exudative chylothorax does not rule out cirrhosis as its cause. Infection of preexisting hydrothorax in cirrhotic patients, spontaneous bacterial empyema, can turn the pleural effusion from transudate to exudate, 25 as occurred in a patient previously described7 with a cirrhotic chylothorax 158

infected with Escherichia coli in whom the pleural LDH concentration was extremely high. The elevation of chemical values of the pleural chyle relative to the ascitic chyle has been attributed to preferential water reabsorption in the pleural space .23 However, while a higher concentration of protein and LD H was herein consistently found, the elevation of pleural fluid triglycerides relative to the abdominal fluid previously reported 23 was not apparent in any case of the present study or in the other three patients with chylothorax secondary to cirrhosis in whom this information is reported. 5 .1 2 Finally, another interesting finding of the present study was the fact that chylothorax secondary to liver cirrhosis, despite its "benign" character, conveys an equivalent or worse prognosis than most chylothoraces associated with malignancy. In conclusion, there are reasons to believe that chylothorax is a rare and apparently underappreciated manifestation of cirrhosis resulting from transdiaphragmatic passage of chylous ascites. When ascites is scanty, the abdominal origin of the chylothorax may become unapparent and provoke useless and potentially harmful diagnostic and therapeutic procedures. As the results of the present study demonstrate, the biochemical characteristics of cirrhotic chylothorax, always of a transudate in the absence of infection, are useful for diagnosis.

REFERENCES 1 Nix JT, Albert M, Dugas JE, et al. Chylothorax and chylous ascites: a study of 302 selected cases. Am J Gastroenterol 1957; 28:40-55 2 Serra Batlles J, Xaubet A, Picado C, et at. Etiologfa de los quilot6rax de origen no trammltico. Med Clin (Bare) 1986; 86:187-89 3 Yunis EJ, Moran TJ. Chylothorax and portal cirrhosis. JAMA 1965; 192:150-51 4 Lenci G. Chylothorax bei leberzirrhose: kasuistik. Pneumologie 1990; 44:704-07 5 Rodriguez E, Aliaga JL, Vila A. Quilot6rax y cirrosis hepatica. Arch Bronconeumol1992; 28:401-02 6 Staats BA, Ellefson RD , Budahn LL, et la. The lipoprotein profile of chylous and nonchylous pleural effusions. Mayo Cljn Proc 1980; 55:700-04 7 Romero Candeira S, Navarro Tellez P, Trigo Maestro C, eta!. Utilidad de !a determinacion de parametros grasos en los derrames pleurales. Med Clin (Bare) 1989; 92:450-53 8 Coifs B, Verheyden J. Electrophoresis and Sudan black staining of lipoproteins on gelatinised cellulose acetate. Clin Chern Acta 1967; 18:325-34 9 Coe JE , Alkawa JK. Cholesterol pleural effusion. Arch Intern Med 1961; 108:163-74 10 Light RW, MacGregor MI, Luchsinger PC, et al. Pleural effusions: the diagnostic separation of transudates and exudates. Ann Intern Med 1972; 77:507-13 11 Light RvV. Chylothorax, hemothorax, and fibrothorax. In : Murray JF, Nadel JA, eds. Textbook of respiratory medicine. Philadelphia: WB Saunders, 1988; 1760-69 Clinical Investigations

12 Vidal Marsal F, Pujol Ingles F , Bove Ribe A, et a!. Ascitis quilosa del adulto. Rev Clin Esp 1985; 177:31-34 13 Sultan S, Pauwels A, Poupon R, et al. Ascite chyleuse du cirrhotique: etude retrospective de 20 cas. Gastroenterol Clin Bioi 1990; 14:842-47 14 Press OW, Press NO, Kaufman SD . Evaluation and management of chylous ascites. Ann Intern Med 1982; 96:358-64 15 Kelley ML, Butt HR. Chylous ascites: an analysis of its etiology. Gastroenterology 1960; 39:161-82 16 Lieberman FL, Hidemura R, Peters RL, et al. Pathogenesis and treatment of hydrothorax complicating cirrhosis with ascites. Ann Intern Med 1966; 64:341-51 17 Lieberman FL, Peters RL. Cirrhotic hydrothorax: further evidence that an acquired diaphragmatic defect is at fault. Arch Intern Med 1970; 125:114-17 18 Singer JA, Kaplan MM, Katz RL. Cirrhotic pleural effusion in the absence of ascites. Gastroenterology 1977; 73:575-77 19 Rubinstein D , Mcinnes IE , Dudley FJ. Hepatic hydrothorax in the absence of clinical ascites: diagnosis and management. Gastroenterology 1985; 88:188-91

20 Malagelada JR, Iber FL, Linscheer WG. Origin of fat in chylous ascites of patients with liver cirrhosis. Gastroenterology 1974; 67:878-86 21 Rector WG. Spontaneous chylous ascites of cirrhosis. J Clin Gastroenterol 1984; 6:369-72 22 Villena V, De Pablo A, Martfn-Escribano P. Chylothorax and chylous ascites due to heart failure. Eur Respir J 1995; 8: 1235-36 23 Moss B, Hinds S, Fedullo AJ. Chylothorax: a complication of the nephrotic syndrome. Am Rev Respir Dis 1989; 140: 1436-37 24 Lindenbaum J, Scheidt SS. Chylous ascites and nephrotic syndrome: report of a case, associated with renal vein thrombosis. Am J Med 1968; 44:830-36 25 Xiol X, Castellote J, Baliellas C, et al. Spontaneous bacterial empyema in cirrhotic patients: analysis of 11 cases. Hepatology 1990; 11:365-70 26 Pugh RNH , Murray-Lyon IM , Dawson JL, et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973; 60:646-49

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