Hepatic Hydrothorax

Hepatic hydrothorax is an important and difficult-tomanage complication of cirrhosis and portal hypertension. Here, we aimed to study its clinical features and natural history. Complete clinical data, including outcomes, were abstracted from hospital records of patients with cirrhosis and ascites admitted to University of Texas Southwestern University teaching hospitals from January 2001 to July 2012. Hepatic hydrothorax was diagnosed based on currently accepted clinical characteristics of the disease, including a known diagnosis of cirrhosis, the presence of portal hypertension, pleural fluid analysis, and the absence of primary cardiopulmonary disease. Seventy-seven of 495 (16%) hospitalized cirrhotic patients with pleural effusion (28 female; mean age, 52 yr) met the criteria for diagnosis of hepatic hydrothorax. Resting dyspnea and cough were the most prominent presenting symptoms, occurring in 34% and 22% of patients, respectively. Pleural effusions were most often right-sided (56/77; 73%), followed by left-sided only (13/77; 17%) and bilateral effusions (8/77; 10%); 7 (9%) patients did not have detectable ascites. The mean Model for End-Stage Liver Disease (MELD) score at presentation was 16. The serum to pleural fluid albumin gradient (SPAG) was ≥1.1 in all 48 patients in whom it was measured. Most patients (64/77; 83%) were managed with diuretics and/or thoracentesis, while 8 (10%) underwent transjugular intrahepatic portosystemic shunt (TIPS) and 5 (7%) underwent liver transplant. A total of 44 of 77 (57%) patients died during a mean follow-up of 12 months. The average time from presentation to death for all patients was 368 days, while for those after TIPS it was 845 days. No deaths were reported in the liver transplant group. The data indicate that a substantial number of patients with hepatic hydrothorax had what may be considered atypical presentations, including left-sided only effusions, or pleural effusion without ascites. Here, we propose that the term “serum to pleural fluid albumin gradient (SPAG)” be used to describe the gradient between serum and pleural fluid albumin levels and suggest that not only is it consistent with the portal hypertensive pathophysiology of hepatic hydrothorax, but also it is a useful criterion for diagnosis of hepatic hydrothorax. Finally, the overall outcome of hepatic hydrothorax was extremely poor, except in those undergoing TIPS or liver transplantation. (Medicine 2014;93: 135–142) From the Department of Medicine (RB), University of Texas Southwestern, and Parkland Memorial Hospital (RB), Dallas, Texas; and Department of Medicine (DCR), Medical University of South Carolina, Charleston, South Carolina. Financial support and conflicts of interest: The authors have no funding or conflicts of interest to disclose. Reprints: Don C. Rockey, MD, Department of Internal Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 803, Charleston, SC 29425 (e‐mail: [email protected]). Copyright © 2014 by Lippincott Williams & Wilkins ISSN: 0025-7974 DOI: 10.1097/MD.0000000000000025 Medicine • Volume 93, Number 3, May 2014 Copyright © 2014 Lippincott Williams & Wilkins. Unaut Abbreviations: LDH = lactate dehydrogenase, MELD = Model for End-Stage Liver Disease, PMH = Parkland Memorial Hospital, RBC = red blood cell, SAAG = serum to ascites fluid albumin gradient, SPAG = serum to pleural fluid albumin gradient, TIPS = transjugular intrahepatic portosystemic shunts, UH = University of Texas Southwestern University Hospital, UTSW = University of Texas Southwestern, WBC = white blood cell count. INTRODUCTION Hepatic hydrothorax is an important complication of cirrhosis and portal hypertension. It has been historically described in patients with a large transudative pleural effusion (typically >500 mL), in whom a primary cardiopulmonary or malignant process has been excluded.17,31 Hepatic hydrothorax has been reported to occur in an estimated 4%–12% of patients with cirrhosis. The most commonly reported clinical manifestations of hepatic hydrothorax include symptoms associated with the complications of decompensated cirrhosis and may also include those associated with the pleural effusion, such as pleuritic symptoms: cough and shortness of breath.4,17 Hepatic hydrothorax is classically believed to present as an isolated right-sided pleural effusion, although bilateral effusions have been reported rarely. It is thought to be most common in patients with cirrhosis and severe ascites, but there are reports of hydrothorax in patients with little to no ascites.6,10,14,15,35 The management of hepatic hydrothorax typically includes medical management with diuretics and sodium restriction and therapeutic thoracentesis as needed. Dietary sodium restriction and diuretics are favored for long-term management or for treatment of mild pleural fluid accumulation, while therapeutic thoracentesis is commonly performed for acute relief of symptoms. However, transjugular intrahepatic portosystemic shunts (TIPS), liver transplant, and surgical repair of diaphragmatic defects have also been advocated in some patients, typically those with refractory disease. Further, TIPS has been suggested as an ideal approach to bridge patients to liver transplantation. We conducted the current study to better understand the natural history of hepatic hydrothorax, including clinical manifestations, objective findings, and outcomes. After carefully defining the criteria for a diagnosis of hepatic hydrothorax, we identified 77 patients, and herein describe their clinical phenotype and outcomes. PATIENTS AND METHODS The current study was a retrospective cohort investigation of patients admitted to the University of Texas Southwestern teaching hospitals, University of Texas Southwestern University Hospital (UH) and Parkland Memorial Hospital (PMH) from January 2001 to July 2012. Institutional review board approval was received from both institutions prior to data collection. www.md-journal.com 135 horized reproduction of this article is prohibited. Badillo and Rockey Medicine • Volume 93, Number 3, May 2014 Patients were identified by matching International Classification of Diseases, 9th revision (ICD-9) codes for chronic liver disease and cirrhosis (ICD-9: 571.0–571.3, 571.40–571.41) and pleural effusion (ICD-9: 511.8, 511.9) using electronic medical records. Patient data, comorbidities, reported respiratory symptoms, radiologic tests, and pleural and peritoneal fluid analysis were abstracted. In patients with multiple admissions before, during, and after the time period noted above, the earliest admission data were included in the study. Patients included in the study met the following criteria: 1) known diagnosis of cirrhosis, either biopsy-proven or based on the presence of clinical complications in the setting of a clinical scenario consistent with cirrhosis; 2) known diagnosis of pleural effusion based on plain film or computed tomography imaging; 3) pleural fluid consistent with the known characteristics of hepatic hydrothorax and not considered to be consistent with the presence of infection, malignancy, or other known chronic disease (outlined below); 4) no history of primary cardiopulmonary disorder, including but not limited to congestive heart failure; 5) evidence of portal hypertension as established by the presence of esophageal varices, portal hypertensive gastropathy, ascites, portal vein thrombosis, or an elevated hepatic venous pressure gradient (HVPG). Patients were excluded if they had known primary pulmonary malignancy or metastatic pulmonary lesions or tuberculosis, or were incidentally found to have a clinically insignificant pleural effusion, which was not evaluated by thoracentesis (Figure 1). Pleural fluid was characterized as being consistent with hepatic hydrothorax in patients with cirrhosis when the pleural fluid analysis was categorized as a transudate without evidence of primary cardiopulmonary disease, primary malignancy or metastatic disease, or active pulmonary infection. A transudate was defined as having either a pleural fluid to serum protein ratio of ≤0.50, a pleural fluid to serum lactate dehydrogenase (LDH) ratio of ≤0.6, or a pleural fluid LDH <143 units/L, which is two-thirds of the upper limit of normal for serum LDH (214) at our institutions.12,23 Patients were excluded in the setting of known infection, positive Gram stain, culture, or glucose <65 mg/dL. Clinical data abstracted included patient demographics (age, sex, and race), presenting clinical features and symptoms, extensive laboratory data, and imaging that focused on laterality and sizing of pleural effusions and amount of ascites. The size of ascites was differentiated into the following categories based on predefined criteria assigned as previously described by the FIGURE 1. Patients. Using an ICD 9-CM based search of patients with cirrhosis and pleural effusion as in Methods, a total of 495 patients were identified. Of those patients, 77 met the criteria for diagnosis of hepatic hydrothorax as outlined in Methods. 136 www.md-journal.com Copyright © 2014 Lippincott Williams & Wilkins. Unau International Ascites Club25 as follows: 1) minimal to small (only detectable by imaging studies), 2) moderate (symmetrical abdominal distension seen on physical exam), 3) large (gross ascites with significant abdominal distension), and 4) none. Laboratory data abstracted included the following: 1) hemogram (white blood cell count [WBC], hematocrit, and platelets); 2) serum chemistries (creatinine, LDH, and total protein); 3) liver studies (albumin, total bilirubin, and international normalized ratio [INR]); 4) pleural fluid (pH, glucose, LDH, albumin, total protein, and cell count); and 5) ascites fluid (albumin, total protein, and cell count). Treatment modalities and deaths were identified via the electronic medical record as well as public death records. Three main treatment modalities were identified: 1) diuretics and/or therapeutic thoracentesis alone, 2) TIPS, and 3) liver transplant. The average presentation time to death was calculated based on the date of first hospital admission to UH/PMH to the date of recorded death. The hospital admission to UH/PMH was recorded as either the initial presentation with hepatic hydrothorax or was identified as a subsequent admission. Causes of death were classified into 8 categories, based on clinical judgment according to the information provided by electronic medical records, as follows: gastrointestinal bleeding, cardiac or respiratory failure, renal failure, liver failure or cirrhosis complications, sepsis, multiorgan dysfunction syndrome, terminal malignancy, or other using predefined definitions as previously reported.1,2,7,18,34,38 Gastrointestinal bleeding (also hemorrhage) was defined as ongoing bleeding in the setting of multiple transfusions. Respiratory failure was defined as evidence of primary respiratory diseases with need for mechanical ventilation. Renal failure or hepatorenal syndrome was defined as dialysis requirement with no urine output. Sepsis was defined as sepsis syndrome, including positive blood cultures, hypotension, and fever or hypothermia. Multiorgan dysfunction syndrome was defined as the presence of altered organ function in acutely ill patients such that homeostasis could not be maintained without intervention. We (RB and DCR) adjudicated the cause of death in a blinded fashion (without knowledge of the primary physician’s conclusion as to the cause of death), and agreed on the cause of death in all cases that could be determined. The cause of death was able to be clearly determined in 16 of 44 (36%) cases, because many patients died out of the hospital, and records surrounding the immediate cause of death were not available.