Ascites

Gastroenterology

1. EVALUATION OF ASCITES- Short review

2. Causes of Ascites CAUSES OF ASCITES* Percentage Cirrhosis (with or without peritoneal infection) 85 Miscellaneous portal hypertension-related disorder (including 5% with two causes) 8 Cardiac disease 3 Peritoneal carcinomatosis 2 Miscellaneous nonportal hypertension–related disorders 2 * Runyon BA, Montano AA, Akriviadis EA, Antillon MR, Irving MA, McHutchison JG. The serum-ascites albumin gradient is superior to the exudate-transudate concept in the differential diagnosis of ascites. Ann Int Med. 1992 Aug 1;117(3):215-20.

3. DATA IN INDIA * Mehra D, Thakur D, Sultania S, Chaturvedi A, Agarwal G, Kumar A. Etiology of ascites in adults living in Rohilkhand region, India: A hospital-based study. IJAR. 2016;2(12):01-4. Causes of Ascites* Percentage Cirrhosis 60.79 Tuberculosis 15.69 Pancreatitis 7.84 Malignancy 5.88 Constrictive pericarditis 5.88 Nephrotic syndrome 3.92

4. DATA IN INDIA Causes of Ascites* Percentage Cirrhosis 60.7 Tuberculosis 13.0 Mixed Ascites 1.78 Malignancy 7.7 Cardiac 7.7 Renal 5.9 Scrub typhus 1.1 Inconclusive 3.5 *Kumar B, Sharma B, Raina S, Sharma N, Gupta D, Mardi K. Etiology of ascites in adults living in the Hills of Himachal Pradesh, India: A hospital-based study. CHRISMED Journal of Health and Research. 2016 Jan 1;3(1):41.

5. Pathophysiology of Ascites in the setting of Cirrhosis Portal Hypertension Increased Nitric Oxide Vasodilation Increased symphathetic activity,Renin , Aldosterone Overfill of Intravascular volume Ascites Renal Sodium retention Increase in the hydrostatic pressure within the hepatic sinusoids Transudation of fluid into the peritoneal cavity

6. PATHOPHYSIOLOGY IN NON CIRRHOTIC ASCITES Peritoneal carcinomatosis appears to cause ascites through the production of proteinaceous fluid by tumor cells lining the peritoneum. Extracellular fluid enters the peritoneal cavity to re-establish oncotic balance. liver metastases - portal hypertension caused by stenosis or occlusion of portal veins by tumor nodules or tumor emboli HCC - Underlying cirrhosis related portal hypertension, tumour induced portal vein thrombosis or both Chylous ascites in patients with malignant lymphoma appears to be caused by lymph node obstruction by tumor and rupture of chyle -containing lymphatics . Tuberculosis -production of proteinaceous fluid, as in peritoneal carcinomatosis . Biliary/Pancreatic ascites - leakage of pancreatic juice or bile into the peritoneal cavity.

7. CLINICAL FEATURES FOR EVALUATION Ascites frequently develops during a patient’s first episode of decompensation of alcoholic liver disease. Patients with a long history of stable cirrhosis and the sudden development of ascites should be suspected of harbouring a hepatocellular carcinoma Malignancy-related ascites frequently is painful, whereas cirrhotic ascites usually is not, unless bacterial peritonitis or alcoholic hepatitis is superimposed. SISTER MARY JOSEPH NODULE in umbilicus- Malignancy Tumors causing Malignant ascites --ovarian, colorectal, pancreatic and uterine; extra-abdominal tumors originating from lymphoma, lung and breast* Cardiac Disease- Elevated JVP Collaterals in the back may indicate an obstruction of the inferior vena cava. Presence of enlarged lymph nodes may suggest tuberculosis or lymphoma. * Sangisetty SL, Miner TJ. Malignant ascites: a review of prognostic factors, pathophysiology and therapeutic measures. World J Gastrointest Surg. 2012 Apr 27;4(4):87 .

8. CLASSIFICATION OF ASCITES GRADE 1- Mild ascites only detectable by ultrasound GRADE 2- Moderate ascites evident by moderate symmetrical distension of abdomen GRADE 3- Large or gross ascites with marked abdominal distension The ascites that recurs at least on three occasions within a 12-month period despite dietary sodium restriction and adequate diuretic dosage is defined as recidivant * *Arroyo V, Ginès P, Gerbes AL, Dudley FJ, Gentilini P, Laffi G, Reynolds TB, Ring‐Larsen H, Schölmerich J. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. Hepat . 1996 Jan;23(1):164-76.

9. Abdominal Paracentasis A diagnostic paracentesis should be performed in all patients with new onset grade 2 or 3 ascites, and in all patients hospitalized for worsening of ascites or any complication of cirrhosis (Level A1).* Contraindications of Paracentasis : Coagulopathy should preclude paracentesis only when there is clinically evident hyperfibrinolysis (three-dimensional ecchymosis/hematoma) or clinically evident disseminated intravascular coagulation.** Other Contraindications:- Pregnancy Abdominal skin infection at the proposed puncture site Severe Bowel distension Uncooperative patient * Angeli P, Bernardi M, Villanueva C, Francoz C, Mookerjee RP, Trebicka J, Krag A, Laleman W, Gines P. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol . 2018 Apr. **Runyon BA, AASLD Practice Guidelines Committee. Management of adult patients with ascites due to cirrhosis: update 2012. Hepatology . 2013 Feb;57(4):1651-3.

10. ASCITIC FLUID ANALYSIS GROSS APPEARANCE: This can range from water-clear to frankly purulent, bloody, or chylous . The opacity of many cloudy ascitic fluid specimens is caused by neutrophils. Fluid with an absolute neutrophil count less than 1000/mm3 may be nearly clear. Fluid with a count greater than 5000/mm3 is quite cloudy Ascitic fluid with a very low protein concentration may have no pigment and look like water. An RBC count of 10,000/mm3 is the threshold for a pink appearance; lower concentrations result in clear or turbid fluid. Ascitic fluid with an RBC count greater than 20,000/mm3 is distinctly red. Blood stained fluid is usually due to malignancy but may occur with tuberculosis, pancreatitis, hepatic vein thrombosis, or due to a traumatic tap* Samples from patients with hepatocellular carcinoma are regularly bloody, but only about 10% of samples from patients with peritoneal carcinomatosis are red** * Sood R. Ascites: diagnosis and management. Journal of Indian Academy of Clinical Medicine 2000; 5: 80. 2000;9. ** Runyon BA, Hoefs JC, Morgan TR. Ascitic fluid analysis in malignancy‐related ascites. Hepatology . 1988 Sep 1;8(5):1104-9.

11. Opaque milky fluid- Chylous ascites (TG >200 mg/dl) Cloudy ascites, also known as pseudochylous ascites, may indicate peritonitis, pancreatitis or a perforated bowel* Deeply jaundiced patients have bile-stained ascitic fluid Dark-brown fluid with a bilirubin concentration greater than that of serum usually indicates biliary perforation** Pancreatic ascites may be pigmented because of the effect of pancreatic enzymes on RBCs. The degree of pigmentation ranges from tea- colored to jet black, as in pancreatic necrosis. Black ascitic fluid also may be found in patients with malignant melanoma * Oey RC, van Buuren HR, de Man RA. The diagnostic work-up in patients with ascites: current guidelines and future prospects. Neth J Med. 2016 Oct 1;74:330-5 ** Runyon BA. Ascitic fluid bilirubin concentration as a key to the diagnosis of choleperitoneum . J Clin Gastroenterol 1987; 9:543-5

12. TESTS CELL COUNT: The WBC count in uncomplicated ascites in the setting of cirrhosis is usually less than 500/mm3. The upper limit of normal for the absolute PMN count in uncomplicated ascitic fluid in cirrhosis is usually stated to be lower than 250/mm3. SBP is the most common cause of an elevated ascetic Fluid WBC count An ascites-specific dipstick has been developed and calibrated to 100% sensitivity in detecting a neutrophil count greater than or equal to 250 cells/mm* Leakage of blood into the peritoneal cavity leads to an elevated ascitic fluid WBC count.To correct for this, 1 PMN is subtracted from the absolute ascitic fluid PMN count for every 250 RBCs * Mendler MH, Agarwal A, Trimzi M, et al. A new highly sensitive point of care screen for spontaneous bacterial peritonitis using the leukocyte esterase method. J Hepatol 2010; 53:477-83.

13. SERUM ASCITIS ALBUMIN GRADIENT Calculating the SAAG involves measuring the albumin concentration of serum and ascitic fluid specimens obtained on the same day and subtracting the ascitic fluid value from the serum value. If the SAAG is greater than or equal to 1.1 g/ dL (11g/L), the patient has portal hypertension, with approximately 97% accuracy.* Conversely, if the SAAG is less than 1.1 g/ dL (11 g/L), the patient is unlikely to have portal hypertension If the first result is borderline (e.g., 1.0 or 1.1 g/ dL )repeating the paracentesis and analysis usually provides a definitive result *Runyon BA, Montano AA, Akriviadis EA, Antillon MR, Irving MA, McHutchison JG. The serum-ascites albumin gradient is superior to the exudate-transudate concept in the differential diagnosis of ascites. Ann Intern Med 1992;117:215-220

14. CLASSIFICATION OF ASCITES BY SAAG HIGH SAAG ( > 1.1 gm /dl) Cirrhosis Alcoholic hepatitis Cardiac ascites Portal vein thrombosis Budd- Chiari syndrome Fatty liver of pregnancy Fulminant hepatic failure Massive liver metastases “Mixed” ascites Myxedema Sinusoidal obstruction syndrome LOW SAAG(<1.1gm/dl) Peritoneal carcinomatosis Tuberculous peritonitis Nephrotic syndrome Biliary ascites Pancreatic ascites Bowel obstruction or infarction Postoperative lymphatic leak Serositis in connective tissue diseases

15. Distribution of ascites on the basis of SAAG HIGH SAAG Percentage LOW SAAG Percentage Cirrhosis 74.28 Peritoneal Carcinomatosis 26.27 Decompensated heart failure 17.14 Tuberculous Ascites 26.27 HCC 5.71 Nephrotic Syndrome 26.27 Tuberculous Ascites 2.85 Pancreatits 13.33 Cirrhosis 6.66 * Sastry AS, Mahapatra SC, Dumpula V. Ascitic fluid analysis with special reference to serum ascites cholesterol gradient and serum ascites albumin gradient . Int J Res Med Sci. 2017 Jan 23;5(2):429-36.

16. FALSE LOW SAAG: SR. Albumin <1 gm /dl Hypotension Sr. Globulins >5 gm /dl To correct the SAAG in the setting of a high serum globulin level, the following formula is used * :- Corrected SAAG= Uncorrected SAAG X 0.16 X (Sr. Globulin + 2.5) FALSE HIGH SAAG Chylous ascites * Hoefs J. Globulin correction of the albumin gradient Correlation with measured serum to ascites colloid osmotic gradient. Hepatology 1992; 16:396-403.

17. ASCITIC FLUID TOTAL PROTEIN Ascitic fluid total protein concentration <2.5 g/dl:- Uncomplicated Cirrhotic ascites* Nephrotic ascites HCC Massive Liver Metastasis *(Almost 20% of ascitic fluid samples in patients with cirrhosis will have a protein concentration greater than 2.5 g/ dL ) Ascitic fluid total protein concentration >2.5 g/ dL :- Cardiac Ascites (In patients with cardiac ascites, the SAAG may narrow with diuresis; such narrowing does not happen in patients with cirrhosis.) A total protein concentration <1.5 g/dl is generally considered a risk factor for SBP

18. Ascitic fluid Culture The most common bacterial infection of ascitic fluid, SBP, is monomicrobial , with a low bacterial concentration (median colony count of only 1 organism/mL). * Multiple prospective trials have shown that bacterial growth occurs in only about 50% of instances when ascitic fluid with a polymorphonuclear leukocyte (PMN) count greater than or equal to 250 cells/mm3 is cultured by older methods, i.e. sending a syringe or tube of fluid to the laboratory, as compared to approximately 80% if the fluid is inoculated into blood culture bottles at the bedside and prior to administration of antibiotics ** A single dose of an effective antibiotic usually leads to a negative bacterial culture. *Runyon BA, Canawati HN, Akriviadis EA. Optimization of ascitic fluid culture technique. Gastroenterology 1988; 95:1351-5 **Runyon BA, Antillon MR, Akriviadis EA, McHutchison JG. Bedside inoculation of blood culture bottles is superior to delayed inoculation in the detection of spontaneous bacterial peritonitis. J Clin Microbiol 1990;28:2811-2812.

19. ASCITIC FLUID GLUCOSE : Ascitic fluid glucose can drop significantly in severe infections like secondary peritonitis or late stage of SBP. Low glucose can also be found in malignant ascites. In early SBP, the ascitic fluid glucose concentration is similar to that of sterile fluid. ASCITIC FLUID pH: Can be used for the diagnosis of SBP In a study*,the mean (±S.E.) ascitic fluid pH in the SBP group was 7.25 ± 0.06 with a range of 7.12 to 7.31, while the ascitic fluid pH in the group with sterile ascites was 7.47 ± 0.07 with a range of 7.39 to 7.58. The pH of the blood in both groups was 7.47 ± 0.03 . The ascitic fluid pH is recommended as an easy, quick, sensitive, and specific means of diagnosing SBP* * Gitlin N, Stauffer JL, Silvestri RC. The pH of ascitic fluid in the diagnosis of spontaneous bacterial peritonitis in alcoholic cirrhosis. Hepatology . 1982 Jul;2(4):408S-11S .

20. Ascitic Fluid LDH: Elevated in:- Secondary peritonitis Malignant Ascites * Ascitic Fluid Amylase:- In patients with acute pancreatitis or intestinal perforation (with release of luminal amylase into the ascitic fluid), the fluid amylase concentration is elevated markedly, usually greater than 2000 U/L, and approximately 5-fold greater than simultaneous serum values * Sevinc A, Sari R, Fadillioglu E. The utility of lactate dehydrogenase isoenzyme pattern in the diagnostic evaluation of malignant and nonmalignant ascites. J Nat Med Asso . 2005 Jan;97(1):79.

21. Ascitic fluid Bilirubin :- An ascitic fluid bilirubin level greater than 6 mg/ dL and greater than the serum level of bilirubin suggests biliary or proximal small intestinal perforation into ascitic fluid Ascitic Fluid Triglyceride: Chylous ascites has a TG concentration greater than 200 mg/ dL (2.26 mmol /L) and greater than the serum level. Abdominal malignancy and cirrhosis are the commonest causes in developed countries and account for over two-thirds of all cases, whereas chronic infections like tuberculosis and filariasis account for the majority of the cases in developing countries* *Al- Busafi SA, Ghali P, Deschênes M, Wong P. Chylous ascites: evaluation and management. ISRN hepatology . 2014 Feb 3;2014 .

22. Peritoneal Tuberculosis Ascitic fluid for AFB and Mycobacterial culture: Examination of an Acid fast stained smear of ascitic fluid has a disappointingly low yield. Direct smear for Ziehl-Neelson stain has a reported sensitivity of 0 to 6 percent * The sensitivity of ascitic fluid mycobacterial culture (20–50%) is low ** , and because of the delay in obtaining the results of mycobacterial cultures of ascitic fluid, the mortality is high *** , and the value of these tests in the differential diagnosis of ascites is limited. * Chow KM, Chow VC, Szeto CC et al. Indication for peritoneal biopsy in tuberculous peritonitis. Am J Surg 2003; 185:567-73 ** Suceveanu AI, Todescu D, Mazilu L, Manousos FG, Hulea R, Voinea F, Dumitru E, Suceveanu AP. Modern Tools for Diagnosis in Tuberculous Ascites. InAscites -Physiopathology, Treatment, Complications and Prognosis 2017. InTech . ** Hillebrand DJ, Runyon BA, Yasmineh WG, Rynders G. Ascitic fluid adenosine deaminase insensitivity in detecting tuberculous peritonitis in the United States. Hepatology 1996;24:1408-1412 . ***Chow KM, Chow VC, Hung LC, Wong SM, Szeto CC. Tuberculous peritonitis–associated mortality is high among patients waiting for the results of mycobacterial cultures of ascitic fluid samples. Clinical infectious diseases. 2002 Aug 15;35(4):409-13.

23. ASCITIC FLUID ADA Gupta VK,  Mukherjee S,  Dutta SK et a Diagnostic evaluation of  ascitic  adenosine deaminase activity in tubercular peritonitis. J Assoc Physicians India 1992; 40:387-9 Liao YJ, Wu CY,  Lee SW et al Adenosine deaminase activity in tuberculous peritonitis among patients with underlying liver cirrhosis. World J Gastroenterol 2012; 18:5260-5 Kang SJ,  Kim JW,  Baek JH, et al. Role of  ascites  adenosine deaminase in differentiating between tuberculous peritonitis and peritoneal carcinomatosis . World J Gastroenterol  2012; 18:2837-43 KRISHNASWAMY DR, Narayan S, Priyadharshini K. Evaluation of The Use of Ascitic Fluid Adenosine Deaminase Activity in The Diagnosis of Tuberculous Ascites. J Res Analysis. 2018 Feb 17;5(9). Ali N, Nath NC, Parvin R, Rahman A, Bhuiyan TM, Rahman M, Mohsin MN. Role of ascitic fluid adenosine deaminase (ADA) and serum CA-125 in the diagnosis of tuberculous peritonitis. Bangladesh Med Res Counc Bull. 2014 Dec;40(3):89-91. STUDY CUT OFF LEVEL SENSITIVITY SPECIFICITY Gupta et al 1 30 100 94.1 Liao et al 2 27 100 93.3 Kang SJ groups 3 21 92 85 Krishnaswamy et al 4 30 86.8 97.5 Ali N et al 5 24 93 96

24. T-cell Based Testing for Mycobacterium Tuberculosis (ELISPOT) FDA approved Enzyme Linked Immunospot Assay (ELISPOT) measuring gamma producing T-cell responses to early secreted antigenic targets of mycobacterium tuberculosis Sharma et al * evaluated the diagnostic accuracy and cost-effectiveness of ascitic fluid interferon-gamma (IFN - gamma) and Adenosine deaminase (ADA) assays in the diagnosis of tuberculous ascites. (IFN - gamma and ADA assays showed equal sensitivity (0.97) and differed marginally in specificity (0.97 vs. 0.94). Difference in AUCs was not significant (0.99 vs. 0.98, p<0.62) For differentiating TB from non-TB ascites, optimal cut off points were 112 pg /mL for IFN-gamma and 37 IU/L for ADA. Tissue Xpert ™ MTB/Rif assay Its of limited use in diagnosing peritoneal tuberculosis in patients with exudative ascites** *Sharma SK,  Tahir M,   Mohan A et al Diagnostic accuracy of ascitic fluid IFN-gamma and adenosine deaminase assays in the diagnosis of tuberculous ascites. J Interferon Cytokine Res 2006; 26:484-8 . ** Bera C, Michael JS, Burad D, Shirly SB, Gibikote S, Ramakrishna B, Goel A, Eapen CE. Tissue Xpert ™ MTB/Rif assay is of limited use in diagnosing peritoneal tuberculosis in patients with exudative ascites. Indian Journal of Gastroenterology. 2015 Sep 1;34(5):395-8 .

25. Real time PCR bacterial DNA for M.Tuberculosis PCR can be performed when tuberculous ascites is suspected. This method has a high sensitivity (94%) * PCR offers a timesaving method in contrast to current Mycobacterium culture techniques. *Tan MF, Ng WC, Chan SH, Tan WC. Comparative usefulness of PCR in the detection of Mycobacterium tuberculosis in different clinical specimens. J Med Microbiol . 1997;46:164-9. *Portillo-Gomez L, Morris SL, Panduro A. Rapid and efficient detection of extra-pulmonary Mycobacterium tuberculosis by PCR analysis. Int J Tuberc Lung Dis. 2000;4:361-70.

26. Ascitic Fluid cytology: The ascitic fluid cytology is positive only in the setting of peritoneal carcinomatosis . The sensitivity of cytology in detecting peritoneal carcinomatosis is 96.7% if 3 samples (from different paracentesis procedures) are sent and processed promptly; the first sample is positive in 82.8% and at least 1 of 2 samples is positive in 93.3%. * Crucial factors are avoiding any time delay between obtaining the ascitic fluid and cytology processing as well as obtaining at least 50 ml ascitic fluid, or even 1000 ml if the first test was negative .** The sensitivity of cytology in patients with hepatocellular carcinoma and ascites is low (~27%) *** *Runyon BA, AASLD Practice Guidelines Committee. Management of adult patients with ascites due to cirrhosis: update 2012. Hepatology . 2013 Feb;57(4):1651-3. **Runyon BA, Hoefs JC, Morgan TR. Ascitic fluid analysis in malignancyrelated ascites. Hepatology . 1988;8:1104-9. *** Colli A, Cocciolo M, Riva C, et al. Ascitic fluid analysis in hepatocellular carcinoma. Cancer. 1993;72:677-82

27. Ascitic Fluid Cholesterol and SACG Ascitic fluid cholesterol and Mean SACG are highly sensitive, specific and are having high Diagnostic accuracy of 90% and 93% with a a cut off level of 70mg% and 54 mg% respectively. Hence being simple and cost effective, these can be widely utilized to separate malignant ascitis from nonmalignant causes* * Sastry AS, Mahapatra SC, Dumpula V. Ascitic fluid analysis with special reference to serum ascites cholesterol gradient and serum ascites albumin gradient. Int J Res Med Sci. 2017 Jan 23;5(2):429-36.

28. Others Ascitic Fluid CA-125 Essentially all patients including men with ascites or pleural fluid of any cause have an elevated serum CA-125; when ascites is controlled, the CA-125 level decreases dramatically. This test is elevated when mesothelial cells are under pressure from the presence of fluid; it is very nonspecific. Patients with ascites should not have serum tested for CA-125. Leucocyte esterase reagent strips : Leukocyte esterase reagent strips are widely used for urinary analysis with the advantages of a simple, inexpensive and rapid bedside test. Several studies have examined the usefulness of this method for diagnosing SBP and found this test had a sensitivity and specificity ranging from 80-93% and 93-98%, respectively. The negative predictive value is remarkably high ranging from 97-99%, which makes it an ideal tool to rule out SBP * * Rerknimitr R, Limmathurotsakul D, Bhokaisawan N, Kongkam P, Treeprasertsuk S, Kullavanijaya P. A comparison of diagnostic efficacies among different reagent strips and automated cell count in spontaneous bacterial peritonitis. J Gastroenterol Hepatol . 2010;25:946-50

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