CHAPTER - From Basics to Bedside

71 Harbir Kaur Rao, Rajinder Singh Gupta

INTRODUCTION little or no fluid in the peritoneal cavity but women The term ascites denotes the pathological accumulation normally may have up to 20ml depending on the phase of fluid in the peritoneal cavity. Healthy men have of menstrual cycle. Causes of ascites may be classified into two pathophysiologic categories: That associated Table 1: Causes of Ascites with the normal and that which occur due to Normal Peritoneum Diseased peritoneum a diseased peritoneum. accounts for 84 percent (SAAG < 1.1g/dL) of all cases of ascites, whereas Cardiac ascites, peritoneal Portal hypertension carcinomatosis and mixed ascites resulting from cirrhosis (SAAG > 1.1g/ dL) Infections and a second disease account for 10-15% of cases. Less 1. Hepatic congestion Bacterial peritonitis common causes of ascites include massive hepatic Congestive heart failure Tuberculous peritonitis metastasis, peritoneal tuberculosis, and pancreatitis and Nephrotic syndrome. Various causes of ascites are Constrictive pericarditis Fungal peritonitis enumerated in Table 1. Tricuspid insufficiency HIV-associated peritonitis PATHOGENESIS Budd-Chiari syndrome Malignant conditions Pathogenesis of ascites is different in cases with cirrhosis Veno-Occlusive disease Peritoneal carcinomatosis and without the cirrhosis. 2. Liver Disease Primary mesothelioma Pathogenesis in Cirrhosis Cases Cirrhosis Pseudomyxoma peritonei The presence of portal hypertension contributes to the Alcoholic Hepatitis Massive hepatic development of ascites in patients who have cirrhosis. metastases There is an increase in Intrahepatic resistance, causing Fulminant hepatic increased portal pressure, but there is also vasodilatation failure Hepatocellular carcinoma of the splanchnic arterial system, which in turn Massive hepatic Other Conditions results in an increase in portal venous inflow. Both of metastases Familial mediterranean these abnormalities result in increased production of Hepatic Fibrosis fever splanchnic lymph. Vasodilating factors such as vascular endothelial growth factor and nitric oxide are responsible Acute Fatty liver of Vasculitis for the vasodilatory effect. These hemodynamic changes pregnancy Granulomatous peritonitis cause activation of the RAAS with the development of 3. Portal vein occlusion Eosinophilic peritonitis hyperaldosteronism and hence sodium retention. These Hypoalbuminemia renal effects of increased aldosterone also contribute (SAAG < 1.1g/dL) to the development of ascites. Sodium retention causes

Nephrotic syndrome Cirrhosis

Protein- losing enteropathy Portal Hypertensi on Severe malnutrition

with Anasarca

Splanchnic vasodiltation Miscellaneous

conditions (SAAG < 1.1g/dL)

↑ Splanchnic pressure Arterial underfilling Chylous ascites

Pancreatic ascites Lymph formation ascites Activation of vasoconstrictors and Formation of ascites Nephrogenic ascites antinatriuretic factors

Myxedema (SAAG >

1.1g/ dL) Plasma Volume Expansion Sodium Retention

Ovarian disease Fig. 1: Development of Ascites in Cirrhosis 330 fluid accumulation and expansion of extra cellular fluid may be present. Anasarca results from cardiac failure volume which results in the formation of peripheral or nephrotic syndrome with hypoalbuminemia. Finally, oedema and ascites. Sodium retention is the consequence firm lymph nodes in the left superclavicular region or of a homeostatic response caused by the under filling of umbilicus may suggest intra-abdominal malignancy. arterial circulation secondary to arterial vasodilatation in The physical examination is relatively insensitive for the splanchnic vascular bed. Because the retained fluid is detecting ascitic fluid. In general, patients must have constantly leaking out of the intravascular compartment in at least 1500mL of fluid to be detected reliably by this to peritoneal cavity, the sensation of vascular filling is not method. Even the experienced clinician may find it achieved and the process continuous. Hypoalbuminemia difficult to distinguish between obesity and small-volume and reduced oncotic pressure also contribute to the loss of ascites. Abdominal ultrasound establishes the presence of fluid from the vascular compartment into the peritoneal fluid. cavity. Hypoalbuminemia is due to decreased synthetic function in the liver. Figure 1 is brief illustration of Physical Examination Pathogenesis of ascites in cirrhosis. Physical examination should include an assessment for signs of systemic disease. The presence of Pathogenesis in the Absence Of Cirrhosis lymphadenopathy, especially supraclavicular HEPATOLOGY Ascites in the absence of cirrhosis generally results lymphadenopathy (Vorchow’s node), suggests metastatic from peritoneal carcinomatosis, peritoneal infection or abdominal malignancy. Care should be taken during the pancreatic disease. Peritoneal carcinomatosis can result cardiac examination to evaluate for elevation of jugular from primary malignancies such as mesothelioma or venous pressure (JVP); Kussmaul’s sign (elevation of sarcoma, secondary to abdominal malignancies such as the JVP during inspiration); a pericardial knock, which gastric or colon adenocarcinoma, metastatic disease from may be seen in heart failure of constrictive pericarditis; breast or lung carcinoma or melanoma. Tumour cells or a murmur of tricuspid regurgitation. Spider angiomas, lining the peritoneum produce a protein rich fluid that palmar erythema, dilated superficial veins around the contributes to the development of ascites. Fluid from the umbilicus (caput medusae), and gynecomastia suggest extra cellular space is drawn into the peritoneum, further chronic liver disease. contributing to the development of ascites. Tuberculous peritonitis causes ascites via a similar mechanism; tubercles The abdominal examination should begin with inspection deposited on the peritoneum exude a proteinaceons fluid. for the presence of uneven distention or an obvious Pancreatic ascites results from the leakage of pancreatic mass. Auscultation should follow. The absence of bowel enzymes into the Peritoneum. sounds or the presence of high-pitched localized bowel sounds points toward an ileus or intestinal obstruction. CLINICAL FEATURES An umbilical venous hum may suggest the presence of Symptoms and Signs portal hypertension, and a harsh bruit over the liver is The history usually is one of increasing abdominal girth, heard rarely in patients with hepatocellular carcinoma. with the presence of abdominal pain depending on the Abdominal swelling caused by intestinal gas can be cause. Because most astices is secondary to chronic differentiated from swelling caused by fluid or a solid liver disease with portal hypertension, patients should mass by percussion; an filled with gas is be asked about risk factors for liver disease, especially tympanic, whereas an abdomen containing a mass or fluid alcohol consumption, transfusions, tattoos, injection drug is dull to percussion. The absence of abdominal dullness, use, a history of viral hepatitis or jaundice, and birth in an however, does not exclude ascites, because a minimum area endemic for hepatitis. A history of cancer or marked of 1500 ml. of ascites fluid is required for detection on weight loss arouses suspicion of malignant ascites. physical examination. Finally, the abdomen should be Fever may suggest infected peritoneal fluid, including palpated to assess for tenderness, a mass, enlargement bacterial peritonitis (spontaneous or secondary). Patients of the spleen or liver, or presence of a nodular liver with chronic liver disease and ascites are at greatest suggesting cirrhoses or tumor. Light palpation of the liver risk for developing spontaneous bacterial peritonitis. In may detect pulsations suggesting retrograde vascular immigrants, immunocompromised hosts, or severely flow from the heart in patients with right-sided heart malnourished alcoholics, tuberculous peritonitis should failure, particularly tricuspid regurgitation. be considerd. EVALUATION Physical examination should emphasize signs of portal Once the presence of ascites has been confirmed, the hypertension and chronic liver disease. Elevated jugular etiology of the ascites is best determined by . venous pressure may suggest right-sided congestive heart The left lower quadrant is preferred because of the failure or constrictive pericarditis. A large tender liver is greater depth of ascites and the thinner abdominal wall. characteristic of acute alcoholic hepatitis or Budd-Chiari Paracentesis is a safe procedure even in patients with syndrome. The presence of large abdominal wall veins coagulopathy; complications, including abdominal wall with cephalad flow also suggests portal hypertension; hematomas, hypotension, hepatorenal syndrome, and inferiorly directed flow implies hepatic vein obstruction. infection are infrequent. Signs of chronic liver disease include palmar erythema, Once ascitic fluid has been extracted, its gross appearance cutaneous spider angiomas, gynecomastia, and muscle should be examined. Turbid fluid can result from wasting. Asterixis secondary to hepatic encephalopathy presence of infection or tumor cells. White, milky fluid CHAPTER 71 331 Laboratory Evaluation Laboratory evaluation should include liver biochemical testing, serum prothrombin albumin normalized ratio) level time to assess hepatic function measurement, a as complete well blood as count to determination and evaluate for the cytopenias presence that of may result from portal hypertension or (international of leukocytosis, anemia, and thrombocytosis result from systemic infection. that Serum amylase and lipase may should levels be checked to the evaluate patient for acute pancreatitis. Urinary protein quantitation when is nephrotic syndrome, indicated which may cause ascites, is suspected. In selected cases, the hepatic venous pressure (pressure across gradient the liver between the portal and hepatic veins) can be measured via some In cirrhosis. cannulation by caused is ascites that confirm to vein of the hepatic cirrhosis. confirm to necessary be may biopsy liver a cases, Imaging presence the confirming in useful is ultrasound Abdominal of ascites and in ultrasound and CT imaging the are useful in distinguishing guidance of between paracentesis. causes of Both portal thrombosis detect can CT and and ultrasound Doppler ascites. non-portal hypertensive of the hepatic veins (Budd-Chiari syndrome) veins. or In portal patients with non-portal hypertensive ascites, these studies are useful in detecting lymphadenopathy and masses of the mesentery and of solid organs such as permit they Furthermore, pancreas. and ovaries, liver, the directed percutaneous needle biopsies of these Ultrasound and CT are poor lesions. procedures for the detection emission position of role the carcinomatosis; peritoneal of tomography (PET) imaging is unclear. volume volume and ventricular BNP wall in serum occur stretch. in heart failure High and may be in useful levels identifying heart of failure as the cause ascites. of high-SAAG Further tests circumstances. are indicated When only secondary from in a peritonitis specific perforated clinical resulting hollow glucose viscus dehydrogenase (LDH) is levels can suspected, be measured. ascitic In contrast to “spontaneous” bacterial peritonitis, which may complicate cirrhotic ascites. Secondary is peritonitis suggested by an ascitic glucose level <50.0Mg/dL, an ascitic LDH level higher than the culture. serum fluid LDH ascitic level, on and pathogens multiple of detection the When pancreatic ascites is suspected, the ascitic amylase level should be measured and is typically >1000mg/dL. At least 50mL of fluid shouldtypically is peritonitis be obtained Tuberculous processing. immediate and sent for associated with ascitic fluid acid-fast for A smear lymphocytosis paracentesis. by diagnose to but difficult can be culture a 3%; to 0 only of sensitivity diagnostic a has bacilli increases the sensitivity to 35-50%. In patients cirrhosis, an without elevated ascitic adenosine deaminase level has a sensitivity of>90%when a cut-off value of 30-45% U/L is used. When the cause of ascites remains uncertain, laparotomy or laparoscopy with peritoneal biopsies for standard. histology and culture remains the gold

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e e l d s u as ve t om osi B r h e as d r 2.5g/dL t assi r at e < Ascites pr i syn M m C L indicates a triglyceride level>200 mg/dL (and often >1000 mg/dL), which is hall mark of chylous ascites. Chylous ascites results from lymphatic disruption that may occur with trauma, cirrhosis, tumor, tuberculosis, congenital or abnormalities. Dark certain brown fluid cana high bilirubin reflect concentration and indicates biliary tract perforation. Black fluid may pancreatic necrosis or metastatic melanoma. indicate albumin of measurement the presence for sent of be should fluid ascitic The and total protein levels, cell and differential counts, and if infection is suspected, Gram’s stain and culture, with inoculation into blood culture bottles at the patient’s bed should level albumin serum A yield. the maximize to side be measured simultaneously to permit calculation of the serum ascites albumin gradient (SAAG). The SAAG is useful for distinguishing ascites caused by ascites. hypertensive portal non from hypertension portal (Figure 2). The SAAG reflects thehepatic sinusoids and correlates with pressurethe hepatic venous within the subtracting by calculated is SAAG The gradient. pressure albumin serum the from concentration albumin ascitic the level and does not change with A diuresis. SAAG > 1.1g/ dL reflects theindicates presence the ascites is due to of portal increased pressure in hepatic hypertension the sinusoids. and According to Starling’s SAAG reflects law, the oncotic pressure a that counterbalances high the portal pressure. Possible cardiac causes ascites, include hepatic cirrhosis, vein thrombosis Syndrome), (Budd-Chirari sinusoidal obstruction Occlusive Disease), or massive liver A metastases. SAAG syndrome (Veno- < 1.1g/dL indicates that the ascites is not related to portal hypertension, as in tuberculousis peritonitis, peritoneal carcinomatosis, or pancreatic ascites. For high-SAAG (> 1.1) ascites, the can ascitic provide further protein clues level to the etiology (Figure hepatic the that indicates g/dL 2). >2.5 of level protein ascites An are normal and are allowing passage of protein sinusoids into the ascites, as occurs in cardiac ascites, early Budd- Chiari syndrome, or sinusoidal hepatic the that indicates obstruction <2.5g/dL level protein ascitic An syndrome. sinusoids have been damaged and scarred and no longer allow passage of protein, as occurs with Budd-Chiari cirrhosis, late syndrome, or Pro-brain type massive natriuretic peptide (BNP) is liver a natriuretic metastases. hormone released by the heart as a result of increased 332 Refractory ascites of fluid drained) accompanying LVP decrease the risk of post paracentesis circulatory dysfunction. TIPS is

superior to LVP in reducing the reaccumulation of ascites Large volume paracentesis (LVP) + but is associated with increased frequency of hepatic albumin encephalopathy.

Tuberculous Ascites Dietary sodium restriction + diure�cs Tuberculous involvement of the peritoneum is significant problem in the developing world including India. The incidence is higher in those with uncontrolled HIV disease, Ascites reaccumulation the urban poor, patients with cirrhosis and nursing home residents. The presenting symptoms include low grade fever, Consider TIPS Continue LVP with Consider liver abdominal pain, anorexia and weight loss. Most patients albumin as needed transplantation have symptoms for months before the diagnosis is Fig. 3: Treatment of Refractory Ascites established. On physical examination patient may have HEPATOLOGY generalized abdominal tenderness and distention. There Laparoscopy may be clinically evident ascites. Ultrasonography or CT Laparoscopy is an important test in the evaluation of imaging of the abdomen reveals free or localated ascites some patients with non-portal hypertensive ascites (low in >80% of patients. Mantoux test is positive in 50% of SAAG) or mixed ascites. It permits direct visualization cases. Ascitic fluid smear for AFB is usually negative and biopsy of the peritoneum, liver, and some intra- and fluid cultures are positive in 35% cases. Ascitic abdominal lymph nodes. Cases of suspected peritoneal fulid total protein is more than 3g/dL, LDH >90 units/ tuberculosis or suspected malignancy with non-diagnostic L or mononuclear cell predominant leucocytes >500/cc. CT imaging and ascitic fluid cytology are best evaluated Ascitic adenosine deaminase activity > 36-40 IU/L has a by this method. sensitivity of 100% and a specificity of 97% for diagnosis Treatment of tuberculous peritonitis. In doubtful cases laparoscopy confirms the diagnosis. 1. The initial treatment for cirrhotic ascites is restriction of sodium intake to 2 gl /day. Malignant Ascites 2. When sodium restriction alone is inadequate Two-thirds of cases of malignant ascites are caused by oral diuretics typically the combination of peritoneal carcinomatosis. The most common tumors spironolactone and furosemide are used. causing carcinomatosis are primary adenocarcinomas of Spioronolactone is an aldosterone antagonist that the ovary, uterus, pancreas, stomach, colon, lung or breast. inhabits sodium resorption in the distal convoluted The remaining one-third is due to lymphatic obstruction tubule of kidney. Prolonged use of spironolactone or portal hypertension due to hapatocellular carcinoma may lead to hyponatremia, hyperkalemia and or diffuses hepatic metastases. Patients present with non painful gynecomastia. In such cases amiloride specific abdominal discomfort and weight loss associated 5-40mg/day may be substituted for speronolactone. with increased abdominal girth. Nausea or may be caused by partial or complete intestinal obstruction. 3. Malignant acites does not respond to sodium Abdominal CT may be useful to demonstrate the primary restriction or diuretics. Patient may undergo large malignancy or hepatic metastases but seldom confirms the volume paracentesis (LVP’s), transcutaneous diagnosis of peritoneal carcinomatosis. In patients with catheter placement or rarely creation of carcinomatosis, paracentesis demonstrates a low serum peritoneovenous shunt. ascites-albumin gradient (<1.1 mg/dL), an increased total 4. Ascites caused by tuberculous peritonites is treated protein (> 2.5 g/dL), and an elevated white cell count with standard antituberculous therapy. (often both neutrophils and mononuclear cells) but with Refractory Ascites a lymphocyte predominance. Cytology is positive in over 95%, but laparoscopy may be required in patients with Refractory cirrhotic ascites is defined by the presence of negative cytology to confirm the diagnosis and to exclude ascites despite sodium restriction and maximal diuretic tuberculousis peritonitis, with which it may be confused. dose. Pharmacological therapy for these cases (Figure Malignant ascites attributable to portal hypertension 3) include the addition of Midodrine and a adrenergic usually is associated with an increased serum ascites- antagonist or clonidine an a adrenergic antagonist to 2 albumin gradient (>1.1 g/dL), a variable total protein, and diuretic therapy. These agents act as vasoconstrictors, negative ascitic cytology. Ascites caused by peritoneal counteracting splanchnic vasodilatalion. Beta blockers carcinomatosis does not respond to diuretics. are often prescribed to prevent variceal hemorrhage in patient with cirrhosis.When medical tharpy alone Patient may be treated with periodic large-volume is insufficient refractory ascites can be managed by paracentesis for symptomatic relief. Intra peritoneal repeated large volume paracentesis (LVP) or transjugular chemotherapy is some time used to shrink the tumor, intrahepatic peritoneal shunt (TIPS) to decompress the but the overall prognosis is extremely poor, with only hepatic sinusoids. I/V infusion of albumin (6-8 gm/l 10% survivor at 6 month. Ovarian cancers represent an CHAPTER 71 333 Am J Am J Gastroenterology Am J Gastroenterology edition MC Graw Hill th 2007; 52:2261-4. edition MC Graw Hill 2015;285-88 th 2015;2058-2067 adenosine of use The JJ. Taljaard CG, Swanepoel LJ, Burgess deaminase as a diagnostic tool for peritoneal tuberculosis. 2001; 81;243-248. Tuberculosis Brune R.Bacon; Cirrhosis and its complications; Harrison’s Principle of internal medicine 19 Med 2009; 122:12-7. Tamsma J. The pathogenesis of malignant ascites, cancer treat Res 2007; 134:109-18. Al. Ghamdi MY pancreatitis. Dig Dis Sci et al. Chylous patients of treatment and Management al. et G Tsao Garcia. ascites secondary hypertension. portal and cirrhosis to with 2009; 104:1802-29. spontaneous reduces prophylaxis antibiotic Oral etal. S Saab bacterial peritonitis occurrence and improves short terms A meta analysis. in cirrhosis. survival 2009; 104:993-1001. Kathleen E, Corey and Lawrence S. Friedman; abdominal swelling and ascites; medicine 19 Harrison Principles of internal Hou W etal. Ascites: Diagnosis and Management, Medical America 2009; 9394:801-17 Clinics of North paracentesis. Abdominal page. patient JAMA al et JL Zeller JAMA 2008; 299:1216. Jacob JT, et al. Acute forms of tuberculosis in adults REFERENCES 10. 9. 4. 5. 6. 7. 8. 1. 2. 3. Treatment Treatment Empiric therapy for cephalosporin third-generation a spontaneous with initiated be should bacterial peritonitis (such as cefotaxime, 2 g intravenously every 8-12 hours, or ceftriaxon 1-2 24 gm hours, I-V or every a combination of β-lactam/ β-lactamase sulbactam, 2g/1g intravenously every 6 agent hours). A course (such of as 5-10 days is ampicillin/ sufficient in most count decreases to < 250 cells/cc. ascites fluid PMN patients, or until the Kidney injury develops in up to 40% of patients and a is major cause of death. Intravenous albumin effective arterial circulating volume increases and renal perfusion, decreasing the incidence of kidney injury and mortality. Intravenous albumin, 1.5g/kg on day 1 and 1g/kg on day 3, should be administrated to patients hepatorenal at failure high (ie, patients risk with baseline for creatinine > 1mg/dl, blood urea nitrogen bilirubin > 4 mg/dL. (BUN) > 30 mg/dL, or in mental status due to exacerbation or precipitation of hepatic encephalopathy, or sudden worsening of function. renal Physical examination typically signs demonstrates of chronic liver disease tenderness is present in <50% of patients and its presence with ascites. Abdominal other causes. suggests Symptoms and Signs Symptoms Eighty to bacterial 90percent peritonitis are symptomatic; in many of cases the presentation patients is subtle. Spontaneous bacterial peritonites with may spontaneous be present in 10-20% of patients hospitalized with chronic liver disease, sometimes in the or signs. symptoms absence suggestive of any The most common symptoms are fever and abdominal pain, present in bacterial two-thirds peritonitis of may also patients. present with Spontaneous the change Spontaneous Bacterial Peritonitis “Spontaneous” bacterial infection of ascitic fluid occurs in the absence of an apparent intraabdominal source of infection. It is seen with few exception in patients ascites with caused by chronic of liver enteric disease. bacteria Translocation across lymphatic the leads to gut seeding of wall the bactiremia ascitic or fluid, from mesenteric as other may sites. Approximately cirrhotic 20-30% of patients with peritonitis; however ascites the incidence develop is with >40% ascitic fluid spontaneous in total patients protein <1g/dL, probably decreased ascitic fluid osmotic activity. due to Virtually all cases of spontaneous are bacterial caused peritonitis by common a pathogens monomicrobial are enteric infection. gram-negative Ecoli, The bacteria klebsiella most Pneumonae or gram-positive (Streptococcus bacteria. pneumoniae, enterrococcus species). viridans associated with spontaneous bacterial peritonitis. Anaerobic streptococci, bacteria are not Pancreatic Ascites Pancreatic It is intra peritoneal accumulations of massive amount of pancreatic of disruption to either due secretion pancreatic duct or to a pancreatic pseudocyst. Its most seen commonly in patients with chronic pancreatitis. Ascitic fluid is characterized by high protein level (>2.5 but g/dL) a low SAAG, Ascitic fluid amylase levels are in excess of 1000 units/L. Non surgical cases are total treated parenteral by bowel nutrition rest, and pancreatic secretion. octreotide to decreased Chylous Ascites Chylous peritoneal the in lymph rich lipid of accumulation a is This cavity. Ascites fluid triglyceride level >1000 mg/dL. Usual causes in adults is is milky lymphatic obstruction or leakage caused by malignancy in appearanceespecially lymphoma. with Non pancreatitis tuberculosis, cirrhosis, trauma, postoperative malignant causes include and filariasis. exception exception to this rule. With newer treatments consisting of surgical debulking and intraperitoneal chemotherapy, possible. cancer is from ovarian term survival long