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A. Causes

  1. Alcoholism
  2. Viral
  3. Hepatic Mass (usually cancer)
  4. Metabolic
    1. Hemochromatosis: iron overload
    2. Wilson's Disease: abnormal copper metabolism
    3. Alpha-1 Anti-trypsin deficiency
  5. Any cause of fulminant hepatic failure
  6. Venous Obstruction
    1. Budd-Chiari Syndrome (hepatic vein thrombosis) [2]
    2. Inferior vena cava (IVC) syndrome (obstruction)
  7. Others
    1. Congestive Heart Failure (CHF)
    2. Abdominal gastrointestinal pathology - cancers, peritonitis, others
    3. Ovarian Hyperstimulation Syndrome [3]

B. Pathogenesis

  1. Systems Involved
    1. Lymph Formation: Hepatic and Intestinal
    2. Renal
    3. Peritoneal Factors
    4. Extrahepatic Factors (such as portal venous obstruction)
  2. Development of intrahepatic (sinusoidal) hypertension
    1. This leads to transudation of plasma across the hepatic sinusoidal bed (Space of Disse)
    2. Plasma eventually enters the lymphatic ducts in the portal triad
    3. Fluid is returned to the circulation via the thoracic duct
    4. Increased portal pressures leads to intestinal venous distension
    5. Increased intestinal pressures appears to cause reduced bacterial containment
    6. Blood endotoxin levels are increased in patients with cirrhosis / portal hypertension
    7. Increased serum endotoxin leads to nitric oxide production (splanchnic vasodilation)
    8. Nitric oxide is a potent vasodilator and is likely responsible for vascular "underfill"
  3. Model for Ascites Formation
    1. Splanchnic vasodilation due to intrahepatic hypertension is basis
    2. Intrahepatic hypertension leads to production strongly vasodilatory substances
    3. Nitric oxide production by liver and endothelium may be major vasodilator
    4. Splanchnic vasodilation triggers peripheral vasoconstrictor substances, renin production
    5. Result is increased Na+ resorption in proximal nephron with plasma volume expansion
    6. Sinusoidal HTN also causes increased formation of lymph (fuild)
    7. Fluid accumulates as ascites if outflow (lymphatic drainage) is insufficient
    8. Once ascites formation begins, plasma volume drops and worsens vascular "underfill"
    9. Vascular underfill leads to elevated anti-diuretic hormone (vasopressin) and endothelin
    10. ADH (vasopressin) induces fluid retention in kidney
    11. Hyperaldosteronism, increased ADH, prostaglandin and kinin systems are found

C. Differential Diagnosis [4]

  1. Normal Peritoneum
    1. Portal Hypertension: Cirrhosis, Heart Failure, IVC Obstruction, Budd Chiari Syndrome
    2. Portal Vein Occlusion: Thrombosis, Compression
    3. Hepatocellular Carcinoma
    4. Hepatic Fibrosis: Hemochromatosis, Polycystic Disease, Syphilis, Sarcoidosis
    5. Hypoalbuminemia (Severe): Nephrotic Syndrome, Malabsorption, Malnutrition
    6. Miscellaneous: Pancreatic Ascites, Ovarian DIsease (Meig's Syndrome, Struma ovarii)
  2. Diseased Peritoneum
    1. Infections: Bacterial Peritonitis, Tuberculous, Fungal, Parasitic Peritonitis
    2. Neoplasia: Primary hepatocellular CA, Metastatic Disease, Primary mesothelioma
    3. Granulomatous Peritonitis: Infections, Cancer, Barium
    4. Vasculitis
    5. Miscellaneous: Eosinophilic Peritonitis, Whipple's Disease, Gynecologic Disease
  3. Evaluation of Portal Pressures and Albumin Ascites Level
    1. Originally, differential of ascites was transudative versus exudative
    2. Differential largely replaced by serum-ascites albumin gradient (SAAG)
    3. SAAG is a measure of net serum oncotic pressure
    4. There is no correlation between gradient and actual portal venous pressures
    5. SAAG >1.1 indicates that portal hypertension is present, driving fluid into peritoneum
    6. SAAG <1.1 indicates that peritoneum is diseased: neoplasms, infection, inflammation, others
  4. Transudative (SAAG >1.1)
    1. Cardiovascular Etiology: Heart Failure Group, Venous Insufficiency
    2. Alcoholic Liver Disease (Micronodular Cirrhosis, Alcoholic Hepatitis)
    3. Hepatic Necrosis
    4. Fulminant Hepatic Failure
    5. Budd-Chiari Syndrome [2]
    6. Inferior Vena Cava Thrombosis
    7. Portal Vein Thrombosis
    8. Venooclussive Disease
  5. Exudative (SAAG <1.1, without portal hypertension)
    1. Neoplastic Diseases / Peritoneal Carcinomatosus
    2. Pancreatic Ascites
    3. Peritoneal Infections - especially tuberculosis, fungi
    4. Chylous Ascites
    5. Meig's Syndrome - Fibromyoma of ovary with hydroperitoneum and hydrothorax
    6. Serositis
    7. Bowel obstruction or infarction

D. Evaluation of New Onset Ascites

  1. Diagnostic (± Therapeutic) Paracentesis [4,8]
    1. In general, >1.5 inch needle is used; 14 gauge generally preferred over 22 gauge
    2. Needle is inserted through skin typically into subumbilical midline region
    3. Left lower quadrant aspiration may also be done
    4. Obtaining coagulation parameters prior to paracentesis generally not helpful
    5. Platelet counts <50K/µL or INR <2.5 are generally not associated with increased complications
    6. Ultrasound guidance can be used if initial aspiration fails
    7. Ascitic fluid should be inoculated into blood culture bottles immediately at the bedside
    8. Ascitic fluid should also be sent for blood counts, albumin, LDH, pH
    9. SAAG >1.1 (transudate) versus SAAG <1.1 (exudate)
    10. Cell counts with differential to indicate infection likelihood and hemorrhage
  2. Ascites in Spontaneous Bacterial Peritonitis [8]
    1. PMN counts >250/µL (likelihood ratio 6.4)
    2. Leukocyte total count >1000/µL (LR 9.1)
    3. BLood-ascitic fluid pH graident >0.09 (LR 11.3)
    4. SAAG >1.1 gm/dL
    5. Fluid Gram Stain and cultures are critical
  3. Hepatitis Screen: Hep B sAg, sAb, cAb; Hepatitis C; Hepatitis Delta (only if HBsAg+)
  4. Radiologic Evaluations
    1. Ultrasound: ~90% sensitive for hepatic mass
    2. Flow Doppler Study: hepatic or portal vein involvement
    3. CT Scan: intravenous and oral contrast most sensitive (~95% for hepatic mass)
  5. Hepatocellular Carcinoma
    1. Alpha-feto protein (AFP) levels >500-1000 indicate hepatocellular CA >95% of cases
    2. Ultrasound or CT scan should immediately follow any abnormal AFP level
  6. Evaluation for Genetic Disorders
    1. Hemochromatosis: iron levels, transferrin saturation, ferritin
    2. Wilson's Disease: ceruloplasmin levels
    3. Alpha-1 anti-trypsin deficiency

E. Management [1]

  1. Underlying Disease
  2. Bed Rest
    1. Will reduce renin-aldosterone production
    2. No proven benefit for reduction in hospital stay or increased weight loss
  3. Sodium Restriction
    1. Measure initial urine creatinine, K+ and Na+
    2. Aim for diet with 1-1.5mEq Na+ per kg body weight
    3. Best effects seen in patients who excrete >10mEq/L Na+ in urine initially
  4. Diuresis
    1. Recommend 1.0kg/d weight loss in patients with peripheral edema
    2. Recommend 0.50kg/d weight loss in patients without edema
    3. Spironolactone shown to be more effective diuretic in cirrhotic ascites than furosemide
    4. Use in combination initially - helps maintain normal K+ and increases Na+ losses
    5. Furosemide used cautiously, up to doses of 160mg/d
  5. Spironolactone
    1. Initially 50-100mg qd-bid (± furosemide 20mg qam for moderate-severe ascites)
    2. May increase spironolactone to 100-250mg tid to maximum dose 600mg qd
    3. Initial response to low dose seen usually in patients with urine Na:K ratio >1
    4. Furosemide may be increased to 80mg bid daily, usually divided dose
  6. Conivaptan (Vaprisol®) [9]
    1. Non-selective V1/2 antagonist
    2. Effective in euvolemic and hypervolemic hyponatremia
    3. Includes SIADH, cirrhosis with ascites, nephrotic syndrome, CHF
    4. FDA approved for intravenous infusions for hyponatremia including SIADH
    5. Potent inhibitor of CYP3A4
    6. Caution with too-rapid correction of hyponatremia, as brain demyelination can occur
  7. Diet (Initial)
    1. 10-20mEq of Sodium qd
    2. High biologic value protein 50g/d (caution: may precipitate hepatic encephalopathy)
    3. Calories: 2000 qd
    4. Fluid Restriction only for hyponatremia Na+ <130mEq/L
  8. Therapeutic Paracentesis [8]
    1. Initially as effective as peritoneovenous shunts, but not over 3-48 months [5]
    2. Large volumes may be removed (4-10 liters) but circulatory dysfunction is a concern
    3. Albumin replacement should be given for high volumes: 8-10gm albumin/L ascites removed
    4. Albumin prevents circulatory collapse after high volume paracentesis
    5. Dextran or polygeline are considerably less effective than albumin and should not be used
    6. Paracentesis reduces risk of developing spontaneous bacterial peritonitis
    7. Large volume paracentesis in Child Class B and C associated with 82% recurrence of ascites within 3 months [5]
  9. Transjugular Intrahepatic Portosystemic Shunt (TIPS) [6]
    1. Treatment for portal hypertension and ascites with recurrent variceal bleeding
    2. Conduit from portal vein to hepatic vein (IVC) placed transvenously
    3. Stenosis or occlusion of stent may occur (~20% in 6 months initially)
    4. Safe and effective therapy for variceal bleeding by reducing portal pressure
    5. Significantly reduces ascites formation with >70% complete response in 3 months [7]
    6. Lttle effect on albumin, PT, or bilirubin levels, but creatinine usually improves
    7. TIPS induces a natriuresis and systemic vasodilation, with mild renal improvement
  10. Hepatorenal Syndrome (HRS) [1]
    1. Serum creatinine >1.5mg/dL or creatinine clearance <40mL/min
    2. Absnce of other causes for renal failure in patients with cirrhosis
    3. Type 1 HRS is subacute progression with creatinine doubling in <2 weeks to >2.5mg/dL
    4. Type 2: stable or slowly progressive impairment in renal function (slower than Type 1)
    5. Multiorgan failure with Urine Na <10, ascites, anuria or oliguria
    6. Vasoconstrictors norepinephrine, midodrine + octreotide, or terlipressin, all with albumin
    7. Treatment bridge to liver transplant
    8. Albumin infusions help reduce risk of HRS in spontaneous bacterial peritonitis

References

  1. Gines P, Cardenas A, Arroyo V, Rodes J. 2004. NEJM. 350(16):1646 abstract
  2. Menon KVN, Shah V, Kamath PS. 2004. NEJM. 350(6):578 abstract
  3. Rosene-Montella K, Keely E, Laifer SA, Lee RV. 2000. Ann Intern Med. 132(12):973 abstract
  4. Chung RT, Iafrate AJ, Amrein PC, et al. 2006. NEJM. 354(20):2166 (Case Record) abstract
  5. Rossle M, Ochs A, Gulberg V, et al. 2000. NEJM. 342(23);1701 abstract
  6. Wong F, Sniderman K, Liu P, et al. 1995. Ann Intern Med. 122(11):816 abstract
  7. Ochs A, Rossle M, Haag K, et al. 1995. NEJM. 332(18):1192 abstract
  8. Wong CL, Holroyd-Leduc J, Thorpe KE, Straus SE. 2008. JAMA. 299(10):1166 abstract
  9. Conivaptan. 2006. Med Let. 48(1237):51 abstract