Cirrhosis and Liver Transplantation

Transcription

1 Cirrhosis and Liver Transplantation 1. A 55 year-old man with a history of IV drug use is found to be anti-hcv positive. He complains of fatigue. On physical exam he has vascular spiders, palmar erythema and a palpable left lobe of the liver. No ascites, no asterixis. Laboratory analysis demonstrates AST 100, ALT 67, alkaline phosphatase 145, platelet count of 120,000. Abdominal CAT scan shows a nodular contour of the liver and portosystemic collaterals. No masses. Which of the following would you recommend as the next step? A. Liver biopsy B. Upper endoscopy C. Start non-selective beta-blockers D. Start spironolactone E. MRI of the liver The recommended response is B. Although the gold standard in the diagnosis of cirrhosis is liver biopsy, this procedure is not always necessary as clinical, laboratory and imaging results may be sufficient to establish the diagnosis. In the setting of chronic liver disease, finding a palpable left lobe of the liver is almost diagnostic of cirrhosis. The most sensitive and specific laboratory finding suggestive of cirrhosis, in the setting of chronic liver disease, is a low platelet count (<150,000/mm 3 ) secondary to portal hypertension and hypersplenism. Confirmatory imaging tests include computed tomography, ultrasound or magnetic resonance imaging. Findings consistent with cirrhosis include nodular contour of the liver, small liver with or without left/caudate lobe hypertrophy, splenomegaly and, particularly, the identification of intraabdominal collaterals (indicative of portal hypertension). A liver biopsy is not required if these findings are present. Any patient with newly diagnosed cirrhosis should undergo upper endoscopy to investigate the presence/size of gastroesophageal varices. Beta-blockers should be initiated in patients with medium/large varices. Although it has been suggested that universal beta-blockade (foregoing endoscopy) is more cost-effective, beta-blockers are not useful in patients without varices (about half of the patients on screening endoscopy) and are associated with significant adverse events. Studies have not shown diuretics to be useful in patients with compensated cirrhosis. In the absence of masses on CAT scan or ultrasound, performing an MR is unnecessary. Poynard T, Bedossa P, for the METAVIR and CLINIVIR cooperative study groups: Age and platelet count: a simple index for predicting the presence of histological lesions in patients with antibodies to hepatitis C virus. J Viral Hep 1997, 4: de Franchis R: Evolving Consensus in Portal Hypertension Report of the Baveno IV Consensus Workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol 2005, 43:

2 Grace ND: Diagnosis and treatment of gastrointestinal bleeding secondary to portal hypertension. Am J Gastroenterol 1997, 92: Garcia-Tsao G: Current management of the complications of cirrhosis and portal hypertension: varices and variceal hemorrhage, ascites and spontaneous bacterial peritonitis. Gastroenterology 2001, 120: Groszmann RJ, Garcia-Tsao G, Bosch J, Grace N D, Burroughs A K, Planas R, Escorsell A, Garcia-Pagan J C, Patch D, Matloff D S, Gao H, Makuch R W, for the Portal Hypertension Collaborative Group: Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med 2005, 353: A 69-year old man with chronic hepatitis C cirrhosis without a prior history of variceal hemorrhage is noted to have large varices on upper endoscopy. What is the preferred therapeutic agent for the prevention of variceal bleeding? A. Metoprolol B. Nadolol C. Atenolol D. Isosorbide-5-mononitrate E. Pantoprazole The recommended response is B. Non-selective beta-blockers are the treatment of choice for the primary prevention of variceal bleeding. Beta-1-specific blockers (atenolol, metoprolol) are not as effective as nonselective (beta-1 and beta-2) betablockers (nadolol, propranolol), because the most important portal pressure-reducing effect results from beta-2 blockade. Isosorbide-5- mononitrate is comparable to nonselective beta-blockers, but is associated with a higher mortality. Additionally, compared to placebo, isosorbide mononitrate leads to a higher rate of first variceal bleed. Although there appears to be a a benefit in blocking gastric acid with a proton pump inhibitor for the prevention of post-ligation ulcer size and bleeding, there is no benefit in preventing first variceal bleed. de Franchis R: Evolving Consensus in Portal Hypertension Report of the Baveno IV Consensus Workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol 2005, 43: D'Amico G, Pagliaro L, Bosch J: Pharmacological treatment of portal hypertension: an evidence-based approach. Sem Liv Dis 1999, 19: Hillon P, Lebrec D, Munoz C, Jungers M, Goldfarb G, Benhamou J P: Comparison of the effects of a cardioselective and a non-selective -blocker on portal hypertension in patients with cirrhosis. Hepatology 1982, 2:

3 Mills PR, Rae A P, Farah D A, Russell R I, Lorimer A R, Carter D C: Comparison of three adrenoceptor blocking agents in patients with cirrhosis and portal hypertension. Gut 1984, 25: Angelico M, Carli L, Piat C, Gentile S, Capocaccia L: Effects of isosorbide-5- mononitrate compared with propranolol on first bleeding and long-term survival in cirrhosis. Gastroenterology 1997, 113: Garcia-Pagan JC, Villanueva C, Vila M C, Albillos A, Genesca J, Ruiz-del-Arbol L, Planas R, Rodriguez M, Calleja J L, Gonzalez A, Sola R, Balanzo J, Bosch J, MOVE Group.Mononitrato Varices Esofagicas: Isosorbide mononitrate in the prevention of first variceal bleed in patients who cannot receive beta-blockers. Gastroenterology 2001, 121: Shaheen NJ, Stuart E, Schmitz S M, Mitchell K L, Fried M W, Zacks S, Russo M W, Galanko J, Shrestha R: Pantoprazole reduces the size of postbanding ulcers after variceal band ligation: a randomized, controlled trial. Hepatology 2005, 41: A 62 year-old man with cirrhosis secondary to hemochromatosis has very large varices with red wale signs on endoscopy. He is an insulin-dependent diabetic and has had episodes of hypoglycemia. His Child score is 5. First line therapy for primary prophylaxis of variceal hemorrhage in this patient should be: A. Endoscopic variceal ligation (EVL) B. Isosorbide mononitrate C. Transjugular intrahepatic portosystemic shunt (TIPS) D. Endoscopic variceal ligation + beta-blockers E. Non-selective beta-blockers The recommended response is A. Non-selective beta-blockers are first line therapy in the prevention of first variceal hemorrhage in cirrhotic patients with medium or large varices. However, about 30% of these patients have contraindications or intolerance to non-selective beta-blockers. An alternative therapy is EVL. Meta-analyses of 15 trials of EVL vs. beta-blockers show a slight benefit of EVL in reducing first variceal bleeding without a difference in mortality. However, most of these trials are small in size and of short duration and EVL has been associated with lethal complications. Therefore EVL is reserved to patients with high-risk varices who cannot tolerate or have contraindications to beta-blockers. Insulin-dependent diabetes with episodes of hypoglycemia is a contraindication to beta-blockers. A trial comparing placebo vs. isosorbide mononitrate in patients intolerant to beta-blockers showed that isosorbide mononitrate was associated with a higher rate of first variceal bleed, and should therefore not be used in this setting. Of note, beta-blockers + nitrates and beta-blockers + EVL do not seem to be more useful than beta-blockers alone in

4 preventing first variceal hemorrhage. Shunt surgery is very effective in preventing first variceal hemorrhage but is accompanied by an increased incidence of encephalopathy and a higher mortality. Because the physiology of TIPS is the same as that of surgical shunts (i.e. diversion of blood away from the liver), these results can be extrapolated to TIPS. Therefore, shunt therapy (surgery or TIPS) not only is not recommended but should not be used in the primary prevention of variceal hemorrhage. Garcia-Pagan JC and Bosch J: Endoscopic band ligation in the treatment of portal hypertension. Nat.Clin Pract.Gastroenterol Hepatol. 2005, 2: de Franchis R: Evolving Consensus in Portal Hypertension Report of the Baveno IV Consensus Workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol 2005, 43: Garcia-Pagan JC, Villanueva C, Vila M C, Albillos A, Genesca J, Ruiz-del-Arbol L, Planas R, Rodriguez M, Calleja J L, Gonzalez A, Sola R, Balanzo J, Bosch J, MOVE Group.Mononitrato Varices Esofagicas: Isosorbide mononitrate in the prevention of first variceal bleed in patients who cannot receive beta-blockers. Gastroenterology 2001, 121: D'Amico G, Pagliaro L, Bosch J: The treatment of portal hypertension: A meta-analytic review. Hepatology 1995, 22: A 50-year old man with alcoholic cirrhosis is seen in consultation for acute GI bleeding. One year ago, he bled from esophageal varices and underwent emergent sclerotherapy. He was placed on beta-blockers and had been compliant. He now presents with recurrent GI bleeding due to a ruptured esophageal varix. Which of the following is the best management of this patient? A. Vasopressin, flouroquinolone, and endoscopic sclerotherapy B. Octreotide, flouroquinolone, and endoscopic ligation C. Balloon tamponade, amphotericin, and endoscopic ligation/sclerotherapy D. Emergent TIPS E. Endoscopic ligation/sclerotherapy followed by portocaval shunt surgery The recommended response is B. The preferred specific management of acute variceal bleeding is the combination of a safe vasoactive drug (terlipressin, somatostatin or somatostatin analogues) that will lower portal pressure, plus endoscopic therapy (preferably endoscopic variceal ligation. Of the safe vasoactive drugs, the somatostatin analogue octreotide is the only one available in the U.S. Drug safety allows the medication to be initiated prior to diagnostic endoscopy and continued for the next 2-5 days when the risk of rebleeding is highest. Vasopressin, a potent vasoconstrictor, is effective in reducing portal pressure but is associated with

5 deleterious systemic vasoconstrictive side-effects that allows its administration for a maximum of 24 hours. Flouroquinolones significantly reduce bacterial infections (including spontaneous bacterial peritonitis), variceal rebleeding and mortality in cirrhotic patients with an upper GI bleed, and therefore are considered standard of care. Balloon tamponade can acutely control variceal bleeding in the majority of patients in whom pharmacologic and endoscopic treatments fail, but a high incidence of side effects limits its use as initial therapy. The primary indication for TIPS is failure of endoscopic therapy (two sessions for esophageal variceal bleed). Urgent portosystemic shunt surgery has a high morbidity and mortality in the setting of recent variceal hemorrhage, particularly in decompensated patients. Therefore, shunt surgery is best reserved for highly selected patients with compensated disease in whom the episode of acute hemorrhage has been controlled. Banares R, Albillos A, Rincon D, Alonso S, Gonzalez M, Ruiz-del-Arbol L, Salcedo M, Molinero L M: Endoscopic treatment versus endoscopic plus pharmacologic treatment for acute variceal bleeding: a meta-analysis. Hepatology 2002, 35: Bernard B, Grange J D, Khac E N, Amiot X, Opolon P, Poynard T: Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding: a meta-analysis. Hepatology 1999, 29: Rimola A, Garcia-Tsao G, Navasa M, Piddock L J V, Planas R, Bernard B, Inadomi J M: Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. J Hepatol 2000, 32: Avgerinos A and Armonis A: Balloon tamponade technique and efficacy in variceal haemorrhage. Scand J Gastroenterol Suppl. 1994, 207:11-6.: Sanyal AJ, Freedman A M, Luketic V A, Purdum P P, Shiffman M L, Tisnado J, Cole P E: Transjugular intrahepatic portosystemic shunts for patients with active variceal hemorrhage unresponsive to sclerotherapy. Gastroenterology 1996, 111: McCormick PA, Dick R, Panagou E B, Chin J K, Greenslade L, McIntyre N, Burroughs A K: Emergency transjugular intrahepatic portosystemic stent shunting as a salvage treatment for uncontrolled variceal hemorrhage. Br J Surg 1994, 81: Bleeding is controlled with above therapy and the patient described above is free of recurrent hemorrhage 5 days after admission. His Child score is 10, MELD score is 15. Mean arterial pressure is 90 mmhg. What is the best therapy at this point? A. Start propranolol prior to discharge and give appointment for repeat EVL B. TIPS prior to discharge from the hospital C. Shunt surgery prior to discharge from the hospital D. Liver transplant prior to discharge from the hospital

6 E. No specific therapy and give appointment to start liver transplant evaluation The recommended response is A. Since this patient has already failed treatment with beta-blockers, the recommendation is to re-treat with beta-blockers associated to EVL. Once bleeding is controlled, betablockers are started and endoscopic therapy is continued until varices are obliterated and subsequent periodic surveillance is undertaken at regular intervals to monitor for recurrent varices. TIPS is only indicated if a patient rebleeds on combined endoscopic/pharmacological therapy. The same applies for shunt surgery but in this case the patient needs to also be compensated and local expertise needs to be available. Although the patient clearly needs to start liver transplant evaluation, his priority is not sufficiently high to be transplanted prior to discharge from the hospital and therapy to prevent rebleeding needs to be in place prior to discharge as the rate of recurrent variceal hemorrhage without specific therapy is about 60%. Garcia-Pagan JC and Bosch J: Endoscopic band ligation in the treatment of portal hypertension. Nat.Clin Pract.Gastroenterol Hepatol. 2005, 2: Boyer TD: Transjugular intrahepatic portosystemic shunt: current status. Gastroenterology 2003, 124: Henderson JM, Boyer T D, Kutner M H, Galloway J R, Rikkers L F, Jeffers L J, Abu- Elmagd K, Connor J: Distal splenorenal shunt versus transjugular intrahepatic portal systematic shunt for variceal bleeding: a randomized trial. Gastroenterology. 2006, 130: A 56-year old man with chronic hepatitis B and Child-Pugh Class C cirrhosis is transferred to the hospital with upper GI hemorrhage. He had been admitted to another hospital three days before and found to have bleeding gastric varices and was treated with one session of sclerotherapy. Endoscopy shows small 1+ esophageal varices and a large pool of fresh blood in the fundus. What is the most appropriate management of this patient? A. Lavaging the fundus and performing ligation of gastric varices B. Lavaging the fundus and performing sclerotherapy using a large volume of sclerosant (5 to 10 ml), followed by serial endoscopies with sclerotherapy until obliteration of gastric varices C. Emergent transjugular intrahepatic portosystemic shunts (TIPS) D. Insertion of a Sengstaken-Blakemore tube to tamponade the gastric varix followed by portosystemic shunt surgery E. Emergent portosystemic shunt surgery

7 The recommended response is C. This patient has portal hypertensive bleeding from fundic gastric varices, which may bleed massively and are not typically well controlled by endoscopic therapy. There is only anecdotal experience with the use of band ligation for gastric varices, and long-term efficacy remains uncertain. Sclerotherapy may temporarily control active gastric variceal hemorrhage but is even less effective in fundal varices than in GOV1 gastric varices. This patient has already failed one session of sclerotherapy and lavaging the fundus is usually insufficient to clear the clot and allow the performance of endoscopic therapy. Injection of other materials such as tissue adhesives is undergoing study and may provide better control of acute and recurrent gastric variceal bleeding. TIPS has been shown to control portal hypertensive bleeding from both the esophagus and the stomach and plays an important role in the control of variceal bleeding refractory to endoscopic therapy. In patients bleeding from fundal varices, the indication for TIPS should occur sooner (i.e. after one attempted endoscopic therapy) than for esophageal varices (in which two endoscopic therapy sessions are allowed prior to considering TIPS). Balloon tamponade may be effective in the short-term management of gastric varices but is associated with high rates of complications. Portosystemic shunt surgery may be useful in patients with gastric variceal bleeding but is associated with a high operative mortality in patients with poor hepatic synthetic function. Sarin SK, Lahoti D, Saxena S P, Murthy N S, Makwana U K: Prevalence, classification and natural history of gastric varices: a long-term follow-up study in 568 portal hypertension patients. Hepatology. 1992, 16: Ryan BM, Stockbrugger R W, Ryan J M: A pathophysiologic, gastroenterologic, and radiologic approach to the management of gastric varices. Gastroenterology. 2004, 126: Tan PC, Hou M C, Lin H C, Liu T T, Lee F Y, Chang F Y, Lee S D: A randomized trial of endoscopic treatment of acute gastric variceal hemorrhage: N-butyl-2-cyanoacrylate injection versus band ligation. Hepatology. 2006, 43: Sanyal AJ, Freedman A M, Luketic V A, Purdum P P, Shiffman M L, Tisnado J, Cole P E: Transjugular intrahepatic portosystemic shunts for patients with active variceal hemorrhage unresponsive to sclerotherapy. Gastroenterology 1996, 111: McCormick PA, Dick R, Panagou E B, Chin J K, Greenslade L, McIntyre N, Burroughs A K: Emergency transjugular intrahepatic portosystemic stent shunting as a salvage treatment for uncontrolled variceal hemorrhage. Br J Surg 1994, 81: Avgerinos A and Armonis A: Balloon tamponade technique and efficacy in variceal haemorrhage. Scand J Gastroenterol Suppl. 1994, 207:11-6.:11-16.

8 7. Portal hypertensive gastropathy is a manifestation of portal hypertension that: A. Usually results in intermittent massive GI bleeding B. Presents as linear aggregates of red spots in the stomach C. Usually involves the antrum D. May be treated with endoscopic electrocoagulation E. Improves with maneuvers that lower portal pressures The recommended response is E. Two major nonvariceal consequences of portal hypertension are found in the stomach: portal hypertensive gastropathy and gastric antral vascular ectasia. These lesions are recognized increasingly at endoscopy and are distinct entities. Patients with portal hypertensive gastropathy usually have a mosaic mucosal pattern with or without submucosal hemorrhage, particularly in the gastric fundus and corpus, but not typically in the antrum. Gastric antral vascular ectasia typically present as linear aggregates of red spots in the gastric antrum (watermelon stomach) and are not associated with a mosaic mucosal pattern. Both lesions present most commonly as slow or occult blood loss and anemia rather than acute GI bleeding. Gastric antral vascular ectasia may be treated with endoscopic electrocoagulation or laser therapy as lowering of portal pressures is generally ineffective in improving the lesions or blood loss. In contrast, portal hypertensive gastropathy does improve with lowering of portal pressures and nonselective beta-blockers or TIPS (in more severe cases) may control bleeding. Payen JL, Cales P, Voigt J J, Barbe S, Pilette C, Dubuisson L, Desmorat H, Vinel J P, Kervran A, Chayvialle J A,.: Severe portal hypertensive gastropathy and antral vascular ectasia are distinct entities in patients with cirrhosis. Gastroenterology. 1995, 108: Kamath PS, Lacerda M, Ahlquist D A, McKusick M A, Andrews J C, Nagorney D A: Gastric mucosal responses to intrahepatic portosystemic shunting in patients with cirrhosis. Gastroenterology 2000, 118: A 64-year old obese man presents for evaluation of the development of ascites and peripheral edema. He is a heavy smoker and typically drinks 2 to 4 alcoholic beverages daily but has no history of liver disease. Physical examination reveals decreased breath sounds, moderate ascites and peripheral edema but no other abnormalities. Laboratory tests reveal a total bilirubin 1.2 mg/dl, AST 37 IU/mL, ALT 35 IU/mL, albumin 3.7 gm/dl, and INR of 1.4. Paracentesis discloses clear yellow fluid with the following characteristics: total protein 3.5 g/dl, albumin 1.7 g/dl, white blood cells 640/mm 3 (12% neutrophils) Which one of the following is the most appropriate action?

9 A. Begin IV cefotaxime and await ascites culture results B. Perform a liver biopsy C. Perform a cardiac echo and/or right heart catheterization D. Perform an abdominal CAT scan to investigate peritoneal malignancy E. Begin therapy for tuberculosis The recommended response is C. This patient without documented chronic liver disease has ascites with a high serumascites albumin gradient (>1.1 g/dl) indicating ascites that is secondary to sinusoidal hypertension. The fluid also has a high protein content (>2.5 g/dl) indicative of normal leaky sinusoids. The etiology is therefore post-hepatic, e.g. hepatic vein occlusion or right heart failure. In this clinical setting the most likely possibility is right heart failure and workup should be made accordingly, ideally through right heart catheterization, at which time hepatic vein pressure measurements could be obtained. A liver biopsy could also be obtained at the time of right heart catheterization but would not be essential for the diagnosis. Although the ascites total white blood cell count is somewhat elevated, the fluid only contains 77 neutrophils (640 x 0.12) and therefore it is not consistent with bacterial peritonitis (the diagnosis of SBP is made with >250 neutrophils/mm 3 ). In peritoneal causes of ascites (carcinomatosis, tuberculosis) the ascites protein is high and SAAG is low (<1/1 g/dl) since fluid formation does not result from sinusoidal hypertension. Garcia-Tsao, G. Ascites. In: Boyer, T. D., Wright, T. L., and Manns, M. P. Zakim and Boyer's Hepatology. A Textbook of Liver Disease. Philadelphia: Elsevier, 2006: Rimola A, Garcia-Tsao G, Navasa M, Piddock L J V, Planas R, Bernard B, Inadomi J M: Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. J Hepatol 2000, 32: A 56-year old man with cryptogenic cirrhosis and ascites is evaluated for a right hepatic hydrothorax associated with dyspnea. Despite in-hospital diuretic therapy and serial large-volume paracentesis, hydrothorax persists and requires weekly thoracenteses. The patient is undergoing liver transplant evaluation. What is the best management for refractory hepatic hydrothorax? A. Video-assisted thoracoscopy to repair diaphragmatic defects B. Chest-tube drainage C. Transjugular intrahepatic porto-systemic shunt (TIPS) D. Peritoneovenous shunting E. Chemical pleurodesis

10 The recommended response is C. Hepatic hydrothorax develops in approximately 5-10% of patients with cirrhosis and most probably results from the transdiaphragmatic movement of fluid from the peritoneum to the pleural space through diaphragmatic defects. Hepatic hydrothorax should be treated in the same manner as cirrhotic ascites, that is, the mainstay of therapy is sodium restriction and diuretics. Before determining that hydrothorax is refractory, a trial of in-hospital diuretic therapy should be attempted. TIPS is the preferred treatment to control hepatic hydrothorax that is refractory to diuretics. In uncontrolled studies, TIPS leads to resolution of the pleural effusion or a decrease in the need for thoracentesis in 67% of patients, however mortality is high, particularly in non-responders to TIPS. Chemical pleurodesis, peritoneovenous shunts, and attempts at surgical or endoscopic repair of diaphragmatic defects have had limited success. Placement of a chest tube should be avoided as it has been associated with multiple complications, mainly volume and electrolyte disturbances. Cardenas A, Kelleher T, Chopra S: Review article: hepatic hydrothorax. Aliment Pharmacol Ther 2004, 20: Garcia-Tsao, G. Transjugular intrahepatic portosystemic shunt (TIPS) for the management of refractory ascites in cirrhosis. In: Gines, P., Arroyo, V., Rodes, J., and Schrier, R. W. Ascites and Renal Dysfunction in Liver Disease. Pathogenesis, diagnosis and treatment. Blackwell, 2005: Liu LU, Haddadin H A, Bodian C A, Sigal S H, Korman J D, Bodenheimer H C, Jr., Schiano T D: Outcome analysis of cirrhotic patients undergoing chest tube placement. Chest 2004, 126: A 48 year old man with HCV cirrhosis and ascites presents with 2 days of increasing confusion. Denies fever, chills, hematemesis or melena. Medications on admission: spironolactone 200 mg QAM, lasix 80 mg QAM. No sedatives. On physical exam he is afebrile, BP 90/60, heart rate 100 bpm, respiratory rate 30/min, confused and agitated, (+) asterixis, abdomen with tense ascites, non-tender, guaiac negative. Labs: WBC 8.6, creatinine 2.1 (previously 0.8), bilirubin 7.7 (previously 2.3), rest stable. Besides discontinuing diuretics and initiating treatment with lactulose, which of the following is the most appropriate action: A. Start octreotide, midodrine and albumin B. Perform a diagnostic paracentesis and blood cultures C. Perform a large-volume paracentesis D. Perform an upper endoscopy E. Perform a brain CT

11 The recommended response is B. The presence of unexplained encephalopathy and/or deterioration in renal function in a patient with ascites should always raise the suspicion of spontaneous bacterial peritonitis (SBP) and therefore a diagnostic paracentesis should always be performed in this setting. Ascites culture is negative in approximately 40% of patients with SBP and to maximize the possibilities of isolating an infecting organism, both ascites and blood bacteriological cultures should be performed whenever SBP is suspected. In this patient blood cultures are particularly important since he presents with evidence of systemic inflammatory response system (tachycardia, tachypnea) and jaundice and therefore may be septic. Although renal dysfunction in a cirrhotic patient with ascites could represent hepatorenal syndrome, this is a diagnosis of exclusion and specific therapy (e.g. octreotide/midodrine) should not be started until other causes of renal dysfunction are investigated and treated. Large volume paracentesis in this setting could theoretically lead to further deterioration in renal function and should be avoided. There is no evidence of GI bleed and therefore endoscopy is not indicated. Brain scan is not an initial test in a cirrhotic patient with encephalopathy unless there is a story of trauma or other causes of encephalopathy are ruled out. Rimola A, Garcia-Tsao G, Navasa M, Piddock L J V, Planas R, Bernard B, Inadomi J M: Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. J Hepatol 2000, 32: Arroyo V, Gines P, Gerbes A L, Dudley F J, Gentilini P, Laffi G, Reynolds T F, Ring- Larsen H, Scholmerich J: Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. Hepatology 1996, 23: A 46-year old man with hepatitis C cirrhosis and ascites is admitted to the hospital for the sudden onset of abdominal pain and fever. Physical examination shows a temperature of 38.6 C and diffuse abdominal tenderness without rebound. Labs show: creatinine 1.7 mg/dl, BUN 39 mg/dl, WBC 8.9. Paracentesis demonstrates cell count of 800/mm 3 with 60% neutrophils. Ascites culture results are pending. Which of the following is the most appropriate action at this point? A. Begin ampicillin and gentamicin until ascitic culture results are reported B. Administer IV albumin and await culture results before starting specific antibiotic therapy C. Initiate IV cefotaxime and albumin D. Repeat diagnostic paracentesis and get blood cultures E. Perform an abdominal CAT scan The recommended response is C.

12 An ascitic fluid neutrophil (polymorphonuclear cell count) >250 /mm 3 in the absence of an intraabdominal inflammatory condition (e.g. cholecystitis, pancreatitis) is diagnostic of SBP and warrants immediate empirical antibiotic coverage. Aminoglycosides should be avoided in cirrhotic patients due to an increased susceptibility for nephrotoxicity. The ideal antibiotic is a third generation cephalosporin or the combination amoxicillin/clavulanic acid. This patient has renal dysfunction associated to SBP and intravascular volume expansion with albumin has been shown to decrease mortality. Blood cultures should be done at the time of the initial diagnostic paracentesis and this should not be repeated until 48 hours after initiating antibiotic therapy. If ascites cultures reveal more than one organism, fungus or an anaerobe, secondary bacterial peritonitis is suspected and an abdominal CAT scan would then be indicated, but not at this point. Rimola A, Garcia-Tsao G, Navasa M, Piddock L J V, Planas R, Bernard B, Inadomi J M: Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. J Hepatol 2000, 32: Garcia-Tsao G: Spontaneous bacterial peritonitis. Gastro Clin North Am 1992, 21: Garcia-Tsao G: Further evidence against the use of aminoglycosides in cirrhotic patients. Gastroenterology 1998, 114: Sort P, Navasa M, Arroyo V, Aldeguer X, Planas R, Ruiz-del-Arbol L, Castells L, Vargas V, Soriano G, Guevara M, Gines P, Rodes J: Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 1999, 341: A 55-year old man with decompensated hepatitis C cirrhosis admitted with SBP is noted to have a low urine output and increasing creatinine after resolution of the infection. He has jaundice, tense ascites and peripheral edema. Laboratory data reveal a serum creatinine 3.1 mg/dl (4 weeks prior: 0.8 mg/dl, at time of SBP 2.0 mg/dl), BUN 52 mg/dl, serum sodium 123 meq/l Which of the following treatment options is not appropriate at the present time? A. Start IV furosemide B. Obtain urinalysis, urine sodium measurement, and urine sediment C. Obtain renal ultrasound D. Expand intravascular volume with saline or albumin E. Repeat diagnostic paracentesis The recommended response is A. Renal dysfunction in the setting of decompensated cirrhosis is an ominous event. Of great concern is the development of the hepatorenal syndrome (HRS) that occurs in patients with cirrhosis and ascites, frequently after an episode of spontaneous bacterial

13 peritonitis, and has a very poor prognosis. It is a functional renal failure that results from extreme vasodilatation, decrease in effective arterial blood volume and activation of neurohumoral systems that lead to renal vasoconstriction. Clinically, HRS is defined as renal failure occurring in the setting of severe liver disease after exclusion of potentially reversible causes of renal failure (sepsis, hypovolemia, nephrotoxicity) and that does not reverse after diuretic discontinuation and volume expansion with saline or albumin. A urinary sodium <10 meq/ml is typical in HRS. Distinguishing HRS from organic causes of renal insufficiency and quickly attempting to reverse possible contributors is appropriate. Therefore, performing urine studies and performing a renal ultrasound to rule out hydronephrosis is important. In addition, excluding recurrent spontaneous bacterial peritonitis is reasonable. Any measure that will further decrease the effective arterial blood volume, particularly intravenous diuretics, will worsen the hemodynamic abnormalities and should be avoided. Arroyo V, Gines P, Gerbes A L, Dudley F J, Gentilini P, Laffi G, Reynolds T F, Ring- Larsen H, Scholmerich J: Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. Hepatology 1996, 23: Gines P, Guevara M, Arroyo V, Rodes J: Hepatorenal syndrome. Lancet 2003, 362: In which of the following patients would you recommend antibiotic therapy to prevent spontaneous bacterial peritonitis (SBP)? A. A 65 year-old woman with chylous ascites due to non-hodgkin s lymphoma B. A 53 year-old man with alcoholic cirrhosis and ascites with a low protein content (<1.0 g/dl) and no history of SBP C. A 48 year-old man with pulmonary sarcoidosis and ascites secondary to severe cor pulmonale D. A 45-year old man with a history of alcoholic hepatitis and spontaneous bacterial peritonitis who stopped drinking and currently has no ascites E. A 37-year old with alcoholic cirrhosis and ascites who presents with massive hematemesis The recommended response is E. Antibiotic prophylaxis is effective in decreasing the incidence of bacterial infections, including SBP, in cirrhotic patients. However, the widespread use of antibiotics leads to the development of antibiotic-resistant organisms and therefore antibiotic prophylaxis should only be performed in patients at a high risk of bacterial infections and SBP. These are: 1) cirrhotic patients (with or without ascites) presenting with GI hemorrhage (shortterm prophylaxis) and 2) cirrhotic patients who have recovered from an episode of SBP (long-term prophylaxis). Insufficient data are available on the effectiveness of long-term antibiotic prophylaxis in patients with ascites total protein levels of <1.0 g/dl in the absence of prior SBP. Patients in whom ascites has resolved, even those with a prior

14 history of SBP, do not require antibiotic prophylaxis. Patients with cardiac or malignant ascites (i.e. high-protein ascites) and cirrhotic patients with ascites protein > 1.0 g/dl have a very low risk of developing SBP, presumably due to intact opsonic and complement-activating capacity of the ascitic fluid. Fernandez J, Navasa M, Gomez J, Colmenero J, Vila J, Arroyo V, Rodes J: Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis. Hepatology 2002, 35: Garcia-Tsao G: Bacterial infections in cirrhosis: treatment and prophylaxis. J Hepatol 2005, 42 Suppl:S85-S A 55 year-old man with a history of HCV cirrhosis presents to his primary care physician with 6-week history of increasing fatigue and increasing abdominal distension. Laboratory analysis demonstrates: total bilirubin 2.3 mg/dl, alkaline phosphatase 176 IU/L, aspartate aminotransferase (AST) 165 IU/L, alanine aminotransferase (ALT) 90 IU/L, serum albumin 2.9 g/dl, and alpha-fetoprotein (AFP) 224 ng/dl. Which of the following would you recommend at this point? A. Liver-spleen scan B. Abdominal ultrasound with Doppler evaluation of portal blood flow C. Triphasic dynamic computed tomographic (CT) scan D. Endoscopic retrograde cholangiopancreatography (ERCP) E. Transjugular liver biopsy The recommended response is C. Hepatocellular carcinoma (HCC) is a complication of cirrhosis that, in the compensated cirrhotic patient, can precipitate decompensation. It occurs particularly in patients with cirrhosis secondary to chronic viral disease, hemochromatosis, and alcoholic liver disease. AFP levels > 200 ng/ml in this patient with recent decompensation suggests the presence of HCC. The highest sensitivity for detecting and characterizing a liver mass would be obtained with dynamic CT as compared to abdominal ultrasound. Liver-spleen scan is more useful in diagnosing cirrhosis or portal hypertension but is not useful in detecting hepatic masses. In this setting, ERCP would not be an appropriate choice because it is not useful in detecting hepatic lesions. Guided liver biopsy may be useful in confirming that a lesion discovered on imaging is malignant, but is not an appropriate step at this point. Bruix J and Sherman M: Management of hepatocellular carcinoma. Hepatology. 2005, 42:

15 15. In the above patient, an imaging study shows a single 4 cm mass in the right lobe of the liver with arterial hypervascularity and wash out in the early venous phase. Appropriate action at this point is: A. Transplant evaluation B. Surgical resection C. Confirmatory imaging study D. Biopsy of the mass E. Transarterial chemoembolization The recommended response is A. Detection of a hepatic mass within a cirrhotic liver is highly suspicious of HCC. If AFP is greater than 200 ng/ml (as in this patient) and the radiological appearance of the mass is suggestive of HCC (arterial hypervascularity with venous washout), the likelihood that the lesion is HCC is high and biopsy is not required. In fact, it has been suggested that if a lesion shows arterial hypervascularity and washes out in the early or delayed venous phase, only a single imaging modality is required for diagnosis. Surgical resection is not an option in this patient who has decompensated cirrhosis. Liver transplantation is an effective option for patients with HCC that fulfill the Milan criteria: solitary tumor 5 cm in diameter or up to three nodules <3 cm in diameter. Preoperative therapy can be considered if the waiting list exceeds 6 months. Percutaneous ablation (alcohol injection or radiofrequency ablation) is safe and effective therapy as a bridge to transplantation. Transarterial chemoembolization is considered for patients with non-surgical HCC that are also ineligible for percutaneous ablation. Bruix J and Sherman M: Management of hepatocellular carcinoma. Hepatology. 2005, 42: In a cirrhotic patient with acute hepatic encephalopathy, which of the following tests will not be useful: A. Diagnostic paracentesis B. Stool guaiac C. Toxicology screen D. BUN, creatinine E. Ammonia levels The recommended response is E. HE is the neuropsychiatric manifestation of cirrhosis. The diagnosis of HE is clinical and is based on history and physical examination findings. Even though ammonia, a toxin normally removed by the liver, plays a key role in the pathogenesis of hepatic encephalopathy, blood ammonia levels are not useful in the diagnosis and management of HE because they are unreliable and correlate poorly with its stage. The mainstay of

16 therapy of acute HE involves the identification and treatment of the precipitating factor (present in over 80% of cases). Precipitant factors that need to be investigated in any patient with acute encephalopathy are infections (such as spontaneous bacterial peritonitis), prerrenal azotemia, electrolyte disturbances, gastrointestinal bleeding, and use of narcotics and sedatives. Ong JP, Aggarwal A, Krieger D, Easley K A, Karafa M T, Van Lente F, Arroliga A C, Mullen K D: Correlation between ammonia levels and the severity of hepatic encephalopathy. Amer J Med 2003, 114: A 45-year old man with decompensated cirrhosis due to hemochromatosis presents with increasing confusion and difficulty sleeping at night. His primary physician added zolpidem 5 mg before bedtime without benefit. On physical exam he is alert but disoriented in time. He has 2+ asterixis. In addition to a thorough evaluation of potential precipitating factors for hepatic encephalopathy, which one of the following would be the most appropriate next step? A. Increase zolpidem to 10 mg before bedtime B. Discontinue zolpidem and start temazepam 30 mg before bedtime C. Start lactulose enemas every 2 hours for 3 days, then re-evaluate D. Start neomycin orally 1 g TID and a protein-free diet E. Start lactulose 30 ml orally BID and discontinue zolpidem The recommended response is E. Hepatic encephalopathy is a neurophyschiatric syndrome with clinical manifestations ranging from subtle abnormalities detected by psychometric testing to profound coma. A common manifestation of encephalopathy is reversal of the sleep-wake pattern with difficulty sleeping at night. Sedatives given to improve sleep are generally ineffective in patients with encephalopathy and frequently worsen confusion. Treatment of HE involves 1) identifying and treating the precipitating factor, and 2) ammonia-reducing procedures. In this case, the precipitant is the sedative zolpidem and therefore this, and any other sedative, should be discontinued. Protein restriction is not necessary and is proscribed long-term. Agents aimed at decreasing ammonia production in the gut are lactulose or non-absorbable antibiotics such as neomycin, metronidazole, or rifaximin. Lactulose is the preferred agent given its safety profile. Antibiotics, such as neomycin and metronidazole, are generally added to lactulose in patients whose encephalopathy is refractory to lactulose or are used as an alternative in those intolerant of lactulose. Lactulose enemas are used in hospitalized patients unable to take lactulose orally. Blei AT and Cordoba J: Hepatic Encephalopathy. Am J Gastroenterol. 2001, 96:

17 Cordoba J, Lopez-Hellin J, Planas M, Sabin P, Sanpedro F, Castro F, Esteban R, Guardia J: Normal protein diet for episodic hepatic encephalopathy: results of a randomized study. J Hepatol 2004, 41: A 38-year-old woman with cirrhosis due to autoimmune hepatitis presents for an evaluation of a 6-month history of slowly progressive extertional dsypnea. Physical examination reveals multiple spider angiomas, clubbing, and acrocyanosis. Chest and cardiac examination are unremarkable and chest radiology and pulmonary function tests are normal. Arterial blood gases reveals a PAO 2 of 69 mmhg Which of the following tests is the best screening test to define the diagnosis? A. Pulmonary angiography B. Contrast echocardiography with bubble study C. Abdominal ultrasonography with Doppler examination of the hepatic vasculature D. Bronchoscopy E. Right heart catheterization to assess pulmonary arterial pressure The recommended response is B. Insidious onset of exterional dyspnea, digital clubbing, and hypoxemia in the setting of cirrhosis and in the absence of intrinsic lung disease strongly suggests the possibility of hepatopulmonary syndrome. Vasodilatation at the level of the pulmonary circulation is the hallmark of the hepatopulmonary syndrome. In hepatopulmonary syndrome, contrast echocardiography, a qualitative test, demonstrates bubbles in the left atrium and left ventricle >3 beats after opacification of the right ventricle, indicative of intrapulmonary shunting. Pulmonary angiography is frequently normal in HPS and is therefore not a good diagnostic test. Bronchoscopy is not indicated in the absence of chest radiographic or pulmonary function abnormalities. Abdominal ultrasonography will not detect pulmonary vascular alterations. Right heart catheterization is indicated in the diagnosis of portopulmonary hypertension, another pulmonary complication of cirrhosis associated with dyspnea but without hypoxemia. Hoeper MM, Krowka M J, Strassburg C P: Portopulmonary hypertension and hepatopulmonary syndrome. Lancet 2004, 363: Abrams GA, Jaffe C C, Hoffer P B, Binder H J, Fallon M B: Diagnostic utility of contrast echocardiography and lung perfusion scan in patients with hepatopulmonary syndrome. Gastroenterology 1995, 109: Abrams G, Nanda N C, Dubovsky E V, Krowka J J, Fallon M B: Use of macroaggregated albumin lung perfusion scan to diagnose hepatopulmonary syndrome: a new approach. Gastroenterology 1998, 114:

18 19. Which of the following patients (all patients have a MELD score of 20) is the least appropriate for listing for liver transplantation? A. A 50- year old woman with primary biliary cirrhosis, jaundice, and ascites B. A 42-year old man with HBeAg+, HBV DNA + cirrhosis and a 2 cm HCC in the right lobe of the liver with no extrahepatic malignancy C. A 69-year old man with hemochromatosis, diabetes mellitus, on chronic hemodialysis, with a normal total bilirubin and INR D. A 46-year old man with hepatitis C-related cirrhosis with variceal bleed E. A 55-year old man with remote history of alcohol abuse now with jaundice, tense ascites, type II hepatorenal syndrome The recommended response is C. Liver transplantation is proven successful for the treatment of patients with fulminant hepatic failure (with coma), cirrhosis with decompensation, small HCC, and certain metabolic liver disorders. Patients with cirrhosis should be referred for transplantation when they develop evidence of hepatic dysfunction (CTP 7 and MELD 10) or when they experience their first major complication (ascites, variceal bleeding, or hepatic encephalopathy). All clinical scenarios are noted to have a MELD score of 20 points. Clinical scenarios A, D, and E have evidence of portal hypertension with decompensation and have medical indications to list for liver transplantation. Clinical scenario B has a 2 cm HCC that meets medical criteria for listing for a liver transplant since the lesion is less than 5 cm and no evidence of vascular or extrahepatic spread. With the use of hepatitis B (HBV) immune globulin and antiviral nucleoside analogues, graft reinfection with HBV is extremely low. Clinical scenario C has a MELD score of 20 based on his kidney dysfunction alone, but has no evidence of portal hypertension or even cirrhosis. Murray KF and Carithers R L, Jr.: AASLD practice guidelines: Evaluation of the patient for liver transplantation. Hepatology. 2005, 41: Which patient can be listed for a liver transplant? A. A 50-year old man with hepatitis C cirrhosis and a 7 cm HCC B. A 50-year old man with acute alcoholic hepatitis C. A 50-year old man with hepatitis C cirrhosis and a arterial pulmonary pressure of 55 mmhg D. A 50-year old man with hemochromatosis and 2 HCC one measuring 3.9 cm and the other measuring 3.3 cm E. A 50-year old man with hepatitis B cirrhosis, hepatitis B DNA positive, and jaundice The recommended response is E.

19 The UNOS listing criteria attempts to list patients with the greatest need, but still considers long-term survival after liver transplant. There are a few conditions where liver transplantation is a contraindication and these are: acute alcoholic hepatitis, active sepsis, an arterial pulmonary pressure > 50 mmhg and HCC (if a single lesion is greater than 5 cm in diameter; if there are 2 or 3 lesions and either lesion is greater than 3 cm in diameter; if there are 4 or more lesions; or if there is evidence of vascular involvement or extrahepatic spread). Hepatitis B infection used to be a contraindication secondary to the high rate of recurrence, however, with hepatitis B immune globulin and antiviral nucleoside analogs, liver transplantation for hepatitis B infection is no longer contraindicated. 39. Bruix J and Sherman M: Management of hepatocellular carcinoma. Hepatology. 2005, 42: Which one of the following is true regarding the outcome after liver transplantation? A. Viremia recurs in half the patients after transplantation for hepatitis C cirrhosis. B. The 5-year survival rate after transplantation for hepatitis C is increased compared to patients transplanted for other indications C. Fibrosing cholestatic hepatitis occurs in 40% of patients transplanted for hepatitis B cirrhosis D. Primary biliary cirrhosis may recur after transplantation E. Transplantation is the best option for the majority of patients with primary sclerosing cholangitis and cholangiocarcinoma The recommended response is D The average 1-year survival after liver transplantation in the United States is approximately 85%. However, when the survival of patients with specific indications for transplantation is analyzed, the outcome of liver transplantation varies. Recurrence of viremia is universal after transplantation for hepatitis C cirrhosis and 50 to 90% of these patients will develop graft hepatitis. In addition, survival for patients transplanted for hepatitis C cirrhosis is decreased compared to patients transplanted for other indications. Fibrosing cholestatic hepatitis with rapid progression following transplantation for hepatitis B cirrhosis was seen in 10% to 20% of patients prior to the routine use of hepatitis B immune globulin and/or lamivudine. Although protocol-based liver transplantation (preoperative radiation and chemotherapy after which operative staging confirms that tumor is confined to the liver) is the best treatment option for patients with primary sclerosing cholangitis and cholangiocarcinoma, this opportunity is only available for a minority of these patients. Primary biliary cirrhosis and primary sclerosing cholangitis are recognized to recur after transplantation, although primary biliary cirrhosis recurrence is uncommon and generally does not lead to graft failure.

20 Kotlyar DS, Campbell M S, Reddy K R: Recurrence of diseases following orthotopic liver transplantation. Am J Gastroenterol. 2006, 101: Heimbach JK, Gores G J, Haddock M G, Alberts S R, Nyberg S L, Ishitani M B, Rosen C B: Liver transplantation for unresectable perihilar cholangiocarcinoma. Semin Liver Dis. 2004, 24: A 48-year old patient underwent liver transplantation for HCV cirrhosis 3 months ago. T-tube removal was performed 2 days ago. She now presents with increasing abdominal pain and distension. Laboratory studies reveal a WBC of 24,000/mm 3, a serum total bilirubin level of 3.2 mg/dl (1.2 mg/dl 1 week earlier), and alkaline phosphate of 200 IU/dL (130 IU/dL 1 week earlier). What is most appropriate step at this time? A. Intravenous fluids, pain control, and observation B. Endoscopic retrograde cholangiopancreatography (ERCP) C. Liver biopsy D. Immediate surgical exploration E. Increase immunosuppression The recommended response is B. Biliary complications occur after 20% to 30% of liver transplants, the majority consisting of bile leaks. These may occur early (<1 month after transplantation) or late (>1 month after transplantation). Early leaks are generally managed surgically although nonoperative management with ERCP and stent placement has been successful. Late bile leaks usually present as abdominal pain that occurs immediately following T-tube removal or up to 120 hours later. Management commonly consists of ERCP with stent placement or sphincterotomy and nasobiliary drainage. Surgical repair may be necessary if ERCP is unsuccessful. Observation alone is not optimal and may lead to further complications. In the present case, the suspicion for a biliary leak should preclude a liver biopsy to evaluate for rejection unless the ERCP does not reveal a biliary leak. Pascher A and Neuhaus P: Bile duct complications after liver transplantation. Transpl Int. 2005, 18: Which medication will not affect the metabolism of tacrolimus? A. Fluconazole B. Rifampin C. Clarithromycin D. Diltiazem