Cirrhosis is the end-stage manifestation of chronic. Management of the Cirrhotic Patient Prior to Liver Transplantation.

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1 clinical review Management of the Cirrhotic Patient Prior to Liver Transplantation Eric R. Kallwitz, MD, and Scott J. Cotler, MD Abstract Objective: To review common manifestations in patients with end-stage liver disease and highlight effective clinical management strategies. Methods: Review of the literature. Results: The major complications of cirrhosis include variceal bleeding, ascites, hepatic encephalopathy, and hepatorenal syndrome. Management of varices includes primary prophylaxis for prevention of a first bleeding episode, management of active bleeding, and secondary prophylaxis. Management of variceal bleeding includes volume resuscitation, correction of coagulopathy, and achieving hemostasis. Sodium restriction and the use of diuretics is a mainstay of treatment of ascites. Patients with cirrhosis also are at increased risk for hepatocellular carcinoma and require surveillance. Conclusion: Liver transplantation offers good longterm survival in patients with cirrhosis; however, long waiting times and lack of organ availability necessitate meticulous management of patients with complications of liver disease. Cirrhosis is the end-stage manifestation of chronic liver disease. Complications of cirrhosis are related to portal hypertension and hepatocellular dysfunction. Evidence-based approaches to the management of complications of cirrhosis, including variceal bleeding, ascites, hepatic encephalopathy, and hepatorenal syndrome, have led to improved survival, allowing more patients to be considered for liver transplantation. This paper reviews common manifestations of patients with end-stage liver disease and highlights effective clinical management strategies. Complications Related to Portal Hypertension The development of portal hypertension in cirrhosis starts with an increase in intrahepatic vascular resistance due to hepatic fibrosis and nodular regeneration. Subsequently, increased levels of vasodilators such as nitric oxide produce a hyperdynamic circulation with increased cardiac output and splanchnic arteriolar vasodilation, increasing portal venous inflow. Although collaterals form that shunt blood around the liver, the resistance in the collaterals exceeds that of the normal portal circulation. These physiologic events contribute toward many of the complications that develop in patients with advanced liver disease. Varices Variceal bleeding is a major life-threatening complication in patients with cirrhosis, associated with a mortality rate of 20% [1]. Collateral vessels arising in cirrhosis can develop in numerous locations; however, most bleeding complications result from esophageal or gastric varices. Cirrhotic patients develop varices at a rate of 8% per year and 30% have varices at the time of diagnosis [2,3]. Therefore, it is recommended that an upper endoscopy be performed to screen for gastroesophageal varices when the diagnosis of cirrhosis is made [4]. Patients with cirrhosis from primary biliary cirrhosis or other granulomatous diseases often develop portal hypertension early in their disease course, when hepatic function is preserved [5]. However, in most other causes of liver disease, the degree of hepatocellular dysfunction is associated with the risk of developing varices and the size of the varices. Documentation of esophageal varices should be made as either small or large, or if grading is performed, grade I varices should be considered small and grade II III varices categorized as large [4]. The size of esophageal varices, which reflects wall tension, is the most important endoscopic feature associated with risk of variceal bleeding [6]. Gastric varices are classified by location as either isolated gastric varices, gastroesophageal varices type 1 (gastric varices along the lesser curve of the stomach) or gastroesophageal varices type 2 (gastric varices along the greater curve of the stomach) [7]. The hepatic venous pressure gradient (HVPG) provides a more precise way to identify patients at risk for variceal bleeding. In clinical practice, measurement of the HVPG most often is made at the time of transvenous biopsy or transjugular intrahepatic portosystemic shunt (TIPS) procedures. The HVPG is assessed by introducing a catheter into the hepatic From the Section of Hepatology, Department of Medicine, University of Illinois at Chicago, IL. Vol. 15, No. 8 August 2008 JCOM 393

2 complications of cirrhosis Table 1. Endoscopic Surveillance for Gastroesophageal Varices Condition Finding Interval (years) New cirrhotic No varices; compensated 3 No varices; decompensated 1 Small varices; compensated 2 Small varices; decompensated 1 Small varices; advanced disease Start prophylaxis or high-risk features Large varices Start prophylaxis Upper GI bleeding Variceal bleeding Treat, then surveillance every 3 6 months GI = gastrointestinal. vein and wedging the catheter into a hepatic vein branch to measure the portal pressure. The difference between the hepatic and portal vein pressures constitutes the pressure gradient. A normal pressure gradient is between 3 to 5 mm Hg, whereas the development and risk of bleeding from varices occurs with a gradient greater than 10 mm Hg [8]. Recommendations for endoscopic surveillance and screening intervals for gastroesophageal varices are listed in Table 1 [4]. Management of varices. Management of varices can be divided into 3 categories: (1) primary prophylaxis for prevention of a first bleeding episode, (2) management of active bleeding, and (3) secondary prophylaxis against repeated bleeding. Primary prophylaxis is recommended for large varices or small varices with high-risk endoscopic features such as red spots and red wale signs (longitudinal venules upon varices). Primary prophylaxis is not recommended for cirrhotic patients without varices or for small varices without high-risk features. Primary prophylaxis. Primary prophylaxis for variceal bleeding typically consists of treatment with a nonselective b blocker (nadolol or propranolol). These medications reduce portal pressure by decreasing cardiac output and causing splanchnic vasoconstriction. In a large meta-analysis, nonselective b blockers reduced the risk of a first variceal bleed by roughly 50% compared with placebo [9]. More recently, carvedilol also was shown to be effective [10]. Although a reduction in the portal gradient to less than 12 mm Hg is the most sensitive measurement of effective of prophylaxis [11], b blockers are generally titrated to a 25% reduction in heart rate as a surrogate marker for a reduction in portal pressure. Endoscopic band ligation (EBL) was compared with pharmacologic therapy with b blockers in 2 large meta-analyses, both of which showed a reduction in bleeding but no change in mortality [12,13]. However, due to the expense and risk associated with EBL, b blockers remain the preferred modality for primary prophylaxis [4]. EBL should be considered for patients that are intolerant to b blockers, for those who have contraindications to chronic b blockade, and for patients who present with vary large varices that pose a high risk for bleeding. Long-acting nitrates have been studied for primary prophylaxis for esophageal varices, although they are not recommended either alone or in combination with b blockers due to adverse events [4]. Active bleeding. Variceal bleeding is a medical emergency, necessitating admission to a critical care unit. Management includes volume resuscitation, correction of coagulopathy, and achieving hemostasis. Endotracheal intubation is often performed for airway protection in patients who present with massive hematemesis. In the United States, intravenous octreotide is favored as pharmacologic therapy for patients with suspected variceal bleeding. Urgent endoscopy is indicated to confirm the diagnosis and to provide therapeutic intervention. EBL is the preferred endoscopic treatment modality [4]. In fact, EBL in combination with octreotide is superior to EBL alone, so these 2 modalities together comprise the current standard of care [14]. TIPS provides an effective means to decompress the portal circulation in patients who do not respond to octreotide and EBL [15]. Balloon tamponade can be used as a temporizing measure for patients who fail endoscopic therapy and are awaiting TIPS. Bleeding gastric varices are managed based on location. Gastroesophageal varices type 1 can be managed with banding or sclerotherapy, whereas in the United States gastroesophageal varices type 2 are managed with TIPS [16]. Tissue adhesives, available in Europe but not in the United States, also can be effective for the treatment of gastric varices [17]. Clinicians should be aware of the contraindications to TIPS placement, including congestive heart failure, multiple hepatic cysts or masses, severe pulmonary hypertension, and uncontrolled infection [18]. One-year survival after TIPS placed for bleeding varies from 48% to 90% [18]. The most common complication after placement is new or worsening hepatic encephalopathy [18]. Older age and a prior history of encephalopathy are risk factors for development of encephalopathy after TIPS [19]. Cirrhotic patients with ascites are at high risk for the development of spontaneous bacterial peritonitis after variceal hemorrhage and should receive a 7-day course of antibiotics, which most commonly consists of a fluoroquinolone such as norfloxacin or trimethoprim-sulfamethoxazole [20]. Secondary prophylaxis. Once a patient has recovered from an initial episode of variceal bleeding, preventing additional bleeding events is paramount. The most effective secondary prophylaxis for esophageal variceal bleeding consists of the 394 JCOM August 2008 Vol. 15, No. 8

3 clinical review use of a nonselective b blocker in combination with EBL to obliterate the varices [21,22]. Multiple sessions of EBL may be required to achieve this endpoint, with the main complication of EBL being bleeding from post-ebl esophageal ulcerations. Proton pump inhibitors [23] and sucralfate may reduce ulcer size and decrease dysphagia after EBL. TIPS can be performed in patients with recurrent bleeding despite b blockers and EBL [4]. Finally, the development of variceal bleeding should result in consideration of whether to perform a liver transplant evaluation in an appropriate candidate. Ascites and Hyponatremia Ascites is intraperitoneal fluid that develops in patients with cirrhosis due to a cascade of events, including increased sinusoidal pressure, systemic vasodilation, decreased effective circulating volume, and renal sodium retention. A majority of patients with ascites in the United States have cirrhosis [24]. Signs of ascites on physical examination include abdominal distention, dullness on percussion of the flanks, shifting dullness, and the presence of a fluid wave. New-onset ascites should be investigated by diagnostic paracentesis. Patients with large-volume ascites that is not responsive to medical management require therapeutic paracentesis. Bleeding is an uncommon complication of abdominal paracentesis, and there is no evidence to support the routine use of blood products to correct coagulopathy prior to performing the procedure [25]. However, in rare instances of disseminated intravascular coagulation or fibrinolysis, correction of the coagulopathy prior to the procedure may reduce the risk of bleeding [26]. In 1 study of over 1000 large-volume paracenteses, no significant complications were observed at any prothrombin time or platelet count [27]. Ultrasound can be used when needed to identify small amounts of ascites or to guide sampling of loculated fluid collections. A complete blood cell count with differential, albumin, and total protein level should be sent routinely at the time of paracentesis. A serum ascites albumin gradient (albumin concentration in serum minus albumin concentration in the ascites) of 1.1 g/dl or greater identifies the presence of portal hypertension with almost 97% accuracy [24]. Other studies that can be useful depending on clinical suspicion include bacterial culture and cytology [25]. Clinicians should also be alert for causes of ascites associated with a low serum ascites albumin gradient such as peritoneal carcinomatosis, tuberculous peritonitis, nephrotic syndrome, and chylous ascites. Cytology can detect peritoneal carcinomatosis in more than 95% of cases when 3 samples are analyzed [28]. Management of ascites. The mainstay in the treatment of cirrhotic ascites involves sodium restriction to less than 2000 mg per day and the use of diuretics [29]. Spironolactone is commonly used, either alone for mild ascites or in combination with furosemide for moderate to large ascites. Typically, spironolactone is dosed at 100 mg daily and furosemide is given at 40 mg per day, with dose increases following this ratio to maintain potassium balance [29]. Serum sodium, potassium, and creatinine levels require close monitoring during diuretic therapy. Amiloride can be substituted as a potassium-sparing diuretic should spironolactone lead to the development of gynecomastia. Measurement of urine sodium can be helpful to assess adherence and response to diuretics. A random sodium to potassium ratio greater than 1 has been shown to correlate with adequate diuresis [30]. Worsening ascites or edema in patients with evidence of natriuresis on diuretics suggests excessive dietary sodium intake. Large-volume paracentesis can be used to manage ascites in patients who develop side effects on diuretics such as renal insufficiency, hyponatremia, or encephalopathy, and in those who are refractory to maximal doses of diuretics [31]. A single paracentesis of 5 L or less generally does not necessitate colloid replacement [32]. In patients undergoing serial paracenteses, replacement with albumin was shown to reduce electrolyte and renal abnormalities and may reduce mortality [33,34]. Albumin replacement after a paracentesis generally consists of 8 to 10 g per liter of ascites removed [25]. TIPS was found to be more effective than medical management in selected patients with refractory ascites and may reduce mortality [35,36]. Spontaneous bacterial peritonitis. Spontaneous bacterial peritonitis is a common complication of ascites, found in 10% to 30% of patients who are hospitalized with ascites, and is associated with a mortality rate of 50% within 1 year [20,37]. Many cirrhotic patients with spontaneous bacterial peritonitis lack fever or abdominal pain and presenting symptoms may be limited to worsening hepatic encephalopathy or renal insufficiency. The diagnosis of spontaneous bacterial peritonitis is made when the peritoneal neutrophil count is greater than 250 cells/mm 3 without a secondary cause of intra-abdominal infection [38]. Treatment recommendations call for a third-generation cephalosporin (eg, cefotaxime or ceftriaxone) given intravenously for at least 5 days [20]. In patients with b-lactam hypersensitivities an intravenous quinolone may be substituted [20]. Although recommendations on posttreatment paracentesis have differed, follow-up paracentesis is useful to diagnose treatment failures and should absolutely be performed if the patient does not improve clinically [20,25]. Albumin given at a dose of 1.5 g/kg within the first 6 hours of diagnosis with a follow-up dose of 1 g/kg on day 3 was found to reduce mortality in patients with spontaneous bacterial peritonitis from 29% to 10% [39]. Cirrhotic patients who have an episode of spontaneous bacterial peritonitis should receive long-term prophylactic antibiotic therapy to prevent recurrence. Vol. 15, No. 8 August 2008 JCOM 395

4 complications of cirrhosis Hyponatremia. Hyponatremia and ascites develop through similar mechanisms with a reduction in effective circulating volume resulting in free water retention. Free water retention occurs in an antidiuretic hormone dependent fashion, and medications that promote free water losses may eventually provide benefit in cirrhotic patients with hyponatremia [40]. Currently, severe hyponatremia in cirrhotic patients is generally managed with free water restriction. Discontinuation of diuretics is sometimes required as well. Hyponatremia does correlate with increased mortality such that the development of hyponatremia should prompt consideration of referral to a liver transplant center [41]. Severe hyponatremia should be addressed prior to liver transplantation because central pontine myelinolysis can develop when serum sodium levels are corrected during the surgery [42]. Hepatic Encephalopathy Hepatic encephalopathy describes neuropsychiatric symptoms that occur in both acute and chronic liver disease. The spectrum of hepatic encephalopathy ranges from minimal effects on concentration to coma. The term minimal hepatic encephalopathy describes abnormalities identified by neuropsychiatric testing in patients without overt signs of hepatic encephalopathy [43]. Early hepatic encephalopathy often manifests with disturbances in the sleep wake cycle. Asterixis develops as encephalopathy progresses and in late stages personality changes, somnolence, confusion, and even coma can occur. Hepatic encephalopathy is a clinical diagnosis that requires clinical suspicion, as the symptoms can be subtle, especially when encephalopathy is mild. The finding of an elevated serum ammonia level can be helpful in confirming the diagnosis of hepatic encephalopathy, but measurement of serial ammonia levels does not tend to be useful. Patients presenting with an acute exacerbation of hepatic encephalopathy should be evaluated for precipitating causes including infection, gastrointestinal bleeding, medication or toxin ingestion, hypovolemia, constipation, and medication nonadherence. The mainstay of treatment is the nonabsorbable disaccharide lactulose, titrated to 2 to 3 bowel movements per day. Patients who do not respond to lactulose alone and those with side effects to lactulose can be managed with antibiotics such as rifaximin or metronidazole. Clinicians should be familiar with side effects of these antibiotics, such as the potential for neuropathy with chronic metronidazole administration. Hepatorenal Syndrome Hepatorenal syndrome refers to the development of progressive renal dysfunction arising in patients with advanced liver disease related to either acute liver failure or cirrhosis. Diagnostic criteria for hepatorenal syndrome proposed by the International Ascites Club include the onset of renal insufficiency and oliguria that does not respond to a volume challenge, in the absence of other causes of kidney disease [31]. Type 1 hepatorenal syndrome is defined as a doubling in the serum creatinine to greater than 2.5 mg/dl in less than 2 weeks [31]. Type 2 hepatorenal syndrome has a more indolent progression. Type 1 hepatorenal syndrome is associated with a median mortality of 2 weeks and the diagnosis should lead to prompt referral to a liver transplant center in appropriate cases [44]. The combination of midodrine, octreotide, and albumin is used in many medical centers in the United States to treat type 1 hepatorenal syndrome, based on a small clinical trial [45]. TIPS also was found to be beneficial in a small number of patients with hepatorenal syndrome [46]. Finally, dialysis or hemofiltration can be used as a bridge to liver transplantation in patients with hepatorenal syndrome. Hepatic Pulmonary Disease Pulmonary disorders in cirrhosis include the hepatopulmonary syndrome and portopulmonary hypertension. The hepatopulmonary syndrome develops due to intrapulmonary vasodilation, leading to effective pulmonary shunting and arterial hypoxemia. Symptoms of the hepatopulmonary syndrome include dyspnea, worse in the upright position (platypnea), and cyanosis. Diagnostic criteria include hypoxemia on arterial blood gas, reduced Dlco (diffusing capacity of lung for carbon monoxide) on pulmonary function testing, and positive shunting on contrast echocardiography. A macroaggregated albumin scan can be used to calculate the shunt fraction [47]. The median survival for patients diagnosed with hepatopulmonary syndrome is less than 1 year [48]. Liver transplantation can result in correction of the underlying pulmonary vasodilation and resolution of the hepatopulmonary syndrome, although patients with a Pao 2 less than 50 mm Hg are at increased risk of perioperative mortality with transplantation [47]. Portopulmonary hypertension is defined as a mean pulmonary artery pressure greater than 25 mm Hg at rest or 30 mm Hg with exertion, accompanied by portal hypertension in the setting of a normal pulmonary capillary wedge pressure [49,50]. Patients can be asymptomatic or present with dyspnea. It is important to diagnose patients with severe pulmonary hypertension (mean pulmonary artery pressure 45 mm Hg), as these patients have increased mortality in the peri- and postoperative periods [50,51]. Echocardiography is used routinely to screen for pulmonary hypertension in liver transplant candidates but tends to overestimate pulmonary artery pressures in cirrhotic patients who have a hyperdynamic circulation. Right heart catheterization is used to further evaluate abnormal echocardiographic findings [52]. Small series suggest that medical therapy to reduce pulmonary pressures followed by liver 396 JCOM August 2008 Vol. 15, No. 8

5 clinical review Table 2. Further Evaluation of Liver Nodules Identified During Surveillance for Hepatocellular Carcinoma Lesion Size Imaging Recommendation Intervention < 1 cm Repeat ultrasound every 3 4 months If stable for 24 months continue routine surveillance; otherwise, treat as below 1 2 cm Perform 2 dynamic imaging studies Both with typical vascular pattern: treat as HCC One with atypical vascular pattern: biopsy > 2 cm Perform singular dynamic imaging study Atypical vascular pattern: biopsy Typical vascular pattern or AFP > 200: treat as HCC AFP = alpha fetoprotein; HCC = hepatocellular carcinoma. transplantation might be effective in some cases of even severe portopulmonary hypertension [53]. Hepatocellular Carcinoma The incidence of hepatocellular carcinoma (HCC) has increased dramatically in the United States, and HCC represents a leading cause of cancer mortality worldwide [54,55]. Patients with cirrhosis due to any cause are at risk for HCC, as are patients with hepatitis B in the absence of cirrhosis. Therefore, surveillance for HCC is indicated in these patient populations. The American Association for the Study of Liver Diseases (AASLD) recommends ultrasound on an every 6- to 12-month basis, which can be used in conjunction with alpha fetoprotein, a serum test that should not be used alone for surveillance [56]. The finding of a suspicious lesion (> 1 cm) necessitates a dynamic imaging study such as a triple phase computed tomography scan or magnetic resonance imaging. The AASLD recommendations for lesions found on dynamic imaging are presented in Table 2 [56]. Recognition of small HCC lesions is crucial if effective therapy is to be provided. Treatment options for limited disease include surgical resection, liver transplantation, radiofrequency ablation, and transarterial chemoembolization [57]. Surgical resection is not advisable in patients who present with HCC on a background of portal hypertension (HVPG > 10 mm Hg) or hepatic dysfunction (elevated bilirubin) due to the risk of postoperative hepatic decompensation [56]. Five-year survival after surgical resection and radiofrequency ablation ranges from 37% to 63% and 33% to 40%, respectively [58 64]. Selection of patients for liver transplantation with HCC is based on the Milan criteria, which includes patients with a solitary tumor 5 cm or less or up to 3 tumors 3 cm or less in size, in the absence of vascular invasion or extrahepatic spread [65]. Liver transplantation for patients with HCC who meet these criteria is associated with a 5-year survival rate greater than 69% [60,65,66]. Patients with larger tumors may be listed for transplantation, although tumor exception points consisting of a Model for Endstage Liver Disease (MELD) score of 22 are only provided in cases that meet the Milan criteria. A multidisciplinary approach to the management of HCC includes the involvement of hepatologists, medical oncologists, interventional radiologists, and transplant surgeons. Liver Transplantation in Patients with Cirrhosis Liver transplantation provides life-saving therapy for patients with end-stage liver disease. Data from the United Network for Organ Sharing (UNOS) shows that roughly 12,000 patients are on the liver transplant waiting list in the United States. A shortage of available organs is the major limiting factor in liver transplantation. Currently the mortality rate on the UNOS waiting list is approximately 125 to 150 deaths per 1000 patient-years at risk. Advances in surgical techniques, immunosuppression, and medical management have led to posttransplant patient survival rates of greater than 70% at 5 years. Potential liver transplant candidates undergo an extensive evaluation including laboratory testing, cardiopulmonary evaluation, and psychosocial assessment. Medical contraindications include severe heart or lung disease, prohibitive vascular anatomy, advanced HCC or extrahepatic malignancy, and uncontrolled infection. Examples of psychosocial contraindications include active or recent substance abuse. In some cases, transplantation is precluded by absence of social support or nonadherence to medical care. In appropriate candidates, organ allocation is based on the MELD score, which predicts short-term mortality in patients waiting for transplantation [67,68]. The MELD score ranges from 0 40 and is based on an equation including total bilirubin, serum creatinine, and the international normalized ratio, where creatinine is the most heavily weighted factor. The calculation can be made on the UNOS Web site ( For example, a MELD score greater than 19 is associated with a 3-month mortality of greater than 50% or more and a MELD score greater than 40 has a 3-month mortality of nearly 100% [67,68]. Moreover, for a MELD score less than 15, one-year mortality with liver transplantation exceeds 1-year mortality in patients who do not undergo a transplantation, providing a rough threshold for when transplantation should be considered [69]. Patients with HCC who meet the Milan criteria are given increased priority for transplant consisting Vol. 15, No. 8 August 2008 JCOM 397

6 complications of cirrhosis of 22 points at the time of listing and additional points on 3-month intervals [70]. Summary The major complications of cirrhosis include variceal bleeding, ascites, hepatic encephalopathy, and hepatorenal syndrome. Patients with cirrhosis also are at increased risk for HCC and require surveillance. Liver transplantation offer the best chance of long-term survival for patients with advanced liver disease or small HCC lesions. Meticulous management of complications of cirrhosis affords patients the highest likelihood of reaching liver transplantation and achieving optimal outcomes. Corresponding author: Eric R. Kallwitz, MD, 840 S Wood St., 10th Fl., Chicago, IL 60612, kallwitz@uic.edu. Financial disclosures: None. Author contributions: conception and design, ERK; drafting of article, ERK, SJC; critical revision of the article, ERK, SJC. References 1. McCormick PA, O Keefe C. Improving prognosis following a first variceal haemorrhage over four decades. 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