CLINICAL How Should a Hospitalized Patient with Newly Diagnosed Cirrhosis Be Evaluated and Managed?

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1 CLINICAL How Should a Hospitalized Patient with Newly Diagnosed Cirrhosis Be Evaluated and Managed? The Hospitalist August;2016(8) Author(s): Raj Sehgal, MD; Joshua Hanson, MD, MPH; Division OF The Case A 50-year-old man with no known medical history presents with two months of increasing abdominal distension. Exam is notable for scleral icterus, telangiectasias on the upper chest, abdominal distention with a positive fluid wave, and bilateral pitting lower-extremity edema. An abdominal ultrasound shows large ascites and a nodular liver consistent with cirrhosis. How should this patient with newly diagnosed cirrhosis be evaluated and managed? Background Cirrhosis is a leading cause of death among people ages and associated with a mortality rate of 11.5 per 100,000 people.1 In 2010, 101,000 people were discharged from the hospital with chronic liver disease and cirrhosis as the first-listed diagnosis.2 Given the myriad etiologies and the asymptomatic nature of many of these conditions, hospitalists frequently encounter patients presenting with advanced disease. Evaluation The first step in evaluation is to differentiate cirrhotic from non-cirrhotic liver disease. Figure 1 lists physical exam and laboratory findings helpful in staging liver disease. Imaging (ultrasound, computerized tomography [CT], or magnetic resonance imaging [MRI]) is not diagnostic in isolation but can be used to confirm cirrhosis in the presence of associated findings on exam and laboratory studies. The gold standard for diagnosis is liver biopsy, although this is now usually reserved for atypical cases or where the etiology of cirrhosis is unclear. Alcohol and viral

2 hepatitis (B and C) are the most common causes of chronic liver disease, with nonalcoholic steatohepatitis (NASH) increasing in prevalence. Other less common etiologies and characteristic test findings are listed in Figure 2. Recently, the Centers for Disease Control and Prevention < (CDC) recommended that adults born between 1945 and 1965 receive onetime testing for hepatitis C virus (HCV) infection, regardless of other risk factors, given the higher prevalence in this birth cohort and the introduction of newer oral treatments that achieve sustained virologic response.3 Management The three classic complications of cirrhosis that will typically prompt inpatient admission are volume overload/ascites, gastrointestinal variceal bleeding, and hepatic encephalopathy. Volume overload/ascites. Ascites is the most common major complication of cirrhosis, with roughly 50% of patients with asymptomatic cirrhosis developing ascites within 10 years.4 Ascites development portends a poor prognosis, with a mortality of 15% within one year and 44% within five years of diagnosis.4 Patients presenting with new-onset ascites should have a diagnostic paracentesis performed to determine the etiology and evaluate for infection. Ascitic fluid should be sent for an albumin level and a cell count with differential. A serum-ascites albumin gradient (SAAG) of greater than or equal to 1.1 g/dl is consistent with portal hypertension and cirrhosis, while values less than 1.1 g/dl suggest a non-cirrhotic cause, such as infection or malignancy. Due to the high prevalence of spontaneous bacterial peritonitis (SBP) in hospitalized patients, fluid should also be immediately inoculated in aerobic and anaerobic culture bottles at the bedside, as this has been shown to improve the yield compared to inoculation of culture bottles in the laboratory. Other testing (such as cytology for the evaluation of malignancy) should only be performed if there is significant concern for a particular disease since the vast majority of cases are secondary to uncomplicated cirrhosis.4 In patients with a large amount of ascites and related symptoms (eg, abdominal pain, shortness of breath), therapeutic paracentesis should be performed. Although there is controversy over the need for routine albumin administration, guidelines currently recommend the infusion of 6 8 g of albumin per liter of ascites removed for paracentesis volumes of greater than 4 5 liters.4 No data support the routine administration of fresh frozen plasma (FFP) or platelets prior to paracentesis. Although significant complications of paracentesis (including bowel perforation and hemorrhage) may occur, these are exceedingly rare. Ultrasonography can be used to decrease risks and identify suitable pockets of fluid to tap, even when fluid is not obvious on physical exam alone.5

3 For patients with significant edema or ascites that is due to portal hypertension (SAAG >1.1 g/dl), the first-line therapy is sodium restriction to less than 2,000 mg/day. Consulting a nutritionist may be beneficial for patient education. For patients with significant natriuresis (>78 mmol daily urine sodium excretion), dietary restriction alone can manage fluid retention. Most patients (85% 90%), however, require diuretics to increase sodium output. Single-agent spironolactone is more efficacious than single-agent furosemide, but diuresis is improved when both agents are used.4 A dosing regimen of once-daily 40 mg furosemide and 100 mg spironolactone is the recommended starting regimen to promote diuresis while maintaining normokalemia. Due to the long half-life of spironolactone, the dose can be increased every three to five days if needed for diuresis.4 Gastroesophageal variceal bleeding. Approximately 50% of patients with cirrhosis have gastroesophageal varices as a consequence of portal hypertension, with prevalence increasing in those with more severe disease.6 As many patients with cirrhosis have advanced disease at the time of diagnosis, it is recommended that patients be referred for endoscopic screening when diagnosed.6 Nonselective beta-blockers decrease the risk of bleeding in patients with known varices but should not be initiated empirically in all patients with cirrhosis given significant side effects, including worsening of ascites. There is increasing evidence that there is a window period for beta-blocker use in cirrhosis with the window opening after the diagnosis of varices and the window closing at advanced stages of disease (marked by an episode of spontaneous bacterial peritonitis, refractory ascites, or hepatorenal syndrome, for example).7 Hepatic encephalopathy. Hepatic encephalopathy (HE) is another complication of portal hypertension and is seen in 10% 14% of patients at the time of cirrhosis diagnosis.8 Overt HE is estimated to occur in 30% 40% of patients with cirrhosis at some point during their disease course, and more subtle forms (minimal or covert HE) are seen in up to 80%.8 HE can cause numerous neurologic and psychiatric issues including personality changes, poor memory, sleep-wake disturbances, and alterations in consciousness. In patients with an episode of encephalopathy, precipitating factors should be evaluated. Typical precipitants include infections, bleeding, electrolyte disorders, and constipation. Ammonia levels are frequently drawn as part of the evaluation of hepatic encephalopathy, but elevated levels do not significantly change diagnostic probabilities or add prognostic information.8 A low ammonia level, on the other hand, may be useful in lowering the probability of hepatic encephalopathy in a patient with altered mental status of unknown etiology.8 Routine primary prophylaxis of HE in all patients with cirrhosis is not currently recommended. Treatment is only recommended in patients with overt HE, with secondary prophylaxis administered following an episode due to the high risk for recurrence.

4 Other Issues VTE prophylaxis. Although patients with cirrhosis are often presumed to be auto-anticoagulated due to an elevated international normalized ratio (INR), they experience thrombotic complications during hospitalization at the same rate or higher than patients with other chronic illnesses.9 Unfortunately, studies examining venous thromboembolism (VTE) prophylaxis in hospitalized patients have generally excluded cirrhotics. Therefore, risks/benefits of prophylaxis need to be considered on an individual basis, taking into account the presence of varices (if known), platelet count, and other VTE risk factors. Drugs to avoid. As detailed above, nonselective beta-blockers should be avoided when outside the window period of benefit. Patients with cirrhosis should be counseled to avoid nonsteroidal antiinflammatory drugs (NSAIDs) due to an increased risk of bleeding and renal dysfunction. ACE inhibitors (ACE-Is) and angiotensin-receptor blockers (ARBs) can also precipitate renal dysfunction and should generally be avoided unless strongly indicated for another diagnosis. There is conflicting evidence with regard to whether the use of proton-pump inhibitors (PPIs) in cirrhotics increases the risk of SBP.10,11 Nevertheless, it is prudent to reevaluate the need for PPIs in patients with cirrhosis to determine where a true indication exists. Post-hospitalization care. Patients with a new diagnosis of cirrhosis require screening for esophageal varices and hepatocellular carcinoma (HCC), with frequency of subsequent testing based on initial results. They should also be immunized against hepatitis A (HAV) and hepatitis B (HBV), if not already immune. Specific treatments are available for many causes of cirrhosis, including new antiviral agents against hepatitis C (HCV), and liver transplantation is an option for select patients. Given the complexity of subsequent diagnostic and treatment options, patients with new cirrhosis should be referred to a gastroenterologist or hepatologist, if possible. Back to the Case The patient is hospitalized, and a large-volume paracentesis is performed. Four liters are removed without the administration of albumin. Ascitic fluid analysis reveals a SAAG of greater than 1.1 g/dl and a polymorphonuclear cell count of 50 cell/mm3, suggesting ascites due to portal hypertension and ruling out infection. Nutrition is consulted and educates the patient on a restricted-sodium diet. Furosemide is started at 40 mg daily; spironolactone is started at 100 mg daily. Initial workup and serologies demonstrate active HCV infection (HCV RNA positive), with immunity to HBV due to vaccination. HAV vaccination is administered given lack of seropositivity. The patient is screened for alcohol and found not to drink alcohol. By the time of discharge, the patient is experiencing daily 0.5 kg weight loss due to diuretics and has stable renal function. The patient is referred to outpatient gastroenterology for gastroesophageal variceal screening and consideration of HCV treatment and/or liver transplantation.

5 Bottom Line Workup and management of cirrhosis should focus on revealing the underlying etiology, managing complications, and discharging patients with a comprehensive follow-up plan. TH Dr. Sehgal and Dr. Hanson are hospitalists in the division of hospital medicine at the University of Texas Health Science Center at San Antonio and the South Texas Veterans Health Care System. References 1. Heron M. Deaths: leading causes for 2012 < Natl Vital Stat Rep. 2015;64 (10): Chronic liver disease and cirrhosis < Centers for Disease Control and Prevention website. Accessed March 17, Smith BD, Morgan RL, Beckett GA, Falck-Ytter Y, Holtzman D, Ward JW. Hepatitis C virus testing of persons born during : recommendations from the Centers for Disease Control and Prevention < Ann Intern Med. 2012;157(11): doi: / Runyon BA, AASLD. Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline management of adult patients with ascites due to cirrhosis 2012 < Hepatology. 2013;57(4): doi: /hep Udell JA, Wang CS, Tinmouth J, et al. Does this patient with liver disease have cirrhosis? < JAMA. 2012;307(8): doi: /jama Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W, Practice Guidelines Committee of the American Association for the Study of Liver Diseases, Practice Parameters Committee of the American College of Gastroenterology. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis < Hepatology. 2007;46(3): doi: /hep Mandorfer M, Bota S, Schwabl P, et al. Nonselective β blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis < Gastroenterology. 2014;146(7): e1. doi: /j.gastro Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver < Hepatology. 2014;60(2): doi: /hep

6 9. Khoury T, Ayman AR, Cohen J, Daher S, Shmuel C, Mizrahi M. The complex role of anticoagulation in cirrhosis: an updated review of where we are and where we are going < Digestion. 2016;93(2): doi: / Terg R, Casciato P, Garbe C, et al. Proton pump inhibitor therapy does not increase the incidence of spontaneous bacterial peritonitis in cirrhosis: a multicenter prospective study < J Hepatol. 2015;62(5): doi: /j.jhep Deshpande A, Pasupuleti V, Thota P, et al. Acid-suppressive therapy is associated with spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis < J Gastroenterol Hepatol. 2013;28(2): doi: /jgh Key Points Cirrhosis has many etiologies, and new diagnoses require further investigation as to the underlying etiology. Initial management should focus on evaluation and treatment of complications, including ascites, esophageal varices, and hepatic encephalopathy. A diagnostic paracentesis, salt restriction, and a nutrition consult are the initial therapies for ascites although most patients will also require diuretics to increase sodium excretion. Once stabilized, the cirrhotic patient will require specialty care for possible liver biopsy (if etiology remains unclear), treatment (eg, HCV antivirals), and/or referral for liver transplantation. Copyright by Society of Hospital Medicine or related companies. All rights reserved. ISSN X