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516 SECTION 9: Gastrointestinal Disorders Acalculous cholecystitis represents a small minority of cholecystitis cases and most often occurs in the inpatient setting among patients with critical illness. Nevertheless, it may be occasionally encountered in the ED, particularly in immunocompromised patients. Diagnosis is chal lenging because the clinical presentation is variable and no test result is pathognomonic. US, IV contrast-enhanced CT, and cholescintigraphy are helpful in establishing the diagnosis, but sensitivity and specificity are less than for calculous cholecystitis. Acalculous cholecystitis runs a more fulminant course than cholecystitis associated with gallstones. Complications such as gangrene and perforation are common, and mortality is high. Chronic cholecystitis is gallbladder inflammation and scarring that occurs over time, usually secondary to intermittent cystic duct obstruc tion. It presents in a manner similar to biliary colic or acute cholecysti tis, although symptoms and examination findings may be more subtle. Patients may report recurrent episodes of pain. Postcholecystectomy syndrome refers to a heterogeneous group of disorders that present with persistent abdominal symptoms after removal of the gallbladder. In the early postcholecystectomy period, bile leak is the principal concern. Choledocholithiasis is a common cause of postcholecystectomy pain. Symptom-producing common bile duct stones may be “retained” (present at the time of surgery) or may develop postoperatively, formed primarily in the bile ducts often in the setting of bile stasis. 97 Postcholecystectomy syndrome may result from nonbiliary pain that was erroneously attributed to a biliary cause and therefore not remedied by cholecystectomy. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Hepatic Disorders Susan R. O’Mara Lauren Wiesner INTRODUCTION AND EPIDEMIOLOGY This chapter discusses the ED presentation, evaluation, and treatment of acute hepatitis, chronic liver disease, and fulminant liver failure. Specific entities addressed in this chapter include viral and toxic hepatitis, nonalcoholic fatty liver disease (NAFLD), and complications of cirrhosis including coagulopathy, ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, and hepatic encephalopathy. Cholecystitis and biliary colic are addressed in Chapter 79, “Pancreatitis and Cholecystitis. ” Variceal bleeding is addressed in Chapter 75, “Upper Gastrointestinal Bleeding. ” PATHOPHYSIOLOGY Acute hepatitis is caused by an infectious, toxic, or metabolic injury to hepatocytes. The initial injury leads to inflammation, cellular death, and eventual scarring in the liver. In chronic disease, liver parenchyma is replaced by fibrous tissue, which separates the functioning hepatocytes into isolated nodules. This disruption of the normal tissue structure can become severe and lead to the central characteristics of cirrhosis and liver failure: loss of metabolic and synthetic function at the cellular level, and portal hypertension, ascites formation, and portal-systemic shunt ing at the gross level. Hepatic disease impairs the liver’s synthetic functions, including production of albumin as well as coagulation and anticoagulation factors . The liver is responsible for production of the vitamin K–dependent clotting factors II, VII, IX, and X; proteins C and S; and other elements of the clotting and thrombolytic processes.

c disease impairs the liver’s synthetic functions, including production of albumin as well as coagulation and anticoagulation factors . The liver is responsible for production of the vitamin K–dependent clotting factors II, VII, IX, and X; proteins C and S; and other elements of the clotting and thrombolytic processes. 1 Inadequate production of these CHAPTER clotting factors makes uncontrolled bleeding one of the life-threatening features of liver disease and a potentially serious complication of hepatic failure. Portal hypertension is the increased hydrostatic pressure in the portal vein and its feeder vessels caused by resistance to blood flow through the cirrhotic liver. It eventually causes esophageal and gastric varices and portal-systemic shunting. Increased hydrostatic pressure in the intraperitoneal veins, hypoalbuminemia, and poor renal management of sodium and water lead to ascites in the cirrhotic patient. Ascites can cause respiratory compromise when abdominal distention increases intrathoracic pressure. It can also lead to spontaneous bacterial peritonitis (SBP), which occurs when normal flora translocate across an edematous bowel wall into the peritoneal cavity. Bacteremia and infection of preexisting ascitic fluid ensue. Encephalopathy is a pivotal characteristic of chronic liver disease and is a hallmark of liver failure. Ammonia is often presumed to be the cause of confusion and lethargy in encephalopathic patients but, in fact, the pathophysiology is not completely understood. In cirrhosis, portal hypertension allows ammonia formed by colonic bacteria to enter the general circulation through portal-systemic shunting. Large intestinal protein loads, such as a high-protein meal or GI bleeding, fuel this process. Although levels of ammonia do not reliably correlate with mental status, it is reasonable to think of ammonia as a contributing factor to alterations in mental status. In fulminant liver failure, cerebral edema and resulting increased intracranial pressure can develop. In this end-stage state, loss of autoregulation of cerebral blood flow, ammoniarelated edema, and a systemic inflammatory response are all thought to contribute to this deadly complication. Jaundice can be present in any stage of liver disease. Jaundice is caused by elevated levels of bilirubin in the circulation, leading to bile pigment deposits in the skin, sclerae, and mucous membranes. Hyper bilirubinemia can occur for one of three reasons: overproduction, inadequate cellular processing, or decreased excretion of bilirubin. Another way to think about this is prehepatic, hepatic, and posthepatic jaundice. Prehepatic jaundice is caused by any form of hemolysis, including inborn errors of bilirubin metabolism, which overwhelm the liver’s ability to conjugate bilirubin. Viral infection and ingested toxins are typical causes of hepatic jaundice. When hepatocytes necrose, the liver’s ability to conjugate bilirubin is impaired, and the level of unconjugated biliru bin rises in the blood. Unlike prehepatic and hepatic jaundice, which present with elevated unconjugated (indirect) bilirubin, posthepatic jaundice produces a rise in conjugated (direct) bilirubin. Typical causes of posthepatic jaundice are a pancreatic tumor or a gallstone in the common bile duct. Parasitic infestation and biliary atresia are rare causes of posthepatic jaundice in the United States but are more common in other parts of the world. CLINICAL FEATURES At ED presentation, a chief complaint of jaundice, nausea, vomiting, diarrhea, right upper quadrant or epigastric pain, pruritus, inappropri ate bruising or bleeding, or altered mental status should raise the ques tion of liver disease.

he United States but are more common in other parts of the world. CLINICAL FEATURES At ED presentation, a chief complaint of jaundice, nausea, vomiting, diarrhea, right upper quadrant or epigastric pain, pruritus, inappropri ate bruising or bleeding, or altered mental status should raise the ques tion of liver disease. In the history of present illness , pay attention to onset of symptoms after eating out or reported ingestion of acetamino phen (in one-time overdose or chronically high doses), mushrooms, or raw oysters. Past medical history can reveal risk factors for liver disease, which include chronic hepatitis, transfusion of blood products, positive human immunodeficiency virus status, frequent use of pain medica tions, and depression. Obesity, type 2 diabetes, and hyperlipidemia are risk factors specific to NAFLD. A social history positive for injection drug use, chronic alcohol abuse, sexual promiscuity, or travel to coun tries with endemic parasitic liver diseases represents increased risk for liver disease. Several elements of the review of systems can suggest liver pathology. Weight loss is common at the end stage of chronic liver disease. Cholestasis causes white (acholic) stools and brown or tea-colored urine. Stools can be black or bloody from variceal or other GI bleeding. Patients may notice yellow skin or sclerae, indicating elevated bilirubin. Ascites can increase abdominal girth or cause shortness of breath, and portal hypertension leads to generalized weakness, encephalopathic Tintinalli_Sec09_p0473-0562.indd 516 8/2/19 6:49 PM

be black or bloody from variceal or other GI bleeding. Patients may notice yellow skin or sclerae, indicating elevated bilirubin. Ascites can increase abdominal girth or cause shortness of breath, and portal hypertension leads to generalized weakness, encephalopathic Tintinalli_Sec09_p0473-0562.indd 516 8/2/19 6:49 PM CHAPTER 80: Hepatic Disorders 517 changes in mental status, and lower extremity edema. Lightheadedness or near-syncope can result from intravascular depletion and abnormalities in renal sodium and water excretion. A number of findings on physical examination are hallmarks of liver disease. Liver enlargement and tenderness with or without jaundice are characteristic of acute hepatitis. Chronic liver disease is accompanied by a number of physical findings, including sallow or jaundiced complexion, extremity muscle atrophy, Dupuytren’s contracture, palmar erythema, cutaneous spider nevi, distended abdomen with a fluid wave, enlarged veins on the surface of the abdomen (caput medusae), and asterixis. Extraordinary bruising or other signs of bleeding diathesis can be seen in liver failure. LABORATORY EVALUATION AND IMAGING Laboratory tests for hepatobiliary disease can be divided into four cat egories: (1) markers of acute hepatocyte injury or death, (2) measure ments of hepatocyte synthetic function, (3) indicators of hepatocyte catabolic activity, and (4) tests to diagnose specific disease entities. Traditional liver function panels include a mix of markers of hepatocyte injury, usually including aspartate aminotransferase, alanine amino transferase, and alkaline phosphatase, as well as indicators of hepato cyte catabolic activity (direct and indirect bilirubin). Tests that reflect hepatocyte synthetic function include prothrombin time and albumin. Ammonia reflects catabolic function of the liver. Viral hepatitis serolo gies are used to differentiate various types of hepatitis; acetaminophen levels can determine whether treatment for poisoning is appropriate; and various tests of ascitic fluid are used to diagnose SBP . Bilirubin is a metabolite of heme proteins. The total level is usually reported along with the levels of conjugated (direct) and unconjugated (indirect) portions. In a functioning liver, unconjugated bilirubin is taken up by hepatocytes, conjugated, and then secreted into bile. Bilirubin is then excreted in the stool, with a small percentage being recirculated through the liver. An increased total and indirect bilirubin signifies either an overwhelming supply of unconjugated bilirubin to the hepatocytes (e.g., hemolytic anemia) or an injury to the hepatocytes themselves that damages their capacity to conjugate a normal supply of bilirubin (e.g., acute or chronic viral hepatitis). Total and direct bilirubin is increased when there is some obstruction preventing the secretion of the conjugated bilirubin that is produced by normally functioning hepatocytes (e.g., obstructing gallstone, pancreatic mass, or biliary atresia). Transaminases (aspartate aminotransferase and alanine amino transferase) are intracellular enzymes found in hepatocytes and some other cell types. Hepatocyte injury or necrosis releases these enzymes into the circulation. Elevations in the hundreds of units per liter suggest mild injury, or smoldering inflammation. Levels in the thousands suggest extensive acute hepatic necrosis. Less significant elevations, less than five times normal, are typical of alcoholic liver disease and nonalcoholic steatohepatitis. Marked elevations are commonly seen with acute viral hepatitis. These enzyme levels may be near normal in end-stage liver failure, when the hepatocytes are beyond the stage of acute injury.

Less significant elevations, less than five times normal, are typical of alcoholic liver disease and nonalcoholic steatohepatitis. Marked elevations are commonly seen with acute viral hepatitis. These enzyme levels may be near normal in end-stage liver failure, when the hepatocytes are beyond the stage of acute injury. An aspartate aminotransferase–to–alanine aminotransferase ratio of greater than 2 is common in alcoholic hepatitis because alcohol stimulates aspartate aminotransferase production. Incidental findings of transaminase elevations of three to five times normal and alkaline phosphatase of up to twice normal in diabetic or obese patients suggest the presence of nonalcoholic steatohepatitis in diabetic or obese patients. 4 Alanine aminotransferase is a more specific marker of hepatocyte injury than aspartate aminotrans ferase. Aspartate aminotransferase is found not only in liver but also in heart, smooth muscle, kidney, and brain. Elevated aspartate aminotransferase can be due to medications, including acetaminophen, NSAIDs, angiotensin-converting enzyme inhibitors, nicotinic acid, isoniazid, sulfonamides, erythromycin, griseofulvin, and fluconazole. γ-Glutamyl transpeptidase production is stimulated by alcohol consumption. It is also elevated by drugs inducing hepatic microsomal enzyme activity, such as phenobarbital and warfarin, and may rise in acute and chronic pancreatitis, acute myocardial infarction, uremia, chronic obstructive pulmonary disease, rheumatoid arthritis, and dia betes mellitus. An elevated γ-glutamyl transpeptidase in the setting of hepatitis suggests an alcoholic cause. Alkaline phosphatase elevation is associated with biliary obstruction and cholestasis. Mild to moderate elevations accompany virtually all hepatobiliary disease, whereas elevations greater than four times nor mal strongly suggest cholestasis. Alkaline phosphatase is a nonspecific marker also derived from bone, placenta, intestine, kidneys, and leuko cytes. A level of up to double the expected value is normal in pregnancy. Lactate dehydrogenase is a nonspecific marker. Moderate elevations are seen in all hepatocellular disorders and cirrhosis, whereas purely cholestatic conditions cause minimal elevations. Hemolysis can produce elevation of lactate dehydrogenase and unconjugated bilirubin. The isoenzyme lactate dehydrogenase-5 is specific to the liver. Tests for lactate dehydrogenase-5 are sometimes useful although not widely available. Ammonia is generated by hepatic metabolism of nitrogen-containing compounds. The hepatic metabolic failure seen in acute and chronic liver disease can, therefore, cause an elevated serum ammonia level. Very high ammonia levels, seen in fulminant liver failure, contribute to overall toxicity and signify poor prognosis. Prothrombin time prolongation in liver disease reflects the decreased synthesis of the vitamin K–dependent coagulation factors II, VII, IX, and X and, as such, serves as a true measure of liver function. Prolonged prothrombin time is a common complication of advancing cirrhosis, although it also occurs in acute hepatitis and exacerbations of chronic compensated liver disease. When present in acute viral hepatitis, prolonged prothrombin time often indicates severe disease with widespread hepatocellular necrosis. There is some correlation between the extent of prothrombin time prolongation and clinical outcome in fulminant liver disease. Although prothrombin time is useful as a marker of hepatic function, abnormal values may occur in the presence of a normal liver. Vitamin K deficiency from another entity (i.e., malabsorption of fat and, therefore, of fat-soluble vitamins) can be distinguished from liver synthetic dysfunction by administration of parenteral vitamin K (phytonadione, 10 mg IV).

marker of hepatic function, abnormal values may occur in the presence of a normal liver. Vitamin K deficiency from another entity (i.e., malabsorption of fat and, therefore, of fat-soluble vitamins) can be distinguished from liver synthetic dysfunction by administration of parenteral vitamin K (phytonadione, 10 mg IV). A 30% reduction in prothrombin time should occur within 24 hours in vitamin deficiency states. Albumin also reflects the liver’s synthetic function. It may decrease in advancing cirrhosis or severe acute hepatitis and suggests a poor shortterm prognosis. Because its half-life is approximately 3 weeks, albumin is less useful than prothrombin time in evaluating fulminant liver disease. Prothrombin time becomes prolonged in a matter of days. Serum albumin levels are also low in malnutrition, so low albumin levels do not necessarily correlate with the degree of hepatic disease in a chronically ill patient. Viral hepatitis serologies are often grouped into screening panels by hospital laboratories. The diagnosis of specific viral hepatitis entities is complicated by phase of illness, preexisting infections, and likelihood of a given type of infection. The patient who is acutely ill with hepatitis A virus will have positive immunoglobulin M anti–hepatitis A virus anti bodies. Acute clinical illness in hepatitis B virus correlates with positive hepatitis B virus surface antigen. Positive immunoglobulin M antibod ies correlate to the hepatitis B virus core antigen. Diagnosis of hepatitis C virus is initiated by ordering anti–hepatitis C virus antibodies. This diagnosis is sometimes masked by the 6- to 8-week delay between infection and antibody detection as well as by the acute asymptomatic phase of the hepatitis C virus infection. Ascitic fluid aspirate is tested for cell count, glucose and protein, Gram stain, and culture to identify bacterial peritonitis. The procedure for obtaining ascitic fluid, paracentesis, is explained in Chapter 86, “Gastrointestinal Procedures and Devices. ” A total WBC count >1000/mm or a neutrophil count >250/mm 3 diagnoses SBP . Low glucose or high protein values suggest infection. Gram stains and culture results can be falsely negative 30% to 40% of the time, so empiric antibiotics should be started in the ED based on clinical suspicion. Culture sensitivity increases by using 10 mL of ascitic fluid per culture bottle and by transferring the fluid to culture bottles at the patient’s bedside. Additional studies of ascites that can help with inpatient evaluation are cytology, albumin, lactate dehydrogenase, and tumor markers.  NONHEPATIC CAUSES OF ABNORMAL LIVER TESTS Multiple nonhepatic causes may lead to abnormal liver function tests. Abnormal liver test results occur in up to one third of those screened, and only 1% of these indicate clinically significant liver disease. Tintinalli_Sec09_p0473-0562.indd 517 8/2/19 6:49 PM

tumor markers.  NONHEPATIC CAUSES OF ABNORMAL LIVER TESTS Multiple nonhepatic causes may lead to abnormal liver function tests. Abnormal liver test results occur in up to one third of those screened, and only 1% of these indicate clinically significant liver disease. Tintinalli_Sec09_p0473-0562.indd 517 8/2/19 6:49 PM 518 SECTION 9: Gastrointestinal Disorders Hypoalbuminemia accompanies protein-wasting enteropathies, malnutrition, and nephrotic syndrome. Alkaline phosphatase elevations occur with a variety of bone diseases, pregnancy, and malignancies. Aspartate aminotransferase elevations accompany acute myocardial infarction and rhabdomyolysis. Bilirubin elevations occur in severe hemolysis, sepsis, and syndromes involving abnormal erythropoiesis. Prothrombin time elevations occur in vitamin K deficiency, chronic antibiotic use, and anticoagulant therapy. 6,7 Urine bilirubin and urobilinogen are sometimes used as screening tests for liver disease in the ED. The sensitivity of these urine assays is 70% to 74% for identifying elevated serum bilirubin. For correlation with other liver function tests, their sensitivity is in the 43% to 53% range. Specificity for showing either bilirubin or transaminase abnor mality is 77% to 87%. Blood-tinged urine will give a false-positive uro bilinogen on a urine dipstick test. Taken together, these statistics do not support screening for liver disease with urine dipstick testing.  IMAGING US and CT scanning are both useful for initial evaluation of liver dis ease. Bedside US can identify ascites and guide paracentesis, whereas formal US with duplex Doppler is the test of choice for identifying portal vein and hepatic vein thrombosis. Both sonogram and CT scan of the abdomen can be used to identify cancerous, vascular, or infectious lesions of the liver. CT scanning of the brain is used to identify intracranial hemorrhage in patients with liver disease and altered mental status. ACUTE, CHRONIC, AND FULMINANT HEPATIC DISEASE Liver disease can be categorized as acute, chronic, or fulminant. Acute hepatitis typically presents with nausea, vomiting, and right upper quadrant abdominal pain. Other symptoms include fever, jaundice, bilirubinuria, and an enlarged, tender liver. The most common causes are viral infection and toxic ingestion. Alcohol and acetaminophen are the most common toxic causes. Patients with chronic hepatitis display evidence of long-standing hepatocellular damage and scarring. Cirrhotic patients with portal hypertension complain of abdominal pain and/or ascitic distention and lower body edema. Abnormal bleeding (excessive bruising, bleeding gums, epistaxis, blood in the stool) is a late finding in chronic disease. The chronic liver patient may also exhibit signs of infection, encepha lopathy, ascites, and electrolyte derangement. Skin examination can reveal spider nevi, caput medusae, and other manifestations of abnormal shunting of blood to surface vessels. Liver failure is the potential final common pathway for both acute and chronic liver disease. If there is a delay in seeking medical attention or a rapid acute course, fulminant liver failure can be the presenting disorder. For cirrhotic patients, the transition to liver failure is marked by the advent of coagulopathy, encephalopathy, abnormal fluid shifts, and hepatorenal syndrome.  ACUTE HEPATITIS—VIRAL Hepatitis A virus is transmitted by fecal–oral contamination. Although it is popularly associated with improper food handling or oyster con sumption, the most common transmission occurs from asymptomatic children to adults. Implementation of the hepatitis A vaccine in chil dren has dramatically decreased overall rates of infection.

irus is transmitted by fecal–oral contamination. Although it is popularly associated with improper food handling or oyster con sumption, the most common transmission occurs from asymptomatic children to adults. Implementation of the hepatitis A vaccine in chil dren has dramatically decreased overall rates of infection. Hepatitis A virus infection has an incubation period of 15 to 50 days, followed by a prodrome of nausea, vomiting, and malaise. About a week into the illness, patients may note dark urine (bilirubinuria). A few days later, they develop clay-colored stools and jaundice. Hepatitis A virus does not have a chronic component, and death from hepatic failure is rare. Hepatitis B virus is transmitted sexually, by blood transfusion, by contaminated needles, and by perinatal transmission. Incubation period is 1 to 3 months, and patients can be infectious for 5 to 15 weeks after onset of symptoms if they clear the infection. Individuals who develop chronic disease will remain infectious indefinitely. Chronic infection occurs in only 6% to 10% of patients who contract hepatitis B virus as adults, whereas 90% of infants and 30% of children under the age of 5 progress to chronic status, which underlines the importance of vaccination of infants and women of childbearing age. 10 In the acute phase of hepatitis B virus, presentation to the ED is similar to that for hepatitis A virus, including complaints of malaise, nausea, vomiting, fever, abdominal pain, and jaundice. Treatment for the acute phase of hepatitis B is supportive. For patients with chronic active hepatitis B, treatment includes antiviral medications and interferon. Side effects of treatment are generally mild (nausea, fatigue, headache), but the interferons can cause neutropenia and thrombocytopenia. Hepatitis C virus transmission occurs primarily through exposure to contaminated blood or blood products. In contrast to hepatitis A virus and hepatitis B virus, hepatitis C virus is most often asymptomatic in the acute phase of infection, and >75% of patients advance to the chronic stage. The rate of progression to liver failure varies and depends on the natural course of the virus and cofactors such as alcoholism and human immunodeficiency virus. Along with hepatitis B virus, hepatitis C virus is one of the most common causes of hepatocellular carcinoma. Of the patients who develop chronic hepatitis C virus, 1% to 5% will die of either cirrhosis or liver cancer. 11 Effective treatment has been developed for hepatitis C: novel antiviral therapy with direct-acting antivirals is curative in more than 95% of infections. However, access to diagnosis and treatment remains a barrier to reducing morbidity and mortality. The drugs themselves are very well tolerated, with fatigue, headache, and nausea as the most common side effects. 13 The most sinister side effect of treatment with direct-acting antivirals is the reactivation of dormant hepatitis B infection. This is a rare event; only 24 cases were reported to the U.S. Food and Drug Administration between 2013 and 2016, with three of these progressing to fulminant liver failure. The U.S. Food and Drug Administration has issued a “Boxed Warning” regarding the use of direct-acting antivirals in patients who have coinfection with hepa titis B. 14 If a patient should present with acute GI illness during treat ment for hepatitis C, the ED workup should include assessment for an acute phase of hepatitis, which could represent emergence of dormant hepatitis B disease. Hepatitis D virus is uncommon and is typically seen in patients with preexisting chronic hepatitis B virus infection. Hepatitis D superinfec tion can result in a rapidly progressive or fulminant form of liver disease that carries a high short-term mortality rate.

ould represent emergence of dormant hepatitis B disease. Hepatitis D virus is uncommon and is typically seen in patients with preexisting chronic hepatitis B virus infection. Hepatitis D superinfec tion can result in a rapidly progressive or fulminant form of liver disease that carries a high short-term mortality rate. This variety of infection is most commonly associated with injection drug use. Acute illness with liver function test abnormalities can also be caused by infection with other hepatotropic viruses such as cytomegalovirus, herpes simplex virus, coxsackievirus, and Epstein-Barr virus. These agents are unlikely to cause clinically significant hepatitis in an other wise healthy host. Treatment for the acute phase of viral hepatitis is primarily sup portive. While treating acute hepatitis, pay attention to any signs of progression to fulminant liver failure signified by worsening signs and symptoms and trending lab abnormalities.  ACUTE HEPATITIS—TOXIC A toxic insult to the liver can cause acute hepatitis and/or fulminant liver failure. The most common of these is acetaminophen overdose. Acetaminophen accounts for >40% of liver failure cases in the United States and one third of deaths secondary to toxic ingestion. Tylenol overdose is reviewed in Chapter 190, “ Acetaminophen. ” In addition to acetaminophen, there are a variety of prescription medications (e.g., phenytoin, valproate, and propylthiouracil), herbal remedies, and dietary supplements that have been associated with acute hepatitis and liver failure. The list of prescription medications that have been implicated in liver disease is so long that it is prudent to refer to a pharmaceutical database to identify a potential culprit when toxic insult is suspected. While statins are commonly associated with liver toxicity, only 3% of patients taking statins have mild transaminase elevations; clinically significant hepatotoxicity is rare. 15 The most common herbal remedies that have been implicated in hepatic injury are listed in Table 80-1. With several multi-ingredient nutritional supplements available to consumers, it is important to review all ingredients for potential hepatotoxic effects. Tintinalli_Sec09_p0473-0562.indd 518 8/2/19 6:49 PM

is rare. 15 The most common herbal remedies that have been implicated in hepatic injury are listed in Table 80-1. With several multi-ingredient nutritional supplements available to consumers, it is important to review all ingredients for potential hepatotoxic effects. Tintinalli_Sec09_p0473-0562.indd 518 8/2/19 6:49 PM CHAPTER 80: Hepatic Disorders 519 Alcoholic liver disease can range from asymptomatic, reversible fatty liver to acute alcoholic hepatitis, cirrhosis, or a combination of acute and cirrhotic features. Consistent heavy alcohol use of six drinks per day will induce alcohol-related steatosis in 90% of drinkers, and 30% of those with alcoholic fatty liver will progress to cirrhosis. The diagnosis of alcoholic liver disease carries a 35% 5-year survival rate. If a patient has asymptomatic liver disease (i.e., fatty liver seen on imaging), but the patient’s drinking continues and acute alcoholic hepatitis develops, the mortality can be much higher. 16 Other nonhepatic features of alcohol abuse, such as malnutrition, stocking-glove neuropathy, and cardiomyopathy, can be clues to alcohol-induced liver disease. Mushroom poisoning is an uncommon but important cause of acute hepatitis with a high risk of liver failure. Amanita phalloides (“death cap”) is the most lethal of the more than 50 types of mushrooms that are toxic to humans. For discussion, see Chapter 220, “Mushroom Poisoning. ” Treatment of acute hepatitis from toxic causes includes supportive care and attention to associated conditions such as hyponatremia, alco hol or narcotic intoxication or withdrawal, alcoholic ketoacidosis, and hypoglycemia. Treatment with N-acetylcysteine should be considered whether the insult is from acetaminophen, nonacetaminophen medica tion, or mushroom toxicity, according to the American Association for the Study of Liver Diseases guidelines.  CHRONIC HEPATITIS AND CIRRHOSIS Most patients live for years with hepatitis B virus, hepatitis C virus, NAFLD, or alcoholic hepatitis without symptoms. During the asymp tomatic period, normal liver parenchyma is being gradually replaced by scar tissue, and hepatic disease can manifest as mild transaminase elevation or, in cases of NAFLD and alcoholic hepatitis, as an incidental finding of fatty liver on abdominal imaging studies. When a critical amount of liver parenchyma is replaced by fibrotic tissue, symptoms of cirrhosis develop, such as abdominal pain, ascites, SBP , general weakness resulting from electrolyte derangement, or altered mental status due to hepatic encephalopathy. Treatment of chronic hepatitis in the ED means taking care of its many sequelae such as ascites, encephalopathy, coagulopathy, and variceal bleeding. Chronic hepatitis infection is typically treated by gastroenterologists in an outpatient setting. Ascites One of the hallmarks of cirrhosis, ascites causes a protuberant abdomen and a fluid wave on physical exam. Intra-abdominal fluid can displace the diaphragm upward and produce sympathetic pleural effu sions with the possibility of respiratory compromise. Smaller amounts of ascites can be difficult to identify on examination; bedside ultrasound can be particularly helpful in patients in whom the presence of ascites is uncertain (Figure 80-1). Mild- to moderate-volume ascites can be managed with a saltrestricted diet and diuretics, both of which create a negative sodium balance and encourage loss of ascitic fluid. Recommended diuretics include spironolactone, 50 to 200 milligrams/d, and amiloride, 5 to 10 milligrams/d. Furosemide can be problematic because it can lead to overdiuresis. 2 To facilitate monitoring for adverse side effects, prescribe diuretics in collaboration with the outpatient physician. Paracentesis is recommended therapy for large-volume ascites.

olactone, 50 to 200 milligrams/d, and amiloride, 5 to 10 milligrams/d. Furosemide can be problematic because it can lead to overdiuresis. 2 To facilitate monitoring for adverse side effects, prescribe diuretics in collaboration with the outpatient physician. Paracentesis is recommended therapy for large-volume ascites. There are several important considerations when performing paracentesis on a cirrhotic patient. First, the patient’s prothrombin time/INR is likely to be elevated. Second, the amount of fluid that can be removed without infusion of albumin to prevent intravascular collapse is controversial. For any tap, guidelines from the American Association for the Study of Liver Diseases state that paracentesis should be considered safe from a FIGURE 80-1. Sonographic image of ascitic fluid showing bowel loops and an edematous gallbladder wall, a common finding in patients with ascites. [Courtesy of and used with permission of Michael S. Antonis, DO, sonographer.] TABLE 80-1 Common Herbal Remedies Associated With Hepatic Toxicity Herbal Remedy Application Nature of Injury Black cohosh (Actea racemosa/Cimiifuga racemosa) Menopausal symptoms Hepatic necrosis and bridging fibrosis Chaparral (Larrea ridentate) Antioxidant, health tonic Cholestasis, chronic hepatitis, cholangitis, cirrhosis Coltsfoot (Tussilago farfara) Cough suppressant, asthma symptoms Hepatic veno-occlusive disease Comfrey (Symphytum) Broken bones, wound healing, reduce joint inflammation Hepatic veno-occlusive disease Echinacea (E. angustifolia, E. pallida, E. purpurea ) Respiratory infections, fever, immune booster Acute cholestatic autoimmune hepatitis Germander (Teucrium chamaedrys) Digestive aid Liver cell necrosis Kava (Piper methysticum) Anxiolytic, sleeping aid Acute and chronic hepatitis, cholestasis, fulminant hepatic failure Kombucha “mushroom” tea (symbiotic colony of bacteria and yeast) and usnic acid Weight loss, increasing T-cell count, well-being, antiaging Acute liver failure and hepatitis Ma huang (Ephedra sinica) Weight loss Acute hepatitis Mistletoe (Viscum album) Hypertension, insomnia, epilepsy, asthma, infertility, urinary disorders Acute hepatitis Noni juice (Morinda citrifolia) Health tonic Subacute hepatic failure, acute hepatitis Saw palmetto (Serenoa repens) Benign prostatic hyperplasia Cholestatic hepatitis Senna (Cassia angustifolia) Laxative Acute hepatitis, acute cholestatic hepatitis, acute liver failure Skullcap (Scutellaria baicalensis) Sedative, anti-inflammatory Hepatic veno-occlusive disease, cholestasis, hepatitis Valerian (Valeriana officinalis) Sedative, anxiolytic Hepatitis Source: Adapted with permission from Abdualmjid RJ, Sergi C: Hepatotoxic botanicals: an evidence-based systematic review. J Pharm Pharm Sci 16: 376, 2013. Tintinalli_Sec09_p0473-0562.indd 519 8/2/19 6:49 PM

ic veno-occlusive disease, cholestasis, hepatitis Valerian (Valeriana officinalis) Sedative, anxiolytic Hepatitis Source: Adapted with permission from Abdualmjid RJ, Sergi C: Hepatotoxic botanicals: an evidence-based systematic review. J Pharm Pharm Sci 16: 376, 2013. Tintinalli_Sec09_p0473-0562.indd 519 8/2/19 6:49 PM 520 SECTION 9: Gastrointestinal Disorders bleeding perspective unless there is evidence of fibrinolysis (i.e., threedimensional bruising, oozing from IV start sites) or overt disseminated intravascular coagulation. For therapeutic paracentesis, American Association for the Study of Liver Diseases guidelines recommend the use of IV albumin, 6 to 8 milligrams/L of fluid removed, for amounts greater than 4 L. Spontaneous Bacterial Peritonitis SBP is the most common lifethreatening complication of ascites. In patients with known ascites, the 1-year incidence of SBP is 30%, and recurrence is as high as 44%. The survival rate for patients with a first episode of SBP is 68.1% at 1 month and 30.8% at 6 months. This is probably a result of acute infection occurring in the fragile setting of advanced liver disease. The classic presentation of SBP is fever and diffuse abdominal pain and tenderness. However, any or all of these features may be absent. Consequently, patients who are diagnosed with ascites for the first time or who have ascites and develop fever, abdominal pain, GI bleeding, vomiting, or encephalopathy should undergo paracentesis to check for SBP . Initial treatment is empiric antibiotic therapy to cover typical enteric flora. The most common isolates in SBP are Escherichia coli, Klebsiella pneumoniae, and Streptococcus pneumoniae . Empiric antibiotic treatment recommendations from the most recent (2012) guideline from the American Association for the Study of Liver Diseases are shown in Table 80-2. 2 Cefotaxime is a widely accepted first-line parenteral treatment for SBP . Oral therapy with broad-spectrum quinolones is an option in patients with mild, uncomplicated disease and close follow-up. Patients may have had prior infections with resistant organisms, so review microbiologic sensitivities from prior admissions, if available. The addition of IV albumin (1.5 grams/kg at diagnosis, 1 gram/kg on day 3) to antibiotic therapy may reduce renal failure and hospital mor tality in patients with SBP . Hepatic Encephalopathy Hepatic encephalopathy is a poorly under stood phenomenon attributed to the accumulation of nitrogenous waste products normally metabolized by the liver. Hepatic encephalopathy causes a spectrum of illness ranging from chronic fatigue or mild confusion to acute lethargy. The development of hepatic encephalopathy suggests either that the liver is no longer able to metabolize the usual supply of nitrogenous waste or that the supply of such waste has increased. Sources of increased supply include protein loads from a large meal or from occult GI bleeding. In addition to progressive liver disease, constipation, hypo- or hyperglycemia, alcohol withdrawal, hypoperfusion states such as sepsis, and iatrogenic interventions can also compromise the liver’s metabolic capacity. Hepatic encephalopathy is a common complica tion after transjugular intrahepatic portosystemic shunt, a procedure in which portal blood is shunted to the inferior vena cava, bypassing the liver. Although this procedure may succeed in reducing portal hyper tension and variceal bleeding, it also slows metabolism of nitrogenous wastes by reducing hepatic blood flow. Adding or removing antibiotics from a patient’s medicine regimen can also precipitate encephalopathy by changing the intestinal flora and altering the gut’s ability to metabolize proteins.

reducing portal hyper tension and variceal bleeding, it also slows metabolism of nitrogenous wastes by reducing hepatic blood flow. Adding or removing antibiotics from a patient’s medicine regimen can also precipitate encephalopathy by changing the intestinal flora and altering the gut’s ability to metabolize proteins. To appreciate the presence or worsening of encephalopathy, deter mine if there are changes in personality, memory loss, a decreased level of consciousness, or declining neuromuscular function. Table 80-3 lists clinical stages of encephalopathy. Asterixis, which characterizes stage II, is elicited by having the patient hold the arms straight up and extending the wrists. The hands begin to flap repetitively. Another manifestation of asterixis is back-and-forth tongue movement when the tongue is extended. A patient with known encephalopathy in stage I or II who is otherwise well and has no other acute comorbidities may be managed as an outpatient after consultation with the primary care physician or gastroenterologist. Hepatic encephalopathy is a diagnosis of exclusion. This holds true even in the presence of an elevated serum ammonia level. Patients with end-stage liver disease are typically coagulopathic and may develop a spontaneous or traumatic intracranial hemorrhage. Decreased hepatic gluconeogenesis and glycogen stores and poor nutritional status increase the risk of hypoglycemia and nutritional encephalopathies such as Wernicke-Korsakoff syndrome. Cirrhotic patients often are treated with diuretics and can develop hyper- or hyponatremia. Altered men tal status can result from decreased hepatic clearance of drugs such as benzodiazepines and opiates, prolonging the effect and resulting in accidental overdose. Renal failure, meningitis, and sepsis are other causes of altered mental status in the cirrhotic patient that could mimic hepatic encephalopathy. Treatment of hepatic encephalopathy is aimed at reducing the pro duction of nitrogenous wastes by reducing protein intake and suppressing the metabolic activity of intestinal bacteria. Lactulose is the current mainstay of therapy for hepatic encephalopathy. Lactulose is a synthetic disaccharide. It is minimally absorbed in the bloodstream. In the colon, it degrades primarily into lactic acid. In the acidified environment, ammonia is trapped and excreted in the stool. Blood ammonia levels can decrease up to 50% using lactulose therapy. Lactulose also inhibits glutamine-dependent ammonia production in the gut wall. Lactulose is given PO or PR. The oral dose is 20 grams diluted in a glass of water, fruit juice, or carbonated drink. For rectal administration, dilute 300 mL of syrup with 700 mL of water or normal saline. The enema should be retained for 30 minutes. Antibiotics including rifaximin, neomycin, vancomycin, and met ronidazole have been suggested as a second-line therapy for hepatic encephalopathy. These agents work by reducing intestinal flora. Of these, rifaximin is best tolerated, but is costly. 22 Although effective, neomycin is limited in use due to its adverse effects of renal toxicity and ototoxicity.23 Hepatorenal Syndrome Hepatorenal syndrome is a complication of cirrhosis that often accompanies SBP . It is defined as acute renal failure in a patient with histologically normal kidneys in the presence of preexisting chronic or acute hepatic failure. The cause is not well understood. There are two types of hepatorenal syndrome. Type 1 is more serious and is identified by progressive oliguria and doubling of serum creati nine over a 2-week period. Type 2 is represented by a gradual impair ment in renal function that may or may not advance beyond moderate dysfunction.

he cause is not well understood. There are two types of hepatorenal syndrome. Type 1 is more serious and is identified by progressive oliguria and doubling of serum creati nine over a 2-week period. Type 2 is represented by a gradual impair ment in renal function that may or may not advance beyond moderate dysfunction. The discovery of abrupt renal failure in a cirrhotic patient that cannot be attributed to any other cause is a marker of extreme morbidity. Median survival for type 1 hepatorenal syndrome without medical treatment is 2 weeks. Coagulopathy Coagulopathy is one of the more dangerous complica tions of cirrhosis. It needs to be treated if the patient has uncontrolled TABLE 80-2 Diagnosis and Treatment of Spontaneous Bacterial Peritonitis Diagnosis Ascitic fluid, obtain 50 mL for cell count, Gram stain, and culture (transfer fluid to culture bottles at the bedside for best results) WBC count >1000/mm Polymorphonuclear leukocytes >250/mL Bacteria on Gram stain Empiric treatment Cefotaxime or other third-generation cephalosporin IV fluoroquinolone (ineffective in patients who have received prophylactic quinolone treatment) Oral fluoroquinolone in a very mild case with close follow-up TABLE 80-3 Stages of Clinical Hepatic Encephalopathy Stage Features I General apathy II Lethargy, drowsiness, variable orientation, asterixis III Stupor with hyperreflexia, extensor plantar reflexes IV Coma Tintinalli_Sec09_p0473-0562.indd 520 8/2/19 6:49 PM

Oral fluoroquinolone in a very mild case with close follow-up TABLE 80-3 Stages of Clinical Hepatic Encephalopathy Stage Features I General apathy II Lethargy, drowsiness, variable orientation, asterixis III Stupor with hyperreflexia, extensor plantar reflexes IV Coma Tintinalli_Sec09_p0473-0562.indd 520 8/2/19 6:49 PM CHAPTER 80: Hepatic Disorders 521 bleeding or is scheduled to undergo a procedure with potential bleed ing complications. Vitamin K deficiency can be treated with vitamin K, 10 milligrams IV or PO. Fresh frozen plasma can be given in doses appropriate for the patient’s prothrombin level. Finally, decreased or malfunctioning platelets should be replaced with pooled donor platelets. Gastroesophageal varices and hemorrhage are complications of cirrhosis that are covered in Chapter 75, “Upper Gastrointestinal Bleeding. ”  HEPATIC FAILURE Liver failure is the final common pathway for several types of liver disease. Progression to liver failure is varied and depends largely on comorbid entities, such as human immunodeficiency virus/acquired immunodeficiency syndrome, diabetes, obesity, continued injection drug use, and alcohol intake. Patients who develop acute liver failure have an extremely poor prognosis, with survival rates of <30%. 25 Among the most common of the entities that present as acute liver failure in the United States are acetaminophen overdose (46%), indeterminate causes (14%), other drugs (11%), hepatitis B virus (7%), and autoimmune hepatitis. The clinical hallmarks of acute liver failure are hepatic encephalopa thy, hepatorenal syndrome, and coagulopathy. The electrolyte imbal ances seen in chronic liver disease can become extreme. Cerebral edema and intracranial hypertension are the most ominous complications. The catabolic nature of liver failure leads to negative nitrogen balance and immunodeficiency. Other clinical findings in acute liver failure include hypotension, hypoglycemia, and relative adrenal insufficiency. ED evaluation should include assessment for sepsis. Liver failure requires critical care in the ED and consultation with a liver transplant center. Recognizing fulminant hepatic failure is critical because transfer to a transplant center may be the most appropriate disposition. Treatment of fulminant liver failure in the ED involves care of the patient’s respiratory status, blood pressure, and encephalopathy; cor rection of electrolyte derangements; identification of cerebral edema or intracranial hemorrhage; attention to active bleeding; and careful disposition, ensuring that the patient will be assessed for liver transplant in a timely fashion. Patients with respiratory failure due to ascites, effusions, or decreased alertness require intubation. Bilevel positive airway pressure is not typically an option in these cases because patients are too somnolent and at risk for aspiration. Blood pressure at this stage of liver disease is typically low due to malnutrition, bleeding, vomiting, diarrhea, and third spacing of fluid. Treat with a judicious initial fluid challenge; normal saline is the recommended resuscitation fluid. Norepinephrine is the initial vasopressor of choice for volume-refractory hypotension in hepatic failure, with the addition of vasopressin when escalating doses of nor epinephrine are required. Take care when using vasopressin in severely encephalopathic patients, due to potential risk of increased cerebral vasodilatation and intracranial hypertension. The American Association for the Study of Liver Diseases also recommends a trial of hydrocorti sone in cases of persistent hypotension. In fulminant liver failure, cerebral edema and intracranial hemor rhage should rise to the top of the differential for altered mental status.

odilatation and intracranial hypertension. The American Association for the Study of Liver Diseases also recommends a trial of hydrocorti sone in cases of persistent hypotension. In fulminant liver failure, cerebral edema and intracranial hemor rhage should rise to the top of the differential for altered mental status. Patients with grade III or IV hepatic encephalopathy and concomitant renal failure, critically elevated ammonia levels, or hypotension are at high risk for cerebral edema; in this case, prophylactic hypertonic saline may be considered with a goal sodium level of 145 to 155 mEq/L. For patients with confirmed increased intracranial pressure, mannitol 0.5 to 1 gram/kg is recommended. 3 In the case of intracranial hemorrhage, treat coagulopathy. Consult neurosurgery or refer to a facility with neurosurgical services if the patient could benefit from hematoma evacua tion or intracranial pressure monitoring.  NONALCOHOLIC FATTY LIVER DISEASE NAFLD is a spectrum of disease ranging from steatosis (fatty liver) and steatohepatitis (nonalcoholic steatohepatitis) to cirrhosis and liver failure. It is strongly correlated with obesity and metabolic syndrome. NAFLD cirrhosis is now the second most common diagnosis among patients awaiting liver transplant (hepatitis C is first, and alcoholic liver disease is third). 4 The most common manifestation of NAFLD is hepatic steatosis or simply fatty liver, affecting approximately 30% of the overall U.S. population and up to 90% of obese individuals. The inflammatory subtype of NAFLD, nonalcoholic steatohepatitis, is less common, estimated to have a prevalence in the United States of 3% overall and 33% among obese patients. In the ED, steatosis and nonalcoholic steatohepatitis usually manifest as an incidental find ing of fatty liver on abdominal imaging or as a mild rise in aspartate aminotransferase and alanine aminotransferase, although nonalcoholic steatohepatitis can produce mild abdominal pain and nausea. While patients with steatosis have a benign course, a percentage of patients with nonalcoholic steatohepatitis will progress to cirrhosis and liver failure over a number of years. The size of this subset has not been accurately established yet. There is no treatment for NAFLD that has been proven to be particularly effective. The mainstays of treatment are weight loss and exercise, which have been shown to reduce fat deposition and inflammation of the liver parenchyma, but not fibrosis. Various medication classes, such as angiotensin-converting enzyme inhibitors, insulin-sensitizing agents, antioxidants, and statins are used, but none of these is considered standard treatment or has been found to make a dramatic difference in outcome. 27 When NAFLD is found incidentally during ED evaluation, the patient should be advised to abstain from alcohol and to pursue outpatient follow-up for further diagnosis and potential treatment.  GENETIC AND AUTOIMMUNE LIVER DISORDERS Gilbert’s syndrome is a familial liver disorder that produces occasional elevations in liver function tests and bilirubin. This syndrome does not cause cirrhosis or affect the synthetic or metabolic functions of the liver. Wilson’s disease, hemochromatosis, and α 1-antitrypsin deficiency are familial disorders that can lead to severe chronic disease and liver failure. Autoimmune hepatitis is a progressive, chronic disease that is presumably triggered by viral hepatitis or by medications. Primary bili ary cirrhosis is considered an autoimmune disorder with a chronic or chronic-degenerative course.  PRE- AND POSTHEPATIC VENOUS THROMBOSIS Vascular diseases of the liver are rare but important, because timely diagnosis and treatment can improve outcome.

mably triggered by viral hepatitis or by medications. Primary bili ary cirrhosis is considered an autoimmune disorder with a chronic or chronic-degenerative course.  PRE- AND POSTHEPATIC VENOUS THROMBOSIS Vascular diseases of the liver are rare but important, because timely diagnosis and treatment can improve outcome. Portal vein thrombosis affects the prehepatic portal venous system and is associated with hypercoagulable states, abdominal trauma, sepsis, pancreatitis, cirrhosis, and hepatocellular carcinoma. In acute thrombosis, the major symptom is colicky abdominal pain caused by venous congestion in the wall of the small intestine. Chronic portal vein thrombosis is usually painless and found inciden tally on imaging studies ordered for other reasons. In long-standing portal vein thrombosis, there is cavernous transformation of the por tal vein due to the development of multiple small collateral vessels. In cirrhotic patients, it can be hard to know if portal vein thrombosis is acute or chronic because the findings for chronic portal vein thrombosis are the same as those for long-standing cirrhosis with portal hypertension. 28 Hepatic vein thrombosis, or Budd-Chiari syndrome , is the thrombotic obstruction of the posthepatic portal venous system and also has both acute and chronic presentations, progressing from abdominal pain and hepatomegaly through ascites. Rather than being caused by cirrhosis, hepatic vein thrombosis is dangerous because it can cause the rapid development of fibrosis, cirrhosis, and liver failure if untreated. Risk factors for hepatic vein thrombosis include coagu lopathies, myeloproliferative disorders such as polycythemia vera, infection, paroxysmal nocturnal hemoglobinuria, and congenital webs of the vena cava. Treatment of thrombotic liver disease varies with the presence or absence of cirrhosis. In the non–cirrhosis-associated cases, anticoagulation is the first-line treatment and can be started in the ED. Cirrhosis raises the issue of increased risk of bleeding from esophageal or gastric varices; patients with this potential for catastrophic bleeding should not be anticoagulated, and the only therapy for consideration is clot removal, transjugular intrahepatic portosystemic shunt procedure, or surgical shunting. Tintinalli_Sec09_p0473-0562.indd 521 8/2/19 6:49 PM

of bleeding from esophageal or gastric varices; patients with this potential for catastrophic bleeding should not be anticoagulated, and the only therapy for consideration is clot removal, transjugular intrahepatic portosystemic shunt procedure, or surgical shunting. Tintinalli_Sec09_p0473-0562.indd 521 8/2/19 6:49 PM 522 SECTION 9: Gastrointestinal Disorders DISPOSITION AND FOLLOW-UP The disposition of a patient with acute or chronic hepatitis is complex and requires careful planning with the patient and caretakers. Discussion with the primary care physician and gastroenterologist can clarify a vague clinical picture. Patients with acute hepatitis require support ive treatment with pain management, antiemetic medication, and fluid resuscitation. Consider admission for high-risk patients, including the elderly and pregnant women, and patients who do not respond adequately to supportive care. Admit those who have a bilirubin ≥20 mg/dL, prothrombin time 50% above normal, hypoglycemia, or GI bleeding, which requires further evaluation to determine the pres ence of varices. In patients with chronic hepatitis, admission may be indicated for patients with ascites if they have significant respiratory compromise or abdominal pain. In addition, admit the patient with fever, acidosis, or leukocytosis and for evaluation and treatment of SBP . 31 Newonset or worsening hepatic encephalopathy, hepatorenal syndrome, and coagulopathy with bleeding are also strong indications for admission. Patients with severe hyponatremia and severe hyper- or hypovolemia should also be managed in the hospital. Consider patient safety in the disposition of patients with advanced cirrhosis. Weakness, muscle wasting, and mild encephalopathy are serious risks for falls, and coagulopathy is a risk for cerebral bleed. Patients must be stable on their feet or have supervised assistance for discharge to home. Discharge planning should include follow-up care by a gastroenter ologist or transplant specialist. Patients and family members can be referred to Alcoholics Anonymous, Al-Anon, or support groups for transplant or other special needs. Discharge medications may include antibiotics, diuretics, lactulose, antiemetics, and pain medications. SPECIAL CONSIDERATIONS  PAIN CONTROL IN PATIENTS WITH HEPATIC DISEASE It can be difficult to decide on appropriate pain medications and seda tives for patients with compromised liver function. Avoid NSAIDs in patients with chronic hepatitis and cirrhosis due to GI toxicity and possible potentiation of renal dysfunction. Acetaminophen has tra ditionally been avoided in patients with any type of liver disease, but there are several trials indicating it to be safe for short-term use, at a reduced dose of 2 grams total per day. Gabapentin and pregabalin are safe options for neuropathic pain. Avoid opioids whenever pos sible because opioids are metabolized by the liver and their sedative effects can be unpredictable in patients with compromised liver func tion. Avoid opioids in patients with a history of encephalopathy or substance use. Only if absolutely necessary, fentanyl and tramadol at reduced doses and increased dosing intervals are possible choices in select patients because they lack the toxic metabolites of traditional opioids. 34 When sedation or pain control is required for the critically ill patient with liver failure, a titratable infusion of a non-benzodiazepine medication with a short half-life and no toxic metabolites is useful. Propofol has been well studied in the setting of endoscopy and is safe at least in the short term for patients with cirrhosis. 35 Fentanyl provides pain relief and some degree of sedation.

liver failure, a titratable infusion of a non-benzodiazepine medication with a short half-life and no toxic metabolites is useful. Propofol has been well studied in the setting of endoscopy and is safe at least in the short term for patients with cirrhosis. 35 Fentanyl provides pain relief and some degree of sedation.  MEDICATION DOSE ADJUSTMENT Patients with liver disease have several factors that contribute to phar macokinetic variability including portal hypertensive gastropathy, por tosystemic shunting, decreased serum protein binding of drugs, high intestinal permeability, impaired gastric motility, impaired hepatic clearance, and impaired enzymatic activity. Be careful with drugs with a narrow therapeutic range and high toxicity. Drugs with high hepatic extraction may have clinically significant increased bioavailability in cirrhotic patients. For drugs with high hepatic extraction, reduce the initial and maintenance doses. For drugs with intermediate hepatic extraction, initially use the low range of the normal dose, and reduce maintenance dosing. For drugs with low hepatic extraction, initial dosing remains unchanged, but reduce the maintenance dose. 36 See Table 80-4 for a list of medications commonly used in the ED, classified by hepatic extraction.  PREGNANCY Pregnant women can present with various hepatic or cholestatic disor ders not specific to pregnancy. HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), however, stands apart as a life-threatening process that must not be missed in the ED. HELLP occurs as part of the pre-eclampsia–eclampsia spectrum in the late third trimester or in the postpartum period. A complete discussion of HELLP is provided in Chapter 100, “Maternal Emergencies After 20 Weeks of Pregnancy and in the Peripartum Period. ”  LIVER TRANSPLANT PATIENT Liver transplant patients can develop a variety of illnesses, most com monly metabolic and infectious in nature. This topic is addressed in Chapter 297, “The Transplant Patient. ”  TRAVELERS AND GLOBAL CITIZENS Travelers who have been outside the United States who present with abdominal pain, vomiting, diarrhea, or fever are at risk for having liver disease caused by parasitic infection. For detailed discussion, see Chapter 162, “Global Travelers. ”  PALLIATIVE CARE Palliative care benefits patients with end-stage liver disease whether or not they are a candidate for transplant. Goals of care and advance care planning should be discussed early in the initiation of care for patients with end-stage liver disease, particularly because disease progression can be rapid, providing little time for patients to develop the coping skills needed to face the progression of their disease and end-of-life consideration. TABLE 80-4 Hepatic Dose Adjustments for Common ED Medications Hepatic Extraction Category and Suggested Dose Adaptation Medication Class Medications High: Reduce initial and maintenance dose Analgesics Morphine Antihistamines Promethazine Antimigraine agents Sumatriptan Antipsychotics Chlorpromazine, quetiapine, perphenazine Anxiolytics Midazolam β-Adrenoceptor antagonists Labetalol, metoprolol, propranolol Calcium channel antagonists Nicardipine, verapamil Vasodilators Nitroglycerin, isosorbide dinitrate Intermediate: Low-normal initial dose and reduce maintenance dose Analgesics Codeine Antiarrhythmics Amiodarone, lidocaine Antibacterials Ciprofloxacin, erythromycin Antipsychotics Haloperidol, olanzapine, clozapine Antiulcer agents Omeprazole, ranitidine Anxiolytics Alprazolam, diazepam, lorazepam Beta-adrenoceptor antagonists Carvedilol Calcium channel antagonists Diltiazem, felodipine, nifedipine Source: Adapted with permission from Delco, F, Tchambaz L, Schlienger R, et al: Dose adjustment in patients with liver disease. Drug Safety.

er agents Omeprazole, ranitidine Anxiolytics Alprazolam, diazepam, lorazepam Beta-adrenoceptor antagonists Carvedilol Calcium channel antagonists Diltiazem, felodipine, nifedipine Source: Adapted with permission from Delco, F, Tchambaz L, Schlienger R, et al: Dose adjustment in patients with liver disease. Drug Safety. 2005; 28(6):529-545. Copyright Springer. Tintinalli_Sec09_p0473-0562.indd 522 8/2/19 6:49 PM