Stacie Zelman
Acute hepatic failure (AHF) differs clinically, therapeutically, and prognostically from hepatic cirrhosis, but priorities for the management of both entities have similar features. AHF is relatively rare with approximately 2,000 cases per year in the United States but is associated with a high mortality rate (1). The majority of cases are due to acetaminophen overdose and drug reactions, followed by viral illness (2). Hepatic cirrhosis is a more common condition in the United States and also has a high mortality rate accounting for approximately 25,000 deaths in 2000 (3). Cirrhosis is most commonly caused by alcoholism or hepatitis C. The presence of ascites in combination with cirrhosis has an association with poor long-term survival (3).
CLINICAL PRESENTATION
The presentation of AHF is, to some degree, dependent on the specific etiologic agent, but the basic definition is altered mental status (encephalopathy) with coagulopathy (INR >1.5) in a patient without previously known liver pathology (1,4). Other symptoms that may be present are jaundice, motor dysfunction, and fetor hepaticus (a sweetish, musty, or pungent odor on the breath). In severe cases, a patient may present with signs indistinguishable from septic shock including tachycardia, hypotension, and multiorgan failure (5).
The manifestations of hepatic encephalopathy in both AHF and cirrhosis are similar, but the onset is generally slower with cirrhosis. Encephalopathy may present anywhere on a continuum of mild confusion to frank coma. Encephalopathic patients with cirrhosis commonly present with euphoria, depression, or muscular incoordination or may demonstrate more obvious mental status changes. Symptoms such as malaise, lethargy, fluid retention, loss of libido, and pruritus are common, and typical physical findings include hepatomegaly, spider angioma, ascites, and jaundice (Fig. 105.1). Asterixis, a flapping tremor best seen with the patient’s arms outstretched and wrists hyperextended, is a classic symptom that is absent in many cases. The factors most commonly precipitating hepatic encephalopathy in patients with cirrhosis are infection, gastrointestinal bleeding, use of tranquilizing drugs or alcohol, and overuse of diuretics.
FIGURE 105.1 Complications of hepatic failure. (Image from Rubin E, Farber JL. Pathology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1999.)
Most patients with hepatic disease are, at baseline, immunocompromised. Thus, any infection, such as spontaneous bacterial peritonitis (SBP), pneumonia, urinary tract infection, and systemic inflammatory response syndrome (SIRS), are serious complications. Infection is a prominent precipitant of acute chronic liver failure and can advance to multisystem organ failure (6,17). Febrile patients with cirrhosis, ascites, and abdominal pain should be considered to have SBP until proven otherwise, as SBP complicates up to 33% of these patients (7,8). Patients admitted with SBP and septic shock have a mortality rate greater than 70% (9). While typical signs of infection may not always be apparent in this population, rapid treatment at first suspicion should be a priority.
Because of portal hypertension and secondary esophageal varices, death from gastrointestinal bleeding is more common with cirrhosis than with AHF. In the later stages of cirrhosis, ascites may become markedly symptomatic with abdominal pain and shortness of breath (3). The hepatorenal syndrome, or functional renal failure, occurs in advanced cirrhosis and is commonly fatal.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of cirrhosis and AHF varies, depending on presenting symptoms and precipitating causes. The differential diagnosis of cirrhosis presenting with jaundice includes hemolysis, biliary tract obstruction, viral hepatitis, hepatotoxic ingestions, septicemia, and numerous minor causes. The association of mental status changes with jaundice should alert the emergency physician to the possibility of hepatic encephalopathy. In the patient without known chronic liver disease, the differential diagnosis of hepatic encephalopathy includes viral hepatitis, fatty degeneration of pregnancy, Reye syndrome, and hepatotoxic ingestions such as acetaminophen, isoniazid, rifampin, Amanita phalloides mushrooms, carbon tetrachloride, or ecstasy. Historical information, such as preillness activity, previous suicidal behavior, and the presence of fever or malaise, may help to differentiate among potential causes.
Patients with hepatic cirrhosis may have chronic jaundice and may sustain acute mental status changes for reasons other than hepatic encephalopathy. Because alcoholic patients are at greater risk for bleeding after a traumatic event, subdural hematoma or other form of ICH must be considered in cirrhotic patients with altered sensorium. Patients with renal failure also may present with features suggestive of severe liver disease—altered sensorium, fluid retention, and coagulopathy. Alcoholics may develop pancreatitis or alcoholic hepatitis, with severe dehydration and associated mental status changes that may mimic hepatic encephalopathy.
ED EVALUATION
Current and past medical information should be sought from the patient, prehospital personnel, family, previous medical records, and the patient’s private physician to differentiate acute from chronic abnormalities. ABCs need to be addressed before secondary evaluation may begin.
Key points of the physical examination include the following:
• Examination of the conjunctiva and skin for the presence of jaundice (Fig. 105.2)
FIGURE 105.2 Jaundice. A patient in hepatic failure displays a yellow sclera. (Image from Rubin E, Farber JL. Pathology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1999.)
• Abdominal examination for the presence of ascites and liver size
• Rectal examination for evidence of gastrointestinal bleeding
• Careful neurologic examination with attention to subtle changes in mental status. Asterixis, alterations in motor tone, or abnormal posturing should be noted.
Appropriate laboratory testing includes blood counts and electrolytes, as well as serum ammonia, coagulation studies (PT/INR), and in some cases toxicologic studies or acetaminophen level. It is important to keep in mind that encephalopathy may precede an elevated ammonia level. Chest radiography may be indicated if pulmonary edema or pleural effusion is suspected. Abdominal imaging with CT or ultrasound may be useful in the evaluation of abdominal pain, excluding biliary tract disease, or localizing ascites. If SBP is suspected or ascites is excessive, paracentesis is indicated, with subsequent laboratory evaluation for cell counts, Gram stain, and culture. The diagnosis of SPB is determined on the basis of positive culture or ascitic fluid with a absolute neutrophil count >250 cells/mL (3).
KEY TESTING
• Lab Studies: complete blood count (CBC), electrolytes, ammonia, INR, and acetaminophen level
• Imaging: chest x-ray (CXR), abdominal ultrasound, and CT of abdomen/pelvis
• Paracentesis
ED MANAGEMENT
The treatment of hepatic encephalopathy in patients with AHF requires a more aggressive approach than in those with an exacerbation of chronic liver disease. Hepatic encephalopathy in AHF develops rapidly and is almost always complicated by cerebral edema, with possible central herniation of the brain (5).
Immediate attention should be given to securing a patent airway and initiating artificial ventilation if the patient is comatose or lacks an active gag reflex. Supplemental oxygen should be given, even in the absence of pulmonary edema. Fluid resuscitation should be aggressive in hypotensive or bleeding patients and should be undertaken despite the possibility of pulmonary edema (5,10). Persistent hypotension signals the need for vasopressors with the preferred drug of choice being norepinephrine (10).
Patients should be placed on a cardiac monitor and quickly assessed for dysrhythmias. Blood glucose should be monitored closely, as impaired glucogenesis and reduced glycogen stores predispose these patients to hypoglycemia (11). Patients who demonstrate clinical signs of significant, increased intracranial pressure, such as abnormal posturing or unreactive pupils, should receive mannitol 0.5 g/kg intravenously over 10 minutes (after head CT) (12). Fresh-frozen plasma (2 to 4 U) should be given when the prothrombin time is >1.5 times normal and there is evidence of active bleeding (12). Platelet infusions (5 to 10 U) are recommended when thrombocytopenia is severe (<10,000 or <50,000 in the presence of active bleeding) (12). Severe variceal bleeding when present should be treated with blood, antibiotics (a quinolone or third-generation cephalosporin), endoscopy within 12 hours, and vasoactive therapy (such as octreotide 25 to 50 μg/hr) (13).
Proven or suspected infection should be treated promptly. Cultures may be used to modify therapy, but if SIRS or septic shock is evident, empiric antibiotics should be started immediately. Responsible organisms are both gram-positive and gram-negative, but gram-negative organisms may have an increased association with worsening encephalopathy (14). Empiric broad-spectrum coverage such as piperacillin–tazobactam (3.375 g intravenously) or cefotaxime (1 to 2 g intravenously) is recommended. Care should be taken not to use nephrotoxic or hepatotoxic antibiotics unless there is a favorable risk/benefit ratio. In addition, aspiration pneumonia should be considered in these patients, and if suspected, it should be treated with pulmonary toilet, ventilatory support, and broad-spectrum antibiotics. Prophylactic antibiotics in AHF are controversial.
Lactulose may decrease the severity of hepatic encephalopathy in cirrhosis, but its benefits in AHF are unproven (5). N-acetylcysteine improves survival from acetaminophen overdose, even late in its course (12).
Decisions concerning potential transplantation for AHF should be made early by a gastroenterologist (12,15). In many cases of severe AHF, transplantation is the only means of increasing the chance of survival (15). Survival after transplantation is nearly 70% (15). Artificial liver support is helpful for acute-on-chronic liver failure (16), but in general is not recommended outside clinical trials (12).
For the management of symptomatic recurrent ascites in cirrhotic patients, large-volume paracentesis is recommended as having fewer side effects than diuretics and a comparable rate of fluid reaccumulation (3,16). Hypovolemia may occur 3 to 6 hours later when volumes of >5 L are removed. Administration of albumin, 8 g/L of ascites removed, is recommended in some cases. Other plasma volume expanders are available, but albumin is thought to have greater circulatory protection (7). Ultrasound-guided paracentesis may lower needle-related intra-abdominal complications.
When patients with hepatic cirrhosis present to the emergency department with nonlife-threatening conditions, care must be taken to avoid interventions (e.g., medications) that may cause clinical deterioration. Sedatives may trigger clinical hepatic encephalopathy. Nonsteroidal anti-inflammatory drugs may induce renal failure in cirrhotic patients and should be used with caution and at appropriate doses.
CRITICAL INTERVENTIONS
• Airway control for obtunded liver failure patients
• Fluid resuscitation and pressor support as indicated for patients in shock
• Fresh-frozen plasma and platelets in patients with bleeding or undergoing invasive procedures
• Appropriate cultures and intravenous antibiotics for suspected or proven infection
• Oral or rectal lactulose for patients with cirrhosis and hepatic encephalopathy
DISPOSITION
Patients with gastrointestinal bleeding, SBP, and hepatic encephalopathy should be admitted to the hospital. Those with severe presentations often require an intensive care setting, and immediate consultation with a gastroenterologist is indicated. For severe cases, consideration should be given to transporting the patient to a facility capable of critical care and liver transplantation (15).
Because patients with chronic liver disease commonly respond poorly to illness or other stresses, indications for admission to the hospital are generally less stringent than for other patients. Thus admission for intravenous antibiotic treatment should be considered for most infections.
Common Pitfalls
• Failure to consider a hepatotoxic drug as the cause of the patient’s symptoms. Patients who have ingested a hepatotoxic drug may be unwilling to give an adequate history and may present early in the course of their illness, before there is obvious clinical evidence of hepatic failure.
• Ruling out the diagnosis of hepatic encephalopathy on the basis of a normal serum ammonia level.
• Failure to adequately treat hypoglycemia. One bolus of 50% dextrose may not be adequate therapy because of depleted glycogen stores; in this case, maintenance infusions of D10 or D20 should be administered.
• Failure to identify causes of coma other than hepatic encephalopathy in patients with cirrhosis. In particular, subdural hematoma/Intracerebral hemorrhage, drug overdose, and meningitis/encephalitis should be ruled out.
REFERENCES
1. Lee WM. Acute liver failure. Semin Respir Crit Care Med. 2012;33:36–45.
2. Ostapowicz G, Fontana RJ, Schiodt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med. 2002;137:947–954.
3. Gines P, Cardenas A, Arroyo V, et al. Management of cirrhosis and ascites. N Engl J Med. 2004;350:1646–1654.
4. Bernal W, Hall C, Karvellas CJ, et al. Arterial ammonia and clinical risk factors for encephalopathy and intracranial hypertension in acute liver failure. Hepatology. 2007;46:1844–1852.
5. Kahn SA, Shah S, Williams R, et al. Acute liver failure: A review. Clin Liver Dis. 2006;10:239–258.
6. Stavitz TR. Critical management decisions in patients with acute liver failure. Chest. 2008;134(5):1092–1102.
7. Kuiper JJ, van Buuren RA. Ascites in cirrhosis: A review of management and complications. Neth J Med. 2007;65(8):283–288.
8. Sheer TA, Runyon BA. Spontaneous bacterial peritonitis. Dig Dis. 2005;23:39–46.
9. Bernardi M. Spontaneous bacterial peritonitis: From pathophysiology to prevention. Intern Emerg Med. 2010;5(suppl 1):S37-S44.
10. Jalan R. Acute liver failure: Current management and future prospects. J Hepatol. 2005;42:S115–S123.
11. Tappy L, Minehira K. New data and new concepts on the role of liver in glucose homeostasis. Curr Opin Clin Nutr Metab Care. 2001;4:273–277.
12. Polson J, Lee WM; American Association for the Study of Liver Diseases. AASLD position paper: The management of acute liver failure. Hepatology. 2005;41:1179–1197.
13. Dib N, Oberti F, Cales P. Current management of the complications of portal hypertension: Variceal bleeding and ascites. CMAJ. 2006;174:1433–1443.
14. Vaquero J, Chung C, Cahill ME, et al. Pathogenesis of hepatic encephalopathy in acute liver failure. Semin Liver Dis. 2003;23:259–269.
15. Ahmed A, Keeffe EB. Current indications and contraindications for liver transplantation. Clin Liver Dis. 2007;11:221–247.
16. Sen S, Williams R. New liver support devices in acute liver failure: A critical evaluation. Semin Liver Dis. 2003;23:283–294.
17. Miyake Y, Iwasaki Y, Terada R, et al. Systemic inflammatory response syndrome strongly affects the prognosis of patients with fulminant hepatitis B. J Gastroenterol. 2007;42:482–492.