Acetaminophen is safe when taken in recommended doses, but ingestion of as little as 6 gm may be fatal. (Usually, a fatal dose exceeds 140mg/kg.) Toxicity is most likely among patients with chronic liver disease and those abusing alcohol. Because acetaminophen is rapidly absorbed and usually quickly metabolized, most AHF patients will have low or undetectable acetaminophen levels at presentation. After ingestion of a toxic dose, symptoms are minimal for the first day, with the exception of nausea and vomiting. One to two days later, deteriorating liver function tests, right upper quadrant pain, and oliguria (because of antidiuretic hormonelike effects) become evident. At this time, transaminases may peak in the tens of thousands of units. Within 3 to 5 days, a rising bilirubin and PT are seen as hepatic transaminases and albumin decline. In this most advanced stage, mental status may decline and renal failure develop. If the patient is to spontaneously recover, improvement is typically noted between days 5 and 7. Of all causes acetaminopheninduced AHF has the highest rate of spontaneous recovery, but predicting who will recover and who will die without transplantation is difficult. Poor prognostic factors are late presentation, the presence of coagulopathy, metabolic acidosis, renal failure, and cerebral edema.

When the time of ingestion is known, the risk of toxicity from an isolated acute acetaminophen ingestion may be predicted from the Rumack-Matthew nomogram. (Concentrations ≥ 140mg/dL > 4h are predictive of toxicity.) Unfortunately, the time of ingestion is rarely certain and patients with chronic exposure, preexisting liver disease, or significant alcohol use may develop toxicity at much lower concentrations than the nomogram predicts. For these reasons, it makes sense to administer N-acetylcysteine (NAC) as quickly as possible to AHF victims unless certain acetaminophen is not the cause. NAC protects by directly binding the toxic acetaminophen metabolites and repleting intracellular glutathione. Historically, an oral loading dose of 140mg/kg followed by 17 additional doses of 70mg/kg at 4-h intervals has been used. Vomiting is so common with oral NAC that “prophylactic”
antiemetics are usually needed. Intravenous NAC, free of emetogenic effects, is available, safe, affordable, and at least as effective as the older, less-convenient oral regimen.

The risk of developing AHF from viral hepatitis is small (<1%), but because viral infection is common, collectively viral infections represent the third most cause of AHF. Numerous agents including hepatitis A to E, Epstein-Barr virus, and cytomegalovirus can cause severe hepatitis. Hepatitis B and C account for more than 90% of cases; with hepatitis A contributing another 5%. Hepatitis B and C are transmitted predominantly through the exchange of body fluids (e.g., transfusion, needle stick, or sexual intercourse). Although blood transfer represents the highest relative risk, saliva and semen are also vehicles. Hepatitis B immunization, testing the donated blood supply and evaluating the liver function tests of donors, has dramatically reduced the risk of transfusion-induced disease. After exposure to the hepatitis B virus, a 2- to 3-month incubation period passes as the virus proliferates. During this time, viral surface antigen (HbsAg) can be detected in the serum of infected patients. Nonspecific, gastrointestinal (GI), systemic, and rheumatologic symptoms precede the onset of jaundice and elevations in liver transaminases and, in most patients, by the disappearance of HbsAg. In a small minority of patients, HbsAg persists in the circulation signifying the presence of chronic disease and high infectivity. Antibodies to the core antigen appear in the serum during the incubation period and are typically present for several months after the illness resolves. Antibodies to HbsAg develop during the period of convalescence and may persist for years. Most patients do not require treatment for acute hepatitis B infection, and the value of antivirals or interferon therapy for patients with hepatitis B induced AHF is debated. The delta agent, or hepatitis D, creates disease by coinfecting or superinfecting patients with hepatitis B, producing a highly lethal combination.

In contrast to hepatitis B, hepatitis C is more likely to be clinically subtle in its initial stages and is a rare cause of AHF. Jaundice is uncommon with the acute illness, and when it does occur, is mild. Despite mild initial illness, hepatitis C is a major cause of chronic liver disease and cirrhosis. Even though 40% of infected individuals clear the virus spontaneously, if persistent infection is discovered, treatment with interferon alpha and antivirals accelerate viral clearance. Because different genotypes of the virus have differential response rates and treatment is complex, expensive, and side effect laden, consultation with a hepatologist is prudent. Because coinfection is common, patients diagnosed with hepatitis C should be tested for HIV and vice versa.

Hepatitis A and E differ in many respects from hepatitis B or C. Both A and E are acquired by the fecal-oral route and often produce asymptomatic infection, especially in children. (Adults often are more symptomatic). After ingestion, an average incubation period of a month precedes the onset of nonspecific constitutional and GI symptoms. In some patients, an icteric phase follows, which is associated with abnormalities of transaminases and coincides with the appearance of IgM antibodies. Fortunately, hepatitis A and E uncommonly are associated with either AHF or chronic infection. The exception to this rule may be pregnant women who appear to be more severely affected by hepatitis E. Cytomegalovirus and Epstein-Barr virus are much less common causes of clinically important hepatitis and only rarely are associated with AHF.

Although ischemic AHF occurs only rarely as a primary process (e.g., Budd-Chiari, sickle cell crisis), life-threatening hepatic dysfunction often develops in patients with limited reserves, when another even relatively minor insult tips the balance. This injury can occur when nutritive flow is compromised by congestive heart failure or shock or when hepatocytes are damaged by circulating inflammatory mediators (e.g., severe sepsis) or severe hypoxemia.

Most patients with AHF should be cared for in an ICU because of their numerous physiologic problems and need for close monitoring. Because AHF patients are complex and encouraging survival rates have been achieved with transplantation, potential candidates should be transferred early in their course to a facility with transplant capability and resources necessary to manage complications. Unfortunately, transplantation carries its own set of risks, and at least half of all good candidates die while waiting for a liver. Transplantation is best
reserved for the otherwise healthy patient with isolated liver failure. For example, it clearly cannot benefit patients with metastatic carcinoma or those who have sustained irreversible brain damage from hypoxia, intracranial bleeding, or intracranial hypertension.

The first step after confirming respiratory and hemodynamic adequacy is to try to determine the etiology of AHF. An in-depth history should be obtained that includes medications (e.g., herbal remedies, vitamins, estrogens); a dietary history targeting potential sources of hepatitis (e.g., travel, raw seafood consumption, and sick contacts) and; hepatotoxin exposure (e.g., alcohol, carbon tetrachloride, mushrooms). Obviously, a detailed history of transfusion, needle sharing, and sexual activity is essential. A toxicological survey should be obtained that includes acetaminophen levels. A panel of serologic tests should be sent to search for viral causes listed in Table 31-1. Although rare in patients under 40, ceruloplasmin, serum copper, and a 24-h urine for copper should be sent to look for Wilson disease. Autoimmune hepatitis can be excluded by laboratory testing for antinuclear antibody, antimitochondrial antibody, and anti-smoothmuscle antibody. A pregnancy test should be obtained for all women with childbearing potential. Basic laboratory studies including blood counts, bilirubin, transaminases, platelets, electrolytes, creatinine, an arterial blood gas, and tests of hepatic synthetic function (albumin and PTs) should be obtained. It is also reasonable to perform an ultrasound examination of the liver to evaluate its size, echogenicity, bile duct anatomy, portal and hepatic vein patency, and to look for ascites. In many cases, and essentially all cases where transplantation is a consideration, a contrasted abdominal computed tomographic (CT) scan will be performed to evaluate liver and spleen size and texture and vascular anatomy. Obviously, the decision to administer contrast media should be well reasoned given the risks of contrast-induced nephropathy. As initial data are being gathered, potential consultants, (e.g., hepatologist, transplant surgeons, and neurosurgeons) should be contacted.