In this case, given the history of excessive acetaminophen intake, this is the most likely cause of hepatic failure. Acetaminophen is the leading cause of acute liver failure in the United States: approximately 18% to 39% of cases.¹ Other drug reactions, including isoniazid, phenytoin, and others, comprise 13% of cases. Viral hepatitis, specifically hepatitis A and B, account for a combined 12% of cases. In contrast, hepatitis E coinfection with hepatitis A is the leading cause of acute liver failure worldwide, reportedly up to 87%. Other more rare causes include autoimmune hepatitis, Wilson disease, Amanita spp (mushroom) poisoning, ischemic injury, Budd-Chiari syndrome, and pregnancy-associated acute liver failure. Importantly, in many patients, the cause of liver failure is not found, which is usually associated with a worse prognosis.²

Acetaminophen-induced acute liver failure (ALF) is associated with a high mortality rate, approximately 50% without transplant.³ Acetaminophen toxicity occurs in the setting of intentional overdose suicide attempt, unintentional overdose, or ingestion of doses considered nontoxic in combination with other hepatotoxic substances (ethanol, ethylene glycol, antiepileptics). Symptoms of hepatotoxicity begin 24 to 48 hours after ingestion, and maximum prothrombin time occurs approximately 72 hours after ingestion. Acetaminophen can also be nephrotoxic, further complicating the clinical management.

Normally, acetaminophen is metabolized by the liver via three different pathways: sulfate conjugation (20-40%), glucuronidation (40-60%), and N-hydroxylation (15-20%) by the cytochrome P450 enzyme CYP2E1 to N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is a toxic intermediate and is conjugated with hepatic glutathione to a nontoxic final product. Glutathione stores can eventually become depleted, causing accumulation of NAPQI and subsequent hepatocellular necrosis^4,5 (Figure 12-1).

In the West Haven Criteria, high-grade (grades III and IV) encephalopathy distinguishes severe acute hepatic failure from ALF (Table 12-1). High-grade encephalopathy predicts a higher mortality rate without transplantation. Patients with grade IV encephalopathy have an 80% mortality rate. Progression to grade III/IV encephalopathy can be rapid and is a sign of intracranial hypertension and impending herniation.^6–8 Detection of high-grade encephalopathy often dictates the need for endotracheal intubation and institution of measures to lower intracranial pressure (ICP). Patients with grades III and IV encephalopathy are also at risk for subclinical seizure activity; a low threshold for continuous electroencephalographic (cEEG) monitoring is prudent.

The King’s College Criteria (Table 12-2) is used to estimate the prognosis of a patient in ALF. The etiology of hepatic failure is emphasized, and acetaminophen and non–acetaminophen-related hepatic failure should be separated.^9,10 Patients with acetaminophen-induced ALF have a 50% mortality rate without transplantation, whereas patients in ALF from other causes, such as hepatitis B, have an approximately 25% survival rate without transplantation.

An early classification applied the term fulminant to describe the onset of hepatic encephalopathy within 2 weeks of jaundice; subfulminant hepatic failure described a disease process with an interval of 3 to 12 weeks.¹¹ More recent classifications define the time between onset of symptoms and the development of encephalopathy as hyperacute (within 7-10 days), acute (10-30 days), and subacute (4-24 weeks). Paradoxically, increased acuity of liver failure correlates with better prognosis.^12,13

Cerebral edema is related to the development of encephalopathy and is a leading cause of death in patients with ALF.¹ Patients who have progressed to grade IV encephalopathy will invariably have evidence of cerebral edema. Many factors have been proposed to contribute to cerebral edema in ALF. Ammonia, glutamine, other amino acids, and proinflammatory cytokines cause cytotoxic edema, vasogenic edema, and breakdown of the blood-brain barrier.

Ammonia, in particular, has been studied extensively in the pathophysiology of encephalopathy. Ammonia is a by-product of normal metabolism of glutamine in the small bowel and is metabolized to urea primarily by the liver. In ALF, this detoxification pathway is impaired, and the concentration of ammonia in the blood rises. Arterial concentrations of ammonia have been shown to correlate with the development of brain swelling and an increase in intracranial pressure.^14,15 Although the mechanism remains unclear, the accumulation of ammonia has been shown to lead to astrocyte swelling and dysfunction. Conversion of ammonia and glutamate into glutamine via glutamate synthetase in astrocytes has been described.¹⁶ Extracellular transfer of osmotically active glutamine is limited by cell membrane transporter capacity. Thus, hyperammonemia causes intracellular accumulation of glutamine, causing cellular edema and intracranial hypertension. ¹⁷ Accordingly high arterial ammonia levels are associated with cytotoxic edema, intracranial hypertension, cerebral herniation, and poor clinical outcomes.¹⁵

In patients with ALF, serum ammonia levels < 75 μM rarely develop intracranial hypertension.¹⁴ Arterial ammonia levels > 100 μM on admission represent an independent risk factor for the development of high-grade hepatic encephalopathy, and a level > 200 μM predicts intracranial hypertension.¹⁸ However, an animal study has shown no direct correlation between glutamine level and astrocyte swelling, suggesting that astrocyte swelling may not be the result of a direct osmotic effect of glutatmine. The excess glutamine synthesized within astrocytes may be transported into mitochondria, where it is metabolized to ammonia and glutamate via phosphate-activated glutaminase. Ammonia and glutamate in the mitochondria of astrocytes may lead to oxidative stress and ultimately astrocyte swelling.¹⁹