Patients often present with a history of self-harm by ingestion. Most patients will state in the history that they have ingested acetaminophen or an acetaminophen-containing combination product. Some patients will not be certain which tablets or pills they have taken, and witness corroboration may be important. Others may be unaware that the preparations ingested in overdose contained acetaminophen. Patients with painful conditions may have taken repeated over-the-counter analgesics for pain relief, resulting in a supratherapeutic overdose of acetaminophen.       It is essential to attempt to establish the timing of the overdose as this will affect subsequent patient management.
Acetaminophen overdose should be suspected in anyone who has taken an overdose of any substances or who has self-harmed in any way. It is equally important to seek evidence of other substance ingestion in patients who have presented with acetaminophen overdose. All patients suspected of having an overdose should have a serum level of acetaminophen checked.
Overall clinical picture
Patients who present within the first 24 hours after ingestion of a potentially toxic dose of acetaminophen may be asymptomatic. Early nonspecific signs that may be present in the first 24 hours include anorexia, nausea, vomiting, or vague abdominal pain. Patients who go on to develop hepatotoxicity (defined as aminotransferase levels >1000 IU/L) are likely to have aminotransferase levels >50 IU/L at 12 hours and >100 IU/L at 24 hours. However, this is not universally true.  Patients may present with reduced consciousness level or coma if they have ingested a combined preparation of acetaminophen and an opioid, have co-ingested alcohol or other drugs that may reduce the consciousness level, or who present after a massive overdose of acetaminophen.
Clinical signs of hepatotoxicity will usually develop about 2 to 3 days after ingestion, with RUQ pain and tenderness, nausea, and vomiting; patients may become clinically jaundiced. Liver injury usually becomes maximal at 48 to 96 hours and, dependent on the severity of the ingestion, may be characterized by massive elevation of serum AST and ALT activity, hyperbilirubinemia, and prolongation of the prothrombin time. Although most patients will recover, some may progress to have fulminant hepatic failure with encephalopathy, coma, and renal failure (hepatorenal syndrome).       Liver biopsies and post-mortem studies reveal extensive centrilobular hepatic necrosis without inflammatory changes.    
In survivors, hepatic regeneration is normally rapid and complete, with normalization of liver function tests within 1 to 3 weeks.    Renal injury is rare, and when it occurs, serum creatinine typically begins to rise soon after serum aminotransferase activity has peaked. Occasionally, renal injury occurs without liver injury.   Early presentation with coma and severe metabolic acidosis without hepatotoxicity is also rare and usually associated with massive overdose (serum acetaminophen level >800 micrograms/mL).  
Special clinical considerations
Certain subgroups of patients may be at higher risk of acetaminophen-induced hepatotoxicity. These include patients with glutathione deficiency from acute (e.g., during a febrile illness) or chronic (e.g., bulimia or anorexia) starvation, those with chronic debilitating illness, patients taking medications that induce CYP2E1, and alcoholics. However, clear evidence supporting increased risk is lacking. With the exception of lowering the threshold for treatment with acetylcysteine, these patients are treated with the standard approach that is utilized for other patients.
Depending on the time of presentation relative to the time of acetaminophen overdose, laboratory investigation may show a positive serum acetaminophen concentration, abnormal serum AST or ALT, abnormal prothrombin time or INR, renal dysfunction, or metabolic acidosis. Initial laboratory investigations should include:      
Serum acetaminophen levels
For acute acetaminophen overdose, specific management is dependent on the serum acetaminophen level and the time of the level relative to the time of ingestion. A timed plasma acetaminophen level is drawn at 4 hours after ingestion to risk-stratify likelihood of liver injury and the need for acetylcysteine treatment. 
The serum level is plotted on the Rumack-Matthew nomogram to determine whether treatment with antidote (acetylcysteine) is required. http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021539s004lbl.pdf [FDA: acetylcysteine/interpretation of acetaminophen assays]
This nomogram was developed by plotting timed acetaminophen concentrations from acetaminophen overdose patients on a graph, and drawing a line to discriminate those who did and those who did not develop hepatotoxicity (defined as aminotransferase levels >1000 IU/L).
The line connects a point at 150 micrograms/mL at 4 hours after ingestion and 4.7 micrograms/mL at 24 hours after ingestion and is termed the "treatment line". It is 25% more conservative than the nomogram as originally developed.
Acetylcysteine treatment is started if the acetaminophen level falls on or above the line.
The nomogram is not applicable in the following circumstances: unknown time of ingestion, chronic supratherapeutic ingestions, late presenting patients, those with co-ingestants that may delay gastrointestinal absorption (e.g., anticholinergic medications such as diphenhydramine), and those with evidence of hepatotoxicity despite undetectable or therapeutic acetaminophen levels.
AST and ALT levels
Levels are done initially and repeated in the course of patient management. The degree of derangement in laboratory results depends on the time of presentation relative to the time of acetaminophen overdose.
Prothrombin time/INR, pH, lactate level, and metabolic panel with serum creatinine
These are used to monitor severity of hepatic failure and assist in patient stratification for optimal benefit in orthotopic liver transplantation.
Renal injury may occur in the absence of significant hepatotoxicity, and is relatively common with significant hepatotoxicity.
Other tests to consider
Serum salicylate level should be considered in patients who have ingested substances in an attempt at self-harm.
Ethanol level and blood glucose level should be obtained in any patient with altered mental status.
Elevated lipase consistent with pancreatitis may occur especially in alcoholic patients.
Phosphate and alpha-fetoprotein may be helpful for prognostication for patients with acute liver failure as a supplement to the King's College Criteria.