Case 12 – Feeling a Little Yellow

Case #12: Feeling a Little Yellow
Author: Michael Gottlieb, MD
Peer Reviewer: Navneet Cheema, MD

A 68 year old male with a history of severe osteoarthritis of his bilateral knees presents with generalized malaise and weakness. He was previously seen in a local free clinic three days prior and given “pain medication”. Yesterday, he had no appetite, felt nauseated, and vomited four times. Today, the nausea subsided, but he still felt ill, which prompted him to come to the ED. He recalls taking two “pain pills” every 2-3 hours because the pain was really bothering him. He does not recall the name of the medication. On physical exam, he is alert, in mild distress, appears jaundiced, and has mild RUQ tenderness to palpation. The remainder of his exam is normal.

Vitals: Temp: 98.0, HR: 92, RR: 14, BP: 132/84, O2 sat: 100% on RA

What is the most likely etiology of this patient’s presentation?
The combination of GI symptoms, jaundice, RUQ pain, and recent increased ingestion of “pain medications” (think NSAIDs, acetaminophen, aspirin, or opioids when given this clue) makes acetaminophen (APAP) toxicity the most likely diagnosis.
What is the typical clinical presentation one would expect to see in this patient?
Phase I (1-24 hours): GI symptoms (anorexia, nausea, vomiting).
Phase II (24-72 hours): “Latent” phase with resolution of GI symptoms and small elevation in liver enzymes.
Phase III (Days 3-4): Severe hepatotoxicity with recurrence of GI symptoms
Phase IV (After Day 5): Clinical recovery or multi-organ failure and death
What is the mechanism of injury in this toxicity?
APAP is broken down via three mechanisms: glucuronidation, sulfonation, and enzymatic conversion to NAPQI (see below). Glucuronidation and sulfonation result in non-toxic APAP metabolites. In therapeutic APAP doses, the small amount of NAPQI produced, easily combines with glutathione to form non toxic metabolites. In overdose, the glucuronidation and sulfonation pathways become saturated resulting in a larger proportion of APAP being metabolized to NAPQI. Eventually the body depletes its store of glutathione and can no longer detoxify NAPQI. This results in liver injury and the clinical picture described previously. N-Acetylcysteine (NAC) regenerates glutathione which is the rate-limiting step of NAPQI breakdown.

APAP Conjugation

What is the initial treatment for this patient?
If acetaminophen toxicity is suspected, begin NAC. Dosing is as follows:

PO: 140 mg/kg Loading Dose, followed by 70 mg/kg Q 4 Hours x 17 doses
IV: 150 mg/kg Loading Dose, followed by 50 mg/kg over 4 hours, followed by 100 mg/kg over 16 hours

NAC should be continued until the labs normalize (specifically INR, bilirubin, AST/ALT), the acetaminophen level is undetectable, and the patient’s condition is improving. Newer literature supports tailoring the NAC to the patient, rather than following set time frames.

How would your management change if this were an acute ingestion?
If the patient presents shortly after ingestion (< 1 hour), consider giving activated charcoal (Adult: 50-100 g, Pediatrics: 1g/kg). Also, remember to plot the APAP level on the Rumack-Matthew nomogram to predict the likelihood of toxicity and need for treatment. The nomogram is NOT intended to be used for chronic ingestions or patients presenting >24 hours after ingestion.
What are the criteria for transplant in these patients?
King’s College Criteria for immediate referral for liver transplant:
1. pH < 7.30 or lactate > 3 mg/dL after full fluid resuscitation at 12 hours.
2. INR > 6.5 (PTT > 100 sec) PLUS Creatinine > 3.4 mg/dL PLUS Grade 3 or 4 hepatic encephalopathy.
Of note, a Lactate > 3.5 mg/dL after fluid resuscitation, Phosphorus > 1.2 mmol/dL at 48 hours, and APACHE II score > 15 have also been shown to be predictive of the need for transplant.


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