Case Of the Month 6 – Answer

Sickle cell disease requires you to broaden any differential diagnosis list for a given presentation, as there are many other conditions which may present secondary to sickle cell disease.  The largest concern in this patient is the transaminitis especially given her relatively stable vitals (aside from tachycardia) and unimpressive exam.  There are many ways to look at transaminitis, but one easy way to break everything down is whether it is caused likely from direct damage to hepatocytes vs. secondary to cholestasis. Grossly, this patient’s bilirubin is elevated, but not greatly, and her alkaline phosphatase is unremarkable.  Cholestasis produces high bilirubin and alk phos values, more so than in changes in AST/ALT.  One way to actually quantify this is to calculate an R ratio: This is the ALT expressed in upper limits of normal divided by the alk phos expressed in upper limits of normal (ULN).  For example, if  ALT ULN is 50 and bili ULN is 1.0, the R ratio in this patient would be about 10/1.5, or ~6.  An R value > 5 indicates a hepatotoxic mechanism, <2 a cholestatic picture, and in between is a mixed picture.

Knowing this we should be thinking of diseases that cause hepatocellular damage.  This would include infectious hepatitis, liver abscess, hepatic thrombosis/infarct, acute hepatic crisis, medication effect, autoimmune hepatitis, hemochromatosis, other metabolic processes, and malignancy to name a few.  However even this list can be reduced further as many of these diseases should present with abdominal tenderness yet our patient has a benign exam.

Further workup would likely include abdominal imaging, as an abdominal ultrasound can help visualize the hepatic veins and characterize the echogenicity of the liver parenchyma.  CT scan could help rule out any large masses or changes within the liver including hepatic abscesses.  But would you send any other labwork?  Think about the above differential and which lab test might be fruitful in ruling out a tie-sensitive diagnosis.

Medication lists should always be reviewed when dealing with new-onset hepatic damage.  This patient isn’t taking much, but the Percocet should raise a red flag given this her presentation.  As we all know, Percocet is a combination pill with oxycodone and acetaminophen.  This patient has been taking Percocet for three days for acute pain crisis and now has transaminitis and N/V without tender hepatopathy.  This all fits with a presentation of acute acetaminophen toxicity and an acetaminophen level should be sent immediately.

Acetaminophen is one of our safest OTC anti-inflammatory and pain medications but only when dosed properly.  With its use in combination opioid pain medications such as Percocet, the risk of overdose is higher if patient’s are unaware of the risks of taking too many doses within a short time course.  The minimum toxic dose of acetaminophen in adults ranges from 7.5-10g.  In this patient with sickle cell disease who is likely very tolerant to opiates, taking many Percocet may not produce the constellation of opiate toxicity symptoms we may expect to see, yet underlying acetaminophen toxicity can develop.

The above image highlights the pathophysiology of acetaminophen toxicity.  In brief, the metabolism of the drug forms toxic NAPQI, which is then converted via a process with glutathione.  As acetaminophen levels grow and glutathione is depleted, NAPQI builds up and causes hepatic damage.  The clinical course of acetaminophen toxicity generally is divided into four phases. Physical findings vary, depending primarily on the level of hepatotoxicity. Phase 1 occurs up to 24 hours after ingestion and patients may be asymptomatic or show fatigue or mild N/V. Phase 2 occurs up to 72 hours after ingestion and may show RUQ pain (although it is not always present), N/V, tachycardia, hypotension, and dehydration. Phase 3 is the hepatic phase that occurs about 72 hours after ingestion where hepatic necrosis and coagulopathy are present and death from multiorgan failure can occur.  It a patient survives phase 3, they enter into a recovery phase, Phase 4 where the organ damage reverses.

Normally acetaminophen overdoses are treated in a fairly algorithmic way, with the Rumack-Matthew nomogram being a cornerstone in therapeutic guidance.  If the acetaminophen value plots above the lines, it is an indication to start N-acetylcysteine therapy.  NAC works essentially by restoring glutathione :

However, we must keep in mind that this chart was developed for single acute ingestions of acetaminophen, not for possible multiple dose ingestions over a period of days.  Furthermore, the reliability of the nomogram decreases with acetaminophen coingestions of opiates.  This patient does not have a necessarily clear-cut single toxic ingestion.  Therefore, it may be better to draw an acetaminophen level and then empirically start NAC therapy.  Being in NYC, you can always call the NYC Poison Center at 1-800-212-POISONS for any guidance, but starting NAC can help prevent serious hepatic damage and/or failure if this is in fact a case of acetaminophen toxicity. Delaying therapy for other workup may prove hazardous.

In summary, accidental overdoses can be easily missed especially when the patient has other potential causes for nonspecific symptoms and general lab findings.  We must always keep our patient’s medication lists in mind especially when managing new-onset hepatic damage.  Tylenol is one of the most easily accessible hepatotoxic medications and getting a thorough history about dosing is imperative as acetaminophen toxicity is a potentially reversible and treatable entity.