Author:  David Rusev, PA-C, Emergency Medicine PA Resident
Faculty:  Alexis Cates, DO, Medical Toxicology/Emergency Medicine Attending

Case #1:

There is a 27-year old male with no significant past medical history who has presented to the emergency department with a complaint of abdominal pain. The pain is localized to the right upper quadrant, is non-radiating, and has been constant since the onset. The patient denies any trauma, alcohol use, acetaminophen ingestion, drugs of abuse or recent viral illness. He does report associated fevers, chills, and nausea, but denies vomiting or changes in bowel habits.

Vital signs are within normal limits and physical exam was largely unremarkable except for mild tenderness to palpation of the abdomen diffusely.

Initial labs were remarkable for AST 345 U/L, ALT 404 U/L, ALP 115 U/L, and total bilirubin of 1.3 mg/dL. His synthetic liver function tests and coagulation studies were normal. A urine drug screen was positive for opiates and tetrahydrocannabinol. Infectious workup, autoimmune panel, and salicylate and acetaminophen concentrations were not diagnostic. Imaging studies, including a right upper quadrant ultrasound (US) and magnetic resonance cholangiopancreatography (MRCP), were not diagnostic.

You question what could have led to this young man’s presumed hepatotoxicity?  One thing that crosses your mind is a drug-induced liver injury.  You actually found that the patient had purchased capsules on the internet.

Learning point 1: An ancient substance

Historically, the plant containing kratom, the culprit in this case, has been widely used in Thailand, Malaysia, and Myanmar for hundreds of years. Kratom has varying names depending on the region of harvest, and is alternatively known as ketum, biak–biak, ithang, or thom. The raw leaves can be chewed, dried and ground into a powder, or smoked. The most common form of use is boiling the leaves in water to produce a strong tea. In the United States, kratom is processed into powder, capsules, and extracts. Kratom was traditionally used to treat a variety of ailments but gained popularity in the 1940s for the treatment of opioid withdrawal.

Kratom is not a specific compound, but rather a concoction of more than 40 psychoactive alkaloids that are naturally occurring. To date, only four of the compounds are known to be active. The four compounds are: mitragynine, 7-hydroxymitragynine (7-OH- mitragynine), speciociliatine, and corynantheidine. The mitragynine is the most prevalent and makes up for 66% of the total alkaloid content. Its highly active oxidized metabolite 7-OH-mitragynine is present in far lower quantities. Kratom has an opiate-like and stimulant effect depending on the dosage (stimulant effect at lower doses and opiate-like effect with higher doses). Mitragynine and 7-OH-mitragynine target opioid receptors.  Mitragynine has less affinity for opioid receptors than that of morphine. However, 7-OH-mitragynine is approximately 46 times more potent that mitragynine and 13 times that of morphine. Mitragynine acts primarily on µ- and δ-receptors and 7-OH-mitragynine is more selective for µ- and κ-receptors. 

Case #1 continued…

Upon further evaluation, the patient admits to treating his osteoarthritis with kratom for two weeks.

The patient was admitted to the hospital and treated for presumed drug-induced liver injury from kratom use. Throughout the course of his stay, his liver enzymes trended downward towards normal, his symptoms resolved, and he was ultimately safely discharged home.

Case #2:

This is a 28-year-old male with a past medical history of alcohol and opioid use disorders.  He also had a documented history of possible seizures though the circumstances surrounding this are unclear.  He was brought into the emergency department via emergency medical services after being found unresponsive at home. No recent surgical history, no history of allergies, and the patient was not found to be on anti-epileptic medications. Home medications included pantoprazole.

The patient was intubated in the field after he received 4 mg of intranasal naloxone but it did not elicit  a response. A noncontrast computed tomography (CT) scan of the head was unremarkable for any acute intracranial pathology. Vital signs revealed a temperature of 90.8 degrees Fahrenheit, blood pressure of 147/89 mmHg, a pulse of 114 beats per minute, respiratory rate 21 breaths per minute, and pulse oximetry 95% on 50% FiO2 on the ventilator. On physical examination, the patient had intermittent myoclonic jerking, pupils were equally round, and reactive to light, normal S1, S2, regular rate and rhythm, lungs were clear to auscultation bilaterally, abdomen was soft, nondistended and extremities had no edema but left lower extremity had a linear rash anteriorly.

Labs were remarkable for creatinine of 3.57, AST 1932 U/L, ALT 2748 U/L, creatinine kinase of 3860 units, potassium of 5.9 mEq/L..  An emergent dialysis catheter was placed and hemodialysis was initiated for the management of hyperkalemia and severe acute tubular necrosis with resultant renal failure secondary to severe rhabdomyolysis.

After discussion with the patient’s roommate, the discovery of this substance was made.

Learning point 2: Kratom in the United States

In the first case, the patient was diagnosed with drug induced liver injury secondary to excessive kratom ingestion. In the United States, poison control centers have experienced a rise in the number of cases associated with exposure to kratom. A recent literature review exploring cases of drug-induced liver injury found that eight out of 404 cases were associated with kratom ingestion. The review determined that on average patients used kratom for up to 22 days before the onset of injury. Symptoms reported consisted of jaundice, itching, abdominal pain, and fever.

In the United States, kratom is perceived as a safe recreational drug, and is identified as a safe and “legal high.” The drug enforcement administration (DEA) proposed to categorize kratom as a schedule I drug. The proposal did not gain the traction the DEA had hoped and was not a popular subject of debate amongst policy makers. Today, kratom remains unrecognized as a controlled substance by the DEA and is not subject to the United States Controlled Substances Act. Kratom is currently listed as a chemical drug of interest. As of 2019, six state legislatures (Alabama, Arkansas, Indiana, Wisconsin, Rhode Island, and Vermont) have criminalized the possession of kratom. Kratom can still be purchased via numerous online stores and is permitted throughout Europe.

Case #2 continued…

The patient’s renal function never returned to baseline and his creatinine was 9.60 upon discharge. The team placed a permanent hemodialysis catheter and the patient was discharged to a rehabilitation program in stable condition.

Learning Point 3: Why is kratom important to the Emergency Medicine team?

The above cases are representative of two probable exposures to kratom and resultant organ damage. Exposure to kratom is increasing as more people seek its use to ease acute or chronic pain or opioid withdrawal symptoms thinking that it is safe. Easy access to kratom without any regulatory bodies created a false and popular misconception that it is safe and legal.  These patients will present to the emergency department with a wide array of symptoms and deny any drug use yet may present similarly to an opioid overdose or even far sicker – where they are already starting to show signs of end-organ dysfunction such as oliguria or jaundice. The healthcare community should start considering exposure to kratom as a possible etiology for drug-induced liver injury and otherwise unexplained liver or renal failure, and push for further research and investigation of kratom. 

References:

Patel P, Aknouk M, Keating S, et al. Cheating Death: A Rare Case Presentation of Kratom Toxicity. Cureus. 2021;13(7):e16582. Published 2021 Jul 23. doi:10.7759/cureus.16582

Eastlack SC, Cornett EM, Kaye AD. Kratom-Pharmacology, Clinical Implications, and Outlook: A Comprehensive Review. Pain Ther. 2020;9(1):55-69. doi:10.1007/s40122-020-00151-x

Botejue M, Walia G, Shahin O, Sharma J, Zackria R. Kratom-Induced Liver Injury: A Case Series and Clinical Implications. Cureus. 2021;13(4):e14679. Published 2021 Apr 25. doi:10.7759/cureus.14679

Eggleston W, Stoppacher R, Suen K, Marraffa JM, Nelson LS. Kratom Use and Toxicities in the United States. Pharmacotherapy. 2019 Jul;39(7):775-777. doi: 10.1002/phar.2280. Epub 2019 Jun 13. PMID: 31099038.

White CM. Pharmacologic and clinical assessment of kratom: An update. Am J Health Syst Pharm. 2019 Nov 13;76(23):1915-1925. doi: 10.1093/ajhp/zxz221. PMID: 31626272.

Singh D, Yeou Chear NJ, Narayanan S, Leon F, Sharma A, McCurdy CR, Avery BA, Balasingam V. Patterns and reasons for kratom (Mitragyna speciosa) use among current and former opioid poly-drug users. J Ethnopharmacol. 2020 Mar 1;249:112462. doi: 10.1016/j.jep.2019.112462. Epub 2019 Dec 7. PMID: 31816368.