Poison And The Pancreas

"Away! Thou'rt poison to my blood." ~ William Shakespeare

Anna is a 62 year old woman who for many years has had a bad relationship with alcohol. She also had a bad and stormy relationship with her husband. One night, after spending a few hours drinking alone, she confronted her husband with one of her many grievances. This ended, as it often did, with her husband screaming at her, throwing a bottle of beer her way and walking out. Anna had enough and would show her husband what trouble really looked like.

She went out into the garage, found a bottle of Malathion, drank about 2 nips worth (about 100 mL) and went to sleep. Her daughter found her about 1 hour later, couldn't wake her and called an ambulance.

On arrival to the Emergency Room, her Glasgow Coma Scale score was 11 (eye, 3; verbal, 2; motor, 6). Both pupils were 2?mm, and pupillary light reflexes were absent. Physical examination revealed a body temperature of 33.8°C, tachypnea with a respiratory rate of 22 breaths/min, tachycardia with a heart rate of 102 beats/min, and normal hemodynamic parameters with a blood pressure of 128/62?mmHg. She had hyperhidrosis, cold extremities, fecal incontinence, and vomitus around the mouth. On auscultation, coarse crackles in the lung fields were detected. There were no murmurs. Bowel sounds were hyperactive.

The white blood cell count was 16.2?×?103/ul. The serum amylase level was high, at 596?IU/l. Serum lipase, trypsin, phospholipase A2 (PLA2), and elastase-1 were 435?IU/l, 900?IU/l, 910?ng/ml, and 1,128?ng/ml, respectively. Cholinesterase was 25?IU/l. Acute pancreatitis due to organophosphate poisoning was diagnosed based on these results. CT scan confirmed severe pancreatic edema and a moderate peri-pancreatic fluid collection.

Drug-induced pancreatitis is quite uncommon, with some estimates suggesting an incidence of 1:10000. A long list of drugs and poisons has been implicated in the development of pancreatic injury but all follow three predictable pathways of damage.

Malathion is a organophosphate pesticide that is widely used in agriculture, residential landscaping, public recreation areas, and public health pest control programs such as mosquito eradication. Malathion itself has low toxicity; however, absorption or ingestion in humans readily results in its metabolism to malaoxon, which is 61 times more toxic.

Organophosphate poisoning is a very common problem worldwide due to the sheer number of compounds that have been developed. One estimate is that 50000 compounds have been tested with 37 registered for use in the United States. Thankfully, in the US, the vast majority have been restricted to non-residential use. Pesticide self-poisoning affected 371,594 individuals globally, accounting for about one-third of all suicides occurring worldwide. ?A 2020 study estimated 740,000 unintentional pesticide poisonings, resulting in 7446 deaths across 141 countries. OP compounds also have a dark military and terrorist history as nerve gas agents, having been used against Iranians by Iraqi troops and in the 1994-95 Japan subway attacks.

Organophosphate poisoning was identified in sporadic case reports to cause acute pancreatitis in 6-29% of patients, with an additional 22-66% noted to have elevated amylase levels but no obvious evidence of pancreatitis on CT scan. Acute pancreatitis was reported to be mild to severe and necrotizing, generally resolving in about 5 days.

Organophosphates (OP) work by blocking the function of cholinesterase, resulting in overexposure of the body to the neurotransmitter acetylcholine. How this caused pancreatitis was, for a long time, unknown. However there were clues and we covered a big clue in a previous newsletter that discussed scorpions. As it turns out, scorpion venom, especially from the scorpion family Buthidae, contains a neurotoxin (tityustoxin) that acts the same way as OP pesticides and it too causes pancreatitis.

After treating a 19 year old woman with suspected severe acute pancreatitis from OP poisoning, Dressel's group at the University of Minnesota studied 18 dogs to see if they could reproduce pancreatitis after OP poisoning. Six dogs had operative cannulation of the pancreatic duct so that pancreatic duct pressures could be measured in real-time. The remaining dogs were treated non-operatively.

All dogs received an IV injection of 25-75 mg/kg of the anticholinesterase 0,0-diethyl-0-(2-isopropyl-6-methyl-4-pyrimidinyl) phosphorothioate. The results were startling.

Not only did pancreatic intraductal pressure spike after administration of the OP, but so did pancreatic flow rate. This translated to spikes of hyperamylasemia and clinical pancreatitis.

It appeared that the OP resulted in severe overstimulation of pancreatic function, resulting in acute pancreatitis. Or did it? Another dog study by Dressel's group a few months later helped clarify things further. They found that the administration of the OP resulted not only in overstimulation of the pancreas, but also obstruction of the sphincter of Oddi. All of this could be blocked by the administration of atropine.

This fit in very nicely with the model described by Bartholomew in 1977 and further characterized by Novaes in 1982.

The experimental data support the view that OP poisoning results in functional pancreatic duct obstruction while at the same time over-stimulating the pancreas. This results in uncontrolled release of pancreatic enzymes and interstitial acute pancreatitis.

OP poisoning results in myriad issues, of which pancreatitis is certainly not the most life threatening initially. These include hypersalivation, abdominal pain, nausea, vomiting, diarrhea, muscle fasciculations, bradycardia, and hypotension. In severe case, seizures, respiratory failure, shock, and death may result. A common mnemonic that can be helpful to remember the toxic effects is DUMBELS:

• D = Defecation/diaphoresis
• U = Urination
• M = Miosis
• B = Bronchospasm
• E = Emesis
• L = Lacrimation
• S = Salivation

In one of the larger studies to date, Zobeiri reported on 332 consecutive patients with OP poisoning in Iran. He found that mean serum amylase correlated with ICU admission and mortality, with levels > 60% of normal having the worst outcomes.

Care is improved by the rapid and continuous administration of atropine (which blocks the effects of acetylcholine), followed by the antidote 2-PAM (pralidoxime). 2-PAM binds with the OP and breaks it off cholinesterase, reverting the enzyme back to normal function. Other general supportive care measures are also administered including respiratory support. Mortality remains as high as 25%. If a patient survives, permanent issues can also develop, including neuropsychiatric deficits such as confusion, memory impairment, lethargy, psychosis, irritability, and Parkinson-like symptoms. This is likely due to the fact that OP can accumulate in fatty tissue. This has been implicated in Gulf War Syndrome that affected veterans returning from the Gulf War as well as the Iraq and Afghanistan theaters. During these wars, organophosphate insecticide as well as nerve gas antidote exposure was very common among soldiers.

What about chronic poisoning?

Chronic poisoning is a more recently described entity, especially in workers producing or using the chemicals. It often results in diabetes mellitus through three putative mechanisms. The main pathway to injury is due to the fact that acetylcholine promotes the viability of beta cells. Insulin resistance is also mediated by lipolysis, oxidative stress and chronic inflammation.

At least four published studies between 2008-2020 have confirmed the development of diabetes in this population, from the USA, Egypt and two from India.

Conclusion

Since being first synthesized by the French in 1854 and then streamlined by Gerhard Schrader in Germany in 1936, OP compounds have been produced by the thousands as effective pesticides. Their dark military history as nerve gas notwithstanding, they are in use as major chemicals for pest control due to decades of experience on their use, high effectiveness on many pests, availability of generic products at low cost, and excellent overall environmental profile.

Although the pancreas is not a major target of their action, pancreatitis and diabetes play a large role in their acute and chronic morbidity.

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