Environmental and chemical toxicities: Pathology review
Case Study0:00–1:17
Kristen is a 47 year old female who showed up at the ER due to vomiting and diarrhea. Kristen works as a farmer, and tells you that her symptoms started right after she sprayed her crops with insecticides using her bare hands.
On clinical examination, her pupils appear constricted. And a few minutes later, Kristen has a seizure.
Next comes Federico, a 9 year old boy who is brought to the ER by his parents after accidentally consuming a bottle of insecticide.
His parents mention that he complained of stomach ache, and had repeated episodes of vomiting and diarrhea. Upon clinical examination, you first notice that Federico's breath has a characteristic garlic-like odor.
They seem confused, but they mention that their symptoms started more or less at the same time, while they were both relaxing next to the fireplace.
Upon clinical examination, you realize that their skin looks cherry red, so you decide to run a blood test, which reveals high carboxyhemoglobin levels.Based on their history and presentation, all cases seem to have some form of environmental and chemical toxicity.
Pathology1:17–1:57
Toxicity refers to the extent of poisoning or damage to the body due to exposure to a toxic substance. For your exams, the most high yield toxic substances include acetylcholinesterase inhibitors; methanol and ethylene glycol; heavy metals, including arsenic, iron, lead, and mercury; cyanide and carbon monoxide; as well as methemoglobin, which is an endogenous substance that can become toxic at high levels.
Acetylcholinesterase Inhibitor Poisoning1:57–4:58
Let’s start with acetylcholinesterase inhibitor poisoning. Okay, normally, acetylcholinesterases are enzymes that break down the neurotransmitter acetylcholine, so that it can’t activate the cholinergic receptors in the peripheral and central nervous system.
And there are two types of cholinergic receptors, called muscarinic and nicotinic receptors. Now, acetylcholinesterase inhibitors are substances that can irreversibly inhibit the acetylcholinesterases at the neuromuscular junction.
As a result, acetylcholine builds up in the neuromuscular junction, leading to overstimulation of its receptors. For your exams, the main acetylcholinesterase inhibitors are organophosphates, such as parathion.
These are found in certain insecticides, and can be absorbed through the skin, respiratory or gastrointestinal tract. In a test question, think of acetylcholinesterase inhibitors or organophosphate poisoning if they describe a farmer or an agricultural worker that had an accidental cutaneous exposure, inhalation, or ingestion of excessive amounts of insecticides.
Clinical manifestations of acetylcholinesterase inhibitor poisoning include muscarinic symptoms, which can be easily remembered using the mnemonic DUMBBELSS, that stands for diarrhea, urination, miosis, bronchospasm, bradycardia, emesis, lacrimation, sweating, and salivation.
Individuals can also present nicotinic symptoms, such as weakness, paralysis, and fasciculations, which are spontaneous involuntary muscle contractions.
Additionally, organophosphates can cross the blood brain barrier and cause CNS symptoms, such as lethargy, seizures, respiratory depression, and coma.
Now, treatment of acetylcholinesterase inhibitor poisoning is high yield and relies on giving atropine and pralidoxime. Atropine directly competes with acetylcholine for muscarinic receptors, thus reversing the muscarinic symptoms; and can also cross the blood brain barrier and relieve the CNS symptoms.
On the other hand, pralidoxime reactivates the acetylcholinesterases, so that they can break down acetylcholine in the neuromuscular junction.
As a result, remember that pralidoxime reverses both muscarinic and nicotinic symptoms. However, it can’t cross the blood brain barrier, so it has no effect on CNS symptoms.
Next up, there’s methanol, which is most commonly found in windshield washer fluid, and poisoning typically occurs via ingestion.
Methanol & Ethylene Glycol Poisoning4:58–9:00
Now, methanol is metabolized by the enzyme alcohol dehydrogenase in the liver into formaldehyde and formic acid, which are toxic and can cause serious damage to the eyes, leading to loss of visual acuity or even blindness.
So, on eye examination, there’s usually mydriasis or dilated pupils, as well as optic disc hyperemia or swelling. Methanol poisoning can also cause CNS depression, leading to confusion, stupor, and even coma.
Other common findings include bradycardia or low heart rate, bradypnea or slow breathing, hypotension or low blood pressure, and hyporeflexia or decreased reflexes.Now, it’s very important that you remember that a very similar presentation occurs with ethylene glycol ingestion, which is found in automobile antifreeze, engine coolants, and brake fluids.
Also ethylene glycol is metabolized by the enzyme alcohol dehydrogenase in the liver, but into glycolic acid, which is toxic to the renal tubules, and oxalic acid, which can precipitate with calcium, forming calcium oxalate crystals in the renal tubules.
As a result, a key difference with methanol is that ethylene glycol poisoning usually presents with symptoms of acute renal failure, such as flank pain and oliguria or decreased production of urine, which typically occur 24 to 72 hours after ingestion.
In terms of laboratory findings, remember that both methanol and ethylene glycol poisoning can present with metabolic acidosis, meaning that pH levels are below 7.35, bicarbonate is below 22 mEq/L, and pCO2 levels below 35 mm Hg.
And this is combined with a high anion gap, meaning that sodium minus chloride plus bicarbonate equals greater than 12 mEq/L.
In addition, since both methanol and ethylene glycol are osmotically active, there’s also a high osmolal gap, meaning greater than 10 mOsm/kg, which is calculated as the measured serum osmolality minus the calculated serum osmolality.
Now, for diagnosis, to set methanol and ethylene glycol apart, you need to check their blood levels. Another high yield difference is that, with ethylene glycol poisoning, urine microscopy may show the calcium oxalate crystals, which have a characteristic folded envelope shape; and on a renal biopsy, glomeruli will appear normal, whereas epithelial cells lining the renal tubules will show signs of damage, like ballooning and vacuolar degeneration.
Moving onto treatment, the antidote for both methanol and ethylene glycol intoxication is fomepizole, which blocks alcohol dehydrogenase.
If unavailable, ethanol can be used instead. In severe cases, hemodialysis can be done to quickly remove the toxic metabolites from blood.
Another high yield topic is poisoning by heavy metals, including arsenic, iron, lead, and mercury. Let’s start with arsenic, which is most commonly found in certain herbicides and insecticides, as well as contaminated water used for drinking, food preparation, and irrigation of food crops.
Arsenic Poisoning9:00–10:39
For your exams, remember that acute arsenic poisoning can occur if someone accidentally ingested it, and presents with gastrointestinal symptoms, such as abdominal pain, nausea, vomiting, and diarrhea.
In addition, a very characteristic finding that you must know is garlic-like breath odor. Now, arsenic can also affect the CNS, causing drowsiness, confusion, and even delirium.
Arsenic can also affect the heart, so another high yield manifestation is a prolonged QT interval on ECG, meaning that there’s a delay between heart beats.
On the other hand, chronic arsenic poisoning occurs due to continuous exposure to arsenic. In a clinical vignette, look for an individual who is a vineyard worker.
Now, chronic arsenic poisoning can increase the risk for certain tumors, such as lung cancer, liver angiosarcoma, and squamous cell carcinoma of the skin.
Another clue examiners love to give are Mees’s lines, which are white lines across the nails due to arsenic deposition over time.
The main treatment for poisoning by heavy metals like arsenic consists of chelating agents. The way these work is by trapping free metal ions and sweeping them away through feces or urine.
Iron Poisoning10:39–13:34
Now, acute iron poisoning can be caused by excessive consumption of iron supplement tablets. This mainly occurs due to incidental ingestion by children, who may think it’s candy.
Acute iron poisoning has a high mortality rate, and it’s clinical presentation is divided into five stages. In the first stage, there are gastrointestinal symptoms, such as nausea, diarrhea, and abdominal pain.
More severe cases may also present gastrointestinal bleeding, which may lead to hematemesis or vomiting of blood if it involves the upper gastrointestinal tract, or melena or black and tarry stools if it involves the lower gastrointestinal tract.
Ultimately, the bleeding might lead to hypovolemia and shock. In the second stage, the gastrointestinal symptoms resolve and the individual seems to be getting better.
But in the third stage, they might develop anion gap metabolic acidosis, which can ultimately result in stage four with multiorgan failure, especially involving the liver, and can be life-threatening.
Finally, those who survive may enter the fifth stage, which is characterized by scarring or fibrosis of the gastrointestinal tissue, which can result in bowel obstruction.
The main treatment for acute iron poisoning consists of chelating agents like deferoxamine or deferasirox, as well as gastric lavage to clean out the toxic substances of the stomach.
Now, chronic iron poisoning, also known as iron overload, refers to the accumulation of excess iron over time. The main causes are hereditary hemochromatosis, an autosomal recessive disease where the body absorbs too much iron from food; as well as multiple blood transfusions, mainly in individuals with hematological conditions, such as thalassemia or sickle cell disease.
The chronic accumulation of iron ultimately becomes toxic, most notably to the liver, causing cirrhosis; but also the pancreas, causing diabetes mellitus.
In addition, iron can build up in the heart muscle, leading to cardiomyopathy and arrhythmias. Importantly, accumulation of iron in the pituitary glands can affect the release of sex hormones, leading to hypogonadism; this can result in amenorrhea or absence of menstruation in females, and testicular atrophy in males.
And finally, if iron gets into the joints, it can cause arthropathy or degenerative joint disease. Treatment of chronic iron poisoning can involve chelation, but also phlebotomy, in which blood is withdrawn until the iron load is sufficiently decreased, and then it’s replaced with intravenous fluids.
Moving onto lead poisoning, remember that it usually affects children ingesting lead-containing paint chips, as well as adults who inhale lead while working in mines, or those who are frequently in contact with batteries or bullets.
Lead Poisoning13:34–15:28
What’s important for you to know is that lead inhibits two enzymes involved in heme synthesis. The first enzyme is aminolevulenic acid or ALA dehydratase, which produces porphobilinogen, a precursor of protoporphyrin; and the second enzyme is ferrochelatase, which joins protoporphyrin and iron to form heme.
As a result, the free protoporphyrin builds up inside red blood cells, and there’s a decrease in heme synthesis. For your exams, remember that heme is a fundamental component of hemoglobin, so lead poisoning ultimately leads to anemia.
Another thing to keep in mind is that lead also inhibits the degradation of ribosomal RNA, which in turn forms tiny aggregates inside the red blood cells.
On a peripheral blood smear, these aggregates stain blue, so they are basophilic, and we call this basophilic stippling.All right, some high yield symptoms of lead poisoning include abdominal pain and constipation, as well as headaches and memory loss.
Lead can also accumulate and form ‘lead lines’ on the metaphysis of long bones, which can be seen on x-rays. Another telltale sign are Burton lines, which are blue ‘lead lines’ that can appear at the gingiva.
Finally, some individuals may present with wrist and foot drop due to peripheral neuropathy. The main treatment for lead poisoning consists of chelating agents like succimer for children and dimercaprol or EDTA for adults.Okay, the last heavy metal you should remember is mercury.
Now, mercury poisoning usually occurs from eating seafood, especially shark, tuna, swordfish, tilefish, and king mackerel.
And since mercury is neurotoxic, poisoning usually presents with a variety of symptoms, including anxiety, irritability, and depression, as well as memory deficits, numbness, and tremors.
Mercury Poisoning15:28–16:09
Keep in mind that mercury is also considered teratogenic, so it must be avoided in pregnancy. And again, the main treatment for mercury poisoning consists of chelating agents like succimer for children and dimercaprol for adults.All right, now let’s switch gears and talk about cyanide and carbon monoxide poisoning.
Both cyanide and carbon monoxide bind to and inhibit various enzymes that contain iron in them. The most important enzyme to know for your exams is cytochrome c oxidase, which is the terminal complex or complex IV of the electron transport chain, that’s necessary for oxidative phosphorylation and aerobic metabolism.
Cyanide & Carbon Monoxide Poisoning16:09–17:14
As a result, cyanide and carbon monoxide poisoning can prevent mitochondria from using oxygen to make ATP, leading to what’s known as histotoxic hypoxia.
And what’s characteristic about it is that, since cells are unable to use oxygen, it cannot be treated with supplemental oxygen.
And that’s a high yield fact! To make up for this, anaerobic metabolism ramps up, causing lactic acid to build up, and can rapidly lead to coma and death.
For your exams, remember that a characteristic finding of both conditions is the pink or cherry red skin. Okay, let’s focus on cyanide poisoning first, which most often occurs when inhaling smoke from burning synthetic products that contain compounds like polyurethane.
It can also occur from the ingestion of amygdalin, which can be found in apricot seeds. And another important cause of cyanide poisoning is taking higher than recommended doses of nitroprusside, which is a medication that’s broken down into nitric oxide and cyanide, and can be used to treat hypertensive emergencies.
Cyanide Poisoning17:14–19:23
All right, now cyanide poisoning classically presents with headache, vertigo, and tachycardia. Sometimes, there’s also nausea, vomiting, confusion, and muscle weakness, while in more severe cases, it can even lead to coma and cardiac arrest.
In a test question, a characteristic finding you should look for is the bitter almond breath odor. For diagnosis, laboratory tests show severe lactic acidosis with a decreased arteriovenous oxygen difference, which is the difference between the arterial and the venous oxygen content.
This means that the venous blood is more oxygenated than normal because cells are unable to take up and use oxygen. However, what’s important to remember is that the oxygen-hemoglobin dissociation curve, which shows the relationship between hemoglobin saturation with oxygen and the partial pressure of oxygen in blood, characteristically remains normal.
Treatment of cyanide poisoning is very high yield and includes medications containing nitrites, such as amyl nitrite, along with sodium thiosulfate.
These induce the production of methemoglobin, an oxidized form of hemoglobin that can bind to cyanide, forming cyanmethemoglobin, which is non-toxic.
Another treatment option that you have to remember is hydroxocobalamin, which binds to cyanide to form cyanocobalamin. Okay, now let’s focus on carbon monoxide poisoning, which occurs from inhalation when there’s too much carbon monoxide or CO in the air.
In a test question, you should pay close attention to the individual’s history; some classical scenarios can involve an individual that’s been around a fire and has inhaled smoke; or been in a poorly ventilated area with a running vehicle, fireplace, stove; or maybe they live in an old building with a defective heating system.
Carbon Monoxide Poisoning19:23–21:59
Another clue for the diagnosis is that multiple individuals that were in the same place can be involved, and will thus manifest symptoms at the same time.
Now, once CO is inhaled, it makes its way into the bloodstream and binds competitively to hemoglobin, meaning it displaces oxygen to form carboxyhemoglobin.
As a result, oxygen will attempt to compete with CO to bind hemoglobin, which leads to impaired oxygen unloading and delivery to tissues.
And that’s why CO leads to a left shift of the oxygen-hemoglobin dissociation curve. Now, an important thing to notice is that CO poisoning decreases the oxygen saturation of hemoglobin, meaning the amount of oxygen that’s bound to hemoglobin, but it does not affect the partial pressure of oxygen in blood, or PO2.
So as this graph shows, in normal conditions, the oxygen-hemoglobin dissociation curve has a sigmoidal shape, while as CO increases, the curve flattens out, indicating that even if there’s a high PO2, the oxygen is unable to bind to hemoglobin.
When CO exposure is suspected, high flow of 100% oxygen should be administered as soon as possible. Then, to confirm diagnosis, a blood test should be ordered to measure the carboxyhemoglobin levels.
In addition, if an MRI of the brain is done, a characteristic finding is bilateral globus pallidus lesions. Keep in mind though that these lesions can also rarely occur in cyanide poisoning.Finally, there’s methemoglobinemia, which refers to elevated levels of methemoglobin in blood.
Methemoglobin is an oxidized form of hemoglobin that forms when the iron molecules in some of the heme groups are converted from the ferrous state or Fe2+ into the ferric state or Fe3+.
As a result, the oxidized heme groups have a decreased ability to bind oxygen. To compensate for this, the remaining normal heme groups end up binding to oxygen more tightly, which prevents them from releasing oxygen to the tissues, and can ultimately cause tissue hypoxia.
Methemoglobinemia21:59–24:32
Now, keep in mind that normally a small amount of methemoglobin can be produced spontaneously, but there are enzymes, such as cytochrome b5 reductase, that reduce methemoglobin to convert it back to hemoglobin.
On the other hand, methemoglobinemia can be congenital, when there’s a deficiency of cytochrome b5 reductase, or acquired, which is more common.
Some high yield causes of acquired methemoglobinemia include oxidant substances, such as local anesthetics like benzocaine, some antibiotics like dapsone, and nitrites from dietary consumption of vegetables or processed meats, as well as polluted water.
Symptoms of methemoglobinemia depend on the amount of methemoglobin produced. Most often, it manifests as cyanosis or bluish skin and oral mucosa, as well as dyspnea or shortness of breath, confusion, and drowsiness.
More severe cases can present seizures, coma, and even death. For diagnosis, remember that a fresh blood sample will show a characteristic chocolate-brown color.
And confirmation can be done by measuring the elevated methemoglobin levels in blood. Now, acquired methemoglobinemia can be a medical emergency, and the mainstay of treatment is supplemental oxygen, along with intravenous methylene blue, which reduces methemoglobin back to hemoglobin.
On the other hand, congenital methemoglobinemia can be treated with daily oral methylene blue or vitamin C to help reduce methemoglobin.All right, as a quick recap… Acetylcholinesterase inhibitor poisoning is usually due to organophosphates used as insecticides by farmers and agricultural workers, and can lead to nicotinic, muscarinic, and CNS symptoms.
Treatment includes atropine to reverse the muscarinic and CNS effects, and pralidoxime to relieve the muscarinic and nicotinic effects.
Methanol poisoning can cause serious damage to the eyes, while poisoning with ethylene glycol can cause acute renal failure and calcium oxalate crystals.
Both methanol and ethylene glycol poisoning can present with CNS depression, high anion gap metabolic acidosis, and can be reversed with fomepizole.
Review24:32–27:39
Acute arsenic poisoning can cause gastrointestinal symptom s, and garlic breath odor, delirium, and prolonged QT interval; while chronic arsenic poisoning can cause tumors and Mees’s lines; treatment involves chelating agents.
Acute iron poisoning occurs after excessive consumption of iron supplements, and presents with gastrointestinal symptoms and bleeding, and in later stages, multiorgan failure and gastrointestinal scarring; treatment involves chelation and gastric lavage.
Chronic iron poisoning can be caused by hereditary hemochromatosis or multiple blood transfusions, leading to cirrhosis, diabetes mellitus, cardiomyopathy, hypogonadism, and arthropathy; treatment is with chelation or phlebotomy.
Lead poisoning most commonly occurs in children ingesting paint chips, and the most characteristic findings are basophilic stippling, anemia, Burton lines, and a wrist and foot drop; treatment is with chelation.
Mercury poisoning occurs from eating seafood, causes neurotoxicity, and is treated with chelating agents. Cyanide poisoning can be caused by inhalation of smoke from synthetic products, as well as ingestion of amygdalin or nitroprusside.
The individual has a characteristic bitter almond breath odor, and the oxygen-hemoglobin dissociation curve remains normal.
Treatment includes nitrites or hydroxocobalamin. Carbon monoxide poisoning occurs from smoke inhalation and classically presents with a dull headache, dizziness, and a left shift of the oxygen-hemoglobin dissociation curve.
For treatment, high flow 100% oxygen should be administered. Finally, methemoglobinemia can be caused by benzocaine, dapsone, or nitrites, and treatment involves supplemental oxygen along with methylene blue.
The key here is that Kristen has been spraying insecticides, which often contain organophosphates. And since she was using her bare hands, there was cutaneous exposure.
All this points to acetylcholinesterase inhibitor poisoning, so atropine was administered immediately. Next, Federico is a 9 year old boy who consumed a whole bottle of insecticide, which is an important clue that should make you think of acetylcholinesterase inhibitor or arsenic poisoning.
Federico complains of abdominal pain, vomiting, and diarrhea. The key clue here though is the garlic-like breath odor, which is characteristic for acute arsenic poisoning, and since Federico is a child, succimer was used as an antidote.
Summary27:39–29:00
This, combined with the fact that they have cherry red skin, most likely points to carbon monoxide poisoning. Diagnosis is confirmed with a blood test revealing high carboxyhemoglobin levels, and high flow of 100% oxygen was administered promptly.
complains of abdominal pain, vomiting and diarrhea. The key clue here though is a garlic like breath odor, which is characteristic for acute arsenic poisoning and since Frederico is a child succimer with you does an antidote.
This combined with the fact that they have cherry red skin, most likely points to carbon monoxide poisoning, diagnosis, is confirmed with a blood test, revealing high carboxyhemoglobin levels and high flow of 100% oxygen
- "Robbins Basic Pathology" Elsevier (2017)
- "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2)" McGraw-Hill Education / Medical (2018)
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