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Zinc Toxicity
Introduction
Zinc is a transition metal usually present in nature in its divalent state. It is considered an essential mineral as it is necessary to produce hundreds of enzymes throughout the body. Daily recommended zinc intake differs depending on the patient population, and the normal concentration of zinc in serum is 109 to 130 micrograms/deciliter. It acts as a cofactor in enzymatic reactions involved in DNA expression, membrane stabilization, vitamin A metabolism, and the gustatory and olfactory systems.[1] These functions also contribute to zinc’s importance during fetal growth and development. Additionally, a feature of zinc’s function in the body is its inverse relationship to copper levels, and it is frequently part of the pharmaceutical preparations used in the treatment of Wilson disease.[2] Chronic zinc toxicity manifests primarily as copper deficiency.[3][4][5][6] Exposure and toxicity are not uncommon because there are many sources of zinc throughout the environment. There are case reports of toxicity as a result of inhalation from occupational sources, overuse of dietary supplements, use of denture cream, ingestion of pennies secondary to PICA, and erroneously prepared total parenteral nutrition, to name a few. Some of these cases did have fatal outcomes.[7][8][9][10]
Etiology
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Etiology
The recommended daily adult zinc intake is 15 mg. Symptoms usually do not appear until ingestions exceed 1 to 2 g of zinc.[11] Toxic exposures have occurred through the gastrointestinal, dermal, respiratory, and parenteral routes. Inhalational toxicity can vary in severity depending on the specific compound involved and the duration of exposure. For example, smoke bombs containing zinc chloride can cause chest pain, airway irritation, and even an acute respiratory distress syndrome (ARDS)-like clinical picture with pulmonary fibrosis as long-term sequelae.[12] On the other hand, the inhalation of zinc oxide can lead to an entity known as "metal fume fever," which usually occurs secondary to occupational exposure.[7] In these cases, workers who suffer exposure to fumes through welding, alloy production, and metal soldering can present with flu-like symptoms in addition to cough and dyspnea, presumably due to zinc's direct effects on the pulmonary epithelium.[7] Toxic exposure to zinc can also occur via ingesting nutritional supplements, pennies manufactured after 1981, and zinc chloride solutions in concentrations greater than 20%. Additionally, the application of excessive amounts of denture cream can lead to zinc overdose and secondary copper deficiency.[13] Lastly, toxicity to zinc oxide can occur after exposures through the dermal route, particularly from overuse of makeup, sunscreen, and ointments.[14]
Epidemiology
The 2017 Annual Report of the American Association of Poison Control Centers National Poison Data System counts 1236 cases of exposure to zinc compounds. Most of the incidents were unintentional exposures in children less than 5 years of age (n = 535). There were no reports of deaths or major adverse health events.[15]
Pathophysiology
The pathophysiology of zinc toxicity relates to the route of exposure and the dose delivered. Additionally, toxicity from acute exposure differs significantly from chronic toxicity. Due to their direct caustic effects, acute toxic ingestions of zinc sulfate and concentrated zinc chloride primarily cause gastrointestinal (GI) symptoms, including hematemesis. Renal injury, ranging from asymptomatic hematuria to interstitial nephritis or acute tubular necrosis, has also been reported. ARDS, liver necrosis, thrombocytopenia, coagulopathy, and even death have been reported from acute exposures, though primarily due to iatrogenic parenteral administration of toxic doses.[11] Exposure to zinc-containing fumes causes irritation and potentially direct cellular damage to the respiratory canal, leading to the syndrome known as ”metal fume fever.” While the pathophysiology is not entirely understood, it is thought that the cellular injury caused by the zinc nanoparticles activates an inflammatory immune response, causing flu-like symptoms and local tissue damage.[7] With chronic GI exposures, bone marrow and neurologic effects can also manifest. Chronic zinc and resultant copper deficiency ingestion can lead to sideroblastic anemia, granulocytopenia, and myelodysplastic syndrome.[8][16] Additionally, an ascending, sensorimotor polyneuropathy syndrome has been seen with elevated levels of zinc and copper deficiency. The actual cause of this syndrome remains unknown thus far.[17][18]
Toxicokinetics
Oral zinc is primarily absorbed in the jejunum. A metallothionein protein complex in the villi of the enterocytes primarily facilitates absorption. Most zinc is then bound to the metallothionein, a primarily intracellular protein that regulates levels of many other metals, including copper. Plasma zinc is mostly bound to albumin, with a small fraction found free in the plasma. The body's response to excess zinc is to produce more metallothionein to decrease free zinc concentrations.[19] However, as copper is the metal with the highest affinity to metallothionein, this inadvertently leads to decreased copper levels instead. By this mechanism, a high level of zinc always lowers the level of copper in a dynamic antagonistic relationship.[20] The excretion of the metallothionein-zinc complex somewhat controls homeostasis via bile and feces. However, this mechanism is not fast enough after large overdoses.[21]
History and Physical
The clinical presentation of zinc toxicity from acute ingestion includes vomiting, hematemesis, nausea, muscle cramps, watery diarrhea, and diffuse abdominal pain, which has a broad differential with many possible causes. Thus, a very high level of suspicion is required to diagnose zinc toxicosis. Certain patient populations may be at higher risk, such as pediatric patients or patients with psychiatric illnesses who may ingest nutritional supplements in a large volume or a foreign body containing zinc.[22] When zinc toxicity is suspected, a full dietary, occupational, and life history is vital because it may reveal hidden sources of zinc exposure. Metal fume fever or "zinc shakes" from acute inhalation present with flu-like symptoms such as cough, fever, chills, headache, malaise, nausea, and muscle aches.[23] The patient may have symptom-free intervals over days when not working, and a detailed occupational history is necessary.[7] Chronic ingestion of zinc can manifest as a syndrome referred to as "swayback," leading to a slow progression of neuropathy and anemia with increasing fatigue, spasticity, gait abnormalities, and sensory ataxia. The symptoms of swayback syndrome are related to the superimposed deficiency of copper. Copper supplementation and normalizing intake of zinc reverse hematologic abnormalities within weeks, though neurologic deficiencies remain despite therapy.[18] Acute toxic ingestions of zinc sulfate and concentrated zinc chloride \ primarily cause GI effects, with abdominal pain, diarrhea, nausea, vomiting, and hematemesis due to caustic effects. There are also rare reports of renal injury.[11]
Evaluation
Early contact with a Poison Control Center or medical toxicologist is essential to guide the management of specific exposure. Obtaining zinc, copper, and ceruloplasmin levels is the first step when suspecting zinc poisoning from any source. Workup for acute toxicity caused by ingestion includes liver function tests such as aspartate aminotransferase (AST), alanine transaminase (ALT), prothrombin time (PT), international normalized ratio (INR), pancreatic lipase, complete blood count for platelet count, creatinine and BUN for renal function.[24] If ingestion of solid zinc is suspected, obtain an abdominal X-ray to see if any radio-opaque foreign bodies are present. A chest X-ray is an option when inhalation toxicity is suspected, though it is likely to be negative.[21] When chronic zinc toxicity is suspected, evaluation of zinc, copper, and ceruloplasmin levels is the initial approach, which bone marrow studies could follow.[16]
Treatment / Management
The primary treatment of acute toxicity secondary to oral ingestion is supportive. Antiemetics and fluids should be given, as well as proton pump inhibitors (PPIs) or H2-blockers.[22] In addition to helping with symptoms, PPIs and H2-blockers may help reduce gastric acid production, minimizing the digestion of zinc-containing foreign bodies (eg, pennies) and resulting in zinc release. If an abdominal X-ray confirms significant gut burden in the setting of toxicity, whole bowel irrigation (WBI) may be a consideration.[25] Indications for decontamination through WBI are similar to those for other potentially dangerous metals such as iron, potassium, or lithium.[26] Additionally, source control through surgical management may be an option in massive foreign body ingestions.[21] Chelation with calcium disodium edetate (CaNa2EDTA) or DTPA has also been shown to successfully decrease zinc levels in patients with toxicity.[22] The treatment for inhalation of metal fumes is supportive, focusing on antipyretics, oral hydration, and NSAIDs. Bronchodilators and supplemental oxygen may also be used as needed.[7] Finally, chronic zinc toxicity is primarily treated with copper sulfate, though severe cases may also require chelation. Of course, identifying and eliminating the exposure source is vital.[16](B2)
Differential Diagnosis
Most acute zinc ingestions present with gastrointestinal symptoms alone, making the diagnosis difficult when there is no reported history of exposure. Severe toxicity may also mimic many other pathologies and rarely present with acute kidney injury, pancreatic injury, liver failure, and hemodynamic instability. Septic shock, acute GI bleeding, and other toxic ingestions may present similarly, to name a few. The clinical challenge is considering zinc toxicity as a potential diagnosis among many more common causes. Inhalation injury from zinc compounds such as smoke bombs may lead to acute respiratory distress syndrome, which is seen in many other disease processes. Metal fume fever can present as an upper respiratory infection, though the clinician should suspect it in patients who are only symptomatic after occupational exposure. Chronic toxicity of zinc should be considered when iron-deficiency anemia does not respond to iron supplements. More common causes of anemia would be blood loss, an iron-deficient diet, and bone marrow abnormalities, among many others. Sideroblastic myelodysplastic syndrome, unresponsive to conventional therapy, may be caused by copper deficiency due to chronic zinc toxicity.
Prognosis
There is a very low probability of zinc toxicity being fatal; however, the prognosis largely depends on how quickly the patient receives treatment. Large intentional ingestions are most likely to cause significant toxicity.[27]
Complications
Complications of zinc toxicity include recurrent dyspnea or airway inflammation after inhalation exposure or GI effects with dehydration and potential GI bleeding after ingestion. Additional effects include lethargy, anemia, and dizziness.[27] Chronic exposures can lead to bone marrow effects and polyneuropathy due to concomitant copper deficiency. Zinc toxicity also impairs copper metabolism, causing anemia. Excess zinc intake for an extended period increases the risk of prostate cancer and prostate cancer-related mortality.[28]
Deterrence and Patient Education
It is best to take precautions and carefully read labels when taking zinc supplements or tablets readily available at most drug stores. A large overdose of zinc sulfate tablets requires medical attention.[29] Another common issue is overusing denture cream, which can lead to ingesting an excess amount of zinc and depleted copper levels.[30] Always carefully read instructions for any prescribed or over-the-counter supplement or medication. Always seek medical attention or contact a poison center if you suspect you may have taken too much of your medication or supplement. Some cosmetic creams contain considerable amounts of zinc and should be used with caution.
Enhancing Healthcare Team Outcomes
An interprofessional team approach is crucial to suspecting and correctly identifying zinc toxicity. An interprofessional team that manages a patient with zinc toxicity includes triage staff, nursing staff, ancillary staff, physicians, and pharmacists. It is also important to develop liaisons with a local poison control center. Zinc toxicity can cause morbidity and mortality, and improving the interprofessional team's understanding of how to evaluate and treat zinc toxicity promptly leads to better patient outcomes. Once zinc toxicity is identified, it is essential to define the route, initiate appropriate treatment, and consult a toxicologist or certified poison control specialist. Obtain zinc, copper, and ceruloplasmin levels, monitor for hemodynamic instability, consider WBI to decrease GI absorption in cases of ingestion, and determine the required level of care. Thorough patient education is important to avoid future overdoses or chronic toxicity. The evidence regarding zinc toxicity and management is primarily based on case reports of ingestions and inhalation exposures. A few epidemiologic studies have focused on long-term zinc exposure outcomes in occupational settings. There are no RCTs available. This research was supported (in whole or part) by HCA Healthcare or an HCA healthcare affiliated entity. The views expressed in this publication represent those of the author(s) and do not necessarily represent the official views of HCA Healthcare or any affiliated entities.
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