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Aluminum Toxicity
Introduction
Aluminum (Al) is widely used in everyday life and is the most abundant metal in the earth's crust, occurring in various forms.[1] Although aluminum has no known biological role in humans, it is present in concentrations similar to essential metals, such as copper. Human exposure to aluminum has increased since the rise of industrialization due to exposure from cosmetic and antiperspirant products, food packaging (such as beverage cans), food additives, drinking water, medications (such as phosphate binders), total parenteral nutrition (TPN), vaccines, pesticides, aerosols, and dialysate.[2][3][4][5]
Aluminum toxicity is a significant concern for patients with renal insufficiency, who cannot efficiently clear the metal, and those with heavy industrial exposure. While aluminum toxicity primarily affects the nervous system and bones, it can impact nearly every organ system.[6] Aluminum's neurotoxicity was demonstrated by high levels found in the brains of encephalopathic dialysis patients, resulting from accumulation in contaminated dialysate.[1]
Etiology
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Etiology
Due to the ubiquity of aluminum, sources of aluminum exposure are numerous. Aluminum exposure in the air can occur naturally through dust from soil and rocks or from man-made sources, including particulate matter from vehicle emissions, cigarette smoke, coal combustion, metal refineries, and other industrial activities. Aluminum naturally occurs in water, often dissolving from rocks, and its concentrations can be seasonal, with higher levels typically observed in the spring.[7]
The most significant exposures of aluminum that lead to toxicity are iatrogenic, stemming from aluminum-containing phosphate binders (such as aluminum hydroxide), buffered aspirin, and aluminum-contaminated dialysate.[8] Aluminum toxicity was once prevalent among dialysis patients, giving rise to the term "dialysis dementia" to describe encephalopathy caused by aluminum exposure, with contaminated dialysate being the primary source.[8]
Aluminum is commonly present in foods or introduced during food processing, with widely varying quantities. Aluminum can also leach from cookware, especially when cooking acidic foods. Daily aluminum intake from food is estimated to range from 3.4 to 9 mg—a level that may increase with the presence of lactate, citrate, maltol, or fluoride.[1]
Epidemiology
Although the incidence of aluminum toxicity is unknown, cases have significantly decreased since the regulation of aluminum levels in dialysate, which are now recommended to be below 10 μg/L according to the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) guidelines.[9]
Pathophysiology
Aluminum exerts its toxic effects on the body through various mechanisms, including disrupting or inhibiting enzymatic activity, altering protein synthesis and nucleic acid function, and modifying cell membrane permeability. This also inhibits DNA repair, degrades the stability of DNA organization, and inhibits protein phosphatase 2A activity. Furthermore, aluminum catalyzes the production of reactive oxygen species (ROS), leading to cellular damage through oxidative stress, decreases antioxidant activity, disrupts cellular iron homeostasis, and affects nuclear factor kappa-B (NF-kB), p53, and JNK pathways, ultimately resulting in apoptosis.[10]
Acute Versus Chronic Exposure
Acute aluminum toxicity is rare due to the low levels of exposure encountered in everyday life; most current scientific literature focuses on chronic exposures. In developing countries, aluminum toxicity is most commonly caused by exposure to dialysate, medication contamination, and TPN. Additionally, intravesical irrigation with aluminum for treating hemorrhagic cystitis has also been reported as a source of aluminum toxicity.[11][12] Although acute aluminum toxicity is sparsely documented in the literature, it may present with symptoms such as nausea, mouth ulcers, skin ulcers, skin rashes, vomiting, diarrhea, and arthritic pain.[13]
Bone
Bones act as a long-term reservoir for various metals, including aluminum.[14] Accumulation of aluminum in bones can lead to osteoporosis by decreasing osteoblast-mediated bone formation and altering osteoclast function, resulting in increased bone fragility and a higher risk of fractures.[12][15][16] Plasma aluminum levels are strongly associated with aluminum bone disease. However, patients with plasma aluminum levels below 40 μg/L are considered to be at low risk for aluminum bone disease.[16] Aluminum causes bone demineralization through various mechanisms, including calcium replacement, decreased levels of insulin-like growth factor-1 (IGF-1) and type 1 collagen, inhibition of the Wnt/β-catenin pathway, apoptosis of osteoblasts, and reduced differentiation of osteoblasts.[14]
Cardiovascular
Elevated levels of aluminum are associated with a higher incidence of cardiovascular diseases, including hypertension, coronary artery disease, and dyslipidemia.[17] Significant exposure can lead to an inverted QRS complex on electrocardiogram (ECG), indicating significant cardiotoxicity.[17] The mechanism behind cardiovascular toxicity is believed to involve oxidative stress, apoptosis, and an inflammatory response resulting from aluminum accumulation.[17] Other severe complications may include toxic myocarditis, myocardial wall hypokinesia, and left ventricular thrombus.[1]
Central Nervous System
The central nervous system is the primary target of aluminum toxicity. This toxicity is well-studied and occurs through several mechanisms, including neuronal oxidative stress, apoptosis, neuroinflammation, neurotransmitter disruption, and cytoskeletal dysregulation.[17] Aluminum affects numerous proteins and biomolecules, resulting in lipid peroxidation, inhibition of mitochondrial membrane potential, reduced ATP levels, neurotransmitter dysfunction, decreased DNA and RNA strand formation, and inhibition of DNA repair. Aluminum also inhibits protein phosphatase 2A, leading to hyperphosphorylation of tau and neurofilament proteins, increases the biosynthesis of transferrin receptors, prevents ferritin production, and raises free iron levels, which further contribute to oxidative stress.
Corticoneuronal apoptosis occurs via the SAPK/JNK pathway, NF-kB activation, increased p53 and BAX expression, and reduced expression of neurofilaments, tubulins, transferrin receptors, amyloid precursor proteins, and neuron-specific enolase. In addition, aluminum toxicity can alter the expression of RNA polymerase I and beta-amyloid precursor protein secretase, resulting in amyloid beta accumulation and hyperphosphorylation of tau proteins in the brain.[8][10]
Gastrointestinal
Aluminum ingestion and toxicity can impact the intestinal microbiome, intestinal permeability, immune responses, and inflammatory reactions. Additionally, it can lead to epithelial degeneration, goblet cell proliferation, and lymphocyte infiltration in the intestines.[1][18]
Hematopoiesis
Aluminum toxicity may inhibit or reduce hemoglobin synthesis, leading to anemia with anisocytosis and poikilocytosis. This can result in the formation of leptocytes, acanthocytes, echinocytes, stomatocytes, and target cells.[10]
Pulmonary
Pulmonary tissue damage occurs due to an increased influx of polymorphonuclear neutrophils, interstitial inflammation, type II cell hyperplasia, and reduced alveolar lavageable macrophages. These changes can lead to various respiratory conditions, including asthma, chronic bronchitis, chronic pneumonia, pulmonary alveolitis, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, alveolar proteinosis, pneumoconiosis, pulmonary granulomatosis, and potroom asthma.
Potroom asthma is characterized by a decrease in peak expiratory flow rates due to aluminum exposure, resulting in mild-to-moderate bronchial hyperresponsiveness that is reversible upon removal from aluminum fumes. Symptoms include wheezing, shortness of breath, dyspnea, cough, and phlegm production. This condition has historically been observed among workers in aluminum plants, particularly those involved in the electrolysis process, where aluminum fumes are generated.[1][10][19]
Renal
Aluminum is primarily cleared by the kidneys, increasing the risk of aluminum poisoning in patients with chronic kidney disease. The toxic effects of aluminum can reduce glomerular filtration, leading to elevated serum uric acid levels. Additionally, aluminum exposure may result in nephrotic syndrome and acute renal glomerulonephritis. Aluminum's toxic effects on renal parenchyma stem from increased oxidative stress, leading to lipid peroxidation, DNA oxidative damage, and protein oxidation. This results in reduced activity of glutathione, glutathione peroxidase, glutathione S-transferase, and catalase.
Additionally, aluminum disrupts renal tubular transport of p-amino hippuric acid, phosphate reabsorption, and sodium or water balance. This can also affect sodium-potassium ATPase activity, while elevated intracellular free iron exacerbates oxidative stress.[10]
Reproductive
Reproductive health may be compromised by aluminum exposure. Studies show that patients with oligozoospermia exhibit significantly higher aluminum concentrations in their semen, indicating a potential link between aluminum toxicity and fertility issues.[20] Aluminum exposure in rats over 60 days was associated with decreased sperm count, reduced daily sperm production, impaired sperm motility, lower production of normally shaped sperm, and altered testicular histology.[21]
Histopathology
Intracellular aluminum is stored in the lysosomes of brain neurons, in most liver cells (excluding Kupffer cells), myocytes of the heart, mesenchymal glomerular cells of the kidneys, and within the mitochondria of osteoblasts.[10]
Histopathology of cardiac tissue demonstrates that aluminum toxicity significantly alters the structure of cardiac tissues by inducing cardiac fibrosis, resulting in necrotic foci around blood vessels and disarrangement of cardiomyocyte nuclei.[17] Additionally, aluminum exposure has been shown to upregulate C-reactive protein (CRP) expression in human brain microvessel endothelial cells, contributing to the inflammatory response. Aluminum exposure also significantly increases blood-brain barrier permeability by altering F-actin expression and downregulating occludin expression.[17]
Analysis of pulmonary tissue in rats exposed to aluminum in drinking water revealed infiltration of neutrophils and mononuclear cells in the alveoli.[1] Pulmonary lesions are more common in individuals exposed to aerosolized particles. Additionally, pulmonary vascular congestion in inter-alveolar spaces has been reported following gavage administration in mice.[1]
Toxicokinetics
Absorption
Aluminum exposure can occur IV through dialysate or TPN and through the gastrointestinal tract, where it is absorbed by the mucosa of the small intestines. Aluminum enters the bloodstream through 2 mechanisms—passive diffusion and active transport through transferrin-mediated mechanisms. Aluminum exposure through the respiratory tract (inhalation) and subsequent absorption of aluminum fumes occurs at approximately 1.5% to 2%. Aluminum found in inhaled dust can potentially stay in lung tissue indefinitely.[22]
Oral absorption of aluminum from food is estimated at 2 to 5 mg/d, with gastrointestinal (or fractional) absorption varying between 0.04% and 1.0%, depending on the chemical form ingested. Intestinal absorption of aluminum is speculated to occur through both paracellular pathways along enterocytes and tight junctions via passive transport, as well as transcellular pathways through enterocytes via both passive and active processes. Factors reported that can alter aluminum absorption include calcium levels, iron status, parathyroid hormone, vitamin D levels, and the degree of uremia.[22]
No significant evidence suggests that aluminum applied to the skin can enter the bloodstream. If any aluminum does enter the body through dermal absorption from cosmetics or antiperspirants, the quantity is insufficient to cause significant accumulation.[23]
Distribution
Approximately 90% of plasma aluminum binds to transferrin, which accommodates two aluminum ions—one at the C-lobe and the other at the N-lobe. Aluminum competes with iron for transferrin binding, and iron levels affect how much aluminum transferrin carries. When iron-transferrin saturation is high, more serum aluminum will be deposited in bone and brain tissues. The remaining aluminum binds to low molecular weight compounds. Aluminum is widely distributed throughout the body, with about 60% stored in bones, 25% in the lungs, 10% in muscles, 3% in the liver, and 1% in the brain.[10][22]
Elimination
The majority of aluminum (approximately 99%) is cleared through the kidneys, making individuals with renal insufficiency particularly vulnerable to aluminum accumulation and toxicity. A small portion is excreted in the bile. Healthy adults with normal renal function can tolerate daily aluminum intakes of 3500 to 7200 mg without experiencing adverse effects.[22]
History and Physical
A thorough history and physical examination are essential for diagnosing aluminum toxicity. Identifying individuals at increased risk is crucial, including those taking aluminum-containing medications, patients with end-stage renal disease on dialysis, individuals with chronic kidney disease, neonates receiving TPN, aluminum factory workers, and patients undergoing irrigation for hemorrhagic cystitis. Asking about patients' hobbies and their professions can help identify potential risks in healthy young individuals who may not otherwise appear to have an increased risk of aluminum toxicity.
Findings from the physical examination are broad and primarily affect the nervous, skeletal, and pulmonary systems, as mentioned below.
- Musculoskeletal examination may reveal bony tenderness from fractures due to osteoporosis.
- Cardiovascular damage may lead to pitting edema due to worsening ischemic heart failure.
- Gastrointestinal manifestations are nonspecific and include abdominal pain, nausea, vomiting, and diarrhea.
- Reproductive system manifestations may include infertility.
- Pulmonary examination findings may include wheezing, cough, dyspnea, and respiratory distress, particularly in aluminum factory workers with potroom asthma. Additionally, cases of pulmonary edema have been reported.
Generalized symptoms include fatigue or somnolence, confusion, and dizziness.
Neurological complications may include tremors, stuttering dysarthria, diminished coordination, motor weakness, ataxia, myoclonus, agitation, confusion, and a distinctive wave and spike pattern on EEG. Severe cases may lead to grand mal seizures, obtundation, coma, and even death. Additionally, aluminum toxicity can induce Parkinson-like symptoms, such as slowness of movement, gait disturbances, cogwheel rigidity, tremors, and stiffness.[24][25]
Evaluation
In patients suspected of aluminum toxicity, aluminum levels can be measured in blood, bone, urine, and feces. A variety of methods are available for detecting aluminum in these biological specimens, including accelerator mass spectroscopy, graphite furnace atomic absorption spectrometry, flame atomic absorption spectrometry, electro-thermal atomic absorption spectrometry, neutron activation analysis, inductively coupled plasma atomic emission spectrometry, inductively coupled plasma mass spectrometry, inductively coupled plasma optical emission spectroscopy, and laser microprobe mass spectrometry. Care must be taken to ensure that none of the containers used to store samples contain aluminum additives.[1]
Laboratory abnormalities may include elevated creatinine and blood urea nitrogen (BUN) levels in patients with intact renal function due to aluminum-induced renal damage, decreased sperm count on semen analysis, and anemia on complete blood count.
Chest x-rays may reveal unspecific changes and evidence of pulmonary fibrosis in patients with chronic aluminum exposure.[26]
Other test abnormalities may include decreased forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) in patients with pulmonary manifestations, reduced bone density on plain radiographs, and changes on ECGs.
Treatment / Management
Aluminum chelation with deferoxamine serves as the primary treatment for both acute and chronic aluminum toxicity. Although deferoxamine is the standard treatment for iron toxicity, its use extends to aluminum toxicity due to the similarities between iron and aluminum. This chelator effectively reduces total body aluminum levels and mitigates bone and brain injury. Given its poor gastrointestinal absorption, deferoxamine is administered via intramuscular, subcutaneous, or intravenous (IV) routes. Once in the plasma, it binds aluminum to form aluminoxane, which is renally cleared. In patients with end-stage renal disease or chronic kidney disease, aluminoxane can be dialyzed using a high-flux dialyzer membrane.
Although deferoxamine is effective, it is not entirely benign and can cause allergic reactions, including itching, abdominal pain, diarrhea, and tachycardia. Acute adverse reactions may include gastrointestinal complaints, skin discoloration and irritation, and anaphylaxis. Chronic deferoxamine therapy may lead to sensorineural hearing loss and retinopathy, both of which are reversible with early discontinuation of treatment. Please see StatPearls' companion resource, "Deferoxamine," for more information. Additionally, case reports suggest that intraperitoneal administration of deferoxamine may be more effective than IV administration, although this is not considered standard therapy.[27]
Additional chelators include CaNa2EDTA, malic acid, meso-2,3-dimercaptosuccinic acid (succimer or dimercaptosuccinic acid [DMSA]), ascorbate (vitamin C), Feralex-G (FG), and N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA)—a molecule similar to ethylenediaminetetraacetic acid (EDTA). However, data demonstrating their effectiveness in treating aluminum toxicity do not exist. Non-chelator treatments, such as propolis, serve as antioxidants and anti-lipid peroxidation agents that may help prevent oxidative stress. Studies have shown that propolis can improve damaged cellular membranes and organ function when used alongside chelators, particularly HEDTA, in mice.[28]
Differential Diagnosis
The differential diagnosis for aluminum toxicity includes conditions that cause altered mental status or dementia. Infectious causes may involve sepsis, urosepsis, pneumonia, bacteremia, meningitis, or brain abscess. Metabolic causes include hepatic encephalopathy, hypertensive encephalopathy, uremia, prion disease, hypoxic encephalopathy, or other toxic encephalopathies.
Neurodegenerative disorders that can mimic aluminum toxicity or dialysis dementia include Alzheimer disease, Lewy body dementia, vascular dementia, frontotemporal dementia, and Wernicke encephalopathy.
Prognosis
The prognosis of aluminum toxicity varies based on several factors, including the duration and level of exposure, individual susceptibility, and promptness of medical intervention. Acute aluminum poisoning, if treated promptly with chelation therapy such as deferoxamine, often results in favorable outcomes. However, severe or untreated cases can lead to significant neurological impairment or death.
In chronic aluminum toxicity, the prognosis depends on early recognition and intervention. Reducing ongoing exposure and addressing symptoms such as neurological deficits and bone disease can improve long-term outcomes. Patients with renal impairment may require continuous monitoring and treatment to prevent further aluminum accumulation.
Complications
Complications of aluminum toxicity are extensive, affecting nearly every organ system. Neurological and musculoskeletal complications are common and include osteoporosis, bone fractures, dementia, seizures, tremors, dysarthria, impaired coordination, motor weakness, ataxia, myoclonus, agitation, and confusion. Cardiovascular complications involve an increased risk of hypertension, coronary artery disease, and dyslipidemia.
Additional complications may include exacerbation of inflammatory bowel disease, anemia, pneumoconiosis, potroom asthma, COPD, pulmonary alveolitis, chronic pneumonia, pulmonary fibrosis, pulmonary granulomatosis, reduced glomerular filtration rate, and decreased fertility.
Deterrence and Patient Education
Individuals with end-stage renal disease or chronic renal insufficiency, as well as workers in industries exposed to aluminum, are at a greater risk for aluminum poisoning compared to the general population and should take special precautions. Patients should be educated about the signs and symptoms of aluminum toxicity and advised to avoid excessive exposure. Individuals with impaired renal function should avoid aluminum-containing products, including phosphate binders, antacids, aluminum-coated aspirin, certain hemorrhoidal treatments, and some antidiarrheal medications.
Pearls and Other Issues
Key facts to keep in mind regarding aluminum toxicity include:
- Patients at high risk for aluminum toxicity include those with end-stage renal disease on dialysis, neonates receiving TPN, and industrial workers exposed to aluminum.
- A common cause of aluminum toxicity is the use of aluminum-containing phosphate binders by dialysis patients.
- Anemia and reduced bone density, often seen in dialysis patients, can complicate the distinction between aluminum toxicity and renal disease.
- Aluminum toxicity can be challenging to diagnose due to its broad differential diagnosis associated with its presenting symptoms, which may include encephalopathy, osteoporosis/osteomalacia, and anemia.
- Symptomatic patients with aluminum toxicity may require inpatient treatment with deferoxamine and careful monitoring.
- Prevention strategies focus on patient education about sources of aluminum exposure and eliminating those sources where possible.
Enhancing Healthcare Team Outcomes
The incidence of aluminum toxicity has declined due to improved identification of at-risk patients, sources of aluminum exposure, and preventive measures, such as reducing aluminum levels in dialysate. Managing aluminum toxicity requires a multidisciplinary team of healthcare professionals, including laboratory technicians, nursing staff, and physicians. Treatment may involve various specialists, such as medical toxicologists or regional poison centers, nephrologists, neurologists, orthopedic surgeons, pulmonologists, gastroenterologists, hematologists, cardiologists, and emergency medicine physicians.
Patients at risk for aluminum toxicity include those with renal dysfunction and neonates with immature renal systems. Current treatment recommendations emphasize avoiding aluminum-containing drugs and products, along with chelation therapy using deferoxamine. A strategic approach is equally crucial, involving evidence-based strategies to optimize treatment plans and minimize adverse effects. Ethical considerations must guide decision-making, ensuring informed consent and respecting patient autonomy in treatment choices. Each healthcare professional must be aware of their responsibilities and contribute their unique expertise to the patient's care plan, fostering a multidisciplinary approach.
Effective interprofessional communication is crucial for seamless information exchange and collaborative decision-making among healthcare team members. Care coordination is vital in managing the patient's journey from diagnosis to treatment and follow-up, minimizing errors and enhancing patient safety. By embracing principles of skill, strategy, ethics, responsibilities, interprofessional communication, and care coordination, healthcare professionals can deliver patient-centered care, ultimately improving patient outcomes and enhancing team performance in managing aluminum toxicity.
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