Aluminum Toxicity

Toxic effects of aluminum depend on the amount of metal ingested, entry rate, tissue distribution, concentration achieved, and excretion rate.[8, 9, 10, 11] Fatty acids common in food may facilitate the paracellular intestinal absorption of aluminum.[12]

Mechanisms of aluminum toxicity include inhibition of enzyme activity and protein synthesis, alterations in nucleic acid function, and changes in cell membrane permeability.

Aluminum toxicity is usually found in patients with impaired kidney function. Acute intoxication is extremely rare; however, in persons in whom aluminum clearance is impaired, it can be a significant source of pathology. Aluminum toxicity was originally described in the mid-to-late 1970s in a series of patients in Newcastle, England, through an associated osteomalacic dialysis osteodystrophy that appeared to reverse itself upon changing of the dialysate water to deionized water (ie, aluminum-depleted water).[13]

Previously, the only known dialysis-associated bone disease was osteitis fibrosa cystica, which was the result of abnormalities in vitamin D production that resulted in a secondary hyperparathyroidism, increased bone turnover, and subsequent peritrabecular fibrosis. In aluminum-related bone disease, the predominant features are defective mineralization and osteomalacia that result from excessive deposits at the site of osteoid mineralization, where calcium would normally be placed.

Since the role of aluminum in disease has been identified, more attention has been paid to the element, leading to its recognition in several other processes. For example, among patients with osteomalacia, there has been a closely associated dialysis encephalopathy, thought to be caused by aluminum deposition in the brain. Aluminum brain concentrations should be lower than 2 μg/g.[14] A 10-fold increase in aluminum concentrations was reported in patients with aluminum intoxication through the use of hemodialysis solutions with high levels of aluminum.[15]

Aluminum causes oxidative stress within brain tissue.[16] Since the elimination half-life of aluminum from the human brain is 7 years, this can result in cumulative damage via the element's interference with neurofilament axonal transport and neurofilament assembly.

A possible etiologic link between aluminum exposure and Alzheimer disease emerged from a 1965 study showing that aluminum causes neurofibrillary tangles in the brains of rabbits. Subsequent research has largely failed to support this hypothesis, however. For example, the clinical manifestations and underlying neuropathology of aluminum-induced encephalopathy in dialysis patients bear no resemblance to those of Alzheimer disease.[17]

Blaylock et al suggest that the heterogeneous symptoms of autism spectrum disorders have a connection with dysregulation of glutamatergic neurotransmission in the brain, along with enhancement of excitatory receptor function by proinflammatory immune cytokines, as the underlying pathophysiological process. These authors suggest that aluminum and other environmental and dietary excitotoxins (eg, mercury, fluoride) can exacerbate the pathological and clinical problems by worsening excitotoxicity and by microglial priming.[18]

This possibility opens the discussion to the use of nutritional factors that reduce excitotoxicity and brain inflammation as a maneuver to alleviate neurotoxic effects of aluminum.[19, 20] The central nervous system appears to be extremely sensitive to metal-induced oxidative stress. High aluminum concentrations have been found in postmortem brain specimens of patients with Parkinson disease and in animal models where administration of aluminum caused a strong decrease in dopamine content of the striatum.[21]

Aluminum also has a direct effect on hematopoiesis.[22] Excess aluminum has been shown to induce microcytic anemia. Daily injections of aluminum into rabbits produced severe anemia within 2-3 weeks. The findings were very similar to those found in patients suffering from lead poisoning.

Aluminum may cause anemia through decreased heme synthesis, decreased globulin synthesis, and increased hemolysis. Aluminum may also have a direct effect on iron metabolism: it influences absorption of iron via the intestine, it hinders iron's transport in the serum, and it displaces iron's binding to transferrin. Patients with anemia from aluminum toxicity often have increased reticulocyte counts, decreased mean corpuscular volume, and mean corpuscular hemoglobin.

Other organic manifestations of aluminum intoxication have been proposed, such as a slightly poorer immunologic response to infection, but the mechanism by which it exerts its effect is complex and multifactorial. It has also been linked to vaccine-associated macrophagic myofasciitis and chronic fatigue syndrome, thus highlighting the potential dangers associated with aluminum-containing adjuvants as described recently.[23]

Aluminum toxicity is usually found in patients with impaired kidney function. Acute intoxication is extremely rare; however, in persons in whom aluminum clearance is impaired, it can be a source of significant toxicity.

Intravesical irrigation with aluminum is used as a treatment for hemorrhagic cystitis, a life-threatening complication of bone marrow transplantation, chemotherapy, and radiotherapy. Bogris et al reported a case of aluminum toxicity in a pediatric patient with leukemia who received this treatment.[24]

A number of vaccines contain aluminum salts as adjuvants. As a result, fully vaccinated children are exposed to up to 4 mg of aluminum in the first 2 years of life.[25]  Mitkus et al reported that in an infant's first year of life, the body burden of aluminum from vaccines and diet is significantly less than the corresponding safe body burden of aluminum modeled using the regulatory minimal risk levels.[26]  However, adjuvant aluminum in vaccines has been reported to cause local inflammatory reactions (eg, erythema, subcutaneous nodules, contact hypersensitivity).[27, 28]

Inbar et al posited that data on vaccine-related aluminum toxicity may have been limited by the use of aluminum adjuvants as placebos in most human vaccine trials, and suggested (on the basis of their study showing behavioral changes in mice) that aluminum adjuvants may trigger neuroinflammation and autoimmune reactions.[29] The study, however, was later withdrawn from the journal where it was originally published, in view of “severely flawed” methodological issues and unjustified claims.[30]

Brown et al determined the potential for aluminum toxicity caused by parenteral nutrition in patients (n=36; age 50.4±20.4 y, weight 90.2±32.8 kg) who have risk factors of both acute kidney injury and parenteral nutrition support.[6] Aluminum exposure was determined for each patient by multiplying the volume of each parenteral nutrition component by its concentration of aluminum. The initial serum urea nitrogen and serum creatinine levels were 47±23 and 3.3 ± 1.4 mg/dL, respectively. Twelve patients received supportive dialysis. The mean aluminum exposure was 3.8±2 μg/kg/day in the 36 patients; the majority of patients, 29 out of 36, had safe calculated aluminum exposure (< 5 μg/kg/d), and 7 had high calculated aluminum exposure (> 5 μg/kg/d). Patients with high aluminum exposure received more aluminum from calcium gluconate compared with those who had safe aluminum exposure (357±182 vs 250±56 μg/d).

Brown et al concluded that, using their calculations, most patients with acute kidney injury who require parenteral nutrition do not receive excessive exposure to aluminum from the parenteral nutrition formulation. The limitation of the study was its retrospective design, which resulted in calculated versus direct measurement of aluminum.

In an analysis of 30 samples of parenteral nutrition infant formulations, Hall and colleagues found aluminum contamination of almost 3 times higher than the advised maximum exposure of < 5 mcg/kg/d recommended by the US Food and Drug Administration (FDA). The mean (SD) aluminum contamination of infant PN was 14.02 (6.51) mcg/kg/d. Only 3 samples contained < 5 mcg/kg/d.[31]

Some evidence suggests that, in developing countries where contaminated dialysis water is still used, aluminum-related disease is more prevalent. In addition, aluminum-containing phosphate binders remain available over the counter, and regular use of these products will result in aluminum deposition in bone, which will serve as a reservoir because of its long elimination half-life.

The American Association of Poison Control Centers’ National Poison Data System reported 782 single exposures to aluminum in 2021, with 7 moderate outcomes and 1 major outcome but no deaths.[32] However, the overall incidence of aluminum toxicity is unknown. The greatest incidence is observed in patients with any degree of kidney insufficiency. A higher incidence is observed in populations who have aluminum-contaminated dialysate or who are taking daily oral phosphate-binding agents. Patients who require long-term total parenteral nutrition are at increased risk as well.

Aluminum toxicity has no predilection for any race, and has no predilection for either sex. Aluminum toxicity is observed in all age groups, but its end-organ effects are more prevalent in elderly persons, who may have diminished kidney function.

Depending upon the degree of dementia and overall medical frailty of the patient, most improve with deferoxamine therapy. Some patients, however, succumb to their underlying disease processes before any noticeable improvement in mental status or anemia occurs. Whether aluminum toxicity itself is fatal is unknown. Typically, patients' underlying diseases and medical frailty lead to early morbidity and mortality.

The mortality rate may be as high as 100% in patients in whom the condition goes unrecognized. Currently, however, recognition by nephrologists is the norm, and increased awareness by all practitioners has led to earlier detection and overall avoidance of the syndrome. Morbidity and mortality have been diminished significantly. In the past, bone pain, multiple fractures, proximal myopathy, and the sequelae of dementia have been the main sources of morbidity.

Animal studies in rats and case reports have implicated the use of oral aluminum-containing antacids during pregnancy as a possible cause for abnormal fetal neurologic development.[33, 34]

Advances in nanotechnology have led to the exposure of humans to engineered aluminum nanomaterials (NMs) that could potentially induce genomic changes (using a rat model, Balasubramanyam et al[35]  found that Al2 O3 NMs were able to induce size- and dose-dependent genotoxicity in vivo[35]

Educate pregnant and breastfeeding females, and any patient with compromised kidney function, about the potential dangers associated with the use and overuse of aluminum-containing antacids. A safe alternative includes calcium carbonate, such as found in Tums.

Educate patients to refrain from driving or operating hazardous machinery if they develop dizziness or impaired vision or hearing during treatment.

The signs and symptoms of aluminum toxicity are usually nonspecific. Typical presentations in chronic toxicity may include proximal muscle weakness, bone pain, multiple nonhealing fractures, acute or subacute alteration in mental status, and premature osteoporosis. These patients almost always have some degree of kidney disease; most of them have end-stage kidney disease and are on hemodialysis or peritoneal dialysis.

In the past, aluminum toxicity, including osteomalacia, was seen in patients on long-term hemodialysis, due to exposure to dialysate containing high concentrations of aluminum. However, aluminum toxicity is not a concern with modern dialysis protocols, which use water purified with reverse osmosis.

Some of the clinical symptoms of the disease entity reflect the chief complaint. An emergency physician will rarely consider aluminum toxicity as a possible diagnosis in a patient on dialysis who presents with an acute mental status change; however, these patients constitute the specific group most closely associated with the syndrome.

When obtaining the history, ask specifically about the use of oral aluminum hydroxide antacids, particularly if the patient has diminished kidney function but does not undergo dialysis.

A history of long-term total parenteral nutrition (TPN) is also a risk factor. This especially true in infants, as elevated aluminum levels have been found in infant TPN formula.[31]

Unfortunately, physical findings are often noticeably lacking in patients with aluminum toxicity, and findings usually mimic other disease processes.

Patients can present with multiple fractures (particularly of the ribs and pelvis), proximal muscle weakness, mutism, seizures, and dementia.

Some studies have shown a direct correlation between aluminum levels and intensity of uremic pruritus.[36]

In children, bony deformity is more commonly due to the increased rate of growth and remodeling. The areas of deformity in children usually involve the epiphyseal plates (ie, femur, wrist).Children may also demonstrate varying degrees of growth retardation. In adults, thoracic cage abnormalities, lumbar scoliosis, and kyphosis can be present.

In general, the concentration of aluminum in the blood will be less than 10 mcg/L, or less than 60 mcg/L in patients undergoing dialysis.[37] Toxicity is usually present at concentrations higher than 100 mcg/L.[38] Urinary aluminum concentrations less than 55 mcg/g creatinine are safe. Urinary thresholds for aluminum neurotoxicity have variously been reported as 100 mcg/L and 108 to 162 mcg/L.[39]

Generally, findings from an aluminum level blood test are unreliable, as most of the body's stores are bound in bone and tissue and are not reflected in the serum value. A deferoxamine infusion test can be performed but may take more than 48 hours to yield a result (see Medical Care). Deferoxamine liberates aluminum from tissues by chelating it and leads to an increased serum level compared with one taken prior to infusion. The combination of a baseline immunoreactive parathyroid hormone level of less than 200 mEq/mL and a change in serum aluminum value of 200 ng/mL after deferoxamine is 90% specific and has a positive predictive value of 85% for aluminum toxicity.

Aluminum excess has a direct effect on hematopoiesis and has been shown to induce anemia.[22] Findings on peripheral smears in patients with aluminum toxicity include microcytic anemia (hypochromic, normochromic), anisocytosis, poikilocytosis, chromophilic cells, and basophilic stippling. Note that these are the same findings observed in patients with lead poisoning. Aluminum can also be found in bone marrow macrophages.

In radiographs, Looser zones (ie, lines of radiolucency parallel to the plane of growth in long bones) may be observed in severe cases, although they are more common with other causes of adult osteomalacia. Pathological fractures may also be observed. Bone scintigraphy shows a characteristic pattern in aluminum toxicity.

Bone biopsy from the iliac crest is frequently performed to determine the etiology of bone disease in patients on dialysis because renal osteodystrophy can be multifactorial (eg, osteomalacia, uremic bone disease, hyperparathyroidism, aluminum deposition). Histochemical staining for aluminum and determination of osteoid volume, bone turnover rate, and osteoblast/clast cell count are some of the methods used for subtyping the bone disease.

Histologic findings in aluminum-related osteomalacia reflect the decrease in mineralization of newly formed bone matrix. An increase in the surface covered by osteoid occurs, as does an increase in the osteoid seams. Osteoid volume and thickness also increase. In histologic sections stained with eosin, the areas of greater mineralization tend to appear violet or blue, whereas the osteoid seams appear pink. 

The most important part of emergency medical treatment is the recognition of possible aluminum toxicity based on risks (eg, kidney insufficiency, aluminum exposure) and clinical manifestations (eg, altered mental status, anemia, osteoporosis).

Treatment of aluminum toxicity includes elimination of aluminum exposure (eg, from diet, total parenteral nutrition, dialysate, medications, antiperspirants) and an attempt to eliminate the element from the body's stores through chelation. Avoidance of aluminum is easily achieved in most cases, once the need to do so is recognized.

A serum aluminum level greater than 50-60 µg/L suggests aluminum overload, may correlate with toxicity, and can be used as an indication to start chelation therapy in symptomatic patients. Chelation may also be considered in patients with clinical manifestations of chronic aluminum toxicity (eg, osteomalacia, anemia, hypercalcemia, dialysis dementia) who have serum aluminum levels greater than 20 mcg/L.[40] Chelation therapy should be initiated in consultation with a nephrologist and a medical toxicologist, and can be performed upon hospital admission.

Chelation for aluminum toxicity involves off-label use of agents approved for chelation of other heavy metals. Reports describe effective use of the following, with improvement in symptoms that correlated with a reduction of aluminum levels:

• Deferoxamine, which is approved for iron chelation
• Edetate calcium disodium (calcium disodium ethylenediaminetetraacetic acid, EDTA), which is approved for lead chelation
• Succimer (meso-2,3-dimercaptosuccinic acid, DMSA), which is approved for lead chelation in pediatric patients, and has an orphan designation for treatment of mercury intoxication in adults

Deferoxamine is the agent that has been most widely used for aluminum chelation. It can be administered subcutaneously, intramuscularly, or intravenously; for chronic iron overload, subcutaneous infusion is generally preferred. Deferoxamine binds with aluminum in plasma to form aluminoxane, which is excreted by the kidneys; in patients with chronic kidney disease or end-stage kidney disease who are on renal repacement therapy, hemodialysis using a high-flux membrane can remove the aluminoxane.[40] However, since deferoxamine can draw aluminum from tissues into the plasma, it should not be used in patients with a measured serum aluminum concentration > 200 mcg/L, as it may lead to severely high levels of aluminum and life-threatening neurotoxicity.[40]

Kan et al suggested that a low dose of deferoxamine (2.5 mg/kg/wk) is as effective as standard dose (5 mg/kg/wk) for the treatment of aluminum overload.[41]

EDTA is administered in an intravenous infusion of 2 g/10 mL diluted in 500 mL of normal saline, infused over 2 hours, once a week for 10 weeks.[42] In a study by Fulgenzi et al, EDTA chelation was continued after the initial 10 weeks and given once every two weeks for six or 12 months.[43]

Succimer is administered orally. Ordog reported a positive clinical response to treatment with succimer, 900 mg twice daily for 19 days, in seven aluminum factory workers.[44]

Because the  it is reasonable to suggest that the ensuing cell dysfunction is due in part to their high content of polyphosphorylated nucleic acids, nucleotides, and nucleoproteins, Kruck et al investigated . Therefore, chelation therapies dealing with the

An in vitro study by Kruck et al using intact human brain cell nuclei suggested that combination therapy, through a mechanism termed molecular shuttle chelation, may enhance the removal of aluminum from the nuclear matrix and help alleviate central nervous system dysfunction from aluminum accumulation. In this mechanism, small chelating molecules such as ascorbate may penetrate the nucleus, bind aluminum, then diffuse to cell regions accessible to larger chelating molecules (eg, deferoxamine), where the small chelating molecules transfer the aluminum to the larger molecules.[45]

If chelation therapy and hemodialysis/peritoneal dialysis cannot be provided, transfer the patient to an institution with a higher level of care.

Usually, a nephrologist is already a part of the patient's medical team. If not, one should be consulted early in the course. A hematologist and a neurologist may be able to assist with the patient's care.

Since dietary aluminum is ubiquitous, no specific dietary guidelines are available for its avoidance. Special diets should be maintained for specific associated disease entities (eg, diabetes mellitus, chronic kidney disease).

Activity modification may not be necessary unless the patient is at risk for frequent falls. If this is the case, a home attendant or family member should assist the patient with daily living activities.

Avoid all aluminum-containing antacids, antiperspirants, dialysate, immunizations, and total parenteral nutrition (TPN) solutions.

Many dialysis units routinely measure aluminum levels in their patients, because excessive aluminum in dialysate has historically been a cause of toxicity. However, modern reverse osmosis water should be aluminum free. A single-center retrospective Australian study found that although aluminum levels in feed water were sometimes as high as 48 μmol/L, after reverse osmosis, aluminum was almost always undetectable (< 0.1 μmol/L).[46]

The study also included 2058 plasma aluminum tests performed between 2010 and 2013 in 755 patients (61.9% male, mean age of 64.7 years), and found that the mean level was 0.41 ± 0.30 μmol/L. Aluminum levels were > 0.74 μmol/L in 111 tests from 61 patients, 45 of whom (73.8%) had been prescribed aluminum hydroxide as a phosphate binder. The authors concluded that routine testing of plasma aluminum in dialysis patients appears unnecessary and selective testing should be considered.[46]

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Deferoxamine can be used for chelation therapy.

Class Summary

These agents bind free metal and do not chelate other trace metals of nutritional importance. Metals are excreted in the urine and bile.

Deferoxamine (Desferal mesylate)

Metal-free ligand of the iron chelate isolated from the bacterium S pilosus. Used for acute and chronic iron toxicity as well as aluminum toxicity and has a high affinity for ferric iron. Does not affect iron in cytochromes or hemoglobin. PO/IM administration not established. Several case reports and cohorts using varying doses indicate effectiveness when administered IV.