Introduction
Background
Aluminum is a trivalent cation found in its ionic form in most kinds of animal and plant tissues and in natural waters everywhere.1 It is the third most prevalent element and the most abundant metal in the earth's crust, approximately 8% of total mineral components.2 Dietary aluminum is ubiquitous but in such small quantities that it is not a significant source of concern in persons with normal elimination capacity. Urban water supplies may contain a greater concentration because water is usually treated with the element before becoming part of the supply. Subsequent purification processes that remove organic compounds take away many of the same compounds that bind the element in its free state, further increasing aluminum concentration.
All metals can cause disease through excess, deficiency, or imbalance.3 Malabsorption through diarrheal states can result in essential metal and trace element deficiencies. Toxic effects are dependent upon the amount of metal ingested, entry rate, tissue distribution, concentration achieved, and excretion rate. Mechanisms of toxicity include inhibition of enzyme activity and protein synthesis, alterations in nucleic acid function, and changes in cell membrane permeability.
No known physiologic need exists for aluminum; however, because of its atomic size and electric charge (0.051 nm and 3+, respectively), it is sometimes a competitive inhibitor of several essential elements of similar characteristics, such as magnesium (0.066 nm, 2+), calcium (0.099 nm, 2+), and iron (0.064 nm, 3+). At physiological pH, aluminum forms a barely soluble Al(OH) 3 that can be easily dissolved by minor changes in the acidity of the media.2
Approximately 95% of an aluminum load becomes bound to transferrin and albumin intravascularly and is then eliminated renally. In healthy subjects, only 0.3% of orally administered aluminum is absorbed via the GI tract and the kidneys effectively eliminate aluminum from the human body. It is only when the GI barrier is bypassed, such as IV infusion or there is advanced renal dysfunction, that aluminum has the potential to accumulate. As an example, with intravenously infused aluminum 40% is retained in adults and up to 75% is retained in neonates.4
Up to this time, no biological function has been attributed to this metal, and, more importantly, aluminum accumulation in tissues and organs result in their dysfunction and toxicity.2 Aluminum is absorbed from the GI tract in the form of oral phosphate-binding agents (aluminum hydroxide), parenterally via immunizations, via dialysate on patients on dialysis or total parenteral nutrition (TPN) contamination, via the urinary mucosa through bladder irrigation, and transdermally in antiperspirants. Lactate, citrate, and ascorbate all facilitate GI absorption. If a significant load exceeds the body's excretory capacity, the excess is deposited in various tissues, including bone, brain, liver, heart, spleen, and muscle. This accumulation causes morbidity and mortality through various mechanisms.
Pathophysiology
Aluminum toxicity is usually found in patients with impaired renal 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).
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, which is thought to be caused by aluminum deposition in the brain. Aluminum brain concentrations should be lower than 2 μ g/g.5 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.6
Aluminum causes an oxidative stress within brain tissue. 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. Some experts believe it plays a role in leading to the formation of Alzheimerlike neurofibrillary tangles.
Aluminum also has a direct effect on hematopoiesis. 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.
Frequency
United States
The actual incidence of toxicity is unknown. The greatest incidence is observed in patients with any degree of renal 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 TPN are at increased risk as well.
In a recent study, 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.4 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.
Animal studies in rats and recent case reports have implicated the use of oral aluminum-containing antacids during pregnancy as a possible cause for abnormal fetal neurologic development.7
International
Some evidence suggests that, in developing countries where contaminated dialysis water is still used, aluminum-related disease is more prevalent. Also, as people still use over-the-counter aluminum-containing phosphate binders, aluminum deposition within the bone will continue and serve as a reservoir for continued exposure because of its long elimination half-life.
Mortality/Morbidity
The mortality rate may be as high as 100% in patients in whom the condition goes unrecognized. Today, 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. Prior to this, bone pain, multiple fractures, proximal myopathy, and the sequelae of dementia have been the main sources of morbidity.
Race
Aluminum toxicity has no predilection for any race.
Sex
Aluminum toxicity has no predilection for either sex.
Age
Aluminum toxicity is observed in all age groups but its end-organ effects are more prevalent in the aged, who may have diminished renal function.
Clinical
History
The signs and symptoms of aluminum toxicity are usually nonspecific.
- In patients on long-term hemodialysis, osteomalacia is associated with the accumulation of aluminum in bone. Most evidence to support skeletal toxicity is from animal studies.
- Studies have also shown that hemodialysis patients exposed to dialysate containing high aluminum concentrations are at increased risk of osteomalacia.
- 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 dialysis patient who presents with an acute mental status change; however, these patients are the specific group most closely associated with the syndrome.
- Typical presentations 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 renal disease. Most patients are on hemodialysis or peritoneal dialysis.
- When obtaining the history, ask specifically about the supplemental use of oral aluminum hydroxide, particularly if the patient does not undergo dialysis.
- In children, special awareness must be made in those who require parenteral nutrition so as not to give excessive amounts of aluminum in the TPN.
Physical
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.
- In children, however, bony deformity is more commonly due to the increased rate of growth and remodeling.
- Children may also express varying degrees of growth retardation.
- The areas of deformity in children usually involve the epiphyseal plates (ie, femur, wrist).
- In adults, thoracic cage abnormalities, lumbar scoliosis, and kyphosis can be present.
Causes
- Toxic effects are dependent upon the amount of metal ingested, entry rate, tissue distribution, concentration achieved, and excretion rate.8,9,10,11
- Mechanisms of 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 renal impairment. Acute intoxication is extremely rare; however, in persons in whom aluminum clearance is impaired, it can be a source of significant toxicity.
More on Toxicity, Aluminum |
 Overview: Toxicity, Aluminum |
| Differential Diagnoses & Workup: Toxicity, Aluminum |
| Treatment & Medication: Toxicity, Aluminum |
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| References |
| Further Reading |
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Further Reading
Clinical guidelines
K/DOQI clinical practice guidelines for bone metabolism and disease in children with chronic kidney disease.
National Kidney Foundation - Disease Specific Society. 2005 Oct. 121 pages. NGC:005108
Nutrient requirements. In: Safe practices for parenteral nutrition.
American Society for Parenteral and Enteral Nutrition - Professional Association. 2004 Dec. 6 pages. NGC:006440
American Gastroenterological Association Institute medical position statement on the use of gastrointestinal medications in pregnancy.
American Gastroenterological Association Institute - Medical Specialty Society. 2006 Jul. 5 pages. NGC:005090
Clinical trial
Aluminum and Auditory Function in ESRD
Keywords
aluminum toxicity, hyperaluminosis, aluminum-related illness, aluminum concentration, aluminum intoxication, aluminum clearance, aluminum-related disease, dialysis osteodystrophy, dialysis encephalopathy, aluminum deposition, microcytic anemia, chromophilic cells, basophilic stippling, deferoxamine therapy
