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Critical Care > MEDICAL TOPICS
Toxicity, Aluminum
Article Last Updated: Jun 20, 2006
AUTHOR AND EDITOR INFORMATION
Section 1 of 10  
Author: Michael R Edwards, MD, Medical Director, Department of Emergency Services, Beebe Medical Center
Michael R Edwards is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, and American College of Physician Executives
Coauthor(s):
Barbara Barnett, MD, Associate Program Director, Assistant Professor, Department of Emergency Medicine, Albert Einstein College of Medicine
Editors: Lisa Kirkland, MD, FACP, CNSP, MSHA, Assistant Professor, Department of Internal Medicine, Division of General Internal Medicine, Mayo Clinic; ANW Intensivists, Abbott Northwestern Hospital; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Harold L Manning, MD, Associate Professor, Departments of Medicine, Anesthesiology and Physiology, Section of Pulmonary and Critical Care Medicine, Dartmouth Medical School; Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, Saint Louis University School of Medicine; Michael R Pinsky, MD, CM, Professor of Critical Care Medicine, Bioengineering, Cardiovascular Diseases and Anesthesiology, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center
Author and Editor Disclosure
Synonyms and related keywords:
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
Background
Aluminum is a trivalent cation found in its ionic form in most kinds of animal and plant tissues and in natural waters everywhere. It is the third most prevalent element and the most abundant metal in the earth's crust. 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. 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+). Approximately 95% of an aluminum load becomes bound to transferrin and albumin intravascularly and is then eliminated renally.
Aluminum is absorbed from the GI tract in the form of oral phosphate-binding agents (aluminum hydroxide), parenterally via immunizations, via dialysate 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 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 feel 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.
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.
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.
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.
- 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.
Brain Abscess
Cryptococcosis
Cysticercosis
Delirium
Delirium Tremens
Depression
Eastern Equine Encephalitis
Encephalopathy, Dialysis
Encephalopathy, Hepatic
Encephalopathy, Hypertensive
Encephalopathy, Uremic
Ependymoma
Glioblastoma Multiforme
Head Trauma
Hemolytic-Uremic Syndrome
Hepatorenal Syndrome
Hyperosmolar Coma
Hyperparathyroidism
Hyperphosphatemia
Hypocalcemia
Hypoglycemia
Hypothermia
Hypothyroidism
Other Problems to be Considered
A broad differential exists for each potential problem, depending upon the presenting complaint (eg, musculoskeletal trauma, altered mental status, anemia).
Lab Studies
- 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 to 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. 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.
Imaging Studies
- 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.
Other Tests
- Bone biopsy from the iliac crest is frequently performed to determine the etiology of bone disease in dialysis patients 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.
Procedures
- Very few procedures are involved in the diagnosis of aluminum-related illness. Bone marrow biopsy is performed to distinguish between aluminum osteodystrophy and other causes of osteomalacia.
Histologic Findings
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.
Medical Care
Treatment of aluminum toxicity includes elimination of aluminum from the diet, TPN, dialysate, medications, antiperspirants, and an attempt at the elimination and chelation of the element from the body's stores.
- Avoidance of aluminum is easily achieved once the need to do so is recognized.
- Elimination is accomplished through the administration of deferoxamine through any of several routes.
- Deferoxamine, the metal-free ligand of the iron-chelate isolated from the bacterium Streptomyces pilosus, is used for acute and chronic iron toxicity and aluminum toxicity.
- It has a high affinity for ferric iron and does not affect iron in hemoglobin or cytochromes.
Surgical Care
No surgical care is applicable to this disorder. Hemodialysis is performed in conjunction with deferoxamine as therapy for whole body chelation
Consultations
- 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.
Diet
Since dietary aluminum is ubiquitous, there are no specific dietary guidelines for its avoidance. Special diets should be maintained for specific associated disease entities (eg, diabetes, renal failure).
Activity
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.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Drug Category: Metal chelators
Bind free metal and do not chelate other trace metals of nutritional importance. Metals are excreted in the urine and bile.
| Drug Name | Deferoxamine mesylate (Desferal mesylate) |
|---|
| Description | 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. |
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| Adult Dose | 6 g/wk average at 14.5 mg/kg/h IV 3 times/wk during first 2 h of dialysis or 85 mg/kg/wk at 14.5 mg/kg/h IV CAPD: 500-750 mg added to each 2-L bag of dialysate for approximately 2 mo; varying amount of exchanges using deferoxamine (eg, only hs, once/d) would prolong therapy; alternatively, administer prolonged SC infusion over 8-16 h via pump |
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| Pediatric Dose | Not established; consult nephrologist |
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| Contraindications | Documented hypersensitivity, profound hypotension, anuria, and severe renal disease without ability to dialyze |
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| Interactions | Vitamin C >500 mg/d can cause cardiac dysfunction; concomitant administration with prochlorperazine can cause transient loss of consciousness; gallium-67 scanning results can be affected |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | Tachycardia, hypotension, and shock may occur in patients receiving long-term therapy and could add to the cardiovascular collapse due to iron toxicity; adverse GI effects of the drug include abdominal discomfort, nausea, vomiting, and diarrhea, which may add to the symptoms of acute iron toxicity; flushing and fever are reported |
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Deterrence/Prevention:
- Avoid all aluminum-containing antacids, antiperspirants, dialysate, immunizations, and TPN solutions.
Complications:
Prognosis:
- Depending upon the degree of dementia and overall medical frailty of the patient, most improve in 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.
Patient Education:
- Educate pregnant and breastfeeding females, and any patient with compromised renal function, about the use of aluminum-containing antacids and the potential dangers of their use and overuse. 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.
Medical/Legal Pitfalls
- Failure to educate a pregnant female, particularly in her first trimester, about potential damage to the fetus
- Misdiagnosing abuse in a child or elderly patient with a pathologic rib fracture when the injury is actually secondary to renal/aluminum osteodystrophy
- Prescribing an aluminum-containing antacid to a patient with impaired renal function
- Failure to advise patients to refrain from driving or operating hazardous machinery if dizziness, impaired vision or hearing, or other nervous system dysfunction develops
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Toxicity, Aluminum excerpt Article Last Updated: Jun 20, 2006
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