Emedicine – Aluminium

<p>Source: <a href="http://emedicine.medscape.com/article/165315-overview">http://emedicine.medscape.com/article/165315-overview</a></p>

<p>

Aluminum is a trivalent cation found in its ionic form in most kinds of animal and plant tissues and in natural waters everywhere.<sup ><a href="javascript:showrefcontent('refrenceslayer');" >[1] </a></sup>It is the third most prevalent element and the most abundant <a href="http://emedicine.medscape.com/article/814960-overview" target="_self" >metal</a> in the earth's crust, representing approximately 8% of total mineral components.<sup ><a href="javascript:showrefcontent('refrenceslayer');" >[2] </a></sup>Due to its reactivity, aluminum in nature is found only in combination with other elements.

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 aluminum 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. In addition, essential metals can affect the human body in the case of deficiency or imbalance.<sup ><a href="javascript:showrefcontent('refrenceslayer');" >[3]</a></sup>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<sup >+</sup>, respectively), it is sometimes a competitive inhibitor of several essential elements of similar characteristics, such as magnesium (0.066 nm, 2<sup >+</sup>), calcium (0.099 nm, 2<sup >+</sup>), and iron (0.064 nm, 3<sup >+</sup>). At physiological pH, aluminum forms a barely soluble Al(OH)<sub>3</sub> that can be easily dissolved by minor changes in the acidity of the media.<sup ><a href="javascript:showrefcontent('refrenceslayer');" >[2]</a></sup>

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 intravenous infusion or in the presence of 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.<sup ><a href="javascript:showrefcontent('refrenceslayer');" >[4]</a></sup>

Mayor et al suggested that parathyroid hormone may increase intestinal absorption of aluminum.<sup ><a href="javascript:showrefcontent('refrenceslayer');" >[5]</a></sup>

Up to this time, no biological function has been attributed to this metal, and, more importantly, aluminum accumulation in tissues and organs results in their dysfunction and toxicity.<sup ><a href="javascript:showrefcontent('refrenceslayer');" >[2] </a></sup>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.</p>

<h2 >Pathophysiology</h2>

<p >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 <a href="http://emedicine.medscape.com/article/127351-overview" target="self" >hyperparathyroidism</a>, increased bone turnover, and subsequent peritrabecular fibrosis. In aluminum-related bone disease, the predominant features are defective mineralization and <a href="http://emedicine.medscape.com/article/392997-overview" target="self" >osteomalacia</a> 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 μg/g.<sup ><a href="javascript:showrefcontent('refrenceslayer');" >[6] </a></sup>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.<sup ><a href="javascript:showrefcontent('refrenceslayer');" >[7]</a></sup>

Aluminum causes an oxidative stress within brain tissue.<sup ><a href="javascript:showrefcontent('refrenceslayer');" >[8] </a></sup>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 Alzheimer-like neurofibrillary tangles. 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.<sup ><a href="javascript:showrefcontent('refrenceslayer');" >[9]</a></sup>

In this regard, dietary excitotoxins including aluminum can exacerbate the clinical presentation by worsening of excitotoxicity and by microglial priming. This opens the discussion to the use of nutritional factors that reduce excitotoxicity and brain inflammation as a maneuver to alleviate neurotoxic effects of aluminum.<sup ><a href="javascript:showrefcontent('refrenceslayer');" >[10, 11] </a></sup>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's disease and on animals models where administration of aluminum caused a strong decrease in dopamine content of the striatum.<sup ><a href="javascript:showrefcontent('refrenceslayer');" >[12]</a></sup>

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 <a href="http://emedicine.medscape.com/article/815399-overview" target="_self" >lead poisoning</a>.

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.<sup ><a href="javascript:showrefcontent('refrenceslayer');" >[13]</a></sup></p>

</div>

<h2 >Epidemiology</h2>

<h3 >Frequency</h3>

<h4 >United States</h4>

<p >The actual incidence of aluminum 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.

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.<sup ><a href="javascript:showrefcontent('refrenceslayer');" >[4] </a></sup>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 case reports have implicated the use of oral aluminum-containing antacids during pregnancy as a possible cause for abnormal fetal neurologic development.<sup ><a href="javascript:showrefcontent('refrenceslayer');" >[14, 15]</a></sup>

Potential additional sources of increased chances for contamination are as follows: (1) a role for fatty acids common in food as factors that lead to an increase of the paracellular absorption of aluminum<sup ><a href="javascript:showrefcontent('refrenceslayer');" >[16] </a></sup>; (2) advances in nanotechnology have led to the exposure of humans to engineered aluminum nanomaterials (NMs) that could potentially induce genomic changes. (By using a rat model, Balasubramanyam et al<sup ><a href="javascript:showrefcontent('refrenceslayer');" >[17] </a></sup>found that Al(2)O(3) NMs were able to induce size- and dose-dependent genotoxicity in vivo.<sup ><a href="javascript:showrefcontent('refrenceslayer');" >[17] </a></sup>); (3) intravesical irrigation with aluminum for hemorrhagic cystitis, a life-threatening complication that might occur in bone marrow transplantation, chemotherapy, and radiotherapy, as described in a pediatric patient.<sup ><a href="javascript:showrefcontent('refrenceslayer');" >[18]</a></sup></p>

<h4 >International</h4>

<p >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.</p>

<h3 >Mortality/Morbidity</h3>

<p >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.</p>

<p >Aluminum toxicity has no predilection for any race.</p>

<p >Aluminum toxicity has no predilection for either sex.</p>

<p >Aluminum toxicity is observed in all age groups, but its end-organ effects are more prevalent in elderly persons, who may have diminished renal function.</p>

</div>

<h2 >History</h2>

<p >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 patients on hemodialysis who are 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 patient on dialysis 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.</p>

</div>

<h2 >Physical</h2>

<p >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, 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 <a href="http://emedicine.medscape.com/article/1264959-overview" target="_self" >kyphosis</a> can be present.</p>

</div>

<h2 >Causes</h2>

<p >Toxic effects are dependent upon the amount of metal ingested, entry rate, tissue distribution, concentration achieved, and excretion rate.<sup ><a href="javascript:showrefcontent('refrenceslayer');" >[19, 20, 21, 22]</a></sup>

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.</p>

</div>

<h2 >Differentials</h2>

<ul >

<li ><a href="http://emedicine.medscape.com/article/212946-overview" >Brain Abscess</a></li>

<li ><a href="http://emedicine.medscape.com/article/215354-overview" >Cryptococcosis</a></li>

<li ><a href="http://emedicine.medscape.com/article/215589-overview" >Cysticercosis</a></li>

<li ><a href="http://emedicine.medscape.com/article/288890-overview" >Delirium</a></li>

<li ><a href="http://emedicine.medscape.com/article/166032-overview" >Delirium Tremens</a></li>

<li ><a href="http://emedicine.medscape.com/article/286759-overview" >Depression</a></li>

<li ><a href="http://emedicine.medscape.com/article/233442-overview" >Eastern Equine Encephalitis</a></li>

<li >Encephalopathy, Dialysis</li>

<li ><a href="http://emedicine.medscape.com/article/186101-overview" >Encephalopathy, Hepatic</a></li>

<li ><a href="http://emedicine.medscape.com/article/166129-overview" >Encephalopathy, Hypertensive</a></li>

<li ><a href="http://emedicine.medscape.com/article/239191-overview" >Encephalopathy, Uremic</a></li>

<li ><a href="http://emedicine.medscape.com/article/277621-overview" >Ependymoma</a></li>

<li ><a href="http://emedicine.medscape.com/article/283252-overview" >Glioblastoma Multiforme</a></li>

<li ><a href="http://emedicine.medscape.com/article/433855-overview" >Head Trauma</a></li>

<li ><a href="http://emedicine.medscape.com/article/201181-overview" >Hemolytic-Uremic Syndrome</a></li>

<li ><a href="http://emedicine.medscape.com/article/178208-overview" >Hepatorenal Syndrome</a></li>

<li ><a href="http://emedicine.medscape.com/article/121693-overview" >Hyperosmolar Coma</a></li>

<li ><a href="http://emedicine.medscape.com/article/127351-overview" >Hyperparathyroidism</a></li>

<li ><a href="http://emedicine.medscape.com/article/241185-overview" >Hyperphosphatemia</a></li>

<li ><a href="http://emedicine.medscape.com/article/241893-overview" >Hypocalcemia</a></li>

<li ><a href="http://emedicine.medscape.com/article/122122-overview" >Hypoglycemia</a></li>

<li ><a href="http://emedicine.medscape.com/article/770542-overview" >Hypothermia</a></li>

<li ><a href="http://emedicine.medscape.com/article/122393-overview" >Hypothyroidism</a></li>

</ul>

<h2 >Laboratory Studies</h2>

<p >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. 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 <a href="http://emedicine.medscape.com/article/815399-overview" target="_self" >lead poisoning</a>. Aluminum can also be found in bone marrow macrophages.</p>

</div>

<h2 >Imaging Studies</h2>

<p >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.</p>

</div>

<h2 >Other Tests</h2>

<p >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.</p>

</div>

<h2 >Procedures</h2>

<p >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.</p>

</div>

<h2 >Histologic Findings</h2>

<p >Histologic findings in aluminum-related osteomalacia reflect the decrease in mineralization of newly formed bone matrix.</p>

<ul >

<li >

<div class="topbullet">An increase in the surface covered by osteoid occurs, as does an increase in the osteoid seams.</div>

</li>

<li >

<div class="topbullet">Osteoid volume and thickness also increase.</div>

</li>

<li >

<div class="topbullet">In histologic sections stained with eosin, the areas of greater mineralization tend to appear violet or blue, whereas the osteoid seams appear pink.</div>

</li>

</ul>

</div>

<h2 >Medical Care</h2>

<p >The most important part of emergency medical treatment is the recognition of possible aluminum toxicity based on risks (eg, renal insufficiency, aluminum exposure) and symptoms (eg, altered mental status, anemia, osteoporosis).

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.</p>

<ul >

<li >

<div class="topbullet">Serum aluminum level greater than 50-60 µg/L (mcg/dL) suggests aluminum overload, may correlate with toxicity, and can be used as an indication to start chelation therapy in symptomatic patients.</div>

</li>

<li >

<div class="topbullet">Symptomatic patients with lower serum aluminum levels (eg, greater than 20 mcg/dL) may require chelation therapy.</div>

</li>

<li >

<div class="topbullet">Kan et al suggested that a low dose of deferoxamine therapy (2.5 mg/kg/wk) is therapeutically effective as standard dose (5 mg/kg/wk) for the treatment of aluminum overload.<sup ><a href="javascript:showrefcontent('refrenceslayer');" >[23]</a></sup></div>

</li>

</ul>

<p >Chelation therapy with deferoxamine should be initiated in consultation with a nephrologist and a medical toxicologist, and this can be performed upon admission.</p>

<ul >

<li >

<div class="topbullet">Deferoxamine, the metal-free ligand of the iron-chelate isolated from the bacterium <em>Streptomyces pilosus,</em> is used for acute and chronic iron toxicity and aluminum toxicity.</div>

</li>

<li >

<div class="topbullet">It has a high affinity for ferric iron and does not affect iron in hemoglobin or cytochromes.</div>

</li>

</ul>

</div>

<h2 >Surgical Care</h2>

<p >No surgical care is applicable to this disorder. Hemodialysis is performed in conjunction with deferoxamine as therapy for whole-body chelation.</p>

</div>

<h2 >Consultations</h2>

<p >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.</p>

</div>

<p >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, renal failure).</p>

</div>

<h2 >Activity</h2>

<p >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.</p>

</div>

<h2 >Medication Summary</h2>

<p >The goals of pharmacotherapy are to reduce morbidity and to prevent complications.</p>

</div>

<h2 >Metal chelators</h2>

<h3 >Class Summary</h3>

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

<div class="ref_medicationbtn" ><a href="http://reference.medscape.com/drug/desferal-deferoxamine-343722" onclick="wmdTrack('cr-medlink_b');" >View full drug information</a></div>

<h3 ><a href="http://reference.medscape.com/drug/desferal-deferoxamine-343722" onclick="wmdTrack('cr-medlink_l');" >Deferoxamine (Desferal mesylate)</a></h3>

<p >Metal-free ligand of the iron chelate isolated from the bacterium <em>S pilosus</em>. 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.</p>

</div>

<h2 >Further Inpatient Care</h2>

<p >Start chelation therapy in symptomatic patients with elevated serum aluminum level in consultation with a nephrologist and a medical toxicologist. Use clinical symptoms and serum aluminum levels as indicators of therapeutic success. Reduce exposure to aluminum-containing products.</p>

</div>

<h2 >Transfer</h2>

<p >If chelation therapy and hemodialysis/peritoneal dialysis are not able to be provided, transfer the patient to an institution with a higher level of care.</p>

</div>

<h2 >Deterrence/Prevention</h2>

<p >Avoid all aluminum-containing antacids, antiperspirants, dialysate, immunizations, and TPN solutions.</p>

</div>

<h2 >Prognosis</h2>

<p >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.</p>

</div>

<h2 >Patient Education</h2>

<p >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.</p>

</div>