87: Aluminum

Aluminum (Al) is the most abundant metal in the crust of the earth, where it is found in many types of ores: bauxite, gibbite, boehmite, as alumina, and in gems such as ruby, sapphire, and turquoise. The most naturally occurring isotope is²⁷ Al. Aluminum is a nonessential element and a trace metal with a single oxidation state, Al³⁺.

The aluminum industry is one of the largest industries in the world. Aluminum ores are converted to alumina and then reduced to aluminum metal. The first step usually involves refining bauxite at high temperature and pressure in a caustic soda to form alumina (aluminum oxide, Al₂O₃). The second step occurs by a special method, the Hall-Heroult process, in potrooms and uses electrolytic reduction to form aluminum. Aluminum is then used alone or is processed into alloys to build a variety of products that are anticorrosive.¹⁶ Aluminum is found in cookware, infant formula,²¹ foil, vaccines as an adjuvant to boost immune response,²⁸ antiperspirants, antacids, and previously, in phosphate binders. It also contaminates hemodialysis (HD) fluids, intravenous (IV) fluids, total parenteral nutrition (TPN),³⁸ albumin,³⁹ and as alum solution (potassium aluminum sulfate or ammonium aluminum sulfate)—an astringent for bladder irrigation.⁹⁶ In this chapter, aluminum metal is discussed as an occupational toxin with mainly lung manifestations. Aluminum salts, the more common form discussed in aluminum toxicity, primarily act as neurotoxins, with both acute and chronic toxicity.

The first case of aluminum toxicity with neurologic findings was reported in 1921. This patient had memory loss, tremor, and impaired coordination.⁸⁶ Subsequently, a case series described occupational asthma in Norwegian aluminum (potroom) workers (“potroom asthma”).²² In 1947, 26% of German potroom workers exposed to high concentrations of aluminum dust mixed with mineral oil–based lubricants developed pulmonary fibrosis, “aluminosis”.²⁴ Some potroom workers also developed neurologic findings described as a progressive encephalopathy and termed “potroom palsy,” with balance problems, intention tremors, decreased cognitive ability, and impaired memory, initially described in 1962.^45,51,71

In the 1970s, encephalopathy in patients with chronic kidney disease (CKD) was attributed to using aluminum salt–containing phosphate binders or, more rarely, to aluminum contaminated dialysis fluid. This clinical syndrome, known as “dialysis dementia,” develop after years of HD.⁷⁷ By 1976, elevated serum aluminum concentrations were reported in encephalopathic HD patients.⁶⁶ Both the relationship between aluminum and microcytic anemia as well as the connection between aluminum and osteomalacia in dialysis patients were recognized in 1978.^17,88

In 1982, alum (potassium aluminum sulfate or ammonium aluminum sulfate) was first used in the treatment of hemorrhagic cystitis.⁶⁴ Neurotoxicity can develop if patients absorb alum systemically, especially if kidney insufficiency is present.

More recently, aluminum has been linked to the spongiform leukoencephalopathy that rarely develops in heroin abusers “chasing the dragon.” These patients inhale the pyrolysate of heroin heated on aluminum or tin foil. A 2007 study showed elevated urinary aluminum concentrations in patients using heroin in this manner.¹⁸ They then can develop bizarre behavior, slowed speech and movements, as well as cognitive abnormalities.⁴⁴

There is also a concern over the relationship between aluminum and Alzheimer disease. This linkage was studied because of the dialysis encephalopathy syndrome (dialysis dementia) and the association of aluminum with neuropsychiatric deficits and electroencephalographic (EEG) changes that occur in aluminum welders.⁷² Although aluminum is a component of neurofibrillary tangles in senile plaques associated with Alzheimer disease, to date no studies have proven that aluminum is the cause of the disease.^56,66 Regardless, this association has led several agencies in the United States and Canada to decrease the amount of aluminum contamination allowable in food and water products.⁹²

Antacids

Aluminum-containing products are rarely prescribed. However, patients may take antacids containing aluminum hydroxide for symptomatic control of dyspepsia and gastroesophageal reflux disease. Aluminum hydroxide is usually packaged with magnesium hydroxide to counteract the induced delay of gastric emptying and constipation caused by aluminum hydroxide. These antacids are poorly absorbed and exit the stomach in about 30 minutes. The neutralizing effects of antacids last for 2 to 3 hours, especially in the presence of food.

Sucralfate

Sucralfate, an aluminum-containing salt with sucrose sulfate, is used for symptomatic control of ulcer disease, to accelerate healing of peptic ulcer disease, and as a protectant against stress ulcer formation. This sucrose aluminum complex is poorly absorbed from the gastrointestinal (GI) tract, and the little that is absorbed is excreted by the kidney without undergoing any metabolic changes. Although not approved by the US Food and Drug Administration as a phosphate binder, it does have phosphate binding properties.⁹

Alum

Alum is usually a potassium aluminum sulfate salt [KAl(SO₄)₂*12H₂O] or an ammonium aluminum sulfate salt [NH₄Al(SO₄)₂* 12H₂O], as a 1% solution, and is typically used as an astringent during bladder irrigation for hemorrhagic cystitis, although use is rare. It is poorly absorbed unless there is a defect in the bladder wall.

Aluminum toxicokinetics are difficult to comprehend as many mechanisms have not been elucidated. It is known that daily intake occurs, that absorption is limited, but that the concentrations of aluminum in urine and feces do not equal 100% of the intake.²⁵ More research is necessary to determine the full extent of toxicokinetics.

Absorption

Aluminum is ubiquitous in the food we eat and water we drink.⁶⁵ The daily intake of aluminum in the United States is estimated to be 2 to 25 mg from food and beverages, depending on the diet studied.²⁵ GI absorption mainly occurs in the proximal small bowel with uptake by the intestinal mucosal cells. Uptake occurs through both passive transport methods such as diffusion and active transport methods via transferrin as well as active methods shared by calcium.²⁵ Transferrin may also mediate absorption into the blood from the mucosal cells.²⁵ The exact amount of aluminum absorption in humans is difficult to quantify due to the short half-lives of isotopes and lack of sensitive analysis techniques.²⁵ However, GI absorption increases in the presence of citrate, other small organic acids, and in uremia, based on increases in serum aluminum concentrations.^25,29,62,83 The GI absorption of aluminum is decreased in the presence of phosphorus and silicon.²⁹ There is negligible dermal absorption from the use of antiperspirants containing aluminum.^19,25 Pulmonary absorption of inhaled aluminum particulates is 1.5% to 2%, based on increased urinary aluminum excretion in workers exposed to aluminum containing metal fumes.^25,57,81

Distribution

The initial distribution of aluminum is consistent with blood volume 0.06 L/kg with equal distribution between plasma and red blood cells in the blood.⁸⁹ Aluminum then becomes 90% bound to transferrin, with approximately 10% bound to citrate.^87,91 From the blood, it distributes to many tissues, including 50% to the bone, where it is concentrated at the mineralization front,⁹⁵ and approximately 1% to the brain, primarily in the gray matter.⁶⁶ The remainder of the aluminum appears to distribute variably to the heart, liver, kidney, and other organ systems. The primary carrier in the cerebrospinal fluid (CSF) is citrate.⁹¹ Intracellularly, aluminum localizes in the lysosomes of brain neurons, liver (not the Kupffer cells), spleen, kidney epithelial tubules and glomerular mesangium cells, cardiac myocytes,^5,75 and in the mitochondria of osteoblasts.¹⁵

Metabolism/Excretion

Aluminum is not metabolized in the body and is considered to be greater than 95% excreted unchanged in the urine with a normal daily urinary excretion of less than 50 μg.²⁵ Citrate in the blood may enhance the excretion of aluminum.⁴⁸ Less than 2% of aluminum is excreted by the bile.^40,69,93 Because of the primary renal excretion of aluminum, patients with severe CKD have decreased aluminum excretion. The elimination half-life for aluminum is approximately 85 days in dialysis patients.⁷⁶ Based on urinary excretion in workers (with preserved kidney function) with prolonged occupational exposure, the apparent half-life is extended to years.⁴³ This prolonged half-life may be related to deposits of aluminum metal dust in the lungs of those workers (such as in those patients with pulmonary fibrosis from exposure to the aluminum dust). There is no normal reference point for elimination half-life.

Little is known about the pathophysiology of aluminum toxicity. The information that follows is based on a summary of limited research. Some animal studies provide insight into mechanisms that may be responsible for the toxicity of aluminum, but the studies should not be considered to form a comprehensive understanding of aluminum toxicity as the basic science studies raise more questions. There remain many gaps in our knowledge of aluminum toxicity for different organ systems.

Pulmonary System

In rats exposed to alumina and aluminum through intratracheal injection, fibrosis develops.^35,36 These animals develop epithelialization of alveoli, with focal fibrosis occurring in the respiratory bronchioles and alveolar ducts with alveolar proteinosis.^27,68

Central Nervous System

Aluminum is associated with acute encephalopathy, dialysis encephalopathy, seizures, and Alzheimer disease. The primary site of aluminum entry into the brain appears to be the cerebral microvasculature. Following IV administration in rats and rabbits, aluminum concentrations are higher in the frontal cortex than in the lateral ventricles. The cortex concentrations should result from blood supply, while lateral ventricle concentration may represent blood supply or be CSF derived as the lateral ventricles are bathed in CSF.^94,95 The mechanisms of entry are postulated to be transferrin mediated, endocytosis and other active processes.²² Aluminum interacts with the acetylcholine pathways in the brain and decreases acetylcholine activity. It decreases the amount of high-affinity choline uptake in the brains of rats and also decreases the activity of choline acetyltransferase in rabbit brains.^30,42 Rabbits treated with aluminum have significantly decreased acetylcholine outflow compared with controls; this does not improve with potassium addition to the neurons. This finding suggests that aluminum may attenuate the response of neurons to potassium-induced depolarization.⁹⁴ Adult rabbits exposed to aluminum also have a significant reduction in conditioned responses compared with rabbits exposed in utero or in the first or second month postpartum.

Hematologic System

Prior to alterations in the central nervous system, aluminum affects hematopoiesis. A microcytic hypochromic anemia results. In rats, aluminum inhibits cell growth, while in humans hematopoietic cells are inhibited. In mice, aluminum decreases cell proliferation and hemoglobin synthesis.^3,55 It inhibits δ-aminolevulinic acid dehydrogenase in the heme synthesis pathway,^1,52 leading to the accumulation of erythrocyte protoporphyrins (Fig. 22–3). This effect is most noted in HD patients with aluminum overload.¹⁰

Musculoskeletal System

Vitamin D resistant osteomalacia and osteopathy occurs in patients with aluminum toxicity. It is characterized by hyperosteoidosis, minimal osteoblastic activity, and decreased mineralization. The metabolism and kinetics of calcium, magnesium, and phosphate do not appear to be affected in these patients.¹³ Aluminum concentrates in the mitochondria of the osteoblasts at the mineralization front.¹⁵ It is theorized that aluminum competes and replaces other cations in the bone, leading to osteopathy.²⁶ The osteomalacia is not caused solely by CKD but develops in the presence of aluminum exposure.⁷³ In rat studies, exogenous parathyroid hormone enhanced aluminum deposition into bone, leading to osteopathy.^49,50

Acute Toxicity

Regardless of etiology, patients with acute aluminum toxicity develop encephalopathy, myoclonus, and seizures. The encephalopathy manifests as disorientation, confusion, and coma. All symptoms appear to develop within days to a few weeks of receiving massive systemic aluminum exposure (usually to an aluminum salt). Serum concentrations range from barely elevated to extremely elevated. Most patients who manifest toxicity have systemically absorbed aluminum, usually in the presence of CKD. In several case reports of acute aluminum toxicity, the initial exposure to aluminum was associated with alum bladder irrigations for hemorrhagic cystitis.^34,59,67 In two patients, these symptoms developed after only weeks of exposure to aluminum containing phosphate binders in the presence of citrate.³⁷ Two neonates with uremia developed neurotoxicity after exposure over a 1 to 2 month period to infant formula with high aluminum content.²⁰ Recovery occurs in patients treated with deferoxamine and or HD.^34,58,59 Patients in whom aluminum toxicity is not recognized and or treated late usually die (despite supportive care in the intensive care unit, never recovering a normal mental status).^37,77,80

Chronic Toxicity

Two distinct types of chronic aluminum toxicity are reported: occupationally related lung problems, such as asthma and pulmonary fibrosis, and a multisystem syndrome most often noted in HD patients, which was initially described as dialysis encephalopathy syndrome or “dialysis dementia.” As these names only describe one organ system involvement, they should not be used.

Pulmonary.

Potroom asthma consists of dyspnea, cough, wheezing, bronchitis, and chest tightness.⁵³ These symptoms may present after only a few months of exposure to the metal fumes of aluminum and aluminum dust. The asthma may improve upon cessation of work in the potroom, although some workers never fully improve.⁶³ These symptoms may be a cause for high turnover in potroom workers and appear to have made long-term follow-up difficult.^32,85

Pulmonary fibrosis from aluminum, termed aluminosis, is very similar to the other pneumoconiosis, like silicosis, and appears to progress in a similar manner. This manifestation develops in workers exposed to aluminum dust. Patients experience cough, shortness of breath, and dyspnea on exertion, and they eventually develop restrictive lung disease.^41,54 Abnormal chest radiograph findings include increased pulmonary markings, distortion of pleura and diaphragms, and irregular opacities.^23,30,78 Recovery of lung function does not occur, and several patients have died from complications of pulmonary disease such as pneumonia.

Multisystem Toxicity.

The other form of chronic aluminum toxicity has multisystem manifestations. It primarily affects three organ systems: hematopoietic, nervous, and musculoskeletal. In patients with CKD, the toxicity appears to occur after months to years of exposure to aluminum salt–contaminated dialysate and or aluminum salt–containing phosphate binders such as aluminum hydroxide and sucralfate. A similar presentation has been reported in a patient using aluminum-coated cookware to boil methadone for IV abuse. The patient experienced 3 months of chronic aluminum toxicity (prior to presentation) after 4 years of processing his methadone this way.^21,96 Three industrial workers exposed to aluminum metal powder were reported to have encephalopathy. One of these workers had a brain aluminum concentration 20 times normal.⁴⁵ One infant with kidney insufficiency developed focal seizures, which eventually progressed to generalized seizures, hypotonia, poor head control, ataxia, and developmental delay in the presence of elevated serum aluminum concentration after 10 months of exposure to aluminum salt–containing phosphate binders.⁷⁰

The microcytic hypochromic anemia of aluminum poisoning is unresponsive to iron replacement therapy.³¹ This clinical finding usually precedes encephalopathy and osteomalacia.⁷⁹ The encephalopathy is characterized by speech disturbances, EEG abnormalities, myoclonic jerks, and dementia.⁸⁴ The typical speech disturbances include dyspraxia, dysphasia, stuttering, and possibly mutism.^46,74,84 EEG abnormalities include slowing of the normal rhythm and high voltage biphasic or triphasic spikes.^47,84 The myoclonic activity can include uncontrolled twitching movements, myoclonus, or seizures.⁸⁴ The osteopathy and osteomalacia can lead to bone pain and fractures.^14,92 Death is common in these patients when aluminum toxicity is not recognized and treated.

A normal serum aluminum concentration should be less than or equal to 2 μg/L,²⁵ while a whole blood aluminum concentration should be less than 12 μg/L.⁸² Daily urinary excretion less than 50 μg aluminum is considered normal.^25,61 Toxicity has occurred in a wide range of serum and urine concentrations, with patients dying who had severe manifestations and concentrations only slightly above normal.

Pulmonary function testing can be performed to evaluate for restrictive lung function, as occurs with aluminosis.

Patients should be removed from any aluminum exposure if identified. Exposure to aluminum in industry and exposure to antacids containing aluminum salts should also be limited. Patients with occupational asthma from aluminum exposure should be symptomatically treated with bronchodilators and steroids.

The only chelator with proven benefit is deferoxamine (DFO). Chelation therapy is recommended for both acute and chronic toxicity from aluminum salts. Chelation appears to limit and improve manifestations of neurotoxicity, anemia, and osteomalacia (Antidotes in Depth: A7). Other chelators such as d-penicillamine and 2,3-dimercapto-1-propanol (BAL) have been tried in chronic HD patients without any improvement in their manifestations or aluminum concentrations.¹² A review of numerous chelator studies revealed that no other chelator has been found as an alternative to DFO.⁹⁰

Acute Toxicity

A DFO dose of 15 mg/kg/d intravenously is recommended. Adults have received doses ranging from 1 to 2 g for aluminum toxicity. DFO chelates the aluminum to form aluminoxamine, which is excreted in the urine or removed by HD.⁹¹ Chelation mobilizes aluminum from its storage sites in blood and increases its renal elimination.

In patients with stage 5 CKD, chelation therapy is usually followed 6 to 8 hours later by HD with a high-flux membrane in order to clear the aluminoxamine (the aluminum-DFO product).⁵⁸ Patients with normal kidney function may not require HD, as the aluminoxamine is excreted in the urine.

Chronic Toxicity

Chelation therapy with DFO reverses encephalopathy, osteomalacia, and anemia. Numerous case reports demonstrate the reversal of the neurotoxicity, vitamin D–resistant bone disease, and iron-resistant anemia.^4,8,11 The National Kidney Foundation has issued complicated guidelines for the treatment of dialysis encephalopathy. It consists of 4 months of once weekly DFO 5 mg/kg over 1 hour given 5 hours before a regularly scheduled HD session in patients with an aluminum concentration greater than 300 μg/L. In patients with aluminum concentrations between 50 and 300 μg/L, DFO 5 mg/kg is given the last hour of HD, once a week for 2 months. Serum aluminum concentrations are then monitored, and this therapy is repeated as needed.⁶⁰ Recent studies have evaluated the effect of lower doses of DFO (2.5 mg/kg/week) for treatment of chronic toxicity in dialysis patients.³³

• Inhalational exposure to aluminum metal causes pulmonary toxicity, primarily manifested as bronchospasm, but progresses to restrictive lung disease.

• Acutely, aluminum salts are neurotoxins with manifestations of encephalopathy and seizures.

• Chronically, aluminum salts affect at least three systems with manifestations of anemia, encephalopathy, dementia, and osteomalacia.

• Treatment involves limiting or terminating exposure, chelation with DFO, and HD in patients with CKD.

References