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Aluminum Accumulation in the Bones of Patients on Long-term PN
Pamela C. Kruger, PhD; Patrick J. Parsons, PhD, FRSC; Aubrey L. Galusha; Michelle Morrissette; Robert R. Recker, MD; Lyn J. Howard, MB, FRCP
The purpose of parenteral nutrition (PN) formulations is to provide a healthy diet for patients who are unable to process or absorb nutrients through their gastrointestinal tract. But while health care providers are trying to formulate a perfect balance of necessary components, what other ingredients, or contaminants, are slipping into these solutions? We do know that aluminum (Al) contamination of PN formulations is widespread and variable.
Since Al is the most abundant metal, making up 8 percent of Earth’s crust, human exposure is inevitable. Al is present in the food we eat, the water we drink, and the air we breathe. Normal gastrointestinal function keeps absorption of Al into our bloodstream at a minimum (less than 1 percent of ingested Al gets absorbed), and healthy kidneys help our bodies remove any Al that has been absorbed into the bloodstream.
However, patients supported on PN, which bypasses the gastrointestinal barrier, are at risk for acquiring a significant amount of Al in their tissue. Patients with renal impairment will be less able to excrete Al, and may be at risk for Al buildup. Most Al exposure in PN patients comes from contamination of the ingredients that make up PN solutions, and further contamination occurs when these ingredients are stored in glass containers, since over time, Al leaches out of glass.
Early Sources of Al Contamination
Accumulation of high levels of Al in the body can adversely affect bone, brain, and other organs. However, Al accumulates mostly in bone, and its toxicity usually appears in bone first. Too much Al in the bone reduces bone density and can lead to bone fractures.
In the 1960s, patients receiving PN for several months complained of bone pain, and some developed osteomalacia and other bone-related disorders. Shortly before these PN issues arose, similar problems were reported in patients receiving hemodialysis for renal failure. In the case of dialysis, the water used to prepare the dialysate solutions was identified as the source of Al contamination. So, when PN patients began to exhibit the same problems, Al was the prime suspect. PN solutions were tested, and Al contamination was found.
Most of the contamination was traced to hydrolyzed proteins, used early on as a source of amino acids. Later, when synthetic crystalline amino acid solutions were developed, the Al contamination dropped remarkably. Subsequent studies reported improvements in bone formation rates in PN patients receiving crystalline amino acids rather than hydrolyzed proteins. It was thought that the Al problem had gone away!
However, investigations of Al levels in the bones of infants, and neurological function in neonates receiving PN, revealed that exposure via PN solutions remains, despite the discontinued use of hydrolyzed proteins. Concern shifted from Al contamination in large volume parenterals (LVPs) to contamination in small volume parenterals (SVPs), especially those sterilized and stored in glass containers. Glass contains Al that can leach into the stored solution. (LVPs are the PN components that are added in large amounts, such as dextrose, amino acids, and IV fats; SVPs are the components that are added in small amounts, such as electrolytes and micronutrients.)
Measuring Al in Bone
We became very aware that infants are especially vulnerable to the toxic effects of Al due to their underdeveloped bone, brain, and other organs, and several studies have been conducted on Al toxicity in infants. Our next question was whether adults who have been on PN long-term might also remain at risk for Al toxicity. To answer this question, we measured the Al content in autopsy bones of seven long-term adult PN patients, who had never received hydrolyzed proteins. These patients were enrolled in the Albany Medical College home PN program in Albany, NY, and had been cared for through this program the entire time they were on home PN, which spanned from two to twenty-one years.
None of the patients had symptoms of excessive Al exposure, such as bone fractures or bone pain. Three of the seven patients developed some degree of renal failure toward the end of their lives; this could be an additional factor affecting Al toxicity. Table 1 (below) lists additional patient details.
The Al content in hip or knee bones from eighteen patients who had undergone hip or knee replacement surgery was also measured. These patients did not have gastrointestinal or renal problems and were not on PN. Their bones provided us with a control group for our study.
As the PN patients died, over a period of several years, small pieces of their bone were collected at autopsy. These bones were kept in a freezer until they were analyzed. To prevent contamination from Al, knives made of ultrapure tantalum metal were used to scrape adhering tissues from each bone sample. The bones were first soaked in peroxide to remove trapped blood, then soaked in ether to remove fat deposits, and rinsed with ultrapure water. Bone samples were freeze-dried to remove water content. A diamond disc saw was used to divide each bone sample into smaller sections, and two samples from each patient were selected for analysis. Photos of some of the bone samples can be seen in figure 1. Each bone sample was then dissolved with nitric acid and heated in a microwave.
These digested bones, now in liquid form, were analyzed for Al using atomic absorption spectrometry. In this technique, a tiny drop of dissolved bone is heated in a tube made of graphite. The water evaporates and the remaining bone minerals are converted into a gas (atomized). At the same time, a special beam of light, unique to Al, shines through the tube and is absorbed by the gaseous Al atoms. The amount of light absorbed tells us how much Al is in the sample. The Al content in bone is measured in micrograms of Al per gram of bone (µg/g).
The average Al content of the control patient bones was 2.6 ± 1.8 µg/g, while the average Al content in long-term adult PN patient bones was 32.0 ± 18.7 µg/g. Thus, PN patient bones had on average about ten times more Al than control patient bones. The levels of Al in each of the seven long-term PN patients are shown as purple and green bars in figure 2. The green bar indicates the PN patients who developed renal failure at the end of their lives. These patients had even greater Al accumulation in their bones; the difference between the Al content found in their bones was statistically significant from the amount of Al found in the rest of the PN patient bones. Al levels in the non-PN control group are shown as the orange bar. One PN patient’s bone Al level was only slightly higher than the control patient average, but that patient had only received PN treatment for two years before death.
The results indicate that Al exposure through contamination of PN solutions is highly significant for long-term PN patients, and especially for those with kidney impairment (up to twenty times greater). These results support the earlier studies of infants, demonstrating that Al contamination is still a problem for adult PN patients. However, the problem is now in the SVPs rather than the LVPs.
Monitoring Al Levels in the Body
In 2004, following recommendations from the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.), the U.S. Food and Drug Administration (FDA) mandated that LVPs should contain no more than 25 micrograms of Al per liter (µg/L). The FDA also required SVPs to be labeled with the maximum amount of Al that may be present at the expiration of the solution (due to Al leaching from the container). Manufacturers must also provide a warning label, disclosing that toxicity may result if more than 5 micrograms of Al per kilogram body weight per day (µg/kg/d) are infused. Currently, there are no restrictions on Al content in SVPs.
Monitoring and reducing Al accumulation in the body and preventing Al exposure remain important issues for long-term PN patients. While monitoring bone Al provides the most reliable assessment of Al accumulation in the body, obtaining serial bone biopsies from PN patients is not feasible. Further, few laboratories are capable of accurately measuring bone Al content from biopsies. Measuring Al in blood serum may be a viable option. Serum Al measurements can provide some information about the amount of Al circulating in the body. Researchers are working on an assessment tool that is similar to tests used for measuring bone density. This may allow us, in the future, to recognize patients who are getting into trouble with Al levels and to modify their PN solution accordingly.
A new study is being considered, in collaboration with Albany Medical College, through which we may determine the best time to monitor serum Al levels (e.g., before, during, or after infusion, two days after infusion, etc.) to assess exposure. This knowledge might help health care providers monitor Al accumulation in patients more accurately.
Considering viable techniques for reducing potential Al contamination in PN solutions is crucial. Research has shown that replacing certain SVPs with others containing less Al may significantly reduce contamination in formulations. However, it is imperative that any changes made are safe and effective for patients. Packaging SVPs in plastic containers, rather than in glass bottles, could reduce Al contamination. Additional studies of Al exposure and effects of Al accumulation in PN patients are needed to assist the FDA with further regulations restricting Al contamination.
This study was funded in part by the Oley Foundation, which acknowledges support from Baxter Healthcare. The tables and figures presented here have been reproduced with kind permission from the Journal of Parenteral and Enteral Nutrition (Kruger PC, Parsons PJ, Galusha AL, Morrissette M, Recker RR, Howard LJ.Excessive aluminum accumulation in the bones of patients on long-term parenteral nutrition: postmortem analysis by electrothermal atomic absorption spectrometry. JPEN 2014; 38(6):728-735).
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