Download Aluminium: gastrointestinal absorption and renal excretion

Clinical Science (1991) 81,289-295
289
Editorial Review
Aluminium: gastrointestinal absorption and renal excretion
C. J. LOTE
AND
H. SAUNDERS
Department of Physiology,The Medical School, University of Birmingham, Birmingham, U.K.
INTRODUCTION. SOURCES
ABILITY OF ALUMINIUM
AND
BIOAVAIL-
Aluminium is the most abundant metal and constitutes
8% of the earth’s crust. It is a normal constituent of
vegetable and animal tissues and is present in raw
untreated water. In domestic tap-water supplies, aluminium may be present in high concentrations either from
its presence in raw water or, more commonly, as a result
of its use during the water-purification process. Aluminium in the metallic form is widely used for both
industrial and domestic purposes, and a variety of aluminium salts are used in foods, fluids, cosmetics and medications.
The toxicity of aluminium in patients with renal failure
is now well documented, and dialysis encephalopathy,
osteomalacia and anaemia are recognized hazards in such
patients if aluminium is not excluded from dialysis fluids
and medications. The safe levels of aluminium in food,
water, medications and infusion fluids for subjects with
normal renal function are unknown, but aluminium has
been implicated as causative agent in a number of
dementia diseases, including Alzheimer’s disease.
There are a number of recent reviews of aluminium
toxicity [l-51. In contrast to these, in the present review,
we concentrate on the mechanisms of absorption and
excretion of aluminium, rather than the consequences of
aluminium deposition in the body. The normal dietary
source of aluminium is food and water to which
aluminium has been added or in which there is naturally a
high content [6,7]. The normal daily intake of aluminium
is estimated to be approximately 9 mg/day in teenage and
adult females and 12-14 mg/day in teenage and adult
males [7]. However, it has been stated that “the inappropriate choice of foods, methods of food preparation and
non-prescription drugs can readily increase the daily
intake of aluminium to several thousand mg each day” [8].
Such high aluminium intakes are particularly likely in
Correspondence: Dr C. J. Lote, Department of Physiology,
The Medical School, University of Birmingham, Birmingham
B15 2TT, U.K.
individuals who ingest aluminium-containing drugs as
antacids or phosphate-binders. Tea leaves contain relatively large amounts of aluminium, since tea plants
accumulate aluminium from the soil [9]. Koch el al. [lo]
reported “that at least some of the aluminium present in
tea is absorbed and that tea consumption must be considered in any assessment of the total dietary intake of
aluminium in human beings”. However, tannin, also
present in tea, is an inhibitor of gastrointestinal aluminium
absorption [loa], and hence the bioavailability of the
aluminium in tea is relatively low.
Aluminium salts have a number of functions when used
as food additives [8]. For example, the acidic forms of
sodium aluminium phosphate are added to commercial
cake mixes and self-raising flour as E541, where they act
as leavening agents in reaction with sodium bicarbonate.
The alkaline forms of these aluminium salts are added to
processed cheeses as emulsifying agents.
Another source of aluminium is baby-milk powder.
Freundlich et al. [l11reported that the aluminium content
of a variety of milk powders that they analysed ranged
from 124 to 351 pg/l, although values as high as 2346
pg/l have been reported in highly processed and modified
milk powders [12]. The aluminium content of normal
breast milk is 2-10 pg/l. Koo el al. [12] proposed that
aluminium contamination of baby-milk powders was due
to the use of raw materials such as soya bean, additives
(for example calcium and phosphorus), manufacturing
processes and the type of storage container.
The aluminium contpt of domestic water supplies is
recognized as a potential major source of exposure for
this metal ion in patients with chronic renal failure, since
dialysis fluids may contain aluminium, and such patients
may also be taking oral aluminium-containing drugs as
phosphate-binders. The critical concentration of
aluminium in dialysis fluid (above which there will be a
significant net transfer of aluminium to the patient) is a
matter of some debate, but ranges from about 14 ,ug/l[13]
to 27 pg/l [ 141; ideally, the dialysate aluminium concentration should be well below this. An epidemiological survey
of haemodialysis patients, indicated that those who were
C. J. Lote and H. Saunders
290
receiving haemodialysis therapy using water with an aluminium content greater than 50 pg/l had an increased
incidence of both fracturing osteodystrophy and dialysis
encephalopathy [ 151. During a single haemodialysis
session with such a high aluminium concentration in the
water, up to 100 mg of aluminium could be transferred to
the patient. In normal subjects, drinking about 2 litres of
water/day, it is unlikely that more than about 2 mg of
aluminium would be ingested, only a proportion of which
is absorbed (see below). Nevertheless, a recent epidemiological survey [16] has indicated a link between the
aluminium content of drinking water and the prevalence
of Alzheimer’s disease, although it should be mentioned
that the risk of Alzheimer’s disease was only 1.5 times
higher in districts where the mean aluminium concentration in drinking water was high ( > 0.11 mg/l) than in
districts where the aluminium concentration was low
( < 0.01 mg/l), and the data were adjusted to take account
of differences in diagnostic rate of Alzheimer’s disease
with distance from a computed tomography scanning unit.
GASTROINTESTINAL
MINIUM
ABSORPTION
OF
ALU-
The gastrointestinal tract is a major cellular barrier to
aluminium absorption, and, furthermore, most naturally
occurring aluminium compounds are highly insoluble.
The normal daily aluminium uptake from food and
drinking water is approximately 10 mg. That gastrointestinal absorption of aluminium does occur is clearly
demonstrated by the fact that both plasma aluminium
coacentration and urinary aluminium excretion are
increased after high oral doses (i.e. greater than 10 mg/kg
body weight) of aluminium (for example, [17-211).
Wilhelm et al. [5] have recently surveyed the data in the
literature on gastrointestinal absorption of aluminium,
and it is clear that the methodology employed to assess
gastrointestinal absorption can have a major bearing on
the interpretation of the findings.
Aluminium absorption from the intestinal lumen is
initially into the intestinal mucosal cells, and only a small
proportion of this uptake continues into the blood [22].
The aluminium in the mucosal cells is subsequently
excreted in the faeces when the cells desquamate. Consequently, balance studies (where aluminium uptake is
determined as intake minus faecal elimination and urinary
excretion) tend to overestimate uptake.
Absorbed aluminium is primarily excreted in the urine,
but the urinary excretion of aluminium is not an infallible
guide to absorption because aluminium may accumulate
in body tissues, and a very minor fraction is excreted in
the bile [20-241. This biliary excretion (0.1% of total
aluminium-polyoxo complexes at pH values over 4, but
insufficiency [25].
Factors affecting aluminium absorption
The details of the mechanism of aluminium absorption
remain unclear. The factors which influence aluminium
absorption are listed in Table 1, and provide clues to the
physiological processes involved.
Physicochemical factors. The solubility of aluminium
salts in aqueous solution is complex, and is influenced by
pH and by other ionic species [26].
In acidic solutions (below pH 4), aluminium in solution
is found as A1(H20)63+,often written in an abbreviated
form simply as A13+.This A1(H20)63+
can form colloidal
aluminium-polyoxo complexes at pH values over 4, but
these redissolve if the pH is lowered or raised, since in
alkaline solutions aluminium is again soluble as
AI(H0);. Free A13+ is decreased by the presence of
phosphate, which forms insoluble salts. In contrast, citrate
enhances the solubility of A13+, and at pH 2-5 a neutral
soluble citrate-aluminium complex exists [26,27].
How d o the above facts relate to aluminium absorption? There is considerable evidence that citrate enhances
the intestinal absorption of aluminium [29-321, and this
effect is largely attributable to the formation of the soluble
citrate-aluminium chelate. However, citrate may have
additional effects on aluminium absorption, either by
facilitating transcellular absorption or by opening the tight
junction and enhancing the paracellular movement of
aluminium [33]. Citrate is known to open epithelial tight
junctions in cultured cells [34], and this finding has been
supported by work on proximal (rat) jejunal segments in
Ussing chambers [21].
The interactions of citrate with calcium are also likely
to have effects on aluminium absorption. Calcium inhibits
the absorption of aluminium, and thus more aluminium
will be absorbed from water with a low calcium concentration. These observations suggest that the mechanism of
aluminium uptake in the gut may share some features of
the calcium absorption process [35, 361. In isolated rat
jejunal slices, aluminium uptake was reduced by calciumchannel blockers and increased by calcium-channel activators [37]. These findings raise the possibility that the
effects of citrate on aluminium absorption may involve
calcium. Citrate is an effective chelator of calcium, and in
the renal proximal tubule such complex formation inhibits
citrate and calcium absorption [38]. In the gut, similar
complexation of calcium with citrate may make calcium
unavailable for absorption, thereby enhancing aluminium
absorption. However, it is not entirely clear why citrate
may inhibit calcium absorption but facilitate aluminium
absorption.
There are also antagonistic interactions between
aluminium and fluoride absorption in the gut. Ingestion of
aluminium hydroxide decreases the intestinal absorption
of fluoride [39]. High aluminium and low fluoride
concentrations in the water supply for dialysis patients
increases the incidence of encephalopathy and bone fractures [40]. Related to these findings is the observation
from an epidemiological study [41] that in areas where
domestic tap water was highly fluorinated, there were
fewer reported cases of Alzheimer’s disease compared
with areas with low fluorinated water. Aluminium ( A P + )
forms strong complexes with F- [26]. The above findings
Gastrointestinal absorption and renal excretion of aluminium
291
Table 1. Factors affecting aluminium absorption
Effect on aluminium absorption
Physical factors
Citrate
Silicic acid
Iron
Fluoride
Physiological factors
Pathophysiological factors
Enhances
Inhibition?
?(seethe text)
Inhibition
PH
Calcium
Changes from neutral enhance absorption?
PTH
Enhances
Enhances
1,12-DihydroxyvitaminD,
Uraemia
imply that such complexes, if formed in the gut, are not
readily absorbed.
Silicic acid [Si(OH),] has a strong affinity for
aluminium. A recent report has indicated that the silicic
acid content of water has a major effect on the bioavailability of aluminium, with aluminium bioavailability
decreasing with increasing silicic acid content [42]. The
same authors suggest that this could occur in the gut as a
result of the formation of hydroxy-aluminosilicates [43].
There is persuasive evidence that aluminium can
substitute for iron in a number of sites in the body [44,
451, and several research groups have investigated the
possibility that the mechanisms of iron absorption from
the gut may be involved in aluminium absorption. The
mucosal cells of the small intestine (primarily the
duodenum) take up iron, and it is bound intracellularly to
a protein, apoferritin, to form ferritin. Some of the iron
enters the plasma where it is bound to the protein transferrin. Aluminium can be bound by both ferritin and
transferrin. It is likely that the aluminium which binds to
ferritin in the mucosal cells is largely not absorbed into
the plasma, but remains bound and is eliminated from the
body when the cells are shed into the intestinal lumen.
Whether iron in the intestinal lumen influences
aluminium absorption is a question which cannot be
answered with certainty at present. Van der Voet & de
Wolff [46] concluded that Fe2+ reduced aluminium
absorption, whereas Fe3+ had no effect. Cannata et al.
[47] proposed that the mechanism for intestinal absorption of aluminium might involve a ‘common pathway’ for
metal ions including iron, since they found that iron
uptake by ferritin prevented aluminium absorption.
However, Blaehr et al. [48] found that iron in the intestine
stimulates aluminium absorption. A variety of metal ions
can bind to transferrin, but they do not bind to the ironbinding site. It may be that Fe2+has an allosteric effect on
the transferrin molecule, preventing aluminium from
fitting its binding site. The interrelationships between iron
and aluminium absorption remain confused. There is also
some evidence for a negative interaction between
aluminium and sodium during intestinal absorption [49].
Physiological and pathophysiological factors. Parathyroid hormone (PTH) increases the gastrointestinal
absorption of aluminium [50, 511; in patients with renal
failure who were not on dialysis or receiving aluminium-
Inhibition
Enhances
containing phosphate-binders, those patients who
developed osteomalacia had high serum PTH levels
(3.1 k 1.4 ng/ml compared with a normal value of less
than 0.5 nglml), with the implication that this led to
increased dietary aluminium absorption [52]. However, it
is reported that in uraemic rats, in which gastrointestinal
aluminium absorption is enhanced (see below), PTH does
not further increase aluminium absorption [53].
In addition to the above reports of effects of PTH on
aluminium absorption, there are also reports that
aluminium depresses PTH release [54].
Burnatowska-Hledin et al. [55] have shown that 1,12dihydroxyvitamin D, increases the gastrointestinal
absorption of aluminium, a finding which, like the PTH
data above, supports the view that aluminium and calcium
absorption may have related mechanisms.
The kidneys are the main route of aluminium excretion, and consequently the gastrointestinal absorption of
aluminium is of great importance in patients with compromised renal function. There is evidence that uraemia per
se increases gastrointestinal absorption of aluminium in
man and the rat [56, 571. Uraemic children also have an
increased incidence of aluminium loading and toxicity
[58],perhaps because they need large doses of phosphatebinders relative to body weight; and the effects of uraemia
and citrate on aluminium absorption appear to be synergistic [21]. Fig. 1 illustrates the factors which influence
gastrointestinal absorption of aluminium.
Fate of absorbed aluminium
What happens to the fraction of dietary aluminium
which does enter the plasma? Aluminium binds to plasma
proteins, mainly to the iron-binding protein transferrin
and to albumin [44]. There are wide variations in the
reported values for the extent of aluminium binding to
protein: the range is 8% [59] to 98% [60]. Although the
former of these studies was in man, and the latter in the
rat, nevertheless species variation seems to be of minor
importance. Much more important is the methodology
used to assess binding. In general, the findings are based
on ultrafiltration experiments. Gidden et al. [59] have
demonstrated that the ultrafilterability of plasma aluminium depends on aluminium concentration, i.e. increasing the aluminium concentration decreases aluminium
C. J. Lote and H. Saunders
292
Gut lumen
ultrafilterability. This finding has been essentially
confirmed in many other studies (for example, [20,
60-621).
It is unlikely that the ultrafilterable fraction of plasma
aluminium represents a single form of aluminium, since
there are a number of low-M, binders of aluminium in
plasma, including citrate, fluoride, phosphate, bicarbonate and silicates. Fig. 2 shows some of the effects of
absorbed aluminium.
Duodenal cells
Aluminium
0Inorganic
Organic
relatively insoluble
A13+
absorption
t
1
1
RENAL EXCRETION OF ALUMINIUM
Enhanced by:
1,12-Dihydroxyvitamin D,
1
t
1
I
I
Inhibited by:
calcium
tannin
fluoride
Complex with
iron-binding
Return to gut
lumen when cells
1
,
sloughed off
Faecal excretion
Fig. 1. Gastrointestinal absorption of aluminium.
Urinary aluminium excretion increases after oral aluminium loading in subjects with normal renal function
[63].The M , cut-off of the renal glomerular filter is
70 000 (e.g. [64]).Consequently, transferrin ( M , 77 000),
the main aluminium-binding protein in plasma, is not
filtered. Hence it is likely that only a small fraction of
plasma aluminium will be filterable, although as the
preceding section indicates, this fraction will be variable,
depending on the plasma concentration of aluminium.
The aluminium clearance is normally less than 5% of the
glomerular filtration rate in individuals with normal renal
function.
The dangers of aluminium toxicity were initially recognized in patients with renal failure, who were receiving
dialysis treatment. ‘Dialysis dementia’, an encephalopathy
occurring in renal dialysis patients, was first described in
1972 [65], and was found to be associated with the
accumulation of aluminium in the brain [66].The recog-
Plasma aluminium
protein-bound
(mainly to transferrin)
(alumino-silicates)
Tissue uptake
Inhibition of
caffeine-sensitive
Ca2+-channels [76]
Binding to
[73, 741
Disruption of
Biopterin
meta bolism
[72, 73, 751
Gene
transcription
Fig. 2. Some effects of absorbed aluminium.
lnterfe :nce
with cell
signalling
Gastrointestinal absorption and renal excretion of aluminium
nition of this condition led to many more reports of
aluminium-related dementia in renal patients. Other
pathological features, including vitamin D-resistant osteodystrophy, were also evident in such patients and the
condition, first recognized in Newcastle-upon-Tyne
(U.K.), was termed ‘Newcastle bone disease’.
The above conditions are caused by aluminium entering the blood and being deposited in the body tissues,
deposition in the brain leading to encephalopathy, and
deposition in bone leading to osteodystrophy. In the renal
failure patients there were two sources of this aluminium:
(1)the water used for dialysis, and (2) dietary aluminium
hydroxide used as a phosphate-binder in such patients.
The obvious question is whether the aluminium toxicity
was due to impaired excretion consequent upon the renal
impairment, or to excessive amounts of aluminium
entering the plasma by bypassing the gut barrier (or both).
Because of the complex relationship between proteinbinding of aluminium, and the plasma aluminium concentration, it is difficult to assess quantitatively the role of the
kidney in aluminium excretion. Renal aluminium clearance decreases with increasing plasma aluminium concentration [60, 62, 671. However, since plasma aluminium
concentration in healthy subjects is low, 10 pg/l o r less, it
seems likely that the kidneys play an important role in
aluminium excretion.
Little is known of the renal tubular handling of aluminium, and this is a question we are currently investigating. Work by Galle [68] has indicated that, after
filtration, aluminium is reabsorbed by the renal tubule
cells and is bound intracellularly to phosphates and
proteins [60, 691. There is also evidence of distal tubular
secretion [70].
From time to time, incidents of high aluminium
exposure occur (e.g. in Camelford, Cornwall, U.K., where
aluminium sulphate was added in high concentration to
drinking water in July 1988). Clearly, if we had greater
understanding of the renal mechanisms involved in aluminium excretion, this might increase the possibility of
improving aluminium clearance. If renal transport
mechanisms for aluminium resemble those in the gut, then
drugs or procedures which mod@ for example calcium
absorption (see, for example, [71]) might be useful in
modifying aluminium absorption. Clearly, this is an area
in which more research is needed.
ACKNOWLEDGMENTS
Work by C.J.L. on renal aluminium handling is currently
supported by the Wellcome Trust and the Sandoz Foundation for Gerontological Research.
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