that have been shown to be inferior diagnostic tests,
such as plasma folate, are generally not offered by
clinical laboratories, and some of the studies, such
as holo-transcobalamin II, are performed only in a
few research laboratories. Among the studies that
are available, there are a number of clearly preferred
studies. For iron deficiency, the storage marker,
plasma ferritin, is by far the best diagnostic marker
(Guyatt
et al.
1992), although it must be remem-
bered that the plasma ferritin concentration tends to
be increased somewhat (on average 20 µg/L based
on the data reported by Guyatt
et al.
) by the
presence of an inflammatory condition such as an
infection, a rheumatologic disorder, or a
malignancy. The storage marker, (total) plasma
cobalamin, is the best diagnostic marker of cobala-
min deficiency (Chanarin and Metz 1997). Folate
does not have a circulating storage form to utilize
but the circulating supply marker, red cell folate, has
been found to be a reliable marker of folate
deficiency. The hematologic marker, mean red cell
volume, is useful in patients in late stages of micro-
nutrient deficiency as it indicates whether a micro-
cytic disease (such as iron deficiency) or a
macrocytic disorder (such as cobalamin or folate
deficiency) is present. Similarly, megaloblastic
features in the circulating blood cells of patients with
late stage cobalamin and folate deficiency strongly
suggest the deficiency of one of these micronutrients
as the etiology of the anemia. A positive response to
micronutrient administration is an important test of
the validity of the diagnosis. The absence of a
response or a partial response following full replen-
ishment of the micronutrient can be taken either as
evidence of an error in diagnosis or of the existence
of a concurrent disorder, especially of a concurrent
micronutrient deficiency as it is not uncommon for
patients to present with multiple micronutrient
deficiencies.
Micronutrient excess
A trace substance is present in excess, also
called overload, when the storage form of the
substance accumulates to the point of causing
damage to the storage tissue or when, because of
increased body stores, there is sufficient deposition
of the substance in nonstorage tissues to cause injury
to them. The clinical findings are attributable to the
tissue injury and its sequelae. Excessive dietary
intake of micronutrients is very unusual but in
individuals with hereditary hemochromatosis, a not
uncommon autosomal recessive disorder of iron
metabolism in which there is excessive intestinal
absorption of iron (Adams and Valberg 1994), iron
overload can develop despite a normal dietary intake
of iron.
The increased hepatic iron stores in hereditary
hemochromatosis prompt an increased synthesis of
ferritin and a decreased synthesis and secretion of
apotransferrin (Table 8.4). Because of the increased
intrahepatic concentrations of ferritin, the plasma
ferritin concentration (measured as protein) increases
and it does so in rough proportion to the magnitude
of the hepatic ferritin stores. The presence of
increased hepatocyte turnover and decreased hepatic
ferritin clearance further increases plasma ferritin
concentrations in advanced hemochromatosis. The
decreased hepatic secretion of apotransferrin results
in a decreased plasma concentration of the protein
which is manifest as a decreased (total) iron binding
capacity. As there is abundant iron available for
transport to the marrow; plasma transferrin iron
concentrations are normal. However, because
plasma transferrin concentrations are measured as
(total) plasma iron, the contribution of ferritin-bound
iron, which is present in elevated concentrations,
results in an increased total iron concentration. As a
consequence of the opposite direction of change for
plasma iron concentration and plasma iron binding
capacity, transferrin saturation is markedly increased
in hemochromatosis. (Note that the ratio of the two
measures is not the true transferrin saturation
because the numerator includes nontransferrin iron
and the denominator includes nontransferrin iron
binding capacity). Most experts recommend using
transferrin saturation as the screening study for
hereditary hemochromatosis (Adams and Valberg
1994, Phatak and Cappuccio 1994) but the diagnos-
tic performance of plasma ferritin concentration is
much better than that of transferrin saturation in
early disease (Bassett
et al.
1984) making it the
more appropriate screening study.
Nutritional Status
8-8
Table 8.4
Laboratory Studies for the Assessment of Iron Overload
Pathophysiology
Study
↑
Transport form plasma iron
↓
Transport protein plasma iron binding capacity
↑
Tissue stores
plasma ferritin (as protein)
hepatic iron index
