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CHAPTER 43 of iron should be continued for 12 months after correction of anemia, or for as

IRON DEFICIENCY AND long as bleeding continues. Parenteral iron is used in patients who need more
iron than can be delivered by the oral route, patients who do not tolerate oral
OVERLOAD iron salts, patients with gastrointestinal disease or following certain forms of
bariatric surgery, noncompliant patients, and patients undergoing renal dialy-
sis. All current parenteral iron preparations are much less likely to cause serious
adverse events than was the case for high-molecular-weight iron dextran used
Tomas Ganz in the past.
At the opposite end of the iron disorder spectrum, iron storage disease
(hemochromatosis) can be the result of mutations of genes that are involved
SUMMARY in regulation of iron homeostasis or transport, including the genes encoding
HFE, transferrin receptor 2, ferroportin, hemojuvelin, and hepcidin. Because
Iron deficiency and iron-deficiency anemia are common nutritional and hema- iron is not substantially excreted, iron overload commonly results from chronic
tologic disorders. In infants and young children, iron deficiency is most com- erythrocyte transfusions for those anemias that are not caused by blood loss
monly caused by insufficient dietary iron. Rarely, it can result from mutations or iron deficiency.
in TMPRSS6, a gene encoding a membrane protease that serves normally as a Alternatively, iron overload resembling hereditary hemochromatosis can
transcriptional suppressor of the primary negative regulator of iron absorption, be the result of hyperabsorption of iron induced by ineffective erythropoiesis,
hepcidin. In young women, iron deficiency is most often the result of blood including in β-thalassemias, dyserythropoietic anemias, pyruvate kinase
loss in menstruation or as a result of blood loss during pregnancy, childbirth, deficiency, congenital dyserythropoietic anemias and some sideroblastic
and lactation. In older adults, bleeding is often the cause of iron deficiency, anemias. Here iron overload can develop even in the absence of erythrocyte
and may originate from the gastrointestinal tract, as from hemorrhoids, peptic transfusions or the (ill-advised) administration of medicinal iron, but is further
ulcer, hiatus hernia, colon cancer, or angiodysplasia; from the genitourinary aggravated by these events.
tract; from uterine leiomyomas or carcinoma, or a renal tumor; or from the pul- The diagnosis of systemic iron overload depends, in large part, upon
monary tree, through chronic hemoptysis caused by infection or malignancy, or increased serum ferritin levels accompanied by increased transferrin satura-
as a result of idiopathic pulmonary hemosiderosis. Iron deficiency in infants can tion, which tend to reflect increased iron stores. However, ferritin levels are
result in impairment of growth and intellectual development. The hematologic also increased in patients with chronic inflammation or neoplasia or with the
features of iron deficiency are nonspecific and too often confused with other hyperferritinemia cataract syndrome, a disorder caused by mutations in the
causes of microcytic anemia such as thalassemias, chronic inflammation, and iron-responsive element of the ferritin light chain. The transferrin saturation
renal neoplasms. A low serum ferritin concentration is a good indicator of iron is usually increased in patients with hereditary hemochromatosis even when
deficiency, but ferritin levels are increased by inflammation and can be partic- the ferritin level is normal.
ularly high in cancer, macrophage activation syndromes, hepatitis, or chronic Many subjects with genetic hemochromatosis never develop organ
kidney disease, which may mask the detection of iron deficiency coexisting dysfunction, those who do, their clinically significant hemochromatosis is
with the anemia of chronic inflammation. The plasma iron is decreased and the characterized by cirrhosis of the liver, darkening of the skin, diabetes, car-
iron-binding capacity increased in severe iron deficiency, but these alterations diomyopathies, and possibly by arthropathies. Iron deposition is primarily in
are not uniformly present in mild iron deficiency, and low plasma iron levels are hepatocytes, with macrophages and intestinal mucosal cells being relatively
also characteristic of the anemia of inflammation. Other laboratory tests that iron poor. The most common causes of genetic hemochromatosis are muta-
are useful include assays for serum transferrin receptor, reticulocyte hemoglo- tions of the HFE gene. Two common mutations are involved: the c.854G→A
bin content, percent hypochromic erythrocytes and erythrocyte zinc protopor- (C282Y) and c.187C→G (H63D) substitutions. Increased transferrin satu-
phyrin. Diagnosis of iron deficiency, particularly in an adult, obliges the clinician ration values, serum ferritin levels, and iron stores were found in a majority
to determine the site and cause of blood loss, and to rectify it whenever pos- of homozygotes for the C282Y mutation and in many compound heterozy-
sible. Ferrous salts, in doses of 100 to 200 mg of elemental iron daily, are the gotes for C282Y/H63D or rarely in homozygotes for H63D. However, clinical
initial treatment in most patients with iron deficiency. Enteric-coated and pro- manifestations even among homozygotes for the C282Y mutation are rare, in
longed-release preparations should be avoided. Complete correction of anemia contrast to biochemical and/or histologic manifestations of the increased iron
is expected in 8 to 12 weeks, depending on patient’s age. If this response is not levels, which are common. Only a few percent of C282Y homozygous patients
achieved, the patient and the diagnosis require reevaluation. Administration
develop clinically significant disease, and cofactors including male gender and
alcohol intake potentiate disease development. Juvenile hemochromatosis, an
earlier onset and more severe type of hemochromatosis with high penetrance
is the result of mutations of the hemojuvelin or the hepcidin gene. Ferroportin
Acronyms and Abbreviations: BMP, bone morphogenetic protein; cDNA, mutations produced two types of autosomal dominant iron overload. In one
complementary DNA; DMT, divalent metal transporter; HFE, high iron (high of these, the iron is deposited chiefly in macrophages; the other is similar to
Fe)—a mutated protein associated with common hereditary hemochroma- classical hereditary hemochromatosis with iron deposition in hepatocytes and
tosis; HLA, human leukocyte antigen; IL, interleukin; IRE, iron-responsive other parenchymal cells.
element; IRP, iron-regulatory protein; MCV, mean corpuscular volume; MRI, Iron can be removed from patients with hereditary hemochromatosis by
magnetic resonance imaging; RDA, recommended daily allowance; RDW, serial phlebotomy, but in patients with iron-loading anemias iron chelation
red cell distribution width; TfR, transferrin receptor; TIBC, total iron-binding therapy with either parenteral desferrioxamine infusions or the oral chelators
capacity; UIBC, unsaturated iron-binding capacity. deferiprone or deferasirox is required.

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