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642 Part VI: The Erythrocyte Chapter 43: Iron Deficiency and Overload 643

Models Produced by Iron Loading Numerous efforts have been Juvenile Hemochromatosis
made to create models of hemochromatosis by loading laboratory ani- The penetrance of the rare juvenile form of the disease seems to be high
mals with iron, either by the oral or parenteral route. A few of these and cardiomyopathies and endocrine deficiencies are the major clinical
appear to simulate the human disease in one respect or another. For features. Joint manifestations were found to be relatively common in
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example, the iron-loaded gerbil 262–265 develops heart disease, features of patients with juvenile hemochromatosis. 273
which resemble the human disease. Such models have been used for the
study of potential chelating agents. African Iron Overload
Targeted Disruption Models Targeted disruption of most of the It is not clear to what extent African iron overload is symptomatic.
genes associated with human iron disorders has been achieved. Included Among the Bantu, where the disorder was originally described, there
are HFE, TfR-2, ferroportin, hemojuvelin, 255,256 and hepcidin. are many complicating factors, including malnutrition and high alcohol
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The targeted disruption of several genes, including those encoding BMP- intake. Among African Americans various associated disorders have
6, 269,270 or the components of the BMP receptor, caused iron overload been noted, but a cause-and-effect relationship is not clear.
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in mice, but the equivalent human diseases have not yet been found.
Secondary Hemochromatosis
The clinical findings in patients with hemochromatosis secondary
CLINICAL FEATURES to blood transfusion and/or disorders of erythropoiesis are, in gen-
HFE-Related (Type 1) Hereditary Hemochromatosis eral, indistinguishable from those found in patients with the primary
Onset The clinical features of the most common form of hereditary hemochromatosis. 277
hemochromatosis are cirrhosis of the liver, darkening of the skin, car-
diomyopathies, and diabetes. These features are only seen in the fully LABORATORY FEATURES
penetrant form of the disease and may depend on additional cofactors The main laboratory features of hereditary hemochromatosis are an
such as alcohol consumption. In contrast to the juvenile form of the abnormally high transferrin saturation, and increased serum ferritin
disease, in which onset is usually in the second or third decade of life, level. Five to 10 percent of patients with classical HFE hemochroma-
classical hereditary hemochromatosis associated with mutations of the tosis manifest increased liver enzyme levels in the serum. In secondary
HFE gene generally is diagnosed in the fifth or six decade of life. hemochromatosis, anemia and other manifestations of the underly-
General Symptomatology Many symptoms are attributed to ing disorder are found. Macrocytosis of the erythrocytes is a common
hereditary hemochromatosis, including abdominal pain, weakness, feature; this finding seems unrelated to liver disease and its cause is
lethargy, fatigue, loss of libido, impotence, and arthropathies. How- unknown.
ever, all of these symptoms are common in an aging population, and
epidemiologic studies show that none of them are more common in Differential Diagnosis
patients with the HFE hemochromatosis, even those with the biochem- A large number of methods have been introduced that allow the amount
ical phenotype, than they are in the general population. of storage iron to be estimated. The suspicion that a patient may have
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Arthropathies The arthropathy of patients with hemochromato- primary hemochromatosis is generally raised by an increased serum
sis has characteristic features. 218,271,272 It is said to tend to begin at the transferrin saturation, particularly when it is found together with an
small joints of the hands, especially the second and third metacarpal elevated serum ferritin level. Increased transferrin saturation com-
joints, and that in some cases episodes of acute synovitis may occur, as monly occurs in patients with chronic liver disease who have no muta-
in calcium pyrophosphate dehydrate deposition arthropathy (pseudo- tions in the HFE gene. Ferritin is an acute phase protein and levels are
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gout; chondrocalcinosis). Radiologically, the arthropathy resembles that elevated in a variety of disorders. Particularly high levels are encoun-
of osteoarthritis with joint space loss, subchondral cysts, sclerosis, and tered in patients with macrophage activation syndromes, loss-of-func-
osteophytosis. The features that have been considered distinctive include tion ferroportin mutations, acute hepatitis, Gaucher disease, in some
the joint distribution, the presence of shape osteophytes emerging from malignancies, and in patients with the hyperferritinemia-cataract syn-
the radial sides of the metacarpal distal epiphysis, and the presence of drome. The latter disorder is an uncommon autosomal dominant
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radiolucent zones in the subchondral area of the femoral head. It is gen- defect in which a mutation in the 5′ IRE of the ferritin light chain pre-
erally recognized that arthritis does not respond to phlebotomy therapy. vents binding of the IRPs, resulting in unrestrained constitutive produc-
The possibility that this type of arthritis depends on linkage of HFE to tion of the ferritin chains.
other HLA genes is made less likely by the occurrence of similar arthri- Many clinicians have considered a liver biopsy the “gold standard”
tis in juvenile hemochromatosis, which is genetically independent of for the diagnosis of iron overload. The material obtained at biopsy not
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the HLA locus. Hip arthritis at an early age was also noted in a family only provides the opportunity to assess the histopathology of the liver
with hepcidin-resistant ferroportin mutation and iron overload. 239 of the patient, but also to quantitate the amount of nonheme iron in
Liver Patients with hepatic iron overload are at a greatly increased the specimen. Dividing the iron content by the patient’s age provides
risk of developing a hepatocellular carcinoma, especially when cirrho- an iron index; a value greater than 2 implies the presence of hemochro-
sis is present. Occasional patients with hereditary hemochromatosis matosis. Although in some situations liver biopsy may provide useful
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have been reported to develop hepatocellular carcinoma even in the information, it is an invasive procedure that, although low-risk, is no
absence of cirrhosis suggesting that iron overload could be directly longer required for the diagnosis of hemochromatosis. Enthusiasm for
carcinogenic.
subjecting every patient with potential hemochromatosis to liver biopsy
has diminished with the ready availability of genetic analysis. Moreover,
Porphyria Cutanea Tarda a simple way to determine whether a patient is iron overloaded is to
Porphyria cutanea tarda is a disease that is well known to be associated institute a program of phlebotomies. This is an essentially harmless way
with mild iron overload and that responds to phlebotomy treatment to determine how much storage iron the body contains. Magnetic res-
(Chap. 58). Numerous studies document that the prevalence of patients onance imaging (MRI) is also capable of detecting and reliably quan-
with this disorder who also have mutations of the HFE gene is consid- tifying the amount of iron in the liver. For detection of cardiac iron
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erably increased. 275 overload, T2* MRI is a superior diagnostic approach.
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