Page 573 - Hematology_ Basic Principles and Practice ( PDFDrive )

488 Part V Red Blood Cells

neurodegeneration, Friedreich ataxia, and neuroferritinopathy that value for further investigation. In the absence of complicating factors,
reflect the brain distribution of the excess iron. 20,24 elevated concentrations of serum ferritin provide biochemical evidence
In patients with systemic parenchymal iron loading, similar clini- of iron overload. Genetic testing then should be considered in persons
cal features eventually develop with sufficient iron accumulation to with abnormal transferrin saturation, serum ferritin concentration, or
produce organ dysfunction and damage. 13–15 At earlier stages, with both. Liver biopsy may be indicated for prognostic purposes to detect
lower body iron burdens, no distinctive signs or symptoms may be cirrhosis if the serum ferritin concentration is greater than 1000 µg/L
present, and patients may come to attention only because of abnormal and may be contemplated in the presence of hepatomegaly or abnor-
laboratory test results. Symptomatic patients may present with any malities on liver function testing, or in patients older than 40 years.
of the characteristic manifestations of parenchymal iron deposition, Currently, cascade screening of families with affected individuals is
including liver disease, diabetes mellitus, gonadal insufficiency and recommended, but population screening for HFE hemochromatosis is
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other endocrine disorders, cardiac dysfunction, arthropathy, and not advised. Individuals who are simply heterozygous for either the
increased skin pigmentation. Liver disease is the most common C282Y or the H63D mutation in the HFE gene do not develop iron
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complication of systemic iron overload. In all varieties of systemic overload. Persons with phenotypical evidence of iron overload who
parenchymal iron overload, the development and severity of liver are neither C282Y/C282Y homozygotes nor C282Y/H63D heterozy-
damage are closely correlated with the magnitude of hepatic iron gotes can be considered for further genetic testing for less common
deposition. Whether derived from increased absorption of dietary HFE mutations and for non-HFE mutations associated with iron
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iron or from transfused RBCs, progressive parenchymal iron accu- loading, for noninvasive assessment of the liver iron concentration,
mulation eventually produces hepatomegaly, functional abnormali- or for diagnostic liver biopsy.
ties, fibrosis, and finally cirrhosis. 13–15 Hepatocellular carcinoma Liver biopsy can establish a definitive diagnosis of hereditary and
seems to be the ultimate complication of cirrhosis in iron overload. juvenile hemochromatosis regardless of genotype and can demon-
The development of cirrhosis increases the risk of hepatoma by more strate the histologic pattern of iron loading found with ferroportin
than 200-fold. mutations or with chronic liver diseases NAFLD, chronic hepatitis
Diabetes mellitus is another common complication of all forms C infection, and alcohol-related liver disease (see box on Testing for
of systemic parenchymal iron overload. Virtually all of the secondary Iron Overload). A quantitative determination of the nonheme iron
manifestations of diabetes may develop, including retinopathy, concentration in the liver sample should be made, the pattern of iron
nephropathy, neuropathy, and vascular disease. Gonadal insufficiency deposition examined histochemically, and the extent of tissue injury
and other endocrine abnormalities occur. During the 2nd decade of assessed histopathologically. In patients found to have an increased
life, both growth and sexual maturation usually are retarded in body iron load, additional clinical and laboratory studies should seek
untreated patients with transfusional iron overload. evidence of complications of iron overload. Further investigation may
Iron-induced cardiac disease, occurring as a cardiomyopathy with include liver function testing; testing for diabetes mellitus; evaluation
heart failure, arrhythmias, or both, may be a fatal complication of all of hormonal function; cardiac examination; joint and bone radiog-
varieties of systemic parenchymal iron overload. Heart disease is the raphy examination; and, especially if cirrhosis is present, screening
most frequent cause of death in patients with thalassemia major. 16,26 for hepatocellular carcinoma. 13–15
Severe cardiac disease in particular may be the presenting manifesta- Atransferrinemia or hypotransferrinemia is readily demonstrable
tion in young patients with juvenile hemochromatosis. 18 by measurement of the plasma transferrin concentration. Similarly,
Increased skin pigmentation, with a bronze hue in some patients aceruloplasminemia or hypoceruloplasminemia can be diagnosed by
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and a slate-gray coloration in others, often accompanies iron overload. measurement of the plasma ceruloplasmin concentration. For detec-
Chondrocalcinosis and other forms of arthropathy are common tion and diagnosis of iron-loading anemia, measurement of the
complications of hereditary hemochromatosis and may occur in other plasma transferrin receptor and examination of the bone marrow may
forms of systemic parenchymal iron overload. An increased suscepti- be helpful in demonstrating ineffective erythropoiesis in combination
bility to infectious disease may be found in patients with transfusional with the erythroid hyperplasia characteristic of these disorders.
and other forms of iron overload, especially to infections with certain
organisms, including Vibrio vulnificus, Listeria monocytogenes, Yersinia
enterocolitica, Escherichia coli, Candida spp., and Mycobacterium Differential Diagnosis
tuberculosis. 13,14,26
Detection and diagnosis of iron overload are most problematic in the
hereditary forms of iron overload (see Table 36.4). A combination of
Laboratory Evaluation
Testing for Iron Overload
The typical sequences of changes in clinically useful indicators of iron
status as body iron increases from the iron-replete normal to the A direct measure of body iron avoids the uncertainties inherent in
amounts found in hereditary hemochromatosis and transfusional iron the interpretation of indirect indicators of iron status. Liver biopsy
overload are shown in Fig. 36.1. Characteristic changes in laboratory is the definitive direct test for assessing iron deposition and tissue
measures of iron status in the disorders of hereditary iron overload damage in iron overload, permitting measurement of the nonheme iron
are listed in Table 36.4. concentration, histochemical determination of the cellular distribution
Screening for iron overload can use phenotypical methods, geno- of iron between hepatocytes and Kupffer cells, and pathologic examina-
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typical methods, or both. 13,15 Phenotypical screening can provide tion of the extent of tissue injury. When available as appropriately
biochemical evidence of iron overload in patients with hereditary or calibrated and validated techniques, new noninvasive methods using
hepatic magnetic susceptibility and magnetic resonance imaging (MRI)
juvenile hemochromatosis but does not identify all persons geneti- may replace liver biopsy when only determination of the liver iron
cally at risk for iron loading. In populations of northern European concentration is needed. MRI studies of the heart are particularly useful
ancestry, genotypical screening for the C282Y and H63D mutations in patients at risk for cardiac iron deposition. In patients with HFE or
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in HFE can identify most persons at risk for developing HFE hemo- other forms of hemochromatosis undergoing therapeutic venesection,
chromatosis, but it gives no information about the presence or quantitative phlebotomy provides an accurate retrospective determina-
magnitude of iron overload. In most clinical circumstances, a com- tion of the amount of storage iron that can be mobilized for hemoglobin
bination of phenotypical and genotypical methods is the best strategy formation. When liver biopsy is contraindicated in a patient, quantitative
for screening. 13,15 phlebotomy is occasionally useful in establishing the diagnosis of HFE
In individuals of northern European ancestry, measurement of the or other forms of hemochromatosis. Bone marrow aspiration and
serum transferrin saturation usually is the best method for initial biopsy provide no information about the extent of parenchymal iron
loading and are of limited value in the evaluation of iron overload. Iron
phenotypical screening for systemic parenchymal iron overload. 13,15 A overload produces no diagnostic abnormalities in the peripheral blood.
persistent value of 45% or greater often is recommended as a threshold