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CHAPTER 42 DISORDERS OF IRON STORAGE AND TRANSPORT

CHAPTER 42 DISORDERS OF IRON STORAGE AND TRANSPORT
Williams Hematology

CHAPTER 42 DISORDERS OF IRON STORAGE AND TRANSPORT

VIRGIL F. FAIRBANKS
DAVID J. BRANDHAGEN

Disorders of Iron Storage

Definitions and History

Hereditary Hemochromatosis

Other Causes of Hemochromatosis
Disorders of Iron Transport

Congenital Atransferrinemia

Congenital Aceruloplasminemia
Related Conditions

Congenital Cataract with Hyperferritinemia

Superficial Hemosiderosis of the Central Nervous System

Hemochromatosis in other Species
Chapter References

Hereditary hemochromatosis is relatively common in people of northwestern European ancestry, less common in those of southern and eastern European ancestry, and rare in other populations. It is usually due to homozygosity for a mutatant allele [845A(C282Y)] of the HFE gene on chromosome 6. Among Caucasians of the United States, Canada, Australia, New Zealand, Iceland, Ireland, northwestern Europe, Spain, and South Africa, approximately 5 persons per thousand are homozygous for this allele, and more than 10 percent are heterozygotes. Homozygotes are at risk for developing clinical disease; simple heterozygotes are not. The common manifestations of hereditary hemochromatosis are abdominal pains, severe fatigue, joint pains, cardiac arrhythmias or heart failure, hypothyroidism, hypogonadism, impotence, amenorrhea, diabetes mellitus, osteoporosis, hepatomegaly, splenomegaly, hepatic failure, and hyperpigmentation. These manifestations are uncommon before age 40. Diagnosis should be suspected if serum iron concentration is increased and transferrin saturation is 50 percent or greater. Confirmation may be made by testing DNA for the mutant allele, demonstrating elevated serum ferritin concentration, or liver biopsy. For many cases, liver biopsy is not warranted. Treatment requires removal of 500 ml of blood (or less in small patients) once weekly until serum ferritin concentration is 20 µg/L or less. If the diagnosis is made early and treatment is as stated, the prognosis is excellent. There is a 30 percent probability of hepatocellular carcinoma when diagnosis and treatment have been delayed and cirrhosis has developed. Siblings, parents, and children must be studied to identify other affected family members.
Other iron-overloading disorders that occur in humans include porphyria cutanea tarda, sideroblastic anemias, congenital dyserythropoietic anemias, neonatal hemochromatosis, juvenile hemochromatosis, and African hemochromatosis (“Bantu siderosis”) are other iron storage disorders that have a proven or likely genetic basis. Iron overloading is rarely due to chronic excessive ingestion of iron medications. It may also rarely follow portal vein-systemic vein anastamosis. Hyperferritinemia-cataract syndrome is a disorder neither of iron transport nor of storage that may be mistaken for an iron storage disorder.
Rare disorders of iron transport include congenital atransferrinemia and congenital aceruloplasminemia.
These are also associated with excess iron in various organs in addition to anemia. Congenital atransferrinemia has many features in common with hereditary hemochromatosis. Congenital aceruloplasminemia particularly affects the basal ganglia of the brain, the pancreatic islet cells, and the retina. It is characterized by neurological features of dystonia, dysarthria, dementia, degeneration of retina, and late-onset diabetes mellitus. Paradoxically, in this disorder there is no hepatocellular injury despite marked hepatic iron overload.

Acronyms and abbreviations that appear in this chapter include: ALT, alanine aminotransferase; HII, hepatic iron index; IRE, iron-responsive element; MRI, magnetic resonance imaging; PCT, porphyria cutanea tarda; TSH, thyrotropin; TIBC, total iron-binding capacity.

DISORDERS OF IRON STORAGE
DEFINITIONS AND HISTORY
Iron overload denotes excess iron deposition in various tissues of the body. Hemosiderosis refers to greater than normal deposition of iron in a tissue, which may be seen microscopically as hemosiderin. Hemochromatosis is the clinical expression of iron-induced injury to cells of various organs. Table 42-1 lists many of the disorders that are associated with hemochromatosis. Among these, hereditary hemochromatosis is relatively common in people of European origin. In many of the other disorders shown in Table 42-1, the excess accumulation of iron is secondary to chronic anemia.

TABLE 42-1 CAUSES OF IRON OVERLOAD

Hemochromatosis was first described by Trousseau1 and Troisier2 in France and later by von Recklinghausen,3 who coined the term hemochromatosis. In 1935, Sheldon reviewed more than 300 published cases, clearly delineated the clinical and histological features, and noted the frequent association of ethanol abuse. He asserted that hemochromatosis “should be classed as an inborn error in metabolism,” that “it is probably a good deal less rare than is usually believed,” and that a slight increase in rate of iron absorption results, after many years, in the accumulation of a gross excess of iron which causes tissue injury, particularly of liver and pancreas.4 Phlebotomy therapy to reduce iron stores was introduced by Davis and Arrowsmith in 19525 and was stressed by Finch and Finch in 1955.6
In 1975 it was shown that hemochromatosis is due to mutation of a gene on the short arm of chromosome 6, closely linked with the HLA locus.7,8,9,10,11,12 and 13 It was not until 1996 that systematic examination of this region of the DNA revealed an ancestral gene, HFE, with a small number of mutations. Two of these [c.845G®A (845A;C282Y) and c.187C®G(187G;H63D)] were found to be closely associated with hemochromatosis.14,15,16,17 and 18 The mutation primarily responsible for hemochromatosis (845A) was shown to be very common in people of northwestern European ancestry.19,20,21,22,23,24,25,26,27,28,29 and 30
HEREDITARY HEMOCHROMATOSIS
ETIOLOGY AND PATHOGENESIS
The cause of hereditary hemochromatosis is excessive tissue accumulation of iron as a result of increased rate of iron absorption beginning early in life and slowly progressive. It usually results from impaired function of a protein that is now called HFE. (See Chap. 24 and Fig. 42-1.) Normally, HFE complexes with transferrin receptor on the cell membrane and is internalized together with transferrin receptor. Within the endosome, HFE reduces the release of iron from the transferrin receptor-transferrin-Fe+3 complex.31,32 and 33 The 845A(C282Y) mutation prevents the appearance HFE protein on the cell membrane; the 187G(H63D) mutation reduces the affinity of HFE for transferrin receptor. Thus, in hemochromatosis, many cells lack the normal mechanism for restricting the uptake of iron from plasma. It is unknown how alteration of the HFE-transferrin receptor interaction leads to increased iron absorption by the intestinal epithelial cells (enterocytes). The absorbed iron passes rapidly from mucosal epithelium into plasma, with no accumulation of iron in enterocytes. There is an increased expression of divalent cation transporter 1 in epithelial cells of the small intestine (enterocytes),34 but it is not known whether this plays a role in increased iron absorption. In addition to increased iron absorption, there is also an increase in copper and cobalt absorption,35 but this does not seem to play a role in pathogenesis.

FIGURE 42-1 The HFE protein, as predicted from HFE gene sequence,14 and later confirmed by analysis of the crystallized protein,47 is a class I MHC-like protein that contains 321 amino acids. It spans the cell membrane. Its extracellular portion has three domains, shown as a1, a2, and a3. It is closely associated with b2-microglobulin. The a1 domain contains the binding site for transferrin receptor.32 The major hemochromatosis mutation 845A(Cys282®Tyr, or C282Y) disrupts a disulfide bond normally present within the a3 domain, thereby preventing expression of HFE on the cell surface, the association of HFE with b2-microglobulin, and the binding of transferrin receptor, the mechanism that normally modulates iron uptake by the cell. The mutation 187G(His63®Asp, or H63D) prevents formation of a salt bridge that is normally present within the a1 domain and impairs the binding of transferrin receptor by HFE protein. (From Feder and coworkers, by permission.)14

In hemochromatosis, ferritin and hemosiderin accumulate in many tissues but especially in hepatocytes, in b-cells of the islets of Langerhans in the pancreas, in myocardium, in pituitary, and in joints. Macrophages of blood and enterocytes are actually iron-poor. In the liver, hemosiderin first appears in Kupffer cells. Then, as iron overloading develops, deposits of hemosiderin appear in the hepatocytes. When iron is released from ferritin into the cytosol, it is as Fe+2. This is converted to Fe+3 within the cytosol. In this process, free hydroxyl and superoxide radicals are formed. Superoxide, in turn, is converted by superoxide dismutase to hydrogen peroxide, that may injure cells by peroxidation of lipids of the membranes of microsomes, mitochondria, or other cell structures or membranes.36,37 Although cells normally have sufficient peroxidases and catalase to dispose of the H2O2 that forms, harmful amounts of peroxide and active oxygen radicals may be generated when iron stores are greatly increased.
Iron is not the sole factor responsible for tissue injury in hemochromatosis. The high frequency of ethanol abuse in persons with overt hemochromatosis has been recognized for at least 60 years.4 Those who have iron overload and who also habitually consume ethanol have a significantly higher frequency of hepatic fibrosis than do those who abstain.38 Viral hepatitis may also be a contributing factor, as an Italian study revealed an excess frequency of hepatitis C in hemochromatosis.39
An iron-rich environment provides a favorable medium for bacterial growth.40,41 Furthermore, phagocytic functions of monocytes and neutrophils are impaired in persons with iron storage disease.42
PATHOLOGY
Affected tissues and organs exhibit a deep brown color. The liver is enlarged and may weigh as much as 2500 g. After cirrhosis has developed, the organ becomes granular or coarsely nodular. The myocardium is thickened, and the heart is often enlarged. Testes are often atrophic. Histologic examination reveals prominent hemosiderin deposition in many tissues and organs. In the liver, hemosiderin is found primarily in hepatocytes, bile duct epithelium, and, to a lesser degree, Kupffer cells and other mesenchymal cells. Prior to the development of cirrhosis, the hemosiderin accumulates primarily in periportal hepatocytes and is less toward the central veins. The iron of cirrhotic livers is mostly in the periphery of regenerative nodules. Fibrosis begins periportally, then fibrous septa traverse the lobules. Usually, the distortion of the architecture is not as severe or as uniform as in alcoholic cirrhosis.43,44 and 45 In patients with advanced disease the histologic features may be difficult to distinguish from those of alcoholic cirrhosis, except for the marked deposition of hemosiderin in hemochromatosis. In fact, most of the patients with much fatty change probably represent combined alcoholic cirrhosis and hemochromatosis. The pancreas also exhibits diffuse fibrotic change, with loss of islets, and intense hemosiderin deposition. In the pituitary, iron deposition is most pronounced in gonadotroph cells of the anterior lobe.46
Genetics Hemochromatosis is usually due to mutations in the HFE gene. Two mutations of this gene are quite prevalent in North America and in other populations derived predominantly from northwestern Europe (Fig. 42-2). The more important of these is G ® A at nucleotide (nt) 845, resulting in a change from cysteine to tyrosine at amino acid position 282. Accordingly, this mutation may be designated 845A (or C282Y, where C represents cysteine and Y represents tyrosine). The other common mutation is C ® G at nt 187, which results in a histidine to aspartic acid substitution at amino acid position 63. Thus, this mutation may be designated 187G (or H63D, where H represents histidine and D represents aspartic acid). Other terminology has also been used for these mutations, as shown in Table 42-2and Table 42-3. (Furthermore, some protein chemists use yet a different notational system, in which amino acid position 282 is designated 260, and position 63 is designated 41.47 This difference depends on whether the numbering of amino acids begins with methionine at the initiation of the signal sequence or at the first amino acid of the mature protein. To avoid confusion, in this chapter reference will be made consistently to these two mutations as 845A(C282Y) and 187G(H63D). A third mutation of the HFE gene is nucleotide 193 A ® T, corresponding to substitution of cysteine for serine at amino acid position 65. The frequency of this 193T(S65C) allele is approximately 0.025, or an approximately 5 percent prevalence (in France) of 193T(S65C) heterozygotes. It is associated with mild hemochromatosis in 845A(C282Y)/193T(S65C) compound heterozygotes.48 A few other mutations of the HFE gene have been reported.

FIGURE 42-2 The approximate distribution and frequency of the major hemochromatosis allele 845A(C282Y) in Europe. The highest frequency is in the region bordering the North Sea and the North Atlantic and in populations elsewhere in the world that derive from this area of northwestern Europe.

TABLE 42-2 NOMENCLATURE OF THE HFE ALLELES

TABLE 42-3 APPROXIMATE EXPECTED PREVALENCE (%) OF COMBINATION OF HFE ALLELES IN CAUCASIANS OF NORTH AMERICA AND NORTHWESTERN EUROPE*

Of patients of northern European ancestry with clinically defined hereditary hemochromatosis, approximately 83 percent are homozygous for 845A(C282Y) (Table 42-3) and approximately 5 percent are compound heterozygotes, having, on one chromosome 6, the mutation 845A(C282Y) and on the other chromosome 6, 187G(H63D). Clinically significant iron overload has also been described in homozygotes for 187G(H63D), but usually such homozygotes have little or no clinical evidence of hereditary hemochromatosis. The HFE mutations are allelic to each other and to the wild type allele, and each HFE gene contains, at the most one mutation. (In a rare exception to this rule, report has appeared of a meiotic recombination event that resulted in both mutations being “in cis,” that is, on the same chromosome.49) It is inevitable that additional mutations will be described in the future. However, up to 20 percent of patients with northern European ancestry and clinically severe hereditary hemochromatosis do not to have mutations of the HFE gene.14,50 In Italy and in Alabama, an even greater proportion of patients, 35 percent, lack HFE gene mutations. Investigations of such patients are in progress. To date, they do not appear to have mutations of either the b2 microglobulin gene or the DCT1 gene.51
The mode of inheritance of hereditary hemochromatosis is autosomal recessive.13,52,53,54 and 55 However, because of the unusually high 845A(C282Y) gene frequency in affected populations, homozygotes often mate with heterozygotes.54 Such families appear to have dominant inheritance.
Because of the hereditary nature of this disorder, it is imperative that other family members be examined in order to identify affected relatives early. Within such a family, on average, one-fourth of the sibship will have the same mutant alleles, for example, homozygous 845A(C282Y).
The locus of the HFE gene on chromosome 6 is approximately 4 million nucleotide base pairs telomeric to that of the major histocompatibility gene HLA-A. Because of this relatively close proximity, the relatively recent origin of the mutation, and the fact that crossovers appear to be particularly rare in this region of the genome, linkage disequilibrium of HLA and hemochromatosis alleles exists.10,11 and 12,55,56 The frequency of HLA-A3 antigen in the general population is approximately 28 percent, but in patients with hemochromatosis the frequency is 70 percent. The prevalence of HLA antigen B7 in patients is 50 percent, compared with 23 percent in the general population. Some series have shown increased frequency of HLA-B14.7,8,53,57,58 The linkage disequilibrium between HLA and HFE implies an ancestral HFE mutation that occurred before the migration of Europeans to North America, Australia, New Zealand, and South Africa.12 This mutation may have occurred 50 to 70 generations ago in northwestern Europe,59,60 and 61 perhaps sometime between the years 500 and 700 of the common era, then become widely dispersed in this region with the migrations of Celts, Norse, and Goths. The mutation presumably conferred a selective advantage: those with this mutation would recover more quickly from blood loss than would those with only the wild type allele. Both the 845A(C282Y) and 187G(H63D) mutations have been found in Sri Lanka; haplotype analysis indicated that these occurred de novo.62
Prevalence The mutant genes that are responsible for hemochromatosis exhibit high frequencies in people living in the region around the North Sea and in populations that are derived from this region (Fig. 42-2, Table 42-3). Thus, the highest known gene frequencies for the 845A(C282Y) allele are in Iceland, Norway, Denmark, Sweden, the Netherlands, Germany, western France (especially the Brittany Peninsula), northern Portugal, Spain, Ireland, the United Kingdom, Australia, New Zealand, and the Caucasian populations of North America and South Africa.19,20 and 21,23,24,25,26,27 and 28,30,63,64,65,66,67,68 and 69 In these populations, the gene frequency of 845A(C282Y) is 0.05 to 0.1, approximately 1 person out of every 10 is a carrier of this gene, and approximately 1 per 250 is homozygous and at risk of clinical hemochromatosis. The 845A(C282Y) allele is progressively less common to the east and south of the North Sea littoral. It is still common in eastern France and northern Italy but uncommon in eastern Europe and rare in Turkey, the Middle East, among Ashkenazic Jews,70 in North Africa, sub-Saharan Africa, and rare in Asia, among Pacific islanders, and native Americans. Surprisingly, the gene frequency for the 845A(C282Y) allele appears to be lower in Alabama than in the northern and western states of the United States, and in Canada.71,72
Although hemochromatosis appears to be rare in African Americans, the prevalence of homozygosity for the 845A(C282Y) allele in this population should be approximately one-ninth that in the predominantly European-derived population, or about 0.3/1000.
The other common hemochromatosis-associated allele, 187G(H63D), has an even greater frequency, occurring in nearly 30 percent of the people of Europe, Canada, and the United States; 2 or 3 out of every 100 are homozygotes. This allele has a slightly higher frequency in western Europe (and in people of European origin) than elsewhere, but it has a more nearly uniform worldwide distribution.
Clinical Features Hemochromatosis is an insidious disease in which iron accumulation occurs over the course of decades; evidence of tissue injury often does not appear until the fifth decade or later. Further, the hemochromatosis mutations are not completely penetrant: Many persons who are homozygous for the hemochromatosis allele have only moderate iron overload and never exhibit clinical manifestations of the disease.20,54,57 Iron overload sufficient to cause symptoms or signs may occur in approximately 50 percent of persons who are homozygous for the 845A mutation. Increased iron stores may be demonstrated in another 25 percent, and approximately one-fourth of 845A homozygotes may exhibit neither symptoms nor evidence of iron overload.73 Thus, in large, unselected surveys, clinical expression, or penetrance, of the 845A(C282Y) allele was about 50 percent in homozygotes.73,74 and 75 In one study of clinically unselected siblings of 99 previously identified homozygotes, 86 were found also to be homozygotes, and of these, 30 percent had clinically expressed hemochromatosis, that is, there was 30 percent penetrance. However, for homozygotes of age greater than 40 years, 50 percent had clinical manifestations, whereas for those of age less than 40 years, only 12 percent had clinical manifestations.74 This study was later expanded to include 214 clinically unselected homozygotes in 103 kindreds that had a previously identified homozygous hemochromatosis proband.76 Results were the same: 52 percent penetrance was observed in males of age greater than 40 years; 10 percent penetrance in women. Some studies show penetrance to be much less than 50 percent,77,78 whereas some find penetrance to be greater than 50 percent.79,80 Since most of the published data are based on family studies, the level of penetrance in 845A(C282Y) homozygotes of the general population will not be known until more data are available. All agree that penetrance is less for the 845A/187G (C282Y/H63D) heterozygote and much less for the 187G(H63D) homozygote.16,17 and 18,81
Overt disease occurs more commonly in males than in females, by a ratio of 3:1. During the reproductive years women may be protected from iron accumulation because of the iron loss attendant upon menstruation and pregnancy. Thus, women are less often affected than men, and the manifestations of hemochromatosis are uncommon prior to the menopause. However, in some women the disorder may be fully expressed in the third or fourth decade, and pituitary hypogonadism may cause amenorrhea and premature menopause. A French and Canadian study failed to demonstrate any difference between males and females with respect to time of onset or severity of clinical manifestations.82
In view of the high prevalence of the hemochromatosis alleles in European-derived populations, clinicians may wonder why their offices are not full of patients with this disorder. Homozygous hemochromatosis has about twice the prevalence in Caucasians as sickle cell anemia in African Americans. Both are of autosomal recessive inheritance. The hemochromatosis allele 845A(C282Y) has lower penetrance in homozygotes and often is not manifested before the age of 40 years; the Hb S mutation has 100 percent penetrance in homozygotes and is usually manifested in infancy. The recurrent, severe pain and other dramatic manifestations of sickle cell anemia demand medical care from infancy throughout the patient’s life. The manifestations of hemochromatosis, late in onset and of nonspecific character, do not bring this disorder so insistently to the attention of the physician. Neither disorder is sufficiently common to fill clinicians’ offices. A clinician whose patients are predominantly Caucasian should have, on average, 4 or 5 patients who are homozygous for the 845A(C282Y) allele among 1000 patients under his or her care; some have more and some have none. The manifestations of hemochromatosis in this small number of patients may be overlooked when a practice has so many patients with other complaints. “Chi non cerca, nulla trova”; he who doesn’t look doesn’t find.
The most frequent symptoms are abdominal pain, weakness, lethargy, loss of libido, weight loss, and arthralgia. The abdominal pain is nonspecific. Fatigue, asthenia, and mental aberrations affect at least a third of patients.83 Fatigue may be overwhelming and disabling. Dementia is rare. The acute onset of severe adominal pain, distention, and shock is usually a fatal complication that is due to bacterial peritonitis.
The arthralgia typically involves the second and third metacarpophalangeal joints but may also involve interphalangeal joints and large joints, such as the knees.84,85,86 and 87 The joints may be swollen and tender, and these manifestations may be mistakenly ascribed to rheumatoid or degenerative arthritis.
Hyperpigmentation of skin is a common manifestation. The pigment is predominantly melanin, although hemosiderin deposition also occurs in the skin. There may be a diffuse tanning or bronzing, or slate grey appearance of the skin, particularly in axillary, inguinal, and perineal areas, which are not ordinarily exposed to sunlight. Elsewhere, the appearance may be that of a perpetual suntan. Alopecia and cutaneous atrophy may also occur, especially as late manifestations.
Cardiac arrhythmias are common, particularly in young patients. Dyspnea, edema, and other manifestations of cardiac dysfunction may result from restrictive cardiomyopathy, due to impaired contractility of the iron-laden heart or may be due to dilatational cardiomyopathy.88,89 and 90
Coronary artery disease, as manifested by atherosclerosis or by myocardial infarction, is uncommon in patients with severe iron overload or in those who are homozygous for the 845A(C282Y) mutation.91 Speculation about the role of iron in coronary artery disease relates to the generation of free radicals OH– and O–2 when Fe+2 is oxidized to Fe+3. In eastern Finland positive correlations were observed between high normal values of serum ferritin concentration and acute myocardial infarction and also between heterozygosity for the 845A(C282Y) mutation and myocardial infarction.92,93,94 and 95 However, in Helsinki, in southern Finland, a negative correlation was found between 845A(C282Y) gene heterozygosity and myocardial infarction: Heterozygotes appeared to have lower risk of coronary artery disease.96 Most other studies in Europe and North America have shown no relationship between increased iron stores and coronary artery disease.91,97,98,99 and 100
Endocrinopathies that result from hemochromatosis include diabetes mellitus, hypothyroidism, and hypogonadotrophic hypogonadism. There is little correlation between the degree of iron overload and the severity of diabetes.101 Peripheral neuropathy may occur secondary to diabetes.83,102 Approximately half the patients with hemochromatosis have pituitary insufficiency, chiefly affecting gonadotrophins.103,104 and 105 Ten percent of male patients have hypothyroidism, a frequency 80 times that of the general population.106 Testicular atrophy, reduced libido, and impotence are common manifestations. Azoospermia may occur.
Hepatomegaly and splenomegaly are common. Jaundice is unusual except when there is severe cirrhosis or hepatoma. Gastrointestinal hemorrhage from esophageal varices is a late complication and is often fatal. Hepatocellular carcinoma occurs in nearly a third of persons with hepatic cirrhosis from hemochromatosis, a higher frequency than in alcoholic cirrhosis. It is quite rare in the precirrhotic phase of hemochromatosis.
Laboratory Tests The blood hemoglobin concentration, erythrocyte count, hematocrit, erythrocyte indices, leukocyte count and differential, platelet count, and reticulocyte count are normal except late in the course of the disease, when anemia, leukopenia, and thrombocytopenia may be observed as an expression of severe liver disease. Blood glucose concentration may be increased and glucose tolerance test abnormal. The serum iron concentration exceeds the normal range for the method employed, and the transferrin saturation exceeds 50 percent. The total iron-binding capacity of serum (TIBC) is normal except when there is liver cirrhosis; then, the TIBC may be reduced.54,57,107,108 Serum ferritin concentration exceeds 300 µg/liter and may exceed 3000 µg/liter. The serum (AST) transaminase activity is increased in approximately two-thirds of patients. Blood concentrations of pituitary gonadotrophins and androgens are usually markedly diminished. Thyrotropin (TSH) is usually increased in patients with hypothyroidism. An electrocardiogram may demonstrate arrhythmia of atrial or ventricular origin, extrasystoles, low voltage, or repolarization abnormalities of the ST and T segments. Echocardiogram and catheterization data may demonstrate dilated or restrictive cardiomyopathy. Radiographic examination of hands and wrists or of other affected joints reveals soft-tissue swelling, narrowing of the joint space, irregular articular surfaces, and decreased bone density.84,85,86 and 87,109,110,111,112,113 and 114 Osteoporosis and subcortical cysts are also common findings.112,113 Chondrocalcinosis or calcification of periarticular ligaments is a late manifestation of the arthropathy.109 Synovial fluid may contain calcium pyrophosphate and hydroxyapatite crystals.111 Chest x-ray may reveal cardiomegaly, increased pulmonary vascular markings, or pleural effusion.
Differential Diagnosis Because hemochromatosis is a multisystem disease, it has extremely diverse manifestations and thus often masquerades as other disorders. Chronic fatigue is often ascribed to depression or neurasthenia. Impotence is also commonly considered psychological in nature. Hypothyroidism may be considered idiopathic. Palpitations that are due to arrhythmia may lead to a diagnosis of “solitary atrial fibrillation” or other cardiologic diagnosis. Cardiomegaly may be attributed erroneously to myocarditis. Arthropathy may be considered due to degenerative or rheumatoid arthritis. Elevated serum transaminases may be ascribed to ethanol indulgence or viral hepatitis. Elevation in blood glucose may lead to a diagnosis of type II, or adult-onset, diabetes mellitus. Amenorrhea or osteoporosis may be attributed to premature menopause. Hyperpigmentation is often considered due to sun exposure, even in those who have not such exposure. Thrombocytopenia, which reflects chronic liver disease, is unexplained and ignored. Pleural effusions, resulting from cirrhosis and usually accompanied by ascites, may be considered idiopathic.
Because of the diversity of clinical manifestations, and because medical specialists tend to concentrate their attention on abnormalities that are within the sphere of their specialty, the manifestations of hemochromatosis are often treated separately according to the organ system to which symptoms and signs can be related: Cardiologists treat the arrhythmias or the congestive heart failure, “depression” is treated by generalists, neurologists, or psychiatrists with antidepressive medication, urologists attempt to treat the impotence, pulmonologists drain the pleural effusions, endocrinologists treat the hypothyrodism, etc. When clinicians fail to recognize the multisystem nature of the disease, its proper diagnosis and management are delayed, often for 10 years or more, and the opportunity to provide optimal treatment is lost. Quite often, the price of diagnosis-made-too-late is cirrhosis of the liver, liver cancer, insulin-dependent diabetes mellitus, permanent joint deformities, and premature death as a result of hepatic or cardiac failure or hepatocellular carcinoma.
Prevention of organ damage to liver, pancreas, heart, pituitary, and other organs, and of hepatocellular carcinoma requires diagnosis and treatment during the precirrhotic stage, when there may be neither symptoms nor signs of iron overload. For this reason, screening tests have been recommended to ensure early diagnosis and treatment of hemochromatosis.115,116,117,118,119,120,121 and 122 Analyses of costs for screening have shown a high benefit-to-cost ratio. The cost of screening per case identified has been estimated as being between $1000 and $8000.116,117 and 118,122 By comparison, the approximate costs of screening for colon cancer, breast cancer, or for galactosemia (in neonates) are, respectively, $100,000, $70,000, and $140,000 per case identified, costs that society and third-party payers deem acceptable. With universal screening, diagnosis of hemochromatosis could be done at an overall cost of $1000 per case identified, and the average lifetime treatment cost per case should not exceed $6500; whereas, without early identification and treatment, the eventual cost of medical care, per case, would be $46,000.122 By these estimates, universal screening, early diagnosis, and treatment would result in a net saving to society of more than $38,000 per case identified. Thus, there is a compelling financial argument for hemochromatosis screening, in addition to the ethical and humanitarian needs of reducing morbidity and early mortality. However, implementation of universal screening for hemochromatosis is being delayed because of concern over possible adverse psychologic or social effects of positive test results, such as stigmatization and difficulty obtaining life insurance and health insurance.123,124,125 and 126
Of screening tests, the most useful is the assay of serum iron, TIBC, and calculation of transferrin saturation (in percent). When the serum iron concentration is above the normal range for the method used and transferrin saturation is 50 percent or greater, there is a high probability of hemochromatosis. This presumes that other causes of elevated serum iron concentration have been excluded. A common cause for elevated serum iron concentration is exogenous iron, for example from that ingested in medication or in iron-fortified vitamin preparations. Patients often overlook providing this information; a specific inquiry about use of over-the-counter pills is necessary. Iron contamination of glassware or reagents or of the serum specimen itself is rare in a well-managed laboratory. The serum ferritin assay is not sensitive early but is only elevated when iron overload has developed. Marrow examination may or may not show increased stainable iron127,128 and therefore is not a useful diagnostic test. Ringed sideroblasts are absent.
A liver biopsy may be appropriate, particularly in patients more than 40 years of age, who have hepatomegaly or splenomegaly, elevated serum transaminase, especially AST, and serum ferritin concentration greater than 1000 µg/L. Patients who do not meet these criteria are quite unlikely to have hepatic cirrhosis and should not undergo liver biopsy. When needed for diagnosis, liver biopsy provides a specimen for hematoxylin and eosin and Prussian blue stains and usually sufficient material as well for chemical assay of iron content. Thereby, the degree of hepatic injury may be assessed, and the amount of iron deposition estimated microscopically on a scale of 0 to 4+, in addition to the chemical assay of iron.44,129 Microscopic estimation of iron content generally correlates well with the chemical assay. In normal liver, the iron content is estimated at 0 to 1+ histologically and not more than 50 µmol/g (2.8 mg/g) dry weight. In persons with alcoholic liver disease, the iron content of liver is 0 to 2+ microscopically and less than 70 µmol/g (3.9 mg/g) dry weight. In hemochromatosis, liver iron content is 3 to 4+ by microscopic estimation and usually exceeds 70 µmol/g by chemical assay. Most patients with cirrhotic hemochromatosis have liver iron content of 200 µmol/g (11 mg/g) dry weight or more.130 The hepatic iron index (HII) is the ratio of the hepatic iron concentration in µmol/g to the patient’s age in years. This index is not greater than 1.1 in normal persons; it is usually 2.0 or more in hemochromatosis. Exceptionally, it may be as high as 24. The rationale of the HII is questionable because hepatic iron concentration has no correlation with patients’ age,131 as once thought, and since elevated HII may be observed in end-stage liver disease of any cause,132,133 or even in patients following marrow transplant for a variety of disorders.134
Temporary morbidity may follow liver biopsy.135 Serial phlebotomy provides more accurate information concerning total iron burden than does measurement of liver iron concentration. The only additional information that liver biopsy provides is whether there is cirrhosis, but this does not guide therapy. Liver biopsy is unnecessary unless the physician believes that this additional information is important for patient management. An example might be in late-stage liver disease when liver transplantation is considered.
Computed tomography is too insensitive to iron content of liver for diagnostic use. However, magnetic resonance imaging (MRI) can be used for this purpose, since the T2-weighted signal intensity is inversely proportional to iron content, and the correlation of this with iron content of liver is quite satisfactory.136,137,138,139,140,141,142 and 143 MRI may not reveal early cirrhosis. As an indicator of iron overload, MRI is much more costly (in excess of $1000) than serum ferritin assay.
HLA testing, of patients or siblings, is no longer justifiable. Alcoholics who have iron overload cannot be differentiated from other persons with hereditary hemochromatosis on the basis of differences in clinical or laboratory manifestations nor in the frequencies of HLA alleles.9,56 Thus, they have hereditary hemochromatosis complicated by ethanol abuse. On average, such persons have a slightly lower iron burden than do abstemious hemochromatotics.56
Treatment Treatment is by the removal of 500 ml of blood once weekly. Less blood may be removed each week from small patients. Occasionally, when the iron burden seems very great, twice weekly phlebotomy may be worthwhile. Each phlebotomy removes 175 to 225 mg of iron. Thus, in the course of a year, 10 g of iron may be removed as a result of removal of 50 units of blood. Since the total iron burden may be 30 to 40 g, a twice weekly phlebotomy program often requires 1 to 2 years to reduce the body iron content to normal level. A program of weekly phlebotomy may require 2 to 3 years. With this program, there is an initial decline in blood hemoglobin concentration, which returns to normal value within a few weeks, as hematopoiesis is accelerated. A persistently falling blood hemoglobin concentration, after many months of phlebotomy therapy, is the best indicator that treatment has been adequate. By this time serum ferritin levels are usually below 10 ng/ml. Thereafter, 500 ml of blood should be removed every few months, in order to prevent reaccumulation of excess iron stores and to remove additional iron that was not readily available for erythropoiesis but was redistributed with time. Some patients reaccumulate iron slowly; for them, it may suffice to monitor the serum ferritin concentration annually to determine when additional phlebotomies are required.144 In many adequately treated patients, the serum iron concentration and transferrin saturation return to elevated levels long before there is a sufficient increase in iron stores to justify repeat phlebotomy. For this reason, following completion of phlebotomy therapy, the serum ferritin concentration is the better guide to determine the need for, and the frequency of, additional phlebotomies.
Iron chelators, such as desferrioxamine, should not ordinarily be used in the treatment of hereditary hemochromatosis, because such treatment is less efficient, and far more expensive and inconvenient, than is phlebotomy.
Additional therapeutic measures include treatment of diabetes, of cardiac arrhythmias and insuffiency, of variceal bleeding if it occurs, and replacement of androgens or estrogens and progesterone when clinically appropriate.
It is not practical to attempt to alter dietary intake of iron. Alcohol in excess is clearly deleterious. Complete abstinence is prudent until all excess iron has been removed. For those who have evidence of liver or other organ injury, subsequent complete avoidance of alcohol and other hepatotoxins is appropriate. Patients without evidence of organ damage should be admonished to avoid any but the most moderate alcohol indulgence. A practical guideline might be, for example, not more than 1 glass of wine (or 8 oz of beer) with dinner three times weekly. A few glasses of wine per week are probably harmless for such patients once iron stores have been depleted. For some patients complete abstinence may be easier to sustain. Patients should be advised to avoid handling or consumption of marine shellfish unless thoroughly cooked because they are peculiarly susceptible to fatal sepsis from the marine bacterium Vibrio vulnificus.145,146 Peritonitis and septicemia have also been reported due to infection with Yersinia enterocolitica in patients with hemochromatosis or with iron overload from chronic oral ingestion or transfusion or with thalassemia major.147,148 This organism, which causes acute febrile illness accompanied by diarrhea, mesenteric lymphadenitis, tonsillitis, and other systemic symptoms in normal persons, is more virulent in those who are iron-overloaded from any cause.
Patients in whom the diagnosis is made too late and who have advanced cirrhosis or hepatocellular carcinoma may require liver transplantation (see below).
Prognosis Before phlebotomy was widely used as treatment for hemochromatosis, the median survival of untreated patients was estimated as approximately 2 years.6 Subsequent studies indicate much better prognosis in treated patients149,150 and 151 and nearly normal survival in those treated during the precirrhotic phase.149,152 An analysis of survival data for 163 patients reported from Germany indicated a median survival, for all patients, of 20 years, compared with more than 25 years expected for matched age and sex normal persons.149 Adverse survival factors were hepatic cirrhosis, diabetes mellitus, and inadequate iron depletion therapy (Table 42-5). This greatly improved prognosis may reflect earlier diagnosis and treatment.

TABLE 42-4 GENOTYPE FREQUENCIES FOR THE HFE ALLELES IN NORMAL AND HEMOCHROMATOSIS SUBJECTS*

TABLE 42-5 SURVIVAL IN HEREDITARY HEMOCHROMATOSIS

Despite the improvement in survival, many problems remain for hemochromatosis patients. Adequate therapy usually has little effect on the arthritis, diabetes, hypogonadism, or sterility. Rarely, serial biopsies may indicate regression of hepatic fibrosis. The 30 percent probability of hepatocellular carcinoma is not diminished by treatment once there is hepatic fibrosis.153 An increased frequency of extrahepatic carcinomas, such as lung cancer, has also been reported154 but has not been observed in other large series. Dilatational cardiomyopathy may progress despite adequate iron removal.115 Arthritis may first appear after adequate iron depletion. Conversely, the severity of diabetes may lessen or progression of diabetes may be averted, cardiac function is usually improved by iron depletion, the cutaneous hyperpigmentation nearly always clears, and symptoms of debilitating fatigue and abdominal pains may subside. If treatment is begun before age 40, gonadal insufficiency may improve.105,156
Patients who have required liver transplant for late-stage hemochromatosis have a median survival of approximately 3 years, compared with median survival greater than 7 years when liver transplantation has been for other causes such as alcoholic cirrhosis.157,158 This relatively poor posttransplant prognosis applies both to those who have hepatocellular carcinoma and to those who do not.
OTHER CAUSES OF HEMOCHROMATOSIS
CHRONIC ANEMIAS
Many chronic severe anemias are associated with iron overloading. Best recognized is that which accompanies thalassemia major. Severe iron overloading may also occur in patients with congenital dyserythropoietic anemia, pyruvate kinase deficiency anemia, or glucose-6-phosphate deficiency hemolytic anemia, even in patients who have not required transfusion. Iron overload appears to be rare in hereditary spherocytosis and unusual in thalassemia minor. Some patients with these disorders who have iron overload appear independently also to be hereditary hemochromatosis homozygotes or heterozygotes.159,160 and 161 The clinical features of secondary hemochromatosis are the same as those of hereditary hemochromatosis, with the additional feature of anemia. Complications of hemochromatosis, are common causes of fatality. In sideroblastic anemias, iron overloading is the rule. A few such patients can be effectively treated by phlebotomy, particularly if they respond to pyridoxine administration; unfortunately, most cannot. Before erythropoeitin became available for treatment, iron overloading often followed frequent transfusions in chronic renal failure patients who received long-term dialysis therapy.162
Anemic patients with iron overloading may require daily infusion of 1 to 2 g (20–40 mg/kg) of desferrioxamine-B by portable battery-operated pump, for 8- to 12-h intervals, which may be overnight.161,163 The oral administration of 100 to 500 mg of vitamin C, after each infusion has been started, enhances the rate of excretion of iron induced by chelation with desferrioxamine.164 (See Chap. 46 for details.) An orally effective iron chelator is needed, but at this time, none of those that have been tested is safe and effective nor has any been approved for use in the United States. Patients who are not anemic, or only slightly anemic, but who have become iron overloaded as a result of chronic ingestion of iron can be treated effectively by phlebotomy, although it is unusual in nonanemic patients for enough iron to have been accumulated that such therapy is required.
AFRICAN NUTRITIONAL HEMOCHROMATOSIS (BANTU SIDEROSIS)
An endemic form of acquired hemochromatosis occurs in African people who consume a native beer brewed in iron kegs.165,166 A liter of this beer contains 80 mg of iron, so those who drink large amounts may ingest hundreds of milligrams of iron daily. There may also be a genetic factor: In Zimbabwean villages 30 percent of the people were believed to be heterozygotes for a hemochromatosis gene that has not been identified and is not HLA-linked. Both homozygotes and heterozygotes were at risk for hemochromatosis if they consumed the native beer.167 It is not known how widespread this gene is outside of Zimbabwe nor whether it is prevalent in African Americans.
The features of this disorder are similar to those described above for hereditary hemochromatosis except that iron deposition is predominantly in cells of the monocyte-macrophage system. However, iron is deposited in parenchymal cells of various organs, and in the synovial lining cells of joints, concurrently with the development of hepatic cirrhosis.168
SHUNT SIDEROSIS
Splenorenal or portal-caval shunting, in the treatment of portal hypertension, has led to astonishingly rapid iron accumulation in many reported patients.169,170 This may occur in as many as 20 percent of patients so treated. Severe hemochromatosis has developed within 16 months of the shunting procedure, leading to death from cardiomyopathy. In rare instances the rapid development of hemochromatosis in patients with portal hypertension has been ascribed to intrahepatic shunting.171
PORPHYRIA CUTANEA TARDA (PCT)
PCT is a disorder with principally cutaneous manifestations which is also usually associated with iron overload that may result in hepatic cirrhosis. The underlying cause appears to be reduced activity of uroporphyrinogen decarboxylase. (See Chap. 62.) Both in humans with porphyria cutanea tarda and in mice with experimental porphyria induced by injections of iron dextran, uroporphyrin crystals and ferritin accumulate in the same hepatocytes, as demonstrated by electron microscopy.172 Patients with the acquired form of PCT have very high prevalence of mutations of the HFE gene, 845 A in northern Europe173,174 and 175 and 187G in southern Europe.176 Persons with this disease have a higher frequency of hepatitis C infection than in the general population.177 The iron overload that occurs in PCT is less than in hereditary hemochromatosis, but PCT is usually ameliorated by phlebotomy to reduce iron stores.178,179
NEONATAL HEMOCHROMATOSIS
A rare and usually lethal disorder of the newborn is characterized by marked iron deposition in the liver, sometimes in conjunction with giant cell hepatitis.180,181,182 and 183 The cause of this disorder is unknown. No HFE mutations have been found in this disorder.15 Because it has occurred in siblings, and in half-siblings born of two unaffected mothers, it may be conditioned by autosomal recessive inheritance.184,185 Liver transplantation has been successful.186
JUVENILE HEMOCHROMATOSIS
Some patients of hereditary hemochromatosis have presented prior to age 20 with severe manifestations, especially cardiac dysfunction and hypogonadism.184,187,188,189,190,191 and 192 As in the adult form, males predominate. Inheritance appears to be autosomal recessive. Juvenile hemochromatosis is an entity distinct from the commoner adult onset hereditary hemochromatosis, and it is not due to a mutation of the HFE gene.193,194 At least in one family, the disorder has been linked to chromosome 1q.195 Hypogonadism, in a young male, particularly when accompanied by cardiac dysfunction or arrhythmia, should alert the physician to the possibility of juvenile hemochromatosis.
DISORDERS OF IRON TRANSPORT
CONGENITAL ATRANSFERRINEMIA
In 1961, Heilmeyer and coworkers196 described congenital atransferrinemia in a young girl with severe congenital hypochromic anemia and marked, generalized iron overload. Additional patients have been reported from Slovakia,197,198 and 199 two (siblings) from Japan,200,201 and 202 two (siblings) from Mexico,203,204 one from France,205 and one from Samoa.206 To our knowledge, the only patient in the United States is a young woman from Illinois, who has been observed by one of the authors (VFF) for 15 years. An apparently identical disorder has been described in a strain of inbred mice.199,207
Atransferrinemia results in reduced delivery of iron to the marrow and reduced hemoglobin synthesis. Secondarily, there is marked increase in iron absorption by the intestinal mucosa that results in severe iron overload.
The predominant clinical features are pallor and fatigue. A systolic ejection cardiac murmur has been present in most patients. Some patients have mild hepatomegaly. Two patients died at age 7 from refractory congestive heart failure. The autopsy in both showed marked hemosiderosis and fibrosis of liver, pancreas, thyroid, myocardium, and kidneys but no iron in the marrow. Both of these patients had received numerous transfusions. Heilmeyer’s patient suffered from recurrent infections, and another patient died of pneumonia.
The anemia has been of variable severity. Total iron-binding capacity has ranged from 4.1 to 14.0 µmol/liter (24 to 81 µg/dl), and transferrin concentration has been 0 to 5 µmol/liter (0 to 39 mg/dl) [normal value 25 to 40 µmol/liter (200 to 300 mg/dL)]. Measurement of transferrin in these patients has been by radial immunodiffusion method or immunoelectrophoresis. The absence or small diameter of the precipitin ring in reported patients strongly implies a quantitative deficiency of transferrin rather than a functionally abnormal protein. There may be normal to enhanced iron absorption from the gastrointestinal tract, normal to moderately accelerated plasma iron clearance, and diminished incorporation of iron into hemoglobin (ranging from 7 to 55 percent; normal 30 to 100 percent).198,200,206 The infusion of either normal plasma or purified apotransferrin is followed in 10 to 14 days by reticulocytosis and then by a rise in hemoglobin concentration.198,201 If this therapy is repeated once or twice monthly, the patient becomes hematologically normal within a few months, although iron stores and serum ferritin concentration remain elevated. This response permits systematic removal of excess iron by phlebotomy.
DIFFERENTIAL DIAGNOSIS
Congenital atransferrinemia may be differentiated from other causes of hypochromic anemia by low serum iron concentration together with very low total iron-binding capacity, and no transferrin in serum by immunologic test. Atransferrinemia has also been described in association with the nephrotic syndrome208,209 and in a patient with erythroleukemia.210 One patient has been described who had a functional disorder of transferrin due to transferrin-IgG-transferrin immune complexes,211 clinical and laboratory features of hemochromatosis, marked elevation in serum iron concentration, and absence of stainable iron in marrow; the two latter findings distinguish this patient from congenital atransferrinemia.
TREATMENT
Good clinical reponses follow infusion of normal human plasma or of purified apotransferrin. The rise in plasma transferrin concentration does not persist beyond a week. However, the cohort of erythroblasts that take up iron during this time will mature to circulate for as long as 4 months. Therefore it may suffice to infuse normal plasma or transferrin at intervals of 2 to 4 months. The author’s patient received 500 ml of plasma intravenously, from the same small group of donors, immediately preceded by a 500 ml phlebotomy, monthly for more than 10 years. After 120 phlebotomies, she was hematologically normal and completely iron depleted, with serum ferritin concentration less than 5 µg/L. However, she has hypopituitary hypogonadism requiring replacement estrogen therapy. The two Japanese patients have been given 1 to 2 g of highly purified apotransferrin intravenously every 3 to 4 months for 4 to 7 years with good effect and without the development of antitransferrin antibodies.212 The Slovak patient was also given apotransferrin infusions and desferrioxamine to remove excess iron. This patient now has arthropathy and siderosis of synovial membranes. Use of purified transferrin reduces the risk of hepatitis that would attend infusion of whole plasma. The need for erythrocyte transfusion and the consequent long-term risk of hemochromatosis are also obviated by use of transferrin infusion. Purified transferrin is not available for therapy in the United States. However, the monthly infusion of 1 single-donor unit of normal human plasma has enabled the American patient to be treated effectively, including phlebotomies to remove excess iron, and without any complications from this treatment. It does not seem practical to treat with desferrioxamine patients who can be treated more effectively by phlebotomy.
Of the nine known patients, two died of infection, one died of cardiac failure, and one drowned while swimming. The current status of two patients is unknown. Four patients were believed to be still living in 1999. One of the Japanese patients no longer needs injections of apotransferrin.213
CONGENITAL ACERULOPLASMINEMIA
Several cases of congenital aceruloplasminemia have been reported from Japan and from Europe, This disorder is characterized by dementia, dystonia, dysarthria, diabetes, and degeneration of the retina.214,215,216 and 219
Ceruloplasmin converts Fe+2 to Fe+3. In the ferrous form, iron traverses cell membranes but cannot bind to transferrin and thus it cannot be delivered efficiently to erythroblasts. Iron that is absorbed and that enters plasma as Fe+2 is deposited in the liver, pancreas, central nervous system, and retina. Ceruloplasmin does not cross the blood-brain barrier. However, astrocytes and other neuroglia normally contain ceruloplasmin in their cell membranes, where it oxidizes Fe+2 and prevents its entry into cells of the central nervous system. In aceruloplasminemia, neuroglia are unable to synthesize ceruloplasmin.220,221
Retinal degeneration is peripheral, where there is iron deposition and loss of photoreceptor cells but little visual impairment. Other features include late-onset diabetes mellitus, marked iron deposition in liver and pancreatic islets, loss of islet b cells, mild hypochromic, microcytic anemia, and absence of plasma ceruloplasmin. Serum copper concentration is reduced, but copper metabolism is normal, and tissue copper concentration is not increased. Increased plasma lipid peroxidation occurs.222 Hepatocyte injury or cirrhosis are not observed. Iron uptake in basal ganglia can be demonstrated on nuclear magnetic resonance image analysis by decreased T2-weighted signal.
Transmission is as an autosomal recessive disorder. Mutations of the ceruloplasmin gene, which resides on chromosome 3, have been described in patients with this disorder.216,218,219,223
Congenital aceruloplasminemia has some resemblance to Wilson disease in that both conditions are characterized by tremor and low concentrations of ceruloplasmin in serum. In Wilson disease there is usually measurable but low serum ceruloplasmin; in aceruloplasminemia there is none. Wilson disease is characterized by Kayser-Fleischer corneal ring, copper deposition in liver and hepatic cirrhosis, features lacking in aceruloplasminemia. Urinary copper excretion is increased in Wilson disease but not in aceruloplasminemia. Aceruloplasminemia is characterized by iron deficiency anemia, diabetes mellitus, and excess iron in liver and basal ganglia that can be demonstrated by MRI scan, features not found in Wilson disease. Menke disease is a disorder of copper metabolism that is also characterized by very low serum ceruloplasmin and copper concentrations and reduced copper content of liver. Menke disease is manifested in infancy by mental retardation, convulsions, abnormalities of hair, osteoporosis, and death usually within the first few years of life.
Therapy recommended for congenital aceruloplasminemia is iron chelation with desferrioxamine,224 but the effectiveness of this therapy is as yet unknown.
RELATED CONDITIONS
CONGENITAL CATARACT WITH HYPERFERRITINEMIA
Several families have been reported in which congenital nuclear cataracts were associated with hyperferritinemia but without iron overload.225,226,227,228,229,230,231 and 232 Plasma concentrations of iron, TIBC, and transferrin saturation were normal, but serum ferritin concentration values were several thousand µg/liter. The ferritin contained only the L subunit. The inheritance is autosomal dominant. Hyperferritinemia is due to mutations in the iron-responsive element (IRE) of the mRNA for apoferritin, causing unregulated apoferritin synthesis. Iron is not deposited in the lenses. However, the unregulated synthesis of a protein within the cells of the lens may have an adverse colloid osmotic effect. Other cells appear not to be adversely affected.
SUPERFICIAL HEMOSIDEROSIS OF THE CENTRAL NERVOUS SYSTEM
This condition results from recurrent subarachnoid hemorrhages, with deposition of iron in the meninges. It may be associated with ataxia and other central nervous system manifestations.233
HEMOCHROMATOSIS IN OTHER SPECIES
A disorder indistinguishable from human hereditary hemochromatosis has been reported from California in several members of two herds of the Saler breed of cattle234 and also in a Channel-billed Toucan.235 Experimental strains of mice that are homozygous for “knockout” deletions of the HFE gene or b2 microglobulin gene develop increased iron levels.236,237,238 and 239
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Books@Ovid
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology

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14 comments on “CHAPTER 42 DISORDERS OF IRON STORAGE AND TRANSPORT

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