Diabetes mellitus sometimes improves, if temporarily, although it rarely disappears (37) Diabetes mellitus in patients with hemochromatosis should be …
Annals of Internal Medicine
http://wwwacponlineorg/journals/annals/01dec98/mgmthemohtm
SUPPLEMENT
DIAGNOSIS AND MANAGEMENT
Management of Hemochromatosis
Annals of Internal Medicine, 1 December 1998 129:932-939
James C Barton, MD; Sharon M McDonnell, MD, MPH; Paul C Adams, MD;
Pierre Brissot, MD; Lawrie W Powell, MD; Corwin Q Edwards, MD; James D
Cook, MD; Kris V Kowdley, MD; and the Hemochromatosis Management Working
Group
The complications of iron overload in hemochromatosis can be avoided by
early diagnosis and appropriate management Therapeutic phlebotomy is used
to remove excess iron and maintain low normal body iron stores, and it
should be initiated in men with serum ferritin levels of 300 g/L or more
and in women with serum ferritin levels of 200 g/L or more, regardless of
the presence or absence of symptoms Typically, therapeutic phlebotomy
consists of 1 removal of 1 unit 450 to 500 mL of blood weekly until the
serum ferritin level is 10 to 20 g/L and 2 maintenance of the serum
ferritin level at 50 g/L or less thereafter by periodic removal of blood
Hyperferritinemia attributable to iron overload is resolved by therapeutic
phlebotomy When applied before iron overload
becomes severe, this
treatment also prevents complications of iron overload, including hepatic
cirrhosis, primary liver cancer, diabetes mellitus, hypogonadotrophic
hypogonadism, joint disease, and cardiomyopathy In patients with
established iron overload disease, weakness, fatigue, increased hepatic
enzyme concentrations, right upper quadrant pain, and hyperpigmentation are
often substantially alleviated by therapeutic phlebotomy Patients with
liver disease, joint disease, diabetes mellitus and other endocrinopathic
abnormalities, and cardiac abnormalities often require additional, specific
management Dietary management of hemochromatosis includes avoidance of
medicinal iron, mineral supplements, excess vitamin C, and uncooked
seafoods This can reduce the rate of iron reaccumulation; reduce retention
of nonferrous metals; and help reduce complications of liver disease,
diabetes mellitus, and Vibrio infection This comprehensive approach to the
management of hemochromatosis can decrease the frequency and severity of
iron overload, improve quality of life, and increase longevity
Ann Intern Med 1998;129:932-939 Annals of Internal Medicine is published
twice monthly and copyrighted
1998 by the American College of Physicians-
American Society of Internal Medicine
From Southern Iron Overload Disorders Center, Birmingham, Alabama;
Centers for Disease Control and Prevention, Atlanta, Georgia; London Health
Sciences Centre, London, Ontario, Canada; Hôpital Universitaire
Pontchaillou, Rennes, France; University of Queensland, Brisbane,
Australia; University of Utah College of Medicine and LDS Hospital, Salt
Lake City, Utah; University of Kansas Medical Center, Kansas City, Kansas;
and University of Washington, Seattle, Washington For current author
addresses, see end of text
The Hemochromatosis Management Working Group also includes Linda
Cocchiarella, MD, MSc; James S Dooley, MD; Vincent Fellitti, MD; David
Brandhagen, MD; Victor Herbert, MD, JD; and Margit A Krikker, MD
Diagnosis and Initial Evaluation
Diagnosis of Hemochromatosis
Persons with hemochromatosis have an inherited propensity to absorb excess
iron; most persons are of European origin and are homozygotes or compound
heterozygotes for a mutant gene or genes on chromosome 6p 1, 2
Hyperferremia and increased iron saturation of transferrin are essential
attributes of hemochromatosis A
transferrin saturation of 60 or more for
men and 50 or more for women on at least two occasions in the absence of
other known causes of elevated transferrin saturation suggests the
diagnosis of hemochromatosis 1, 2 and permits affected persons to be
identified before iron overload develops Normal or subnormal serum
transferrin saturation values occur in unusual circumstances 3 Many
persons who have hemochromatosis without iron overload are children, young
adults, and premenopausal women Although iron overload often develops in
patients with hemochromatosis, the demonstration of hepatic or systemic
iron overload and associated complications is not needed to confirm the
diagnosis Table 1 1, 2, 4
Evaluation of Iron Overload
Iron overload develops primarily because mechanisms to eliminate excess
iron are limited Many persons, particularly men, eventually develop severe
iron overload Women are at lower risk, partly because of iron losses
during menstruation, childbirth, and lactation 1, 2 The severity of iron
overload is most often determined by measuring the serum ferritin level,
although inflammation or cancer can elevate this level in the absence of
iron overload Approximately 90 of
excess iron is retained in the liver
Therefore, many patients benefit from analysis of liver biopsy specimens to
identify liver disease and to determine the presence or absence of
cirrhosis, which directly affects prognosis Biopsy specimens should be
evaluated for iron by histochemical methods Perls staining and
quantitative techniques atomic absorption spectrometry 4-7 The
quantity of iron removed by therapeutic phlebotomy is a valuable
retrospective indicator of the severity of iron overload 8 Radiologic
imaging techniques are too insensitive for the evaluation of most young,
asymptomatic persons with little or no excess hepatic iron 1, 2 The
hepatic iron index is useful in distinguishing persons who are homozygous
for hemochromatosis from heterozygotes and persons with other hepatic
disorders 5, 9 Some patients have coincidental conditions that augment
iron absorption and thus increase iron overload for example, excessive
dietary iron supplementation, excess ethanol ingestion, porphyria cutanea
tarda, or hemolytic anemia 1, 2, 10, 11 Because serum iron variables in
patients with viral hepatitis can mimic those in patients with
hemochromatosis and because some patients have both
disorders, persons with
hemochromatosis must often be evaluated for hepatitis 12-14
Medical Evaluation before Treatment
From each patient, physicians should collect information that includes a
review of current and past symptoms and health problems, especially those
related to liver, joint, and heart disease; diabetes mellitus and other
endocrinopathic conditions; sexual function; and skin pigmentation 1, 2
A dietary history should focus on general dietary habits and food choices,
use of dietary supplements, and ingestion of ethanol Any history of blood
donation, receipt of blood transfusion, and illness associated with blood
loss should be documented The details of menstruation, childbirth,
lactation, menopause, and hysterectomy are important women taking oral
contraceptives may have decreased menstrual blood loss or may absorb less
dietary iron The history should include inquiries about family members,
especially first-degree relatives The physical examination must include
assessment of the liver, joints, heart, endocrine status, and skin
coloration Certain sequelae of iron overload may require additional
specific evaluations to assess management needs Table 1
Therapeutic
Phlebotomy
Described in 1952, therapeutic phlebotomy was the first successful
treatment for iron overload due to hemochromatosis 15 and is still the
preferred treatment for this condition today 1, 2 The removal of 1 unit
of blood 450 to 500 mL results in the loss of 200 to 250 mg of iron
Although iron chelation and erythrocytapheresis have also been used 16,
17, therapeutic phlebotomy is safer, more efficient, and more economical
1, 2
Selection of Patients for Treatment
Most persons with hemochromatosis benefit from therapeutic phlebotomy
Table 2 Rarely, children and adolescents have severe iron overload
often associated with cardiac and anterior pituitary failure and need
aggressive therapeutic phlebotomy for removal of 15 to 20 units weekly,
if possible 18-20 Withholding therapeutic phlebotomy from older patients
on the basis of age alone is not justifiable In asymptomatic persons with
iron overload Table 2, therapy must not be delayed until symptoms
develop However, some patients are not candidates for treatment because
they are intolerant toward phlebotomy or have limited life expectancy
Patients with severe, refractory anemia require iron chelation therapy
21
Approximately 8
of white persons of western European descent inherit one
detectable hemochromatosis gene and thus are heterozygotes 22 Of the 1
to 3 of heterozygotes who develop iron overload 23, many have a
coincidental disorder that increases iron absorption or alters iron
metabolism 1, 2, 14; others may have an additional hemochromatosis
mutation or mutations undetectable by current testing methods 24 Many
persons with porphyria cutanea tarda have skin lesions that are alleviated
with therapeutic phlebotomy, and many are heterozygous for HFE mutations
2, 25-27 No study has shown the benefits of therapeutic phlebotomy in
other persons with iron overload who are heterozygotes or compound
heterozygotes for the hemochromatosis gene or genes However, we recommend
that all persons with iron overload who have a clinical phenotype
consistent with hemochromatosis, regardless of genotype, receive
therapeutic phlebotomy and management similar to that recommended for
homozygotes for classic hemochromatosis Table 2
Performance of Therapeutic Phlebotomy
Therapeutic phlebotomy should be done by experienced persons and should be
supervised by a physician It is usually performed in a physicians office
but can
be done in a medical laboratory, a blood bank, or a patients home
However, comprehensive management of hemochromatosis is usually
accomplished best in a physicians office For many patients, compliance
with treatment is proportional to the skill of the phlebotomist and the
confidence of the patient in the treatment staff and environment Adequate
hydration and avoidance of vigorous physical activity for 24 hours after
treatment minimize the effects of hypovolemia caused by therapeutic
phlebotomy Persons with a hemoglobin concentration less than 110 g/L or a
hematocrit less than 033 before treatment are more likely to have symptoms
of hypovolemia and anemia, and phlebotomy is less efficient in removing
iron in these patients However, many patients with chronic hemolytic
anemia and iron overload tolerate phlebotomy well The hemoglobin
concentration or hematocrit and volume or weight of blood removed with
each phlebotomy session should be documented
Frequency and Duration of Therapeutic Phlebotomy
Depletion of iron stores typically involves the removal of 1 unit of blood
weekly until mild hypoferritinemia occurs 1, 2 Some men and persons with
large body mass can sustain removal of 15
to 20 units of blood weekly
Some women; persons with small body mass; elderly persons; and patients
with anemia, cardiac problems, or pulmonary problems can sustain removal of
only 05 units of blood weekly After a few weeks of therapeutic
phlebotomy, erythroid hyperplasia permits more blood to be removed more
often in many patients Although recombinant human erythropoietin therapy
also enhances erythrocyte production, this therapy should be reserved for
patients who also have renal dysfunction or anemia of chronic disease 28
Life expectancy may be substantially decreased in patients in whom iron
depletion by phlebotomy cannot be completed within 1 year 29
Serum ferritin and hepatic iron levels permit a relative estimation of the
amount of therapeutic phlebotomy required for iron depletion 2 On
average, men require twice as many units of therapeutic phlebotomy as women
do 24, 30, 31 Older persons typically have more severe iron overload, as
do persons who are homozygous for HFE mutation C282Y 2, 24, 32 Hormonal
factors, diet, abnormalities that alter iron absorption, and blood loss
also influence the severity of iron overload 33 Persons who have been
regular blood donors often have
less severe iron overload than do nondonors
1, 34
The serum ferritin level is the most reliable, readily available, and
inexpensive way to monitor therapeutic phlebotomy; the serum iron level and
the transferrin saturation are less suitable 1, 2 In general, patients
who have higher serum ferritin levels have more severe iron overload and
need more phlebotomy Among patients who have serum ferritin levels greater
than 1000 g/L before treatment, it is sufficient to quantify the serum
ferritin level every 4 to 8 weeks during the initial months of treatment
The serum ferritin level should be measured more often in patients who have
received many phlebotomy treatments and in those who have mild or moderate
iron overload at diagnosis In all patients, serum ferritin levels should
be quantified after each additional one or two treatments once the value is
100 g/L or less Progress of treatment is also monitored by assessing
hemoglobin concentration and hematocrit, their recovery rates, and mean
corpuscular volume Iron depletion is complete when the serum ferritin
level is 10 to 20 g/L or when the hemoglobin concentration is less than
110 g/L or the hematocrit is less than 033 for more than 3
weeks in
patients without chronic anemia These values indicate that mild iron
deficiency has been induced and that potentially pathogenic iron deposits
have been removed Sustaining overt iron deficiency by phlebotomy is not
justifiable After iron depletion, the hemoglobin concentration and
hematocrit are allowed to return to and remain within the normal range
Phlebotomy should be done throughout the patients life to keep the serum
ferritin level at 50 g/L or less This requires the annual removal of 3 or
4 units of blood in men and 1 or 2 units of blood in women, on average 8
Some persons, especially elderly persons, may require no maintenance
phlebotomy, but their serum ferritin levels should be monitored annually
Complications Often Improved by Therapeutic Phlebotomy
Malaise, weakness, and ease of fatigue affect approximately 80 of patients
with iron overload but are often not attributable to specific organ
dysfunction Iron depletion usually alleviates these symptoms, often early
in the course of treatment Table 3 1, 2 Liver-associated abnormalities
other than cirrhosis usually resolve Table 3 1, 2, and benefit may
also be seen with respect to manifestations of viral hepatitis
35, 36
Diabetes mellitus sometimes improves, if temporarily, although it rarely
disappears 37 Cardiomyopathy dilated or restrictive and refractory
arrhythmia caused by myocardial siderosis with or without congestive heart
failure are usually alleviated or cured by the aggressive removal of
stored iron 38-40 The hyperpigmentation associated with iron overload
gradually fades in most patients Hyperferremia due to iron overload
invariably resolves after iron depletion Normal life expectancy has been
noted among patients with hemochromatosis who do not have hepatic
cirrhosis, diabetes mellitus, or cardiomyopathy and who undergo and
maintain iron depletion by phlebotomy 29, 41-43 Among patients who have
these serious complications, therapeutic phlebotomy often improves quality
of life and may increase longevity 29, 41-43
Complications Usually Not Improved by Phlebotomy
Hepatic cirrhosis due to iron overload rarely resolves with therapeutic
phlebotomy Table 3 44-46 A change from a micronodular to a
macronodular pattern of hepatic scarring is the likely explanation for the
disappearance of cirrhosis seen in a few patients 46 Cirrhosis is
associated with an increased risk for primary
liver cancer, and the risk is
not diminished by therapeutic phlebotomy Table 3 1, 2, 29, 47
Significant improvement in joint function and alleviation of deformity
after iron depletion are uncommon, and joint disease may progress despite
therapy Table 3 1, 2, 48 Some patients have exacerbation of joint pain
during phlebotomy that resolves with depletion of iron stores
Hypogonadotrophic hypogonadism is usually not alleviated, but therapeutic
phlebotomy has been associated with the restoration of normal pituitary and
gonadal function if these complications are of recent onset 37, 49-52
Thyroid disorders rarely respond to phlebotomy treatment 54 When
therapeutic phlebotomy is monitored properly by using the serum ferritin
level, serum iron levels and transferrin saturation values usually remain
elevated Table 3 3, 54
Management of Complications of Iron Overload without Phlebotomy
Hepatic Disorders
The estimated longevity of persons with hepatic cirrhosis due to
hemochromatosis is reduced Because hepatic biopsy is the most reliable
means by which to diagnose hepatic cirrhosis 2, 41, this biopsy is
important, especially in patients with hemochromatosis who have elevated
serum
concentrations of hepatic enzymes or a serum ferritin level greater
than 750 mg/L An additional biopsy specimen should be obtained if the
first is unsatisfactory for interpretation, particularly if there is
uncertainty about the presence of cirrhosis 1, 2 However, routine
hepatic biopsy after iron depletion is unnecessary Some persons with
clinical evidence of advanced hepatic cirrhosis and portal hypertension
cannot undergo biopsy safely 14 When a biopsy specimen is not available,
prognosis and estimation of risks for primary liver cancer must be based on
available data Coincidental hepatic disorders occur in approximately 5 of
patients with hemochromatosis, and persons with hepatic abnormalities
atypical of hemochromatosis need further evaluation Table 1 14
Patients with cirrhosis and other important hepatic disease such as
ethanol-associated hepatic injury or active viral hepatitis may have
persistently elevated serum concentrations of hepatic enzymes or more rapid
deterioration of hepatic function than would be expected from iron overload
alone Hepatic failure and hemorrhage from esophagogastric varices cause
substantial illness and require routine medical and surgical
management 1,
2
Primary Liver Cancer
Primary liver cancer causes 10 to 30 of hemochromatosis-related deaths,
and it is the leading cause of death in patients with hepatic cirrhosis
29, 55, 56 With few exceptions, only patients with cirrhosis develop
primary liver cancer The risk is increased approximately 200-fold in
patients with cirrhosis, particularly those older than 55 years of age,
those seropositive for hepatitis B surface antigen, and those who drink
excess ethanol 56-58 Serum concentrations of alpha-fetoprotein are
elevated in one third of patients 1, 2, and occult cancers are sometimes
visualized with hepatic ultrasonography We recommend that patients with
hepatic cirrhosis have measurement of alpha-fetoprotein levels and hepatic
ultrasonography every 6 months, although the efficacy and cost-
effectiveness of this testing are not clearly established Any patient with
cirrhosis who develops hepatic pain, increasing liver size, unexplained
fever, or weight loss should be evaluated for primary liver cancer
Treatment methods for primary liver cancer in hemochromatosis, including
liver transplantation, are reviewed elsewhere 59-64
Joint Disease
Hemochromatosis-related joint
disease often progresses despite therapeutic
phlebotomy 48, 65 Many patients need joint rest, treatment with
salicylates or nonsteroidal anti-inflammatory drugs, or physical therapy
Surgical replacement, usually of the hip or the knee, is necessary in some
patients Other hereditary or acquired joint disorders can also cause
progressive discomfort and disability in patients with hemochromatosis
after therapeutic phlebotomy is complete, and these disorders should be
evaluated and managed independently Table 1
Endocrinopathic Disease
Diabetes mellitus in patients with hemochromatosis should be treated as it
is in other patients In men with hypogonadotrophic hypogonadism, sexual
potency and renewed vigor often return with monthly testosterone
replacement Severe iron overload in women of reproductive age is
frequently associated with hypogonadotrophic hypogonadism After iron
depletion, menstruation and successful pregnancy can occur with appropriate
gonadotrophin and other hormone therapy 52 In older women, estrogen and
progesterone replacement therapy should be considered Thyroid disorders
are more frequent among men with hemochromatosis than among men in the
general population 53 The
management of thyroid dysfunction is the same
for patients with and patients without hemochromatosis Table 1 53
Cardiac Disorders
Severe cardiomyopathy and arrhythmias are typical of the massive iron
overload that sometimes occurs in teenagers or young adults Medical
therapy to control congestive heart failure and minimize serious
arrhythmias must be applied until vigorous therapeutic phlebotomy possibly
combined with iron chelation therapy relieves the myocardial siderosis In
middle-aged or elderly persons, cardiac dysfunction is occasionally due to
iron overload, but atherosclerosis of coronary arteries or other forms of
heart disease are more common Table 1 14, 66
Dietary Recommendations
Iron Intake and Absorption
Patients should consume in moderation foods that contain large
concentrations of bioavailable iron, such as red meats and organ meats 67,
68, and they should not use iron supplements, including multivitamins with
iron Table 4 Dietary changes intended to minimize or eliminate iron
ingestion are usually unnecessary and are often not feasible Furthermore,
the 05 to 10 mg of iron absorbed daily in excess of normal in most
persons with hemochromatosis is small in
comparison with the 200 to 250 mg
of iron per unit of blood removed weekly by therapeutic phlebotomy
Substances in foods and drinks, including tannates, phytates, oxalates,
calcium, and phosphates, can bind iron and inhibit its absorption 67, 68
The consumption of large quantities of tea, which contains tannates, can
decrease iron absorption 69 However, altering a patients diet in an
attempt to inhibit iron absorption is unnecessary unless the patient cannot
tolerate therapeutic phlebotomy persons with severe thalassemia, for
example, cannot tolerate this therapy
Ethanol
Ethanol sometimes increases iron absorption 70, 71, and certain alcoholic
drinks, especially red wines, also contain relatively high concentrations
of iron 70, 71 Ingestion of 30 g or more of ethanol daily can potentiate
hepatic injury due to iron overload 57, 72 and increases the relative
risk for primary liver cancer in persons with cirrhosis 57 Patients with
evidence of hepatic injury should consume little or no ethanol Others
should consume ethanol in moderation Table 4
Vitamin and Mineral Supplements
Vitamin C ascorbic acid increases the intestinal absorption of inorganic
iron 73 However, vitamin C
deficiency sometimes occurs in untreated
patients with hemochromatosis but resolves after iron depletion 74
Rarely, ingestion of large quantities of vitamin C has been associated with
fatal cardiac arrhythmias in persons with iron overload, presumably as a
result of oxidative injury caused by mobilization of stored iron 75
There is no rationale for discouraging patients with hemochromatosis from
consuming fresh fruits and vegetables containing vitamin C, but it seems
prudent to advise them to limit ingestion of vitamin C in supplements to
500 mg/d Table 4
In patients with hemochromatosis, absorption of inorganic forms of some
nonferrous metals, including cobalt, manganese, zinc, and lead, is
increased 76-82 Excess inorganic cobalt is rapidly excreted 79
Manganese and zinc, however, are deposited in the liver and other tissues
80, 82 Lead, which is toxic in small amounts, is retained for prolonged
periods 77 The role of these metals in the pathogenesis of symptoms and
tissue injury associated with hemochromatosis has not been elucidated, but
we suggest that persons with hemochromatosis use dietary supplements
containing these metals only if a specific nutritional deficiency has
been
shown Table 4 83 Because blood concentrations of zinc, manganese, and
lead are low, therapeutic phlebotomy is not effective in reducing retention
of these metals 76, 77
Shellfish
Vibrio vulnificus occurs naturally in many warm coastal waters, including
those along the US shore in the Gulf of Mexico, and it sometimes
contaminates shellfish harvested from these areas This spiral organism can
cause infection when ingested in raw or improperly cooked contaminated
shellfish or when introduced into the open wounds of persons who handle
contaminated seafood or bathe in contaminated waters 84-86 Bacteremia
due to V vulnificus in patients with hemochromatosis may be related to the
availability of iron for microbial metabolism or to the presence of hepatic
cirrhosis 85, and it is often fatal 84-86 Persons with hemochromatosis
should consume seafood from potentially contaminated waters only if it is
thoroughly cooked, and they should take other indicated measures to prevent
infection Table 4 Therapeutic phlebotomy probably does not reduce
susceptibility to infections with Vibrio species
Comprehensive Dietary Management
Many patients appreciate being given a list of dietary
recommendations that
includes the amounts of iron in servings of common foods and beverages
Some patients rigidly and unnecessarily avoid certain dietary items,
usually on the basis of iron content Many patients have iron overload-
associated or coincidental medical conditions such as diabetes mellitus,
hepatic dysfunction, anemia, hyperlipidemia, hypertension, or obesity that
also require changes in diet In patients with complex dietary
requirements, a dietitian who understands hemochromatosis can help
formulate an effective diet that is acceptable to the patient Diets do not
enhance iron excretion, and patients must understand that there is no
substitute for iron depletion therapy
Conclusions
Physicians can expect to diagnose and treat increasing numbers of persons
with hemochromatosis because awareness of the frequency and diagnostic
criteria of hemochromatosis and the multisystem disease caused by iron
overload is increasing Early diagnosis and therapeutic phlebotomy to
maintain low normal body iron stores can prevent all known complications of
hemochromatosis Most patients with hemochromatosis who have developed iron
overload before diagnosis also benefit from therapeutic
phlebotomy Many
will need additional evaluation and treatment of complications of iron
overload, including hepatic disorders, joint disease, diabetes mellitus and
other endocrinopathic conditions, and cardiac dysfunction Proper dietary
management can decrease the rate of iron reaccumulation and can reduce or
avoid complications of hepatic disease, diabetes mellitus, and Vibrio
infection in patients with hemochromatosis This comprehensive approach to
the management of hemochromatosis can decrease the frequency and severity
of iron overload, improve quality of life, and increase longevity
Acknowledgments: The authors thank Dr Anne C Looker of the National
Center for Health Statistics for reviews of data on age, sex, and serum
iron variables from the National Health and Nutrition Examination Survey
Grant Support: In part by Maternal and Child Health Branch, Division of
Nutrition, Centers for Disease Control and Prevention Atlanta, Georgia
and Southern Iron Disorders Center Birmingham, Alabama
Requests for Reprints: James C Barton, MD, Southern Iron Disorders Center,
Suite G-105, 2022 Brookwood Medical Center Drive, Birmingham, AL 35209; e-
mail, ironmd@mempocom
Current Author
Addresses: Dr Barton: Southern Iron Overload Disorders
Center, Suite G-105, 2022 Brookwood Medical Center Drive, Birmingham, AL
35209
Dr McDonnell: Centers for Disease Control and Prevention, Division of
Nutrition and Physical Activity, 4770 Buford Highway Mailstop K-25,
Atlanta, GA 30341-3724
Dr Adams: Department of Medicine, London Health Sciences Centre,
University Campus, 339 Windermere Road, PO Box 5339, London, Ontario N6A
5A5, Canada
Dr Brissot: Clinique des Maladies du Foie, Unite INSERM U49, Hôpital
Universitaire Pontchaillou, 35033 Rennes, France
Dr Powell: The University of Queensland, Queensland Institute of Medical
Research, The Bancroft Center, 300 Herston Road, Brisbane 4029 QLD,
Australia
Dr Edwards: Department of Medicine, University of Utah College of Medicine
and LDS Hospital, Outpatient Clinic, 325 8th Avenue, Salt Lake City, UT
84143
Dr Cook: Division of Hematology, University of Kansas Medical Center, 39th
and Rainbow, Kansas City, KS 66103
Dr Kowdley: Division of Gastroenterology and Hepatology, RG-24, University
of Washington, Seattle, WA 98195
shapeType20lineWidth22225lineColor13948116fShadow1shadowOffsetX0shadowOffset
Y-12700shadowOriginY32385
References
1
Powell LW, Jazwinska E, Halliday JW Primary iron overload In: Brock
JH, Halliday JW, Pippard MJ, Powell LW, eds Iron Metabolism in Health and
Disease Philadelphia: WB Saunders; 1994:227-70
2 Witte DL, Crosby WH, Edwards CQ, Fairbanks VF, Mitros FA Practice
guideline development task force of the College of American Pathologists
Hereditary hemochromatosis Clin Chim Acta 1996;245:139-200
3 Barton JC, Bertoli LF, Janich MR, Arthur MW, Alford TJ Normal
transferrin saturation in hemochromatosis Hosp Pract Off Ed
1991;26Suppl 3:46-8
4 Scheuer PJ, Williams R, Muir AR Hepatic pathology in relatives of
patients with haemochromatosis Journal of Pathology and Bacteriology
1962;84:53-64
5 Bassett ML, Halliday JW, Powell LW Value of hepatic iron measurements
in early hemochromatosis and determination of the critical iron level
associated with fibrosis Hepatology 1986;6:24-9
6 Brissot P, Bourel M, Herry D, Verger JP, Messner M, Beaumont C, et al
Assessment of liver iron content in 271 patients: a reevaluation of direct
and indirect methods Gastroenterology 1981;80:557-65
7 Searle J, Kerr JF, Halliday JW, Powell LW Iron storage disease In:
McSween RN, Anthony PP, Scheuer PJ, Burt AD, Portmann BC,
eds Pathology of
the Liver 3d ed New York: Churchill Livingstone; 1993:219-41
8 Barton JC, Harmon L, Rivers C, Acton RT Hemochromatosis: association of
severity of iron overload with genetic markers Blood Cells Mol Dis
1996;22:195-204
9 Bonkovsky HL, Slaker DP, Bills EB, Wolf DC Usefulness and limitations
of laboratory and hepatic imaging studies in iron-storage disease
Gastroenterology 1990;99:1079-91
10 Roberts AG, Whatley SD, Morgan RR, Worwood M, Elder GH Increased
frequency of the haemochromatosis Cys282Tyr mutation in sporadic porphyria
cutanea tarda Lancet 1997;349:321-3
11 Mohler DN, Wheby MS Hemochromatosis heterozygotes may have significant
iron overload when they also have hereditary spherocytosis Am J Med Sci
1986;292:320-4
12 Edwards CQ, Griffen LM, Kushner JP Coincidental hemochromatosis and
viral hepatitis Am J Med Sci 1991;301:50-4
13 Di Bisceglie AM, Axiotis CA, Hoofnagle JH, Bacon BR Measurements of
iron status in patients with chronic hepatitis Gastroenterology
1992;102:2108-13
14 Barton JC, Barton NH, Alford TJ Diagnosis of hemochromatosis probands
in a community hospital Am J Med 1997;103:498-503
15 Davis WD, Arrowsmith WR The effect of repeated phlebotomies
in
hemochromatosis: report of three cases J Lab Clin Med 1952;39:526-32
16 Wohler F The treatment of haemochromatosis with desferrioxamine Acta
Haematol 1963;30:65-87
17 Kellner H, Zoller WG Repeated isovolemic large-volume
erythrocytapheresis in the treatment of idiopathic hemochromatosis Z
Gastroenterol 1992;30:779-83
18 Haddy TB, Castro OL, Rana SR Hereditary hemochromatosis in children,
adolescents, and young adults Am J Pediatr Hematol Oncol 1988;10:23-34
19 Kaltwasser JP, Schalk KP, Werner E Juvenile hemochromatosis In:
Weintraub LR, Edwards CQ, Krikker M, eds Hemochromatosis Proceedings of
the First International Conference Ann NY Acad Sci 1988;526:339-41
20 Kaikov Y, Wadsworth LD, Hassall E, Dimmick JE, Rogers PC Primary
hemochromatosis in children: report of three newly diagnosed cases and
review of the pediatric literature Pediatrics 1992;901 pt 1:37-42
21 Pippard MJ, Rajagopalan B, Callender ST, Weatherall DJ Iron loading,
chronic anaemia, and erythroid hyperplasia as determinants of the clinical
features of b-thalassaemia intermedia In: Weatherall DJ, Fiorelli G,
Gorini S, eds Advances in Red Blood Cell Biology New York: Raven Pr;
1982:103-13
22 McLaren CE, Gordeuk VR,
Looker AC, Hasselblad V, Edwards CQ, Griffen
LM, et al Prevalence of heterozygotes for hemochromatosis in the white
population of the United States Blood 1995;86:2021-7
23 Bulaj ZJ, Griffen LM, Jorde LB, Edwards CQ, Kushner JP Clinical and
biochemical abnormalities in people heterozygous for hemochromatosis N
Engl J Med 1996;335:1799-805
24 Barton JC, Shih WW, Sawada-Hirai R, Acton RT, Harmon L, Rivers C, et
al Genetic and clinical description of hemochromatosis probands and
heterozygotes: evidence that multiple genes linked to the major
histocompatibility complex are responsible for hemochromatosis Blood Cells
Mol Dis 1997;23:135-45
25 Lundvall O Phlebotomy treatment of porphyria cutanea tarda Acta Derm
Venereol Suppl Stockh 1982;100:107-18
26 Roberts AG, Whatley SD, Morgan RR, Worwood M, Elder GH Increased
frequency of the haemochromatosis Cys282Tyr mutation in sporadic porphyria
cutanea tarda Lancet 1997;349:321-3
27 Sampietro M, Piperno A, Lupica L, Arosio C, Vergani A, Corbetta N, et
al High prevalence of the His63Asp HFE mutation in Italian patients with
porphyria cutanea tarda Hepatology 1998;27:181-4
28 Bilgrami S, Bartolomeo A, Synnott V, Rickles FR Management
of
hemosiderosis complicated by coexistent anemia with recombinant human
erythropoietin and phlebotomy Acta Haematol 1993;89:141-3
29 Niederau C, Fischer R, Sonnenberg A, Stremmel W, Trampisch HJ,
Strohmeyer G Survival and causes of death in cirrhotic and in noncirrhotic
patients with primary hemochromatosis N Engl J Med 1985;313:1256-62
30 Edwards CQ, Dadone MM, Skolnick MH, Kushner JP Hereditary
hemochromatosis Clin Haematol 1982;11:411-35
31 Moirand R, Adams PC, Bicheler V, Brissot P, Deugnier Y Clinical
features of genetic hemochromatosis in women compared with men Ann Intern
Med 1997;127:105-10
32 Sham RL, Ou CY, Cappuccio J, Braggins C, Dunnigan K, Phatak PD
Correlation between genotype and phenotype in hereditary hemochromatosis:
analysis of 61 cases Blood Cell Mol Dis 1997;23:314-20
33 Skikne B, Baynes RD Iron absorption In: Brock JH, Halliday JW,
Pippard MJ, Powell LW, eds Iron Metabolism in Health and Disease
Philadelphia: WB Saunders; 1994:151-88
34 Edwards CQ, Griffen LM, Goldgar D, Drummond C, Skolnick MH, Kushner JP
Prevalence of hemochromatosis among 11,065 presumably healthy blood donors
N Engl J Med 1988;318:1355-62
35 Hayashi H, Takikawa T, Nishimura N, Yano M,
Isomura T, Sakamoto N
Improvement of serum aminotransferase levels after phlebotomy in patients
with chronic active hepatitis C and excess hepatic iron Am J
Gastroenterol 1994;89:986-8
36 Piperno A, Sampietro M, DAlba R, Roffi L, Fargion S, Parma S, et al
Iron stores, response to alpha-interferon therapy, and effects of iron
depletion in chronic hepatitis C Liver 1996;16:248-54
37 Stremmel W, Niederau C, Berger M, Kley HK, Krüskemper HL, Strohmeyer G
Abnormalities in estrogen, androgen, and insulin metabolism in idiopathic
hemochromatosis In: Weintraub LR, Edwards CQ, Krikker M, eds
Hemochromatosis Proceedings of the First International Conference Ann N Y
Acad Sci 1988;526:209-23
38 Cutler DJ, Isner JM, Bracey AW, Hufnagel CA, Conrad PW, Roberts WC, et
al Hemochromatosis heart disease: an unemphasized cause of potentially
reversible restrictive cardiomyopathy Am J Med 1980;69:923-8
39 Candell-Riera J, Lu L, Seres L, Gonzalez JB, Batlle J, Permanyer-
Miralda G, et al Cardiac hemochromatosis: beneficial effects of iron
removal therapy An echocardiographic study Am J Cardiol 1983;52:824-9
40 Rivers J, Garrahy P, Robinson W, Murphy A Reversible cardiac
dysfunction in hemochromatosis Am
Heart J 1987;113:216-7
41 Powell LW Hemochromatosis: precirrhotic therapy restores normal life
expectancy Hepatology 1986;6:1423-5
42 Adams PC, Speechley M, Kertesz AE Long-term survival in hereditary
hemochromatosis Gastroenterology 1991;101:368-72
43 Niederau C, Fischer R, Purschel A, Stremmel W, Haussinger D, Strohmeyer
G Long-term survival in patients with hereditary hemochromatosis
Gastroenterology 1996;110:1107-19
44 Knauer CM, Gamble CN, Monroe LS The reversal of hemochromatotic
cirrhosis by phlebotomies Report of a case Gastroenterology 1965;49:667-
71
45 Weintraub LR, Conrad ME, Crosby WH The treatment of hemochromatosis by
phlebotomy Med Clin North Am 1966;50:1579-90
46 Powell LW, Kerr JF Reversal of cirrhosis in idiopathic
haemochromatosis following long-term intensive venesection therapy
Australas Ann Med 1970;19:54-7
47 Blumberg RS, Chopra S, Ibrahim R, Crawford J, Farraye FA, Zeldis JB, et
al Primary hepatocellular carcinoma in idiopathic hemochromatosis after
reversal of cirrhosis Gastroenterology 1988;95:1399-402
48 Schumacher HR, Straka PC, Krikker MA, Dudley AT The arthropathy of
hemochromatosis Recent studies In: Weintraub LR, Edwards CQ, Krikker M,
eds
Hemochromatosis Proceedings of the First International Conference
Ann N Y Acad Sci 1988;526:224-33
49 Kelly TM, Edwards CQ, Meikle AW, Kushner JP Hypogonadism in
hemochromatosis: reversal with iron depletion Ann Intern Med 1984;101:629-
32
50 Lufkin EG, Baldus WP, Bergstralh EJ, Kao PC Influence of phlebotomy
treatment on abnormal hypothalamic-pituitary function in genetic
hemochromatosis Mayo Clin Proc 1987;62:473-9
51 Siminoski K, DCosta M, Walfish PG Hypogonadotrophic hypogonadism in
idiopathic hemochromatosis: evidence for combined hypothalamic and
pituitary involvement J Endocrinol Invest 1990;13:849-53
52 Farina G, Pedrotti C, Cerani P, Rovati A, Strada E, Bergamaschi G, et
al Successful pregnancy following gonadotropin therapy in a young female
with juvenile idiopathic hemochromatosis and secondary hypogonadotrophic
hypogonadism Haematologica 1995;80:335-7
53 Edwards CQ, Kelly TM, Ellwein G, Kushner JP Thyroid disease in
hemochromatosis Increased incidence in homozygous men Arch Intern Med
1983;143:1890-3
54 Edwards CQ, Griffen LM, Kaplan J, Kushner JP Twenty-four hour
variation of transferrin saturation in treated and untreated
haemochromatosis homozygotes J Intern Med
1989;226:373-9
55 Bradbear RA, Bain C, Siskind V, Schofield FD, Webb S, Axelsen EM, et
al Cohort study of internal malignancy in genetic hemochromatosis and
other chronic nonalcoholic liver diseases J Natl Cancer Inst 1985;75:81-
4
56 Colombo M, de Franchis R, Del Ninno E, Sangiovanni A, De Fazio C,
Tommasini M, et al Hepatocellular carcinoma in Italian patients with
cirrhosis N Engl J Med 1991;325:675-80
57 Deugnier YM, Guyader D, Crantock L, Lopez JM, Turlin B, Yaouanq J, et
al Primary liver cancer in genetic hemochromatosis: a clinical,
pathological, and pathogenetic study of 54 cases Gastroenterology
1993;104:228-34
58 Fargion S, Fracanzani AL, Piperno A, Braga M, DAlba R, Ronchi G, et
al Prognostic factors for hepatocellular carcinoma in genetic
hemochromatosis Hepatology 1994;20:1426-31
59 Nonami T, Harada A, Kurokawa T, Nakao A, Takagi H Hepatic resection
for hepatocellular carcinoma Am J Surg 1997;173:288-91
60 Liu CL, Fan ST Nonresectional therapies for hepatocellular carcinoma
Am J Surg 1997;173:358-65
61 Powell LW Does transplantation of the liver cure genetic
hemochromatosis? J Hepatol 1992;16:259-61
62 Farrell FJ, Nguyen M, Woodley S, Imperial JC, Garcia-Kennedy R, Man
K,
et al Outcome of liver transplantation in patients with hemochromatosis
Hepatology 1994;20:404-10
63 Poulos JE, Bacon BR Liver transplantation for hereditary
hemochromatosis Dig Dis 1996;14:316-22
64 Kowdley KV, Hassanein T, Kaur S, Farrell FJ, Van Thiel DH, Keeffe EB,
et al Primary liver cancer and survival in patients undergoing liver
transplantation for hemochromatosis Liver Transpl Surg 1995;1:237-41
65 Askari AD, Muir WA, Rosner IA, Moskowitz RM, McLaren GD, Braun WE
Arthritis of hemochromatosis Clinical spectrum, relation to
histocompatibility antigens, and effectiveness of early phlebotomy Am J
Med 1983;75:957-65
66 Edwards CQ, Cartwright GE, Skolnick MH, Amos DB Homozygosity for
hemochromatosis: clinical manifestations Ann Intern Med 1980;93:519-25
67 Bothwell TH, Charlton RW, Cook JD, Finch CA Iron absorption In: Iron
Metabolism in Man Oxford: Blackwell Scientific; 1979:256-83
68 Conrad ME, Barton JC Factors affecting iron balance Am J Hematol
1981;10:199-205
69 de Alarcon PA, Donovan ME, Forbes GB, Landaw S, Stockman JA 3d Iron
absorption in the thalassemia syndromes and its inhibition by tea N Engl J
Med 1979;300:5-8
70 Celada A, Rudolf H, Donath A Effect of
experimental chronic alcohol
ingestion and folic acid deficiency on iron absorption Blood 1979;54:906-
15
71 Conrad ME, Barton JC Anemia and iron kinetics in alcoholism Semin
Hematol 1980;17:149-63
72 LeSage GD, Baldus WP, Fairbanks VF, Baggenstoss AH, McCall JT, Moore
SB, et al Hemochromatosis: genetic or alcohol-induced? Gastroenterology
1983;84:1471-7
73 Nienhuis AW Vitamin C and iron [Editorial] N Engl J Med 1981;304:170-
1
74 Brissot P, Deugnier Y, Le Treut A, Regnouard F, Simon M, Bourel M
Ascorbic acid status in idiopathic hemochromatosis Digestion 1978;17:469-
87
75 McLaren CJ, Bett JH, Nye JA, Halliday JW Congestive cardiomyopathy and
haemochromatosis-rapid progression possibly accelerated by excessive
ingestion of ascorbic acid Aust N Z J Med 1982;12:187-8
76 Brissot P, Le Treut A, Dien G, Cottencin M, Simon M, Bourel M
Hypovitaminemia A in idiopathic hemochromatosis and hepatic cirrhosis Role
of retinol-binding protein and zinc Digestion 1978;17:469-78
77 Barton JC, Patton MA, Edwards CQ, Griffen LM, Kushner JP, Meeks RG, et
al Blood lead concentrations in hereditary hemochromatosis J Lab Clin
Med 1994;124:193-8
78 Butt EM, Nusbaum RE, Gilmour TC, DiDio SL Trace metal
patterns in
disease states Hemochromatosis, Bantu siderosis and iron storage in
Laennecs cirrhosis and alcoholism In: Seven MJ, Johnson LA, eds Metal-
Binding in Medicine: Proceedings of a Symposium Philadelphia: JB
Lippincott; 1960:43-9
79 Olatunbosun D, Corbett WE, Ludwig J, Valberg LS Alteration of cobalt
absorption in portal cirrhosis and idiopathic hemochromatosis J Lab Clin
Med 1977;75:754-62
80 Altstatt LB, Pollack S, Feldman MH, Reba RC, Crosby WH Liver manganese
in hemochromatosis Proc Soc Exp Biol Med 1967;124:353-5
81 Spencer H, Sontag SJ, Derler J, Osis D Intestinal absorption of iron
in patients with hemochromatosis Ann N Y Acad Sci 1988;526:336-8
82 Adams PC, Bradley C, Frei JV Hepatic zinc in hemochromatosis Clin
Invest Med 1991;14:16-20
83 Barton JC, Bertoli LF Zinc gluconate lozenges for treating the common
cold [Letter] Ann Intern Med 1997;126:738-9
84 Muench KH Hemochromatosis and infection: alcohol and iron, oysters and
sepsis Am J Med 1989;87:40N-3N
85 Bullen JJ, Spalding PB, Ward CG, Gutteridge JM Hemochromatosis, iron
and septicemia caused by Vibrio vulnificus Arch Intern Med 1991; 151:
1606-9
86 Hlady WG, Klontz KC The epidemiology of Vibrio infections in
Florida,
1981-1993 J Infect Dis 1996;173:1176-83
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