Hemochromatosis
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By
Vincent J Felitti, MD
Introduction
If a person
must have a genetic disease, hemochromatosis is the one to have. Although
its mutation is the most common potentially fatal mutation in North
America, hemochromatosis can be diagnosed early, treated simply and
effectively, and can even be prevented. Hemochromatosis has also recently
been selected by the National Institutes of Health as a model for helping
physicians learn about treating genetic disease.
As an
update to a 1999 clinical article on hemochromatosis that appeared in
The Permanente Journal,1 the present article presents
information from a recent study of 41,038 Kaiser Permanente (KP) members
in San Diego, each of whom had comprehensive biopsychosocial evaluation,
genetic analysis for the HFE (hemochromatosis) gene, and measurement
of iron load; this testing allowed genotype to be matched against iron
load and physical findings. For the first time, a large control group
was included to determine the extent to which the symptoms compatible
with iron overload were actually caused by--not merely coincident with--iron
overload. The purpose of the present article is to help physicians integrate
this new clinical information into daily practice throughout the Kaiser
Permanente Medical Care Program.
Clarifying the Nomenclature
The nomenclature
for hemochromatosis presents a serious problem that has implications
for all genetic disease. For example, the term hemochromatosis is currently
applied to several different conditions (some of which are nongenetic):
- mutation
of the HFE gene regardless of activity or penetrance of the mutation;
- states
of iron overload ranging from trivial to severe regardless of genotype;
- clinical
cases of iron overload disease regardless of genotype; and
- iron
overload disease caused specifically by the HFE mutation.
A moment's
reflection indicates the potential for confusion for patients as well
as for physicians. This article cannot resolve permanently the confusion
caused by such careless use of nomenclature; instead, to describe the
logical progression of iron overload, I use the following nomenclature:
- homozygous
mutation of the HFE gene;
- increased
iron absorption (iron loading);
- iron
overload states;
- clinical
iron overload disease, or hemochromatosis (regardless of genotype);
and
- hereditary
hemochromatosis.
This nomenclature
may be somewhat awkward, but precisely distinguishing these different
states is the only way to prevent confusion about this increasingly
recognized disorder and to promote better understanding of it. Moreover,
the main principle established here is applicable to all other genetic
diseases: Presence of a genetic mutation must not be equated with existence
of a genetic disease. The term hemochromatosis should be reserved
for the disease state (organ damage), not for mutations or preclinical
states.
Pathophysiology of Hemochromatosis
Although
iron is essential for life, substantially excessive levels of iron are
toxic. The essence of iron overload disease (ie, hemochromatosis
and genetic hemochromatosis) is the iron load, not the mutation. In
normal circumstances, iron absorption is constant despite variation
in dietary iron levels because the HFE gene on chromosome six limits
intestinal iron absorption to about 1.5 mg/day. When mutations damage
certain portions of the HFE gene, increased iron absorption may (but
does not necessarily) occur. If increased iron absorption does occur,
the total body iron load may, given enough time, build to toxic levels
because no existing biologic mechanism facilitates excretion of excess
iron. Given enough time, slowly incremental additions to iron load can--like
compound interest--produce major effects that depend on the rate of
iron accumulation. This time factor is important to remember because
it has major clinical implications.
The wide
range of organ damage that potentially ensues from clinically significant
iron overload is termed clinical hemochromatosis or iron overload
disease. Although hemochromatosis
is often remembered as "bronze diabetes with cirrhosis," the
range of clinical presentations is vastly greater, as previously described
in a 1999 article in The Permanente Journal.1 Just
as congestive heart failure is not the same as hypertensive cardiomegaly,
hemochromatosis is not the mutation and not subclinical iron overload;
it is iron overload disease. The genetic (and most common) form
of hemochromatosis is thus properly termed hereditary hemochromatosis,
whereas nongenetic forms of iron overload disease are properly termed
hemochromatosis.
The HFE
gene can be damaged by several mutations (polymorphisms) occurring at
different loci within the gene. One of these mutations is recognized
as the "major" mutation because it is the one most commonly
found in patients with severe clinical iron overload. The major mutation
of the HFE gene is described either as occurring at the 845-nucleotide
locus or as the C282Y mutation, depending on the notation system used.
Patients are also commonly tested for presence of the 187-nucleotide
or H63D mutation, which is much less likely to be associated with clinically
significant iron overload. Other relevant mutations may exist undiscovered
within the HFE gene, and other genes that affect iron absorption may
exist undiscovered. The single heterozygous state (carrier) of either
of these mutations has no currently known clinical consequence. Heterozygotes
are currently believed to function as genetically normal, because they
are not associated with iron overload; more than 30 million Americans
are heterozygous (carriers) for the major HFE mutation. In the unlikely
event that this population does have iron overload, it will not be attributable
to the carrier state of affected persons. By contrast, clinically significant
iron overload develops in about one of every 50 people who are carriers
of both mutations (ie, compound heterozygotes--one copy of each
of the two common mutations).
Kaiser
Permanente (KP) in San Diego was the first institutional setting in
the nation to routinely perform once-in-a-lifetime screening for iron
overload. Because of both our uniquely high volume of iron screening
and our comprehensive program of biopsychosocial evaluation, Dr Ernest
Beutler at Scripps Research Institution proposed a collaborative study
of hemochromatosis to learn more about its clinical manifestation, diagnosis,
and treatment. Results of this study2,3 have led to important
changes in our understanding of iron loading and hemochromatosis.
This study
was the first large, population-based, controlled study done to determine
the symptom prevalence of potentially iron-related findings and iron
loads in patients with and without the homozygous major mutation. This
aspect of the study is of singular importance because the signs or symptoms
of hemochromatosis are compatible with--but not specific for--iron overload
disease, and many of these symptoms are prevalent to a substantial extent
in the general population. For instance, diabetes and arthritis are
common in middle-aged and older adults and can result from iron overload
disease, but how often are these conditions actually caused by it? In
which patients are these conditions part of the population background
prevalence; in which patients are they attributable to the homozygous
HFE mutation? We were surprised to discover that our study was the first
to address this problem in a large sample.
The present
article describes our study findings and discusses their relevance to
daily clinical practice.
Study Design
The study
population consisted of 41,000 consecutive, consenting adults undergoing
comprehensive medical evaluation in the Health Appraisal Center at the
KP San Diego Department of Preventive Medicine. We tested each of these
41,000 study subjects for serum iron saturation, serum ferritin level,
and known HFE mutations. All participants had detailed biomedical, psychologic,
and social evaluation. We recorded all signs and symptoms potentially
attributable to iron overload.
Prevalence
of the homozygous major mutation--approximately five cases per thousand
study subjects--was confirmed within the HFE gene, but we also found
that this mutation was activated in only about half the mutated subjects.
For example, two of my patients are elderly sisters who live across
the street from each other and apparently lead identical lives. Both
sisters are homozygous for the C282Y mutation of the HFE gene and thus
have the two copies of the major mutation necessary for hemochromatosis
to manifest. However, whereas one sister has clinically significant
iron overload that has required lifetime phlebotomy, the other sister
has never had phlebotomy, has never been a blood donor, and verges on
having iron deficiency. We do not yet understand why the major mutation
of the HFE gene shows this difference in activity.
In the
half of C282Y homozygotes who absorb iron excessively, the amount of
iron absorbed is highly variable (in addition to being age-dependent,
as noted earlier in this article). This fact raises two basic questions
that have broad implications for our evolving understanding of all genetic
disease:
- Does
the clinical manifestation of hemochromatosis depend on presence of
the mutation? Or on iron overload?
- If
clinical manifestation of hemochromatosis depends on iron overload,
what level of iron overload induces this clinical condition?
We resolved
these questions by matching iron load against
- presence
of the homozygous major mutation,
- fasting
serum iron saturation level,
- serum
ferritin level, and
- signs
and symptoms compatible with, but not specific for, iron overload
disease.
Total
body iron load was measured inferentially by serum ferritin level and
directly by quantitative phlebotomy. Neither serum iron level nor serum
iron saturation was used to measure total body iron load because these--in
contrast to serum ferritin level and quantitative phlebotomy--are not
valid measures of total body iron load. Serum iron saturation is a measure
of iron in transit and of how much that iron saturates its carrier serum
proteins, known collectively as transferrin.
Results and Discussion
In this
study--possibly the largest genetic analysis study ever carried out
in a well-evaluated population--we found that clinical iron overload
disease--hemochromatosis--is totally a function of iron overload and
not a function of the genetic mutation. In addition, we found that unexpectedly
high body iron loads are required for organ damage. From analysis of
152 study subjects who were homozygous for the major mutation, we concluded
that organ damage begins when serum ferritin level reaches about 1000
ng/mL (1000 mg/L). Given that 81% of all adult Health Plan members pass
through the Department of Preventive Medicine at least once in any four-year
period, we believe that selection bias did not affect our conclusions.
However,
answering the simple question, "What does a physician do with a
patient who has a serum ferritin level of 650 ng/mL (650 mg/L)?"
is complicated by three factors, the first of which is age. A young
patient with ferritin level of 650 ng/mL (650 mg/mL) will probably have
a significantly higher ferritin level later in life, given sufficient
time. The second complicating factor is that hyperferritinemia can be
caused by disorders other than iron overload (eg, alcoholism, chronic
hepatitis, malignancy). The third complicating factor is the difficulty
of balancing low risk of clinically evident hemochromatosis developing
in a patient with a given ferritin level (650 ng/mL, in our example)
against the even lower risk presented to this patient by phlebotomy.
This article explains why clinicians within the Kaiser Permanente Medical
Care Program can answer this third question differently than do clinicians
elsewhere.
We addressed
these questions carefully for our 41,000 comprehensively evaluated patients
and subsequently found that many (but not all) of the symptoms previously
attributed either to the mutation or to iron overload had a more mundane
explanation: They were part of the normal prevalence found in the age-
and sex-matched control group. Indeed, homozygous penetrance of the
major HFE mutation (manifested as clinically significant iron overload)
was lower than we expected and was even lower in terms of clinically
evident hemochromatosis. The
mutation per se was irrelevant if it did not produce clinically significant
levels of iron overload. For example, many diabetic patients who are
homozygous for the major HFE mutation are diabetic because of obesity
and not because of iron overload: In these patients, the mutation is
coincident, not causal.
Patients
in our study were distributed along the following spectrum (Figure 1):
- homozygous
mutation without activation of the gene (these patients had normal
serum iron saturation and normal serum ferritin levels);
- homozygous
mutation with increased serum iron saturation but without meaningful
iron overload (these patients had normal or minimally elevated serum
ferritin level);
- homozygous
mutation with increased serum iron saturation and potentially dangerous
iron overload;
- homozygous
mutation with iron overload and subclinical tissue damage;
- homozygous
mutation with iron overload and overt organ damage.
Diagnostic Screening
At present,
knowledgeable physicians disagree about whether to screen populations
for hemochromatosis. KP San Diego became the first institutional setting
in the world to follow this practice and has screened more than 350,000
adult Health Plan members in the past eight years. (Ideally, children
would be screened instead of adults.) An argument for population screening
for hemochromatosis is that symptoms do not provide a practical basis
for diagnosing hemochromatosis: Symptoms occur late in persons with
iron overload; potential symptoms are numerous, nonspecific, and often
result from causes other than hemochromatosis. Using our approach, the
benefit of screening has distinctly outweighed the cost; however, such
might not be the case elsewhere if screening were done as a stand-alone
test or if genetic analysis were used for screening.
In considering
genetic disease, clinicians must remember the basic concept that genotype
does not equate with phenotype. In particular, our goal as clinicians
working with adult patients is to determine whether they have clinically
significant iron overload, not the genetic mutation. Therefore, all
Health Plan members seen at the KP San Diego Department of Preventive
Medicine are tested once in their lifetime for serum iron saturation.
If the fasting iron saturation of the specimen is >50%, the test
is repeated and the serum ferritin level is measured. This repeat procedure
should be done on an early-morning fasting specimen because of diurnal
variation: Higher iron saturations sometimes occur in the morning.
Treatment
Patients
who have both persistently elevated iron saturation and hyperferritinemia
are entered into the hemochromatosis registry and are seen for consultation
by a physician who has experience treating patients with hemochromatosis.
Most of these patients then go to the Donor Center weekly for phlebotomy,
during which 500 mL of whole blood is removed until the plasma ferritin
level is reduced to approximately 20 ng/mL (20 mg/L). This process is
termed quantitative phlebotomy because its frequency of
application allows blood to be removed faster than iron can be reabsorbed
and thus allows accurate calculation of total body iron stores. If more
than 12 to 16 phlebotomy procedures are needed to attain this endpoint,
the patient is identified as iron-laden and enters the Maintenance Program,
a lifetime program in which most patients have 500 mL of whole blood
removed by phlebotomy every two months (for men) or every three months
(for women). To avoid inducing more than minor anemia, a lower limit
is set for the prephlebotomy hematocrit level. Liver biopsy is never
performed; it is unnecessary, is not dependable for early diagnosis,
has some risk, is costly, and frightens some patients away from completing
prescribed diagnostic studies. Genetic analysis is done for many of
our suspect cases, because this analysis sometimes clarifies confusing
situations and identifies index cases that trigger family screening.
In some
circles, much is made of dietary limitations on ingested iron; under
normal conditions, however, variations in dietary iron play a minor
role that is easily corrected by adjusting the phlebotomy protocol.
Nonetheless, some patients choose to strictly limit their dietary intake
of iron, perhaps to gain a sense of participatory control of the situation--and
this choice is certainly not harmful. Raw shellfish should be avoided
because of its occasional contamination with Vibrio, an organism
that flourishes in high-iron environments and damaged livers. Alcohol
should be avoided or consumed sparingly because of its potential for
additive hepatotoxicity; patients should be immunized against hepatitis
A and B to prevent this additional possible source of liver damage.
Iron supplements should be avoided.
The commonly
used term, "iron-rich blood" is misleading because blood from
a person affected with hemochromatosis has no more iron than has blood
from unaffected persons; blood happens to be the only removable iron-rich
tissue that can be readily regenerated. The process of regeneration
draws iron from potentially damaging tissue stores in organs elsewhere
in the body. This process is why phlebotomy is effective treatment for
hemochromatosis.
 |
| Figure
1: Illustration shows spectrum of conditions distributed among 41,038
KP members in San Diego who had genetic analysis for the HFE (hemochromatosis)
gene and measurement of iron load. (TS= transfusion saturation.) |
Hyperferritinemic
patients with normal fasting iron saturation are evaluated for causes
of hyperferritinemia other than iron overload--most commonly, unrecognized
alcoholism or chronic hepatitis. And because iron overload, alcoholism,
and chronic hepatitis are relatively common conditions, they coexist
in some patients. Quantitative phlebotomy readily identifies the portion
of hyperferritinemia attributable to iron overload.
The therapeutic
benefit of normalizing iron levels in iron-laden patients is obvious:
Hemochromatosis can be prevented in these patients when they are identified
and treated presymptomatically. Moreover, the transfusable blood generated
by treatment creates a valuable byproduct. In 2001, 40% of the blood
transfused at KP San Diego was obtained from the hemochromatosis phlebotomy
program. If purchased from the Red Cross, this blood would have a market
value in excess of $300,000. In addition, we have coincidentally identified
a number of cases of previously unrecognized chronic hepatitis and alcoholic
liver damage.
To make
this areawide screening successful, we have had to solve several problems:
physician unfamiliarity with iron overload, lack of time for patient
education, and the difficulty and complexity of tracking treatment for
a large population. The problem of physician unfamiliarity with iron
overload was initially solved by centralized screening and follow-up,
and this article takes a further step toward decentralizing treatment
and follow-up of iron-laden patients. The next problem was that providing
patients with adequate information about this (or any) genetic disease
is time-consuming and unreliable when done during a traditional office
visit (however lengthy), whether to a physician or to a genetics counselor.
We resolved this problem by developing a videotape4 with
accompanying booklet5 that we mail to patients before they
arrive for their consultation. We solved the third problem by creating
a computerized hemochromatosis registry that allows us to efficiently
follow treatment progress over time and to maximize follow-up. This
solution was enhanced by coordination with the KP San Diego Blood Donor
Center, created earlier by Michael Bonin, MD, Chief of Pathology. This
important resource has been invaluable for simplifying the process of
phlebotomy and has substantially added to our blood supply available
for transfusion. By contrast, phlebotomy in the community is needlessly
time-consuming, remarkably expensive, and often difficult to arrange.
Physicians
whose practice includes treatment of hemochromatosis ultimately are
likely to attract some patients with somatization disorders who desperately
hope they have hemochromatosis so that their medical condition can finally
be diagnosed and treated effectively. Chronic fatigue, arthralgia, and
depression can be caused by iron overload; however, in most patients
with iron overload, these symptoms are not caused by the iron overload.
Understandably, nonetheless, many patients who have heard of hemochromatosis
attribute their symptoms to this condition. This problem is further
aggravated when persons with an inactive HFE mutation or minimal hyperferritinemia
are incorrectly told that they have hemochromatosis. Attempting to correct
this misinformation is a major task that easily triggers patient mistrust
and anger. This problem reflects our general ineffectiveness at dealing
with these psychosomatic symptoms; the solution lies in the difficult
feat of learning to effectively treat somatization disorders.
At KP
San Diego, we tell homozygotes who have no active iron loading process
that they are normal; we do not explain the technical details behind
our conclusion because they are needlessly confusing to patients. In
contrast, anyone who is significantly iron-laden for any reason enters
the phlebotomy program. When an index case is identified--whether by
iron overload or by homozygosity--we give the index patient multiple
copies of a Letter for Relatives that urges primary relatives to be
screened. Only about one third of these relatives follow this advice.
Summary
From our
experience screening more than 350,000 adult Health Plan members for
iron overload, I firmly believe in the value of once-per-lifetime screening
for everyone. Improperly done, the test is unaffordable; but properly
done, the test costs about the same as a complete blood count (CBC).
Because people are damaged by the iron overload and not by the genetic
mutation, screening is done by chemical test, not by genetic analysis.
Moreover, as we described in Lancet,2 half the homozygotes
never begin any iron loading. Of the half that do begin iron loading,
most do so to an inconsequential extent. Problematic levels of iron
overload develop in only a small percentage of the homozygotes. Organ
damage starts when plasma ferritin levels reach approximately 1000 ng/mL
(1000 mg/L). A 70-year-old person with plasma ferritin level of 350
ng/mL (350 mg/L) will never be adversely affected by iron overload,
but the same plasma ferritin level in a 20-year-old person can have
unpredictable consequences.
This problem
of whom to treat for iron overload is similar to that seen with hypertensive
patients: Not every hypertensive patient eventually has a stroke, congestive
heart failure, or renal failure; we safely treat the many to help the
few. One difference between the two conditions, however, is that antihypertensive
medications are often expensive and sometimes have side effects, whereas
phlebotomy is overwhelmingly well tolerated. If we are uncertain about
whom to treat, we should err on the side of safety and, by conducting
quantitative phlebotomy to determine actual iron load, then decide any
mainte
nance strategy on the basis of that iron load.
References
- Felitti
VJ. Hemochromatosis: a common, rarely diagnosed disease. Perm J 1999
Winter;3(1):10-20.
- Beutler
E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T. Penetrance of 845G-->A(C282Y)
HFE hereditary haemochromatosis mutation in the USA. Lancet 2002 Jan
19;359(9302):211-8.
- Waalen
J, Felitti V, Gelbart T, Ho NJ, Beutler E. Prevalence of hemochromatosis-related
symptoms among individuals with mutations in the HFE gene. Mayo Clin
Proc 2002 Jun;77(6):522-30.
- Hemochromatosis:
the disease of iron overload [videocassette]. San Diego (CA): Southern
California Permanente Medical Group, Department of Preventive Medicine;
1999.
- Checkett
KA, Felitti VJ. Hereditary hemochromatosis: the disease of iron overload.
San Diego (CA):
Department of Preventive Medicine, Kaiser Permanente Medical Care
Program; 2000.
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