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a Address for correspondence: Laboratory Control, Ltd., 1005 E. Pennsylvania, Ottumwa, IA 52501. Fax 515-682-8976.
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Abstract |
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 Top Abstract IntroductionHemochromatosisEarly DetectionQuality ImprovementReferences |
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Key Words: indexing terms: iron metabolism • hemochromatosis • iron-binding capacity • ferritin • screening • HLA-H
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Introduction |
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TopAbstractIntroductionHemochromatosisEarly DetectionQuality ImprovementReferences |
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Data are presented that can be used to direct the design of a laboratory-initiated system that should eliminate hemochromatosis as a cause for abnormal liver function. Also presented is the advocacy position for hemochromatosis testing of both asymptomatic individuals and those who encounter the healthcare system for any reason.
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Hemochromatosis |
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TopAbstractIntroductionHemochromatosisEarly DetectionQuality ImprovementReferences |
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Now, hemochromatosis is known to be inherited in an autosomal recessive pattern and associated with a gene tightly linked to the HLA locus on chromosome 6. A specific abnormality, named HLA-H, has been associated with 83–100% of cases (6). The exact molecular mechanism of the abnormality remains a mystery. Homozygous individuals absorb iron at an increased rate and accumulate excess iron in parenchymal organs, leading to organ failure. The normal iron absorption rate of 1 mg/day in males and 2 mg/day in females may increase to as much as 10 mg/day in homozygotes (5). No excretory mechanism for excess iron exists. Therefore accumulated iron causes tissue damage resulting in diabetes mellitus, hepatic failure, cardiomyopathy, arthritis, and pituitary siderosis with secondary decreased gonadal function.
The variety and severity of symptoms lead patients to all types of healthcare providers. Diagnosis can commonly be delayed 5 years from sentinel symptoms and occur after encountering multiple physicians (7)(8).
Hemochromatosis is not rare. Among individuals of Northern European
descent ~5 per 1000 are homozygous. The frequency of heterozygotes is
8% to 13%. The heterozygotes rarely experience organ damage but have
10–20% likelihood of mildly abnormal serum transferrin saturation
(TSAT)1
and ferritin (9). The expression of disease in
homozygotes is quite variable, probably in response to other genetic as
well as dietary or menstrual factors. Most estimates of symptom
frequency in homozygotes are near 50%
(10)(11) (see Fig. 1
).
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Hemochromatosis male predominance is a misconception. Symptoms and severity tend to be more prevalent in males, but with earlier detection now more frequent, the male to female ratio of cases is 1.6:1 in recent studies (5).
The difficult clinical differential is between homozygotes, heterozygotes, and alcoholic liver diseases. Those patients with alcoholic liver disease who accumulate enough iron to cause organ damage most likely are also homozygotes for hemochromatosis (5)(12).
Liver biopsy with chemical quantitation of hepatic iron content is helpful. Iron accumulates with age, and iron content is best interpreted as the hepatic iron index, i.e., hepatic iron content in micromoles per gram dry weight of liver divided by the patient's age. Healthy subjects, heterozygotes, and patients with alcoholic liver disease have an hepatic iron index <2, whereas homozygotes are >2 (5). As homozygotes continue to be detected earlier, these decision points may need to be revised.
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Early Detection |
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TopAbstractIntroductionHemochromatosisEarly DetectionQuality ImprovementReferences |
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To date no randomized trial of screening vs not screening has been performed. Available data strongly support the benefits of early detection through screening. Several nonrandomized trials have been begun or reported (11).
Screening programs for Caucasian-type hereditary hemochromatosis on the
basis of serum TSAT as the first test will also uncover other types of
abnormal iron metabolism. African-Americans are reported to experience
an iron overload disease that is inherited but more dependent on
environmental factors, particularly excess dietary iron
(19). Secondary causes of abnormal iron loading interact
with hereditary hemochromatosis. Most suspect that iron overload in the
conditions listed in Table 1
is related to the presence of one hemochromatosis allele
(5).
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Quality Improvement |
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TopAbstractIntroductionHemochromatosisEarly DetectionQuality ImprovementReferences |
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In the community hemochromatosis was being identified after the development of symptoms, a difference from desired outcome. The testing plan began with the outcome in mind (21). Our goals were to identify both hemochromatosis before symptoms developed and individuals likely to benefit from intervention—not to find and label every individual with two hemochromatosis alleles, nor identify all homozygotes who had not yet accumulated substantially large iron stores.
The process variable most likely to alter the outcome was to initiate testing in asymptomatic people. We realized that the other stakeholders could not be expected to think of it and initiate a screening test, nor could we expect anyone to pay substantially for a screening test. In addition, discussions with care providers revealed their expectation that the positive screening tests would need high positive predictive value; thus the necessity to investigate a false positive would occur infrequently.
We decided to use unsaturated iron-binding capacity (UIBC) as the initial test (5)(22). UIBC can be readily automated, and the reagent cost was pennies per test. UIBC estimates the empty sites on transferrin by adding a known amount of reagent iron to fill those empty sites and then measuring the iron in excess of the transferrin sites with a chromophore. When UIBC is low, high TSAT is very likely. Total iron-binding capacity (TIBC) is calculated by adding the UIBC to serum iron. TSAT is calculated by dividing serum iron by the sum of UIBC plus serum iron, i.e., the TIBC.
We performed UIBC with the Beckman (Brea, CA) CX-7 and Diagnostic Chemicals, Ltd. (Oxford, CN) reagents. The TIBC calculated from UIBC + serum iron compared favorably with the usual Beckman TIBC method, and the between-run precision of UIBC revealed CVs of 7–10%. The reagent cost of $0.02 per test estimates the order of magnitude of the incremental cost of performing UIBC.
We measured UIBC, serum iron, TSAT, and ferritin in the serum from 282
inpatients and 819 ambulatory patients and voluntary participants in
public health screenings (23). We found 14 ambulatory and
13 inpatients with UIBC 1250 µg/L or less. Only 6 of these 27 had
both TSAT >50% and ferritin >90th percentile (24).
Conversely, we found no individual with TSAT >50% and ferritin >90th
percentile who had UIBC >1250 µg/L. The six individuals with TSAT
>50% and >90th percentile ferritin included one case of
hemochromatosis diagnosed during and because of the study, two probable
heterozygotes, one possible homozygote who was lost to follow-up, and
two patients with hematologic diagnosis known to alter iron metabolism
(see Table 2
).
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We decided to act by sharing the data with all the care providers, gaining approval from institutional committees and offering UIBC with some chemistry panels at no additional charge. Also at no additional charge we performed serum iron on all samples with UIBC of 1250 µg/L or less and reported TSAT. If UIBC was 1260 µg/L or more we did nothing.
We continue to follow the results of this program. We have reviewed all
UIBC results between August 1995 and May 1996. The results of this
quality review are shown in Fig. 2
. Health records were reviewed in all cases with UIBC <1260
µg/L. We have identified three new cases and expect several of the
five pending additional work-up will also be hemochromatosis. Thus far
we have found 3 plus maybe 5 new cases and 6 known cases or ~14 in
7093 people in this cohort. This is very close to the expected
frequency of individuals likely to accumulate enough iron to need
intervention (5)(10)(11). If 50%
of 5 per 1000 are expected to accumulate iron, 17 would be expected.
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The other causes of high TSAT include acute alcohol ingestion, iron therapy in hemodialysis patients, and various hematologic diseases. Caregivers have been pleased to find new asymptomatic hemochromatosis. No problems have been reported with understanding the remaining UIBC and TSAT results. As an aside, the very high UIBC values associated with iron deficiency have also been diagnostically useful.
These data represent an experience with no control population. The data also do not rule out the commonly described statistical biases in screening programs (25)(26). We choose to interpret this as clinical quality improvement and trust we will prevent organ failure attributable to hemochromatosis in our community.
New genetic findings regarding iron overload in Caucasians
(6), African-Americans (19), and those with
other iron-loading diseases will initiate further improvements in our
testing scheme. However, we continue to believe that UIBC will help
find iron-loaded individuals likely to benefit from intervention. UIBC
also identifies a portion of the much higher prevalence of iron
deficiency. Future research will guide the choice of genetic tests,
liver biopsy, or phlebotomy to improve the evaluation of iron overload
and enhance the prevention of morbidity and premature mortality (see
Fig. 3
).
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Acknowledgments |
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Footnotes |
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References |
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TopAbstractIntroductionHemochromatosisEarly DetectionQuality ImprovementReferences |
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The following articles in journals at HighWire Press have cited this article:
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  E. Lyon and E. L. Frank Hereditary Hemochromatosis Since Discovery of the HFE Gene Clin. Chem., July 1, 2001; 47(7): 1147 - 1156. [Abstract] [Full Text] [PDF]
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D. R. Dufour, J. A. Lott, F. S. Nolte, D. R. Gretch, R. S. Koff, and L. B. Seeff Diagnosis and Monitoring of Hepatic Injury. II. Recommendations for Use of Laboratory Tests in Screening, Diagnosis, and Monitoring Clin. Chem., December 1, 2000; 46(12): 2050 - 2068. [Abstract] [Full Text] [PDF]
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P. C. Adams and V. Bhayana Unsaturated Iron-binding Capacity: A Screening Test for C282Y Hemochromatosis? Clin. Chem., November 1, 2000; 46(11): 1870 - 1871. [Full Text] [PDF]
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 M Bhavnani, D Lloyd, A Bhattacharyya, J Marples, P Elton, and M Worwood Screening for genetic haemochromatosis in blood samples with raised alanine aminotransferase Gut, May 1, 2000; 46(5): 707 - 710. [Abstract] [Full Text] [PDF]
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E. R. Black Diagnostic strategies and test algorithms in liver disease Clin. Chem., August 1, 1997; 43(8): 1555 - 1560. [Abstract] [Full Text] [PDF]
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