Diagnosis Of Hereditary Hemochromatosis Research Articles

Artrosis unilateral de cadera: manifestación articular de la hemocromatosis

Hereditary haemochromatosis is the most common genetic disorder in the Caucasian population, with an estimated prevalence of 1/200-1/400 (homozygous) and 1/8-1/10 in carriers (heterozygous). The transmission is recessive and linked to HLA. The clinical expression of disease appears only in homozygous and will depend on the time of diagnosis and the degree of organ involvement.The clinical case presented below describes the process of differential diagnosis made in a young patient with unilateral coxarthrosis and clinical suspicion of hemochromatosis.Early diagnosis of hereditary hemochromatosis in primary care can reduce morbidity and mortality of this disease by detecting homozygous at younger ages.

Unsuspected Hereditary Hemochromatosis at Forensic Autopsy

Hereditary hemochromatosis (HH) is one of the most common genetic disorders and may present clinically in a variety of ways. The most common presentation is micronodular cirrhosis with possible associated diabetes. However, HH may also present with cardiac dysfunction and sudden death. The confirmation of unsuspected HH at autopsy is complicated by the growing number of genetic abnormalities, which are not detected by current commercial genetic testing for C282Y and H63D mutations. Consequently, quantitative liver iron studies on fresh or paraffin embedded liver is recommended in confirming HH. The importance of detection and confirmation of HH cannot be overemphasized given the need to screen surviving family members in preventing organ damage of asymptomatic individuals. We present a case of a 38-year-old white woman with micronodular cirrhosis secondary to unsuspected HH that was confirmed by a quantitative liver iron study. The possible presentation of cardiac sudden death from HH, confirmation issues and implications of a HH diagnosis for surviving family members are also discussed.

Hereditary hemochromatosis: patient experiences of the disease and phlebotomy treatment

Hereditary hemochromatosis (HH) is a genetic disorder resulting in increased accumulation of dietary iron. It is associated with various clinical complications such as liver cirrhosis and diabetes. The aim of this study was to explore patients' experiences of living with HH, the diagnosis process, and phlebotomy treatment. An online survey was developed and completed by a total of 210 HH patients across the United States (n = 70), France (n = 50), Ireland (n = 40), and the United Kingdom (n = 50). Of the 210 patients, 30% were induction patients, 49% were maintenance patients, and 22% had never received phlebotomy. The most common route to diagnosis was by chance (42%), although most patients (87%) reported experiencing symptoms they now associated with HH at the time of diagnosis. Fatigue (60%) and joint pain (50%) were the most frequently reported current symptoms. While 87% of patients felt that treatment with phlebotomy was "quite worthwhile" or "very worthwhile," 52% of induction patients and 37% of maintenance patients experienced side effects "always" or "most of the time" after phlebotomy and 16% of patients would "definitely" or "probably" decide not to receive phlebotomy if alternative options were available. Diagnosis of HH is likely made late in many patients and subsequent phlebotomy treatment, while considered worthwhile by most, leads to concerns over side effects and inconvenience, often impacting patients' lives. Greater efforts to promote awareness of the disease and reduce the treatment burden associated with phlebotomy are required to improve detection and management of this disease.

Therapeutic complications in a patient with high‐risk acute lymphoblastic leukemia and undiagnosed hereditary hemochromatosis

Hereditary hemochromatosis (HH) is an autosomal-recessive disorder of iron metabolism that most commonly manifests in the fourth or fifth decade of life. Here, we describe a 14-year-old male who presented with high-risk acute lymphoblastic leukemia and previously undiagnosed HH. His treatment course was remarkable for significant therapeutic complications, including iron overload, hepatic failure, cardiac dysfunction, and death. Postmortem testing revealed homozygosity for the C282Y mutation, confirming the diagnosis of HH. Since HH mutations occur commonly in select populations, screening patients with leukemia for HH may better inform treatment decisions regarding chemotherapy, transfusions, and/or iron chelation therapy.

187 A PHASE I/II, OPEN-LABEL, DOSE-ESCALATION TRIAL USING THE ONCE-DAILY ORAL CHELATOR DEFERASIROX TO TREAT IRON OVERLOAD IN HFE-RELATED HEREDITARY HEMOCHROMATOSIS: FINAL RESULTS

Background and Aims: Hereditary hemochromatosis (HH) is characterized by increased intestinal iron absorption. Consequences of iron overload include organ dysfunction, cirrhosis and hepatocellular carcinoma. Although phlebotomy is the standard of care, it is contraindicated in patients with severe heart disease or anemia, venous access may be difficult and compliance can be variable. The once-daily, oral iron chelator, deferasirox (Exjade®) may provide an alternative treatment. Results of the 6-month core trial were previously reported; 6-month extension data are reportedhere.Methods: Patients with HFE C282Y homozygous HH with serum ferritin (SF) 300–2000 ng/mL, transferrin saturation ≥45% and no known history of cirrhosis were enrolled in this dose-escalation study (deferasirox 5, 10 and 15 mg/kg/day). This multicenter study comprised a core and extension phase (both 24 weeks). The primary endpoint was the incidence and severity of adverse events (AEs). Secondary endpoints included change in SF. Results: 49 patients were enrolled (33 men, 16 women; mean age 50.6 years; mean 3.1 years since HH diagnosis) and received deferasirox 5 (n = 11), 10 (n = 15) or 15 mg/kg/day (n = 23). 37 (75.5%) patients completed the core trial. Of 26 patients whoentered the extension, 23 (88.5%) completed 48 weeks. The most common reasons for discontinuation were AEs, mainly in the 10 and 15 mg/kg/day cohorts. Overall, AEs were dose dependent, including diarrhea, headache and nausea (n = 18, n = 10 and n = 8 in the core and n = 1, n = 1, n = 0 in the extension, respectively). Throughout 48weeks in the 15 mg/kg/day cohort, six patients experienced ALT >3 x baseline and > upper limit of normal (ULN), and eight patients had serum creatinine ≥33% above baseline and >ULN on two consecutive occasions. SF declined in all cohorts; median reduction was 63.5%, 74.8% and 74.1% in the 5, 10 and 15 mg/kg/day cohorts, respectively; in all cohorts, median SF was <250 ng/mL after receiving deferasirox for 48 weeks.Conclusions: Results suggest that deferasirox doses of 5, 10 and 15 mg/kg/day can reduce iron burden in HH patients. Based on the safety and efficacy results, deferasirox 10 mg/kg/day appears to be the most appropriate doses for further study in this patient population.Copyright © 2011 Elsevier B.V. All rights reserved.

Reply†

We thank Dr. Castiella and co-workers for the kind comments on our article. He asked about the characterization of HFE gene mutations of patients defined as non-HFE hereditary hemochromatosis (HH), i.e., non-C282Y homozygotes, and compound C282Y (Cys282 → Tyr282)/H63D (His63 → Asp63) and C282Y/S65C (Ser65 → Cys65) heterozygotes. Of the 114 patients with non-HFE–related hemochromatosis, 12 (10%) were homozygous for the H63D mutation, 29 (25%) were heterozygous for the C282Y mutation, and 16 (14%) were heterozygous for the H63D mutation. Of these patients, only six (5%) had established genetic determinants of iron overload. Three patients had a phenotype consistent with juvenile HH which was linked to chromosome 1q or homozygosity for hemojuvelin missense mutation, one patient had iron overload associated with a missense ferroportin-1 mutation, and two patients had homozygosity for transferrin receptor-2 missense mutation.1, 2 Only a few other patients were found to be affected by possible hereditary risk factors for iron overload: one was a heterozygous carrier of the E302K hemojuvelin mutation, and two were positive for the −72C→T hepcidin promoter mutation. Regarding patients homozygous for the C282Y mutation, we completely agree with Dr. Castiella that the coexistence of non-HFE gene mutations may cause a more severe iron overload, as reported by Island et al.,3 but we have not yet completed the characterization of our patients. The second point raised by Dr. Castiella is that patients negative for HFE mutations usually have milder iron overload. All patients included in our study had iron overload compatible with the diagnosis of HH with no significant difference between HFE and non-HFE HH. In addition, although it has recently been demonstrated that hepatitis C virus infection and alcohol may contribute to iron accumulation by interfering with hepcidin transcription,4, 5 only noncirrhotic patients with HFE-related HH had a significantly more severe iron overload when acquired risk factors coexisted. Heterogeneity of genetic and acquired determinants possibly responsible for iron overload may account for the different severity of iron overload in patients with HH. Silvia Fargion*, * Department of Internal Medicine, Universita' degli Studi di Milano, Milan, Italy.

This Month in Gastroenterology

This Month in Gastroenterology

Identifying Cirrhosis in Patients with Hemochromatosis

Genetic testing for the C282Y mutation can lead to the diagnosis of hereditary hemochromatosis (HH) without the need for invasive liver biopsies.

Hereditary hemochromatosis: a neglected diagnosis in orthopedics

Hereditary hemochromatosis (HH) is a not uncommon autosomal recessive and potentially life-threatening disease. The hemochromatosis gene was identified by Feder et al. in 1996. About 1 in 200 individuals is estimated to be homozygous for the most common mutation—C282Y/C282Y. In the classical form of the disease, cysteine is substituted by tyrosine at amino acid 282 in both alleles. The so-called compound heterozygoty is less common (representing about 10% of cases) but is also compatible with HH. Here, histidine is substituted by aspartic acid at amino acid 63 in one allele and cysteine by tyrosine at amino acid 282 in the other (C282Y/H63D). Due to increased intestinal absorption, homozygotes develop iron overload but penetrance is very variable (McCune et al. 2006). Most orthopedic surgeons meet patients with undiagnosed HH on a yearly basis and an early diagnosis and treatment is important in order to avoid cirrhosis of the liver. Also, the risk of developing hepataocellular cancer is at least 20-fold higher than in their first-degree relatives (Elmberg et al. 2003). Fatigue and arthritis, unspecific and therefore often neglected, are common presentations whereas the classic bronze diabetes (darkened skin, diabetes, and cirrhosis) is the final stage of untreated HH that is very rarely seen (McDonell et al. 1999). A survey of 2,851 patients with hemochromatosis showed that patients had consulted a physician after an average of 2 years of symptoms, and on average it took a further 10 years before the diagnosis was made (McDonell et al. 1999). This is unfortunate, since medical treatment—i.e. regular phlebotomy—is effective. During the period 2001–2008, I replaced 93 ankles in 86 patients and 4 of these patients proved to have hemochromatosis. Here I have reviewed the orthopedic manifestations in 7 patients who had one or both ankles replaced during this period, 3 of whom had had their ankles replaced elsewhere. Cases The original records from all orthopedics departments and units of gastroenterology involved were consulted and the author interviewed the patients at least twice. All but 1 patient were below the age of 45 when they had their first joint symptoms, and there was usually a long patient’s and doctor’s delay before diagnosis and treatment. In 4 cases the hip, knee or ankle joint, and not the MP joints, was the first joint to become symptomatic. Only in one case (patient 5) did the joint symptoms start after the time that the diagnosis of HH had been made (Table 1). Table 1. Demographic data, laboratory findings, and joints replaced in 7 patients with hereditary hemochromatosis

A systematic review of the clinical validity and clinical utility of DNA testing for hereditary haemochromatosis type 1 in at-risk populations

Objective:To evaluate the clinical validity and clinical utility of DNA testing in people suspected of having hereditary haemochromatosis and in family members of those diagnosed with the disorder.Design:A systematic review.Methods:15...

Diabetes como manifestación inicial de Hemocromatosis Hereditaria

Diabetes as an initial manifestation of Hereditary Hemochromatosis. Hereditary hemochromatosis (HH) is an inherited disorder of iron metabolism. It is one of the most common autosomal recessive conditions. In patients with HH the amount of iron absorbed by the intestines is increased, which may lead to excess iron being deposited in different organs of the body, causing organ dysfunction. The frequency of diabetes is increased in HH. A clinical diagnosis of HH can often be established on the basis of blood tests (transferrin saturation index and serum ferritin level), however, a liver biopsy to determine the amount of iron in the liver is often required to confi rm tissue iron overload. The diagnosis of hereditary hemochromatosis before iron overload has developed is diffi cult. However, doctors need to have a higher awareness of HH because with early diagnosis and appropriate treatment, survival of patients is normal.

Diagnóstico y cuantificación de la sobrecarga férrica en el hígado mediante resonancia magnética

Hereditary hemochromatosis is the most common cause of iron overload. The diagnosis of hereditary hemochromatosis has improved since Feder et al. isolated the HFE gene in 1996 and discovered the mutations related with this disease. Nevertheless, in many cases genetic tests for hereditary hemochromatosis are negative. These cases require diagnostic confirmation by quantifying the concentration of iron in the liver (LIC); this has traditionally been accomplished by liver biopsy. Many studies have shown that it is possible to quantify LIC using MRI. However, a consensus has yet to be reached about the most appropriate technique or whether it is possible to reproduce the same methods of calculation on different MRI units. This article reviews the current state of these questions and points to possible lines to standardize this noninvasive method of quantifying LIC in the future.

Clinical Perspectives on Hereditary Hemochromatosis

Hereditary hemochromatosis (HH) comprises a group of inherited disorders of iron metabolism that can result in progressive iron overload, morbidity, and mortality, generally in adulthood. HFE-related HH is the most common type of HH and will form the core of this discussion. The discovery of new proteins and gene mutations has defined other types of HH, termed non-HFE HH. The regulatory protein hepcidin has a central role in iron homeostasis in these disorders. While the liver is the predominant organ of iron deposition and iron-overload-related disease in HFE-related HH, involvement of extrahepatic tissue can also result in morbidity and mortality if the disorder is not diagnosed before organ damage develops. This review traverses the road from HFE genotype to phenotype with a focus on clinical penetrance, modifier factors for disease expression, and current thoughts and controversies on HH diagnosis and screening.

Measurement of urinary hepcidin levels by SELDI-TOF-MS in HFE-hemochromatosis

Introduction Insufficient production of hepcidin, the master regulator of iron metabolism, is recognized as the key pathogenetic feature of HFE-related hereditary hemochromatosis (HH). There is a growing interest in measuring the hepcidin levels, which may improve the diagnosis, prognostic evaluation and clinical management of HH. Nevertheless, few investigative tools are available: an immunodot method for urinary hepcidin developed by a single centre (UCLA), not yet ready for large-scale diffusion, and mass spectrometry (MS) based assays, such as surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF-MS). The latter is well suited to small peptides like hepcidin, and can rapidly analyze crude samples with high throughput. This study measured urinary hepcidin levels by SELDI-TOF-MS in a large group of HH patients at diagnosis and during treatment, including both C282Y homozygous and C282Y/H63D compound heterozygotes. Methods We used a protocol based on PBSIIc mass spectrometer and Normal Phase chips. Urinary samples from 30 control subjects were compared to those obtained from 80 HH patients (57 C282Y homozygotes, 23 C282Y/H63D compound heterozygotes). Eighteen C282Y homozygotes and 11 C282Y/H63D compound heterozygotes were analyzed at diagnosis, the remainder during maintenance phlebotomy. Results C282Y homozygotes either at diagnosis, or after phlebotomy had significantly lower urinary hepcidin levels than controls ( P < 0.05). C282Y/H63D compound heterozygotes had hepcidin levels at diagnosis higher than controls, while the hepcidin/ferritin ratio was significantly decreased ( P < 0.001) suggesting inadequate hepcidin production. After phlebotomy, mean hepcidin levels in the compound heterozygotes were significantly lower than in controls ( P < 0.001). Samples from 12 randomly selected control subjects were sent to UCLA for duplicate measurement by the immunodot method, yielding a significant correlation (rho = 0.64; P = 0.024). Conclusions This study supports the use of SELDI-TOF-MS for measuring hepcidin levels in research and clinical applications. Our results in phlebotomized patients suggest that the depletion of iron stores may further exacerbate the HFE-related hepcidin defect.

Measurement of Urinary Hepcidin Levels by SELDI-TOF-MS in HFE-Hemochromatosis.

Introduction: An insufficient production of hepcidin, the master regulator of iron metabolism, is recognized as the key pathogenetic feature of HFE-related hereditary hemochromatosis (HH). There is a growing interest in measuring the hepcidin levels, which may improve diagnosis, prognostic evaluation and clinical management of HH. Nevertheless, few investigative tools are available: an immunodot method for urinary hepcidin developed by a single centre (UCLA), not yet ready for large-scale diffusion, and mass spectrometry (MS) based assays, such as surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF-MS). The latter is well suited to small peptides like hepcidin, and can rapidly analyze crude samples with high throughput. Until now, urinary hepcidin has been measured by SELDI-TOF-MS only in small groups of C282Y homozygous patients, the majority of them under phlebotomy treatment. No data are available on C282Y/H63D compound heterozygotes, that can develop a milder clinical form of HH. This study was aimed to measure urinary hepcidin levels by SELDI-TOF-MS in a large group of HH patients.Methods: We used a protocol based on PBSIIc mass spectromer and Normal Phase chips similar to that recently proven successful for semi-quantitative detection of urinary hepcidin. Urinary samples from 30 control subjects were compared to those obtained from 80 HH patients (57 C282Y homozygotes, 23 C282Y/H63D compound heterozygotes). Eighteen C282Y homozygotes and 11 C282Y/H63D compound heterozygotes were analyzed at diagnosis, the remainder during maintenance phlebotomy (at least 30 days from last phlebotomy).Results: C282Y homozygotes had significantly lower urinary hepcidin levels vs. controls either at diagnosis, or after phlebotomy (P < 0.05). C282Y/H63D compound heterozygotes had hepcidin levels at diagnosis similar to controls, while the hepcidin:ferritin ratio was significantly decreased (P < 0.001) suggesting a relatively inappropriate hepcidin production. Moreover, also in this group means hepcidin levels after phlebotomy were significantly lower than in controls (P < 0.001). Samples from 12 randomly selected control subjects were sent to UCLA for duplicate measurement by the immunodot method, yielding a good correlation (r= 0.77; P<0.0001).Conclusions: SELDI-TOF-MS assay is confirmed to be a potentially useful tool for measuring hepcidin levels in HH. The very low hepcidin levels observed in both genotypes after phlebotomy, may suggest that iron depletion as currently achieved by standard protocols may not be the best therapy from a pathophysiological standpoint.

A novel mutation of transferrin receptor 2 in a Taiwanese woman with type 3 hemochromatosis

Hereditary hemochromatosis (HH) is very rare in Asia. Here, we describe a Taiwanese woman presenting with fully developed characteristics of HH including bronze skin, DM, decreased MRI T2 signal intensity over liver and pituitary gland. Biochemistry of iron profile indicated a severe status of iron overload by serum iron: 194 microg/dL, serum ferritin: 6640 microg/L, transferrin saturation: 92.8%. By measuring the hepatic iron index 8.48 (>1.9) of her liver biopsy tissue, the diagnosis of HH was established. Diagnosis of non-HFE HH was carried out since the whole HFE genome was sequenced but failed to localize any genetic alterations. The whole genome of transferrin receptor 2 (TfR2) was sequenced and a novel mutation of 13528 G-->A (Arg 481 His) in exon 11 was detected. Therefore, type 3 hemochromatosis was confirmed. The distinct clinical features, extremely high iron index and impressive iron staining in her liver biopsy tissue may represent an aggravated iron deposition in the liver caused by this novel mutation. Our finding implicates functional importance of histidine in exchange of arginine at amino acid 481 of transferrin receptor 2 in iron homeostasis. This case reminds physicians in Asia to keep in mind that hemochromatosis could be a rare cause of DM.

Movement disorder due to aceruloplasminemia and incorrect diagnosis of hereditary hemochromatosis

Movement disorder due to aceruloplasminemia and incorrect diagnosis of hereditary hemochromatosis

An unusual case of cardiomyopathy

A 56-year-old man presented with a 3-week history of worsening dyspnoea and lethargy. Clinical examination revealed signs of marked congestive cardiac failure and hypotension with a systolic blood pressure (BP) of 70 mmHg. Laboratory investigations revealed a urea of 29 mmol/litre and a creatinine of 310 μmol/litre with normal liver function tests, apart from a bilirubin of 40 μmol/litre. Initial treatment included oxygen, intravenous diuretics and ionotropes although his BP remained low. Subsequently, an intra-aortic balloon pump (IABP) was inserted with 1:1 augmentation and his clinical picture improved gradually. Cardiac catheterization was performed which showed normal coronary arteries and high right-sided heart pressures with a right ventricular pressure of 58/14 mmHg, pulmonary artery pressure of 58/28 mmHg, and a mean pulmonary capillary wedge pressure of 29 mmHg. His electrocardiogram (ECG) 1 year before his current admission is shown in Figure 1. This revealed an atrial tachycardia with a cycle length of approximately 320 ms with upright P waves in lead V1 and inverted P waves in the inferior leads. There was a left bundle–branch block morphology with a QRS duration of around 100 ms and relatively high degree atrioventricular block with a ventricular rate of around 60–70 beats per minute. He had initially presented 5 years earlier in congestive cardiac failure. ECG at that time showed first degree heart block with a QRS duration of 100 ms. Transthoracic echocardiography revealed a dilated left ventricle at 6.1 cm in diastole and a left ventricular ejection fraction &lt;20%. Viral serology at the time was negative, he did not drink alcohol and did not suffer from ischaemic heart disease. His only other medical history consisted of hypothyroidism for which he was treated with thyroxine. His brother had died at the age of 44 years suffering from liver cirrhosis, diabetes and heart failure, which raised the question of hereditary haemochromatosis (HHC). The diagnosis of HHC was confirmed by HLA testing showing he was homozygous for the C282Y mutation of the responsible gene, a raised serum ferritin at 900 mg/litre and a liver biopsy in keeping with HHC (increased iron deposition in the liver cells but with normal acinar architecture and no inflammation or cirrhosis). After stabilization with an IABP, his treatment options for cardiogenic shock included either insertion of a left ventricular assist device to improve BP and renal function or cardiac transplantation. Unfortunately the patient became septic from his IABP insertion site and so neither were viable options. He died shortly afterwards.

Hepatocellular Carcinoma Associated with Hereditary Hemochromatosis Occurring in Non-Cirrhotic Liver

The occurrence of primary hepatocellular carcinoma (HCC) in patients with hereditary hemochromatosis (HH) is well known. Thereby, the development of liver cirrhosis seems to be a prerequisite. Whether or not a hepatic iron overload in the context of hereditary hemochromatosis is an independent risk factor for HCC remains unclear. To date there are only a few reports about HCC arising in non-cirrhotic livers in the presence of HH. We report the case of a 64-year-old man who presented to our outpatient clinic with HCC. Liver cirrhosis could be excluded. Detailed exploration of the patient's history revealed that he had been treated by venesection for about 10 years up to 15 years ago. Subsequent investigations showed an elevated serum ferritin and transferrin saturation. The diagnosis of HH was confirmed by genetic testing, with homozygosity for the Cys282Tyr mutation. The patient received palliative chemotherapy and finally died 15 months after initial diagnosis of HCC.

Searching for Hereditary Hemochromatosis

To detect hereditary hemochromatosis (HH) in low-income residents of a medically underserved region through free screening and confirmatory laboratory testing and to raise awareness of HH in the general population. Two-tiered reflexive laboratory testing was used to screen for HH. Participants evaluated the project by written survey upon its conclusion. Data were analyzed by descriptive techniques. Local public health departments in 18 counties in western North Carolina (WNC). PARTICIPANTS/SUBJECTS: Phase 1: adult volunteers age > or = 20 without previous diagnosis of HH; Phase 2: Phase 1 participants with elevated screening results and adult family members of Phase 2 participants found to have HFE mutations; Phase 3: randomly-selected Phase 1 participants (Survey A) and all Phase 2 participants with HFE mutations (Survey B). Phase 1 (initial screening): non-fasting blood collection by venipuncture with testing for transferrin saturation (TS). Phase 2 (confirmatory testing): fasting blood collection by venipuncture for TS, serum ferritin (SF), and cheek swab for DNA analysis for two HFE mutations (C282Y and H63D). Phase 3: written Surveys A and B. Total number participants screened for HH; prevalence of elevated TS in Phase 1 participants; prevalence of HFE genotypes consistent with HH (C282Y/C282Y and C282Y/H63D) in Phase 2 participants; prevalence of elevated SF in subjects with HFE mutations; number of family members tested; number of participants being treated for HH as a result of screening; increase in awareness of HH among Phase 1 participants. 2,034 total subjects participated in screening events and/or family member testing. Of the 1,976 Phase 1 participants, 130 (6.6%) had elevated TS (> or = 45%). Twenty of 130 (15.4%) Phase 2 subjects were homozygotes for C282Y. The prevalence of the C282Y/C282Y genotype among the Phase 1 participants who were tested in Phase 2 was 20/1976 (1.0%). Fourteen of 20 (70%) C282Y homozygotes had elevated SE Eleven of 130 (8.5%) Phase 2 subjects were compound heterozygotes for C282Y and H63D, and none had elevated SE Of 58 family members tested, two (3.4%) were homozygotes for C282Y and eight (13.8%) were compound heterozygotes for C282Y and H63D. One of two (50%) family members homozygous for C282Y had an elevated SE No compound heterozygotes had elevated SE Sixty-four of 120 (54.2%) Phase 1 subjects responded to Survey A. 53.1% of respondents were unaware of HH prior to the screening event. 92.1% of respondents told their family and friends about HH after participating. 73.4% discussed their laboratory results with their healthcare provider. Twenty of 41 participants (48.8%) found to have HFE mutations associated with HH responded to Survey B. Eleven of 20 (55.0%) stated that they were being treated for HH. The prevalence of the major genetic mutation, C282Y/C282Y, associated with HH among Phase 1 study participants in WNC was 1%, more than three times the national prevalence of approximately 0.33%. Results suggest that free screening using laboratory tests in a two-tiered reflexive approach may be an effective means of detecting HH, especially in high-risk populations. Early detection through free laboratory screening tests may reduce morbidity and, ultimately, healthcare costs for low-income individuals. Awareness of HH as a health concern may increase as a result of publicity generated by screening events.