scholarly journals Clinical Manifestations of Hemochromatosis inHFEC282Y Homozygotes Identified by Screening

2008 ◽  
Vol 22 (11) ◽  
pp. 923-930 ◽  
Author(s):  
Gordon D McLaren ◽  
Christine E McLaren ◽  
Paul C Adams ◽  
James C Barton ◽  
David M Reboussin ◽  
...  
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Elevated Serum ◽  
Clinical Signs ◽  
Clinical Manifestations ◽  
Joint Stiffness ◽  
Chronic Fatigue ◽  
Newly Diagnosed ◽  
Wild Type ◽  
Control Subjects

BACKGROUND: Patients with hemochromatosis may suffer organ damage from iron overload, often with serious clinical consequences.OBJECTIVE: To assess prevalences of self-reported symptoms and clinical signs and conditions in persons homozygous for the hemochromatosis gene (HFE)mutation (C282Y) identified by screening.METHODS: Participants were adults 25 years of age or older enrolled in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. C282Y homozygotes (n=282) were compared with control participants without theHFEC282Y or H63D alleles (ie, wild type/wild type; n=364).RESULTS: Previously diagnosed C282Y homozygotes and newly diagnosed homozygotes with elevated serum ferritin levels had higher prevalences of certain symptoms such as chronic fatigue (OR 2.8; 95% CI 1.34 to 5.95, and OR 2.0; 95% CI 1.07 to 3.75, respectively), and had more hyperpigmentation on physical examination (OR 4.7; 95% CI 1.50 to 15.06, and OR 3.7; 95% CI 1.10 to 12.16, respectively) and swelling or tenderness of the second and third metacarpophalangeal joints (OR 4.2; 95% CI 1.37 to 13.03, and OR 3.3; 95% CI 1.17 to 9.49, respectively) than control subjects. Joint stiffness was also more common among newly diagnosed C282Y homozygotes with elevated serum ferritin than among control subjects (OR 2.7; 95% CI 1.38 to 5.30). However, the sex- and age-adjusted prevalences of self-reported symptoms and signs of liver disease, heart disease, diabetes and most other major clinical manifestations of hemochromatosis were similar in C282Y homozygotes and control subjects.CONCLUSIONS: Some symptoms and conditions associated with hemochromatosis were more prevalent among C282Y homozygotes identified by screening than among control subjects, but prevalences of most outcomes were similar in C282Y homozygotes and controls in this primary care-based study.

Symptoms and Signs of Hemochromatosis in HFE C282Y Homozygotes Identified by Screening in Primary Care.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1545-1545 ◽  
Author(s):  
Gordon D. McLaren ◽  
Christine E. McLaren ◽  
Paul C. Adams ◽  
James C. Barton ◽  
David M. Reboussin ◽  
...  
Keyword(s):  
Primary Care ◽  
Transferrin Saturation ◽  
Joint Stiffness ◽  
Chronic Fatigue ◽  
The United States ◽  
Newly Diagnosed ◽  
Control Subjects ◽  
Primary Care Settings ◽  
Clinical Conditions ◽  
Symptoms And Signs

Abstract Some patients with hemochromatosis (HC) experience fatigue, heart failure or arrhythmias, diabetes mellitus, liver damage, impotence, or arthritis. We examined self-reported symptoms and clinical conditions in persons homozygous for HFE C282Y, the major HC-associated gene mutation, identified in the Hemochromatosis and Iron Overload Screening (HEIRS) Study, a multi-center, multi-ethnic study in which 101,168 adults were recruited from primary care settings. Non-Hispanic Caucasian C282Y homozygotes were compared to participants without HFE C282Y or H63D alleles (controls) with transferrin saturation (TfS) and serum ferritin (SF) levels in the middle half of gender-specific distributions. Evaluation included a medical history, focused physical examination, and repeat SF. Among 44,082 non-Hispanic Caucasian participants screened at five Field Centers in the United States and Canada, 282 persons homozygous for C282Y were identified, comprising three groups: newly-diagnosed cases with normal (N=64) or elevated (N=131) SF (>200 μg/L in women, >300 μg/L in men), and previously-diagnosed cases (N=87). There were 364 non-Hispanic Caucasian controls. Significant differences were observed for six of 38 outcomes. Previously diagnosed C282Y homozygotes and newly diagnosed homozygotes with elevated SF reported significantly more chronic fatigue than controls (p=0.002). All groups of C282Y homozygotes reported weight loss more often than controls (p<0.001). Excessive thirst was reported more often than controls by newly diagnosed C282Y homozygotes, regardless of SF level (p=0.004), but there was no difference in self-reported history of diabetes. Joint stiffness was more common among newly diagnosed C282Y homozygotes with elevated SF than among control subjects (p<0.001). Swelling or tenderness of the second and third metacarpophalangeal joints and increased pigmentation were also more common among previously diagnosed C282Y homozygotes and newly diagnosed homozygotes with elevated SF than among controls (p=0.001 and p=0.002, respectively). The prevalences of manifestations related to liver or heart disease among C282Y homozygotes were not significantly different from controls. There were no differences among the three groups of C282Y homozygotes in the prevalences of any symptoms or clinical conditions. In summary, some symptoms and conditions associated with HC were more prevalent among C282Y homozygotes than among controls. However, C282Y homozygotes identified by screening in primary care settings did not have a higher prevalence of most symptoms and signs associated with HC than control subjects.

Prognostic Impact of Elevated Serum Ferritin in Patients Undergoing Myeloablative Stem Cell Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 595-595 ◽  
Author(s):  
Philippe Armand ◽  
Corey S. Cutler ◽  
Haesook T. Kim ◽  
Vincent T. Ho ◽  
John Koreth ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Iron Overload ◽  
Cell Transplantation ◽  
Serum Ferritin ◽  
Ferritin Level ◽  
Elevated Serum ◽  
Albumin Level ◽  
Prognostic Impact ◽  
Disease Free

Abstract Patients undergoing allogeneic stem cell transplantation (alloSCT) for hematologic malignancies are often highly transfused, and thus at risk for transfusion-associated iron overload. In other settings, such as thalassemia or hemochromatosis, iron overload has been associated with organ toxicity, particularly hepatotoxicity, as well as with an increased susceptibility to infection. Since hepatic and infectious complications are frequent and life-threatening in patients undergoing alloSCT, iron overload could potentially be an important contributor to treatment-related morbidity and mortality after transplantation. We studied 935 consecutive patients who underwent myeloablative alloSCT at our institution between 1997 and 2005. A pre-transplant serum ferritin level, which we used as a surrogate measure of iron load, was available for 600 of the 935 patients (64%). The median ferritin level was 864ng/ml. The percentage of patients with serum ferritin ≥1000ng/ml was 47%. This percentage varied significantly between disease types, being lowest (6%) in patients with CML and highest (79%) in patients with AML. A ferritin level ≥1000ng/ml was associated with significantly worse overall and disease-free survival, as shown in the figure. Figure Figure This was confirmed in proportional hazards models using the following covariates: age, type and stage of disease, cytogenetic risk group for AML and MDS, conditioning regimen, HLA match, graft source, GVHD prophylaxis regimen, CMV serostatus, gender, prior transplant, and year of transplantation. In this model, the hazard ratio for mortality associated with ferritin ≥1000ng/ml was 1.7 (95%CI=1.3 to 2.4, p=0.0005). In competing risks regression analysis, using the same covariates, an elevated serum ferritin was associated with a significant increase in non-relapse mortality (NRM) (HR=1.6, p=0.02), but not with a significant increase in the risk of relapse. The greatest impact of elevated serum ferritin on survival and NRM was in patients with MDS (HR for mortality=3.0, p=0.001). Because serum ferritin is an acute phase reactant, we performed the same analyses using pre-transplant albumin level as an additional covariate that could reflect general inflammatory state. Although albumin level was of independent prognostic significance, its inclusion in the multivariate models did not alter the conclusions. Finally, in logistic regression analyses, elevated serum ferritin was associated with a non-significant increase in the risk of veno-occlusive disease (OR=1.6, p=0.09), but not in an increased risk of acute GVHD (OR=0.9, p=0.4) or specifically of acute liver GVHD (OR=1.2, p=0.5). Conclusions: in patients undergoing myeloablative alloSCT, and particularly in those with MDS, an elevated serum ferritin is associated with significantly higher NRM, as well as significantly lower disease-free and overall-survival. Our results could be helpful in estimating prognosis for patients who are candidates for myeloablative alloSCT. They also pave the way for prospective trials on the impact of iron overload and on the possible beneficial role of iron chelation in this patient population.

Clinical Manifestations but not Cytokine Profiles Differentiate Adult-onset Still’s Disease and Sepsis

2010 ◽  
Vol 37 (11) ◽  
pp. 2369-2376 ◽  
Author(s):  
MONIKA RAU ◽  
MARTIN SCHILLER ◽  
STEFAN KRIENKE ◽  
PETRA HEYDER ◽  
HANNES LORENZ ◽  
...  
Keyword(s):  
Differential Diagnosis ◽  
Serum Ferritin ◽  
Elevated Serum ◽  
Clinical Manifestations ◽  
Activity Score ◽  
Adult Onset Still’S Disease ◽  
Bacterial Sepsis ◽  
Serum Cytokine ◽  
Cytokine Profiles ◽  
Cytokine Levels

Objective.To analyze clinical manifestations, serum ferritin, and serum cytokine levels in patients with adult-onset Still’s disease (AOSD) or bacterial sepsis and to evaluate their potential use for differential diagnosis.Methods.Twenty-two consecutive patients with the first flare of AOSD and 6 patients with an established diagnosis of AOSD under immunosuppressive therapy were compared with 14 patients with bacterial sepsis. Clinical manifestations were scored in a Pouchot AOSD activity score including elevated serum ferritin levels to obtain a modified Pouchot score. Serum cytokine profiles were analyzed from each patient.Results.The scores of clinical manifestations using a modified Pouchot activity score were significantly higher in patients with active untreated AOSD (mean 5.60 ± 1.93) compared with patients with chronic AOSD (mean 1.16 ± 0.98; p < 0.001) and patients with sepsis (mean 2.38 ± 1.19; p < 0.001). A modified Pouchot score ≥ 4 shows a sensitivity of 92% and a specificity of 93% for active AOSD. Serum cytokine levels of interleukin 1ß (IL-1ß), IL-6, IL-8, IL-10, IL-12, IL-18, interferon-γ, tumor necrosis factor-α, and calprotectin were elevated in acute AOSD and sepsis. Significant differences were detected only in patients with sepsis who had higher levels of IL-6 and IL-8. The overlap of the 2 groups limits the use of cytokines for differential diagnosis in individual patients.Conclusion.A modified Pouchot AOSD activity score including elevated serum ferritin levels was more useful to confirm the diagnosis of AOSD compared to patients with sepsis. Elevated serum cytokines correlate with inflammation but are of limited use to differentiate between active AOSD and bacterial sepsis.

Estimating Iron Overload in Patients with Suspected Liver Disease and Elevated Serum Ferritin

2014 ◽  
Vol 127 (10) ◽  
pp. 1011.e1-1011.e3 ◽  
Author(s):  
Pietro E. Cippà ◽  
Irena Boucsein ◽  
Heiner Adams ◽  
Pierre-Alexandre Krayenbuehl
Keyword(s):  
Liver Disease ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Elevated Serum

Significant Suppression of the Colony Forming Capacity of Erythroid Progenitors by Iron Overload in Patients with MDS and Sequential Anlyses of BFU-E Under Chelation Therapy.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3826-3826
Author(s):  
Julia Hartmann ◽  
Ursula Sinzig ◽  
Gerald Wulf ◽  
Lorenz Trümper ◽  
Frank Konietschke ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Peripheral Blood ◽  
Chelation Therapy ◽  
Elevated Serum ◽  
Prognostic Impact ◽  
Erythroid Progenitors ◽  
Colony Assays ◽  
Colony Forming Capacity

Abstract Abstract 3826 Poster Board III-762 Introduction The majority of patients with MDS depend on regular blood cell (RBC) transfusions during the course of their disease. Patients with lower-risk MDS are at particularly high risk of developing iron overload because of their longer median survival. Transfusional iron overload is known to be associated with increased morbidity mainly due to cardiac and/or hepatic damage. As a result an excess mortality rate in polytransfused pts. has been demonstrated. A negative prognostic impact of transfusion need is a proven independent marker for a bad prognosis. Jensen et al. (1996) demonstrated that an adequate chelation therapy could improve the transfusion need of pts. with MDS significantly (Br J Haematol 1996, 94, 288-299). This observation was supported by recent findings of another group (Messa, Acta Haematol, 2008, 120, 70-4) with improvement of transfusion need under adequate chelation therapy. Thus iron overload might not only be harmful to hepatocytes and cardiomyocytes but also to bone marrow progenitor cells. Their function is intrinsically impaired by MDS itself and might be further affected by a “second hit” in the form of toxic iron overload which might additionally impair their colony forming capacity. Patients and methods We performed colony assays from the peripheral blood from 52 pts. with MDS (RA/RARS: n=18, RCMD/RS: 12, RAEB-I/II: 13, 5q-syndrome: 3, MDS-U: 2, CMML: 1, and others: 2; age: 39 – 86 yrs. (median: 68 yrs.); cytogenetics: normal: 26, 5q-: 6, -7/7q-: 2, complex: 4, others: 4) with (serum ferritin ≥250 μg/L, range: 273 – 6267 μg/L, median: 664 μg/L) and without iron overload (range: 11 – 213 μg/L). Only pts. without hepatic and/or active infectious diseases, without chemotherapy/epigenetic therapy during the last 6 months and without cytokine and/or corticoid therapy during the last 3 months before performance of colony assays were considered. BFU-E and CFU-GM were analysed by the same person (U.S.) after 12 – 16 days in cultures from peripheral blood, performed as described (Leuk Res, 2001; 25(11):955-9) in 14 (BFU-E)/ 12 (CFU-GM) pts. with normal ferritin-values (normal range: 20-250 μg/L) in comparison to 38/32 pts. with ferritin values surmounting 250 μg/L. Pts. with diffuse growth or cluster formation (leukemic growth) were excluded. Statistical evaluation was performed with SAS 9.1 software using Wilcoxon-Mann-Whitney tests. The results were regarded as significant if the p-value was under 5%. Both patient subgroups were balanced according to cytogenetics, age and MDS WHO-subtype. Results In the patients subgroup with normal ferritin (n=14) the numbers of BFU-E ranged between 0 and 76 (std.dev. 19.63) with a median of 3.5 and a mean of 10.7, the numbers of CFU-GM ranged between 0.5 and 38.5 (std.dev. 13.23), with a median of 6.75 and a mean of 13.2. In the patients with elevated serum ferritin (n=38) the numbers of BFU-E ranged between 0 and 250 (std.dev.40.47) with a median of 0.5 and a mean of 8.86, the numbers of CFU-GM ranged between 0 and 120 (std.dev. 29.62) with a median of 3.0 and a mean of 18.94). Statistical comparison of the numbers of BFU-E and CFU-GM between patients with normal and elevated serum ferritin yielded a highly significant difference (p=0.001348) for BFU-E and no difference for CFU-GM (p=0.570296). Conclusions Our data provide further evidence that in MDS iron overload significantly impairs bone marrow function by suppression of the burst forming activity of erythroid progenitors. If this iron is removed by adequate chelation burst forming activity might be partially restored. Myeloid progenitors do not seem to be affected by iron overload. Perspective To address the question whether chelation therapy could improve erythropoiesis we performed 4 colony assays at minimum as follow up in 32pts the analysis of which is under way. In this group 8 pts. showed a normal ferritin while 26 pts. had an elevated ferritin (> 250 μg/L). Of these, pts. 10 were treated with chelation therapy. Furthermore, 9 pts. were monitored by magnetic resonance imaging (MRT). The results of these examinations will be related to the other parameters evaluated in this study and presented in detail. Disclosures: Haase: Novartis Oncology, Germany: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Elevated Serum Ferritin Levels Are Highly Associated with Diabetes Mellitus and Hypothyroidism in Thalassemia Patients

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5174-5174
Author(s):  
Sasinee Hantrakool ◽  
Adisak Tantiworawit ◽  
Ekarat Rattarittamrong ◽  
Chatree Chai-adisaksopa ◽  
Weerasak Nawarawong ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Risk Factor ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Serum Ferritin Level ◽  
Ferritin Level ◽  
Elevated Serum ◽  
Major Risk Factor ◽  
Maximum Serum ◽  
Hemoglobin E

Abstract Abstract 5174 Background: Endocrinopathiesare well recognized serious complications in thalassemia patients with iron overload. Elevated serum ferritin levels reflect severity of iron overload and are associated with relevant clinical outcomes. Increased serum ferritin > 2, 500 μg/dl has been found to predict the development of cardiac function abnormalities but the predicting serum ferritin level for diabetes and hypothyroidism has not been determined. Method: This is a cross sectional and retrospective study to evaluate the correlation between ferritin levels and endocrinopathies (diabetes, hypothyroidism) in thalassemia patients. All thalassemia patients age > 18 years old, during August 2011 and June 2012 were enrolled. The diagnosis and type of thalassemia were reviewed and confirmed. Diabetes and hypothyroidism were diagnosed by fasting blood sugar and thyroid functions test. Serum ferritin was measured at the same period. The medical record was reviewed for age, sex, splenomegaly, history of splenectomy, transfusion requirement, maximum serum ferritin level, mean serum ferritin level and iron chelation history. Result: Among 92 thalassemia patients [35 male (38%) and 57 female (62%)] with a median age of 30. 6 years (range, 18–71). There were 28 (30. 4%) cases of Homozygous β-thalassemia, 45 cases (48. 9%) of β-thalassemia/Hemoglobin E and 18 cases (19. 5%) of Hemoglobin H or AE Bart's disease. Most patients (60. 9%) underwent splenectomy, while only one third of patients (34. 8%) were NTDT (non-transfusion dependent thalassemia) (Table 1). The mean value of random and maximum serum ferritin levels for the whole group were 2, 408 μg/dl (range279–9, 817) and 5, 101 μg/dl (range 279–37, 656), respectively. The prevalence of diabetes mellitus and impaired fasting glucose (IFG) were 9. 8% (9 cases) and 10. 9% (10 cases), respectively. Patients with diabetes had significantly higher mean maximum serum ferritin levels than those with non-diabetes (11, 241 μg/dl vs. 4, 468 μg/dl, (p=0. 0001) (Table 2). The cut-off point of maximum serum ferritin levels > 2, 500 μg/dl was the major risk factor for the development of diabetes complication in this group of patients. Six patients (6. 5%) and 21 patients (22. 8%) had hypothyroidism and subclinical hypothyroidism, respectively. Patients with hypothyroidism had significantly higher mean maximum serum ferritin levels than those with euthyroidism [(7, 638 vs. 4, 117 μg/dl, (p=0. 003)]. From univariate analysis, the cut-off point of maximum serum ferritin levels > 3, 500 μg/dl was the major risk factor associated with hypothyroidism (p=0. 007). Conclusion: Elevated serum ferritin level is a predictor of the development of diabetes mellitus and hypothyroidism in thalassemia patients with iron overload. The maximum serum ferritin levels of greater than 2, 500 and 3, 500 μg/dl are associated with diabetes mellitus and hypothyroidism, respectively. These findings warrant the value of iron chelating therapy to maintain serum ferritin levels below 2, 500 μg/dl to avoid the development of endocrinopathies in patients with thalassemia. Disclosures: No relevant conflicts of interest to declare.

Primary Hemochromatosis in Children: Report of Three Newly Diagnosed Cases and Review of the Pediatric Literature

PEDIATRICS ◽  
1992 ◽  
Vol 90 (1) ◽  
pp. 37-42
Author(s):  
Yigal Kaikov ◽  
Louis D. Wadsworth ◽  
Eric Hassall ◽  
James E. Dimmick ◽  
Paul C.J. Rogers
Keyword(s):  
Iron Overload ◽  
Iron Content ◽  
Serum Iron ◽  
Hereditary Hemochromatosis ◽  
Elevated Serum ◽  
Significant Decline ◽  
Hepatic Iron ◽  
Unexpected Finding ◽  
Newly Diagnosed ◽  
Review Of The Literature

Hereditary hemochromatosis was diagnosed in three asymptomatic siblings following the unexpected finding of elevated serum iron concentrations. This diagnosis was confirmed by hepatic biopsy. Repeated phlebotomies resulted in a significant decline of serum iron and ferritin concentrations and a decrease of hepatic iron content. This report and a review of the literature indicate that the diagnosis of hereditary hemochromatosis must be considered more frequently in childhood. Organ dysfunction from iron overload may be minimized in children by the early commencement of regular phlebotomy.

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