scholarly journals Seasonal Mixing and Genesis of Endogenic Meromixis in Small Lakes in Southeast Norway

2002 ◽  
Vol 33 (2-3) ◽  
pp. 189-206 ◽  
Author(s):  
Dag Hongve
Keyword(s):  
Chemical Nature ◽  
Dissolved Inorganic Carbon ◽  
Iron Concentration ◽  
Dry Weight ◽  
Lake Area ◽  
Small Lakes ◽  
Water Colour ◽  
Deep Waters ◽  
Temperature Of Maximum Density ◽  
Iron And Manganese

The inland region of Southeast Norway contains many lakes with endogenic meromixis. A synoptic study of seasonal mixing was conducted in 27 oligo- and mesotrophic lakes with surface area 0.0013 – 7.4 km2 and water colour 2-146 Hazen units. The scope was to identify properties of morphometric, optical and chemical nature that lead to development of endogenic meromixis. The summer mixing depths were found to depend on lake area and water colour. Small lakes (< 0.3 km2) were incompletely aerated during the spring circulation and had hypolimnetic temperatures near the temperature of maximum density throughout the summer stagnation. Insubstantial autumn mixing is considered the primary reason lakes in this area develop meromixis. Iron and manganese concentrations in anoxic deep waters depend on concentrations in the sediments and on accumulation of dissolved inorganic carbon in the deep waters. Development of endogenic meromixis is favoured by iron concentration in the sediment more than 5% of dry weight and manganese more than 0.5% of dry weight.

scholarly journals Cadmium, Lead, Copper, Zinc, and Iron Concentration Patterns in Three Marine Fish Species from Two Different Mining Sites inside the Gulf of California, Mexico

2021 ◽  
Vol 18 (2) ◽  
pp. 844
Author(s):  
Elisa Serviere-Zaragoza ◽  
Salvador E. Lluch-Cota ◽  
Alejandra Mazariegos-Villarreal ◽  
Eduardo F. Balart ◽  
Hugo Valencia-Valdez ◽  
...  
Keyword(s):  
Fish Species ◽  
Gulf Of California ◽  
Anthropogenic Activities ◽  
Iron Concentration ◽  
Dry Weight ◽  
Human Consumption ◽  
Metal Concentrations ◽  
Mining Sites ◽  
Copper Zinc ◽  
Cadmium Lead

In the Gulf of California; mineral deposits have contributed to high metal contents in coastal environments. This study examined cadmium; lead; copper; zinc; and iron contents in three fish species; Kyphosus vaigiensis (herbivore), Stegastes rectifraenum (omnivore), and Balistes polylepis (carnivore) at two mining sites. Metal concentrations were analyzed by atomic absorption spectrophotometry and stable nitrogen and carbon isotopes were estimated using mass spectrophotometry. Also, we assessed the risk to human health from the consumption of these three species based on permissible limits; although only two of them (Kyphosus and Balistes) are consumed as food. Metal concentrations differed among fish species; except for iron. The highest concentrations of metals were not always recorded in the species at the highest trophic level; i.e., Balistes. The highest concentrations (dry weight) recorded were cadmium (0.21 ± 0.03 µg g−1) and lead (1.67 ± 0.26 µg g−1), in S. rectifraenum; copper (1.60 ± 0.49 µg g−1) and zinc (67.30 ± 8.79 µg g−1), in B. polylepis; and iron (27.06 ± 2.58 µg g−1), in K. vaigiensis. Our findings show that each element accumulates differently in particular marine organisms; depending on the physiology of the species and the biogeochemistry of its habitat; which in turn is affected by the anthropogenic activities in adjacent areas. No risk of heavy metals toxicity is expected from the human consumption of the species and sites studied

scholarly journals Interannual and Spatial Variability of Cyanotoxins in the Prespa Lake Area, Greece

Water ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 357
Author(s):  
Valentini Maliaka ◽  
Miquel Lürling ◽  
Christian Fritz ◽  
Yvon J.M. Verstijnen ◽  
Elisabeth J. Faassen ◽  
...  
Keyword(s):  
Water Quality ◽  
Spatial Variability ◽  
Spatial Heterogeneity ◽  
Dry Weight ◽  
Ecosystem Functions ◽  
Lake Area ◽  
Total Chlorophyll ◽  
Tissue Samples ◽  
Cyanobacteria Blooms ◽  
Prespa Lake

The Prespa Lakes area in Greece—comprised partly of lake Great and lake Lesser Prespa and the Vromolimni pond—has a global importance for biodiversity. Although the waters show regular cyanobacteria blooms, assessments of water quality threats are limited. Samples collected in 2012 revealed scattered and low microcystin (MC) concentrations in Great Prespa (<0.2 μg MC L−1) whereas considerable spatial heterogeneity in both total chlorophyll (2.4–93 µg L−1) and MC concentrations (0.04–52.4 µg MC L−1) was detected in Lesser Prespa. In 2013, there was far less spatial variability of MC concentrations in Lesser Prespa (0.4–1.53 µg L−1), however in 2014, increased concentrations were detected near the lakeshore (25–861 µg MC L−1). In Vromolimni pond the MC concentrations were on average 26.6 (±6.4) µg MC L−1 in 2012, 2.1 (±0.3) µg MC L−1 in 2013 and 12.7 (±12.5) µg MC L−1 in 2014. In 2013, no anatoxins, saxitoxins, nor cylindrospermopsins were detected in Lesser Prespa and Vromolimni waters. Tissue samples from carps, an otter and Dalmatian Pelicans contained 0.4–1.9 µg MC g−1 dry weight. These results indicate that cyanotoxins could be a threat to the ecosystem functions of particularly Lesser Prespa and Vromolimni.

Effects of iron overload and hepatitis C virus positivity in determining progression of liver fibrosis in thalassemia following bone marrow transplantation

Blood ◽  
2002 ◽  
Vol 100 (1) ◽  
pp. 17-21 ◽  
Author(s):  
Emanuele Angelucci ◽  
Pietro Muretto ◽  
Antonio Nicolucci ◽  
Donatella Baronciani ◽  
Buket Erer ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Iron Overload ◽  
Iron Content ◽  
Hazard Rate ◽  
Iron Concentration ◽  
Dry Weight ◽  
Interquartile Range ◽  
Hepatic Iron ◽  
Fibrosis Progression

Abstract To identify the role of iron overload in the natural history of liver fibrosis, we reviewed serial hepatic biopsy specimens taken annually from patients cured of thalassemia major by bone marrow transplantation. The patients underwent transplantation between 1983 and 1989 and did not receive any chelation or antiviral therapy. Two hundred eleven patients (mean age, 8.7 ± 4 years) were evaluated for a median follow-up of 64 months (interquartile range, 43-98 months) by a median number of 5 (interquartile range, 3-6) biopsy samples per patient. Hepatic iron concentration was stratified by tertiles (lower, 0.5-5.6 mg/g; medium, 5.7-12.7 mg/g; upper, 12.8-40.6 mg/g dry weight). Forty-six (22%) patients showed signs of liver fibrosis progression; the median time to progression was 51 months (interquartile range, 36-83 months). In a multivariate Cox proportional hazard model, the risk for fibrosis progression correlated to medium hepatic iron content (hazard rate, 1.9; 95% confidence interval [CI], 0.74-5.0), high hepatic iron content (hazard rate, 8.7; 95% CI, 3.6-21.0) and hepatitis C virus (HCV) infection (hazard rate, 3.1; 95% CI, 1.5-6.5). A striking increase in the risk for progression was found in the presence of both risk factors. None of the HCV-negative patients with hepatic iron content lower than 16 mg/g dry weight showed fibrosis progression, whereas all the HCV-positive patients with hepatic iron concentration greater than 22 mg/g dry weight had fibrosis progression in a minimum follow-up of 4 years. Thus, iron overload and HCV infection are independent risk factors for liver fibrosis progression, and their concomitant presence results in a striking increase in risk.

Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: efficacy and safety during 5 years' follow-up

Blood ◽  
2011 ◽  
Vol 118 (4) ◽  
pp. 884-893 ◽  
Author(s):  
M. Domenica Cappellini ◽  
Mohamed Bejaoui ◽  
Leyla Agaoglu ◽  
Duran Canatan ◽  
Marcello Capra ◽  
...  
Keyword(s):  
Adverse Events ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Dry Weight ◽  
Thalassemia Major ◽  
Efficacy And Safety ◽  
Liver Iron ◽  
Median Serum

Abstract Patients with β-thalassemia require lifelong iron chelation therapy from early childhood to prevent complications associated with transfusional iron overload. To evaluate long-term efficacy and safety of once-daily oral iron chelation with deferasirox, patients aged ≥ 2 years who completed a 1-year, phase 3, randomized trial entered a 4-year extension study, either continuing on deferasirox (deferasirox cohort) or switching from deferoxamine to deferasirox (crossover cohort). Of 555 patients who received ≥ 1 deferasirox dose, 66.8% completed the study; 43 patients (7.7%) discontinued because of adverse events. In patients with ≥ 4 years' deferasirox exposure who had liver biopsy, mean liver iron concentration significantly decreased by 7.8 ± 11.2 mg Fe/g dry weight (dw; n = 103; P < .001) and 3.1 ± 7.9 mg Fe/g dw (n = 68; P < .001) in the deferasirox and crossover cohorts, respectively. Median serum ferritin significantly decreased by 706 ng/mL (n = 196; P < .001) and 371 ng/mL (n = 147; P < .001), respectively, after ≥ 4 years' exposure. Investigator-assessed, drug-related adverse events, including increased blood creatinine (11.2%), abdominal pain (9.0%), and nausea (7.4%), were generally mild to moderate, transient, and reduced in frequency over time. No adverse effect was observed on pediatric growth or adolescent sexual development. This first prospective study of long-term deferasirox use in pediatric and adult patients with β-thalassemia suggests treatment for ≤ 5 years is generally well tolerated and effectively reduces iron burden. This trial was registered at www.clinicaltrials.gov as #NCT00171210.

Comparison of LIC Obtained from Biopsy, BLS and R2-MRI in Iron Overloaded Patients with β-Thalassemia, Treated with Deferasirox (Exjade®, ICL670).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2689-2689 ◽  
Author(s):  
A. Piga ◽  
R. Fischer ◽  
P. Harmatz ◽  
T. G. St. Pierre ◽  
F. Longo ◽  
...  
Keyword(s):  
Los Angeles ◽  
Iron Concentration ◽  
Weight Ratio ◽  
Reference Method ◽  
Dry Weight ◽  
Phase Iii ◽  
Open Label ◽  
Transfusion Requirements ◽  
Freeze Dried ◽  
Mri Measurements

Abstract Chelation therapy for patients with transfusional hemosiderosis is guided by the degree of iron overload and ongoing transfusion requirements; liver iron concentration (LIC) is one tool for measuring current iron burden. During the clinical development of the novel oral iron chelator deferasirox, LIC was measured in subcutaneous liver biopsy samples, but also non-invasively by biomagnetic liver susceptometry (SQUID-BLS) and magnetic resonance imaging (R2-MRI: FerriScan®). These methods were compared in a substudy of a large, open-label, randomized Phase III study in 586 β-thalassemia patients with transfusional hemosiderosis; the study evaluated the efficacy and safety of long-term deferasirox and deferoxamine treatment. 48 patients (aged 17–35 yrs) gave informed consent for adding BLS and MRI assessments (baseline, 6 and 12 months) to the biopsy assessments (baseline and 12 months) of the main study. At baseline, 47 patients were assessed by BLS and biopsy, 45 by R2-MRI; at 6 months, 42 by BLS and R2-MRI; at 12 months, 41 by BLS and R2-MRI, 39 by biopsy. BLS was performed and evaluated locally at 3 centers in Hamburg, Turin and Oakland. MR images were recorded at 4 centers in Hamburg, Turin, Stanford and Los Angeles and were analyzed centrally. Data from BLS and R2-MRI remained blinded until study completion. LIC from biopsies was determined by AAS from extracted paraffin blocks in a central laboratory and used as the standardized reference method. LIC was expressed as mg/g dry weight for all methods: for BLS, a wet-to-dry weight conversion factor of 3.3 was applied, while MRI was calibrated against fresh freeze-dried liver biopsies. The relationship between BLS or R2-MRI with biopsy measurements was modeled by linear regression after log-transformation of the data. To account for the correlation between baseline and post-baseline measurements of the same patient, mixed-effects models were fitted. On average, the LIC data obtained from BLS and biopsy were related by a factor of 0.46 (95% CI: 0.32, 0.67). With R2-MRI assessment of LIC vs biopsy, the factor was 0.72 (95% CI: 0.54, 0.97). BLS and R2-MRI measurements could not be related appropriately by a factor. Overall, LIC from biopsy was generally larger than that obtained from BLS; R2-MRI measurements fell in-between biopsy and BLS. Differences are caused in part by the variability in the wet-to-dry weight ratio relating in vivo with in vitro methods. In conclusion, LIC data from 3 independent methods were correlated but not equivalent. It is therefore important that for an individual patient, a single method is consistently used under standardized conditions.

Ineffective Erythropoiesis in β-Thalassemia Is Characterized by Increased Iron Absorption Mediated by down Regulation of Hepcidin and up Regulation of Ferroportin.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1543-1543 ◽  
Author(s):  
Sara Gardenghi ◽  
Maria Marongiu ◽  
Pedro Ramos ◽  
Ella Guy ◽  
Laura Breda ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Content ◽  
Iron Absorption ◽  
Hematological Parameters ◽  
Iron Concentration ◽  
Dry Weight ◽  
Heme Iron ◽  
Ineffective Erythropoiesis ◽  
Transfusion Therapy ◽  
Expression Levels

Abstract Progressive iron overload occurs in β-thalassemia as a result of increased gastrointestinal absorption. Our goal is to investigate the relationship between ineffective erythropoiesis (IE), iron-related genes and organ iron distribution in mice that exhibit levels of anemia consistent with thalassemia intermedia (th3/+) and major (th3/th3), as we described previously. The th3/th3 mice die in 8 weeks due to severe anemia but can be rescued by transfusion therapy. We analyzed up to 90 animals at 2, 5 and 12 months, as appropriate. We monitored various hematological parameters, tissue iron content and quantitative-PCR levels of Hamp, Fpn1, Smad4, Cebpa, Hfe, Tfr1 and other genes involved in iron metabolism in liver, spleen, kidney, heart and duodenum. At 2 months, th3/th3 mice had the highest total body iron content and highest degree of IE. The total iron was 53.6±21.0, 406.1±156.1, 657.7±40.3 μg in the spleen, and 107.5±35.7, 208.5±24.9 and 1298.7±427.5 μg in the liver of +/+, th3/+ and th3/th3, respectively (n≥5 per genotype). However, if the organ size was not taken in account, the iron concentration in the spleen of th3/+ was higher, in average, than that of th3/th3 mice (3.8±1.5 and 2.9±0.5 μg/mg), while in the liver was the opposite (0.6±0.1 and 5.1±2.0 μg/mg of dry weight, P<0.001). Heme and non-heme iron analyses provided similar results. Surprisingly, the distribution of iron within organs also differed. In th3/+ mice, the hepatic iron was almost exclusively located in Kupffer cells, whereas in th3/th3 mice in parenchymal cells. Our data suggest that Hamp is responsible for the increased iron absorption, being reduced to 20% and 70% in 2 month-old th3/+ and th3/th3 mice compared to +/+ animals (P<0.001). Hfe was reduced by 50% (P<0.05) in the liver of the animals that expressed low Hamp levels, indicating that Hfe could be directly responsible for Hamp regulation or share the same regulatory pathway. Low levels of Smad4 and Cebpa were observed only in the liver of mice with the lowest Hamp expression (P<0.05), indicating that these proteins might contribute to further decreased Hamp synthesis. In addition, while Tfr1 in th3/+ mice was 40% lower in the liver, it was up-regulated (400%) in th3/th3 mice (P<0.001), which may explain why iron is increased more in the liver of th3/th3 mice. In 5 and 12 month-old th3/+ mice, the surprising observation was the normal expression level of Hamp. However, in the duodenum, the Fpn1 RNA and protein levels were augmented (300%, P<0.001). In transfused th3/+ and th3/th3 animals, Hamp, Hfe, Cbpa and Smad4 expression levels were normalized or increased, while Tfr1 was down-regulated in both groups, which may explain the increased splenic iron deposition in these animals. Our data suggest that IE, together with the relative expression levels of Hamp and Tfr1, is largely responsible for the organ iron overload observed in young thalassemic mice. However, in older mice, it is the increase of Fpn1 levels in the duodenum that sustains iron accumulation, thus revealing a fundamental role of this iron transporter in the genesis of iron overload in β-thalassemia.

Iron Stores in Patients with Myelodysplasia and Aplastic Anemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3726-3726
Author(s):  
Peter Nielsen ◽  
Tim H. Bruemmendorf ◽  
Regine Grosse ◽  
Rainer Engelhardt ◽  
Nicolaus Kroeger ◽  
...  
Keyword(s):  
Risk Factor ◽  
Iron Overload ◽  
Aplastic Anemia ◽  
Myelodysplastic Syndromes ◽  
Iron Concentration ◽  
Dry Weight ◽  
Iron Toxicity ◽  
Intervention Threshold ◽  
Liver Iron Concentration ◽  
Liver Iron

Abstract Patients with myelodysplastic syndromes (MDS), osteomyelofibrosis (OMF), or severe aplastic anemia (SAA) suffer from ineffective erythropoiesis due to pancytopenia, which is treated with red blood cell transfusion leading to iron overload. Especially in low-risk patients with mean survival times of > 5 years, potentially toxic levels of liver iron concentration (LIC) can be reached. We hypothesize that the higher morbidity seen in transfused patients may be influenced by iron toxicity. Following a meeting in Nagasaki 2005, a consensus statement on iron overload in myelodysplastic syndromes has been published, however, there is still no common agreement about the initiation of chelation treatment in MDS patients. In the present study, a total of 67 transfused patients with MDS (n = 20, age: 17 – 75 y), OMF (n = 4, age: 48 – 68 y), SAA (n = 43, age: 5 – 64 y) were measured by SQUID biomagnetic liver susceptometry (BLS) and their liver and spleen volumes were scanned by ultrasound at the Hamburg biosusceptometer. Less than 50 % were treated with DFO. LIC (μg/g-liver wet weight, conversion factor of about 6 for μg/g-dry weight) and volume data were retrospectively analyzed in comparison to ferritin values. Additionally, 15 patients (age: 8 – 55 y) between 1 and 78 months after hematopoietic cell transplantation (HCT) were measured and analyzed. LIC values ranged from 149 to 8404 with a median value of 2705 μg/g-liver, while serum ferritin (SF) concentrations were between 500 and 10396 μg/l with a median ratio of SF/LIC = 0.9 [(μg/l)/(μg/g-liver)] (range: 0.4 to 5.2). The Spearman rank correlation between SF and LIC was found to be highly significant (RS = 0.80, p < 0.0001), however, prediction by the linear regression LIC = (0.83± 0.08)·SF was poor (R2 = 0.5) as found also in other iron overload diseases. Although iron toxicity is a long-term risk factor, progression of hepatic fibrosis has been observed for LIC > 16 mg/g dry weight or 2667 μg/g-liver (Angelucci et al. Blood2002; 100:17–21) within 60 months and significant cardiac iron levels have been observed for LIC > 350 μmol/g or 3258 μg/g-liver (Jensen et al. Blood2003; 101:4632-9). The Angelucci threshold of hepatic fibrosis progression was exceeded by 51 % of our patients, while 39 % were exceeding the Jensen threshold of potential risk of cardiac iron toxicity. The total body iron burden is even higher as more than 50 % of the patients had hepatomegaly (median liver enlargement factor 1.2 of normal). A liver iron concentration of about 3000 μg/g-liver or 18 mg/g-dry weight has to be seen as latest intervention threshold for chelation treatment as MDS patients are affected by more than one risk factor. A more secure intervention threshold would be a LIC of 1000 μg/g-liver or 4 – 6 mg/g-dry weight, corresponding with a ferritin level of 900 μg/l for transfused MDS patients. Such a LIC value is not exceeded by most subjects with heterozygous HFE-associated hemochromatosis and is well tolerated without treatment during life-time. Non-invasive liver iron quantification offers a more reliable information on the individual range of iron loading in MDS which is also important for a more rational indication for a chelation treatment in a given patient.

Liver Histology, Liver Iron Concentration (LIC), and Serum Ferritin in a Large Cohort of Chronically Transfused Children with Sickle Cell Anemia: Limitations of LIC As a Marker for Hepatic Injury and Ferritin as An Indicator for Chelation Initiation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2142-2142
Author(s):  
Erika Vogel ◽  
Jeffrey D. Lebensburger ◽  
Shuting Bai ◽  
Naomi Fineberg ◽  
Lee Hilliard ◽  
...  
Keyword(s):  
Liver Biopsy ◽  
Sickle Cell ◽  
Serum Ferritin ◽  
Sickle Cell Anemia ◽  
Chelation Therapy ◽  
Iron Concentration ◽  
Dry Weight ◽  
Surrogate Markers ◽  
Transfusion Therapy ◽  
Lobular Inflammation

Abstract Abstract 2142 Chronic blood transfusion therapy reduces clinical events and prevents recurrent brain injury in children with sickle cell anemia. The benefit of administering chronic transfusion is weighed against the risk of an increased iron burden leading to chronic organ injury. The gold standard technique for evaluating the adverse effect of iron is to perform a liver biopsy for quantification of hepatic iron content and evaluation of liver pathology. Surrogate evaluations for iron overload include monitoring liver enzymes, serum ferritin and performing r2* MRI of the liver. In order to evaluate the role for utilizing surrogate markers to monitor liver injury, we conducted a retrospective review of 262 liver biopsies in 109 children with sickle cell anemia on chronic transfusion therapy over a nine year period at a single center. Ninety one patients had HbSS, 17 had HbSB0 thalassemia, and one patient had HbSD. Chronic transfusion therapy was performed by either simple transfusion (65%) or erythrocytapheresis (35%) primarily for stroke prevention (n=236), with a few for other indications (n=26) including lung injury and acute vascular necrosis. Patients were initiated on chronic transfusion at a mean age of 6.2 ± 3.6 yrs (0.75–17yrs) with initial biopsy obtained at a mean age of 14.6 ± 5.3 yrs (3–34 yrs). Chelation with deferoxamine or deferasirox was determined by the physician with a practice standard of initiation of chelation once ferritin increased to > 1000ng/mL. All patients at the time of liver biopsy were treated with chelation therapy with either deferoxamine (30%) or deferasirox (70%). Two pathologists reviewed the biopsies and utilized a standardized hepatic scoring system to evaluate the degree of portal/periportal and lobular inflammation and hepatic fibrosis (0= none, 1= mild, 2= moderate, 3= severe). Portal/periportal inflammation was scored 0–3 respectively in 132, 89, 38, and 0 patients and lobular inflammation in 29, 226, 4, and 0 patients. Fibrosis was scored 0–3 respectively in 23, 107, 103, and 26 patients. Ferritin and ALT were recorded prior (median of 3 days) to the liver biopsy. Seven biopsies performed as part of a therapeutic clinical trial were excluded from this analysis. Results show that the mean (± SD) serum ferritin, liver iron concentration (LIC), and ALT were 3509 ± 2617ng/mL, 17.12 ± 13.0 mg Fe/gm dry weight, and 40.2 ± 40.2 IU/L. With respect to histology, ferritin and LIC levels were significantly increased with higher periportal inflammation score (F= 21, p<0.001. F= 20, p<0.001) and severe fibrosis (score 3) (F=36, p<0.001, F=10.4, p<0.001), but not for lower fibrosis scores (0–2), or lobular inflammation score (p=0.20). Despite this significant histologic correlation with surrogate markers, individual overlap exists between ferritin, LIC and liver pathology. A strong linear correlation exists between ferritin and LIC (r=0.74, p<0.001) but with a spread in LIC (R2=55%). With respect to ferritin as a predictor of LIC, all patients with ferritin >1000ng/mL, a standard value for initiation of chelation therapy, had abnormally high LICs, and surprisingly 11 patients were identified with an abnormal LIC despite a ferritin <1000ng/ml. Furthermore, patients with a high LIC (≥ 7 mg Fe/gm dry weight) demonstrate a significantly higher ferritin as compared to patients with lower LIC< 7 (p<0.001) and this positive relationship between LIC and ferritin was replicated in a population with a higher LIC (LIC ≥ 30mg Fe/g dry weight vs. <30) (p<0.001). ROC curves demonstrate an AUC of.88 ± 0.02 (p<0.001) utilizing a LIC of ≥7 or <7 and 0.91± 0.02 (p<0.001) utilizing a LIC of ≥30 or <30. A weak association was noted between ferritin and alanine aminotransferase (ALT) (r=0.27, p<0.001, R2=8%). The results show that although strong statistical correlations exist between liver histology and ferritin or LIC, variability exists. Additionally, a ferritin >1000ng/mL always predicts abnormal LIC, but is inadequate as an indicator for initiation of chelation. The results suggest caution when using surrogate markers alone to predict histological changes in the liver and to initiate chelation therapy in individual patients on chronic blood transfusion therapy. Disclosures: Lebensburger: University of Alabama at Birmingham: Employment.

Exome Sequencing Identifies Genes and Variant Alleles Associated With Severity Of Iron Overload In Hemochromatosis HFE C282Y Homozygotes

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 179-179
Author(s):  
Christine E. McLaren ◽  
Mary J. Emond ◽  
Pradyumna D. Phatak ◽  
Paul C. Adams ◽  
V. Nathan Subramaniam ◽  
...  
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Iron Concentration ◽  
Missense Variant ◽  
Dry Weight ◽  
P Value ◽  
Hepatic Iron ◽  
Common Variants ◽  
Iron Stores ◽  
Hepatic Iron Concentration

Abstract Variability in the severity of iron overload among homozygotes for the HFE C282Y polymorphism is one of the major problems extant in our understanding of hereditary hemochromatosis (HH). We conducted exome sequencing of DNA from C282Y homozygotes with markedly increased iron stores (cases) and C282Y homozygotes with normal or mildly increased iron stores (controls) to identify rare and common causal variants associated with variability of disease expression in HH. Criteria for cases included serum ferritin >1000 µg/L at diagnosis, and (a) mobilized body iron >10 g by quantitative phlebotomy, and/or (b) hepatic iron concentration >236 µmol/g dry weight. Criteria for controls included (a) serum ferritin <300 µg/L, or (b) age ≥50 y with ≤3.0 g iron removed by phlebotomy or age ≥40 y with ≤2.5 g iron removed by phlebotomy to achieve serum ferritin <50 µg/L. Deep sequencing of the full exome was performed in 33 cases and 14 controls. After quality control filtering, the dataset included 82,068 SNPs and 1,403 insertions/deletions (indels). Our initial analysis tested for differences in the distribution of variants between groups for each gene separately using the Sequence Kernel Association Test (SKAT) that includes rare and common variants but downweights the contribution of common variants to the test statistic. Only non-synonymous variants were included in the by-gene tests. Principal components were constructed from the exome variants to adjust for possible confounding by ancestry and to confirm no ancestral outliers. All study participants were male, and all clustered closely together within a larger group of Europeans in a principal components analysis of ancestry. Mean (SD) ages at presentation were 54 (11.0) y and 56 (9.4) y for cases and controls, respectively. Median serum ferritin was 2788 µg/L in those with increased iron stores and 309 μg/L in those with normal or mildly increased iron stores. The median transferrin saturation (94%) was greater in cases than in the comparison group (70%). In a preliminary analysis, we found 9 genes associated with case-control status. To separate effects of alcohol use and/or alcohol addiction variants, an analysis was conducted to compare the 13 controls and 22 cases who reported never using alcohol or only very light use. The two most significant genes identified in this comparison were GNPAT (p=7.4x10-6) and CDHR2 (p=2.8x10-4). A quantile-quantile (QQ) plot is shown in the Figure, comparing the observed distribution of –(log10p-values) from 10,337 genes to the expected uniform distribution if there were no variants modifying severity of expression, and gives evidence of the effect of the GNPAT gene.Figure 1Figure 1. Inspection of the two variants contributing to the GNPAT by-gene p-value revealed one missense variant (rs11558492) for which 0/13 controls had a polymorphism, while 16/22 cases had at least one missense variant, and one case was homozygous for this missense variant. The latter case presented at the early age of 26 with a serum ferritin of 1762 µg/L, 4+ hepatocellular iron and hepatic iron concentration of 284.4 µmol/g dry weight. GNPAT (aka DHAPAT) mutations/deletions have been found in peroxisomal disease, a class of diseases in which increased hepatic iron is observed (Biochim Biophys Acta 1801:272-280, 2010). GNPAT rs11558492 is common among people of European descent but might interact with aberrant HFE to increase risk of hepatic iron overload. Three rare variants in CDHR2 accounted for its low p-value, having a cumulative frequency of 4/13 among controls and 0/22 among cases: rs115050587, rs752138, rs143224505 with minor allele frequencies, MAF = 1.4%, 4.7% and 0.06%, respectively. The first two polymorphisms are predicted to be highly damaging by PolyPhen2 and the third probably damaging. Expression levels of CDHR2 recently have been associated with increased hepatocyte iron and elevated serum ferritin in liver allograft patients (J Clin Invest 122:368-382, 2012). These data indicate associations between iron status in HFE C282Y homozygotes and genes with previous links to iron overload that may modify severity of disease expression. Of note, the data suggest that more than one modifier gene may be involved in determining severity of disease in HFE C282Y homozygotes. Our results identify candidate genes for expanded studies that would examine their functional significance for iron absorption and metabolism. Disclosures: No relevant conflicts of interest to declare.

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