Hard as Iron: A Case of Delayed Presentation of Severe Iron Toxicity With Diagnostic and Treatment Dilemmas.

ABSTRACT: Cases of severe iron toxicity have become increasingly rare; most cases are intentional ingestions by late adolescents and adults who present within 12 hours of ingestion. We present a case of an adolescent girl with metabolic acidosis, hypoglycemia, obtundation, and liver and renal failure of undifferentiated etiology who was eventually discovered to have overdosed on ferrous sulfate tablets 4 days before arrival. The diagnosis was made because the patient had an elevated transferrin concentration in the setting of a minimally elevated serum iron concentration and faint radio-opacities on abdominal plain film imaging. This case presents many diagnostic challenges and treatment dilemmas and is a rare report of survival in delayed presentation of severe toxicity.

Suicidal iron overdose: A case report and review of literature.

Acute iron toxicity in adults is rare, usually occurring due to intentional ingestion in suicide attempts. Few cases of the clinical and autopsy findings in acute iron toxicity have previously been reported in the literature. Ingestion of large amounts of iron salts can lead to hemorrhagic shock, multi-system organ failure, coagulopathy, and death. We present the case of a 25-year-old man who reportedly ingested a large quantity of iron tablets along with ethanol in a suicide attempt and subsequently died approximately 65.5 h later. His clinical course and laboratory findings demonstrated hepatic and renal compromise with markedly elevated serum iron levels. At autopsy, iron encrustations were present over the gastric rugae. Superficial deposits of stainable iron were present overlying areas of mucosal necrosis with underlying submucosal fibrin thrombi. No significant stainable iron was present in the liver. Literature review revealed that the clinical course and laboratory testing of severe acute iron overdose is fairly non-specific. The length and type of treatment may alter the clinical course and laboratory results. Peak serum iron levels may be helpful in differentiating acute toxicity from chronic iron overload states. Gross findings of gastric iron encrustation are specific for acute ingestion when present.

Iron Packaging Regulations in the United States and Pediatric Morbidity: A Retrospective Cohort Study.

Iron poisoning was a leading cause of pediatric morbidity and mortality. We sought to assess whether the removal of strict iron packaging requirements in 2003 resulted in an increase in iron-related morbidity and mortality in pediatric exposures. We performed a retrospective cohort study utilizing the National Poison Data System from 2000 to 2017. A total of 4110 exposures met inclusion criteria: 847 from before (2000-2003) and 3263 after removal of unit-dose package regulations (2004-2017). The incidence of any marker of severity (7.2% vs 3.8%; odds ratio = 0.51, 95% confidence interval = 0.37-0.69) and frequency of deferoxamine use were both higher in the early time period (2.6% vs 1.0%; odds ratio = 0.38, 95% confidence interval = 0.22-0.66). There was no difference in the frequency of key serious effects (acidosis, elevated transaminases, hypotension). Despite removal of iron packaging regulations in the United States, there continues to be a decrease in the incidence of severe iron exposures in children.

[Acute iron poisoning : Successful treatment of a potentially fatal suicidal attempt]. / Akute Eisenintoxikation : Erfolgreiche Therapie einer potenziell tödlichen parasuizidalen Geste.

We present the case of a patient who took 150 mg per kg bodyweight of iron in a suicidal attempt. We illustrate the diagnostic and therapeutic procedures required to successfully cope with this poisoning, which is, by surprise, potentially lethal.

Occupational exposure to inorganic particles during pregnancy and birth outcomes: a nationwide cohort study in Sweden.

OBJECTIVES: The aim of this study was to investigate if occupational exposure to inorganic particles or welding fumes during pregnancy is associated with negative birth outcomes. DESIGN: A prospective national cohort study. SETTING: All single births from 1994 to 2012 in Sweden. Information on birth weight, preterm birth, small for gestational age, smoking habits, nationality, age, occupation, absence from work and education was obtained from nationwide registers. Exposure to inorganic particles (mg/m3) was assessed from a job exposure matrix. PARTICIPANTS: This study included all single births by occupationally active mothers (995 843). OUTCOME MEASURES: Associations between occupational exposures and negative birth outcomes in the form of low birth weight, preterm birth and small for gestational age. RESULTS: Mothers who had high exposure to inorganic particles and had less than 50 days (median) of absence from work during pregnancy showed an increased risk of preterm birth (OR 1.18; 95% CI 1.07 to 1.30), low birth weight (OR 1.32; 95% CI 1.18 to 1.48) as well as small for gestational age (OR 1.20; 95% CI 1.04 to 1.39). The increased risks were driven by exposure to iron particles. No increased risks were found in association with exposure to stone and concrete particles. High exposure to welding fumes was associated with an increased risk of low birth weight (OR 1.22; 95% CI 1.02 to 1.45) and preterm birth (OR 1.24; 95% CI 1.07 to 1.42). CONCLUSIONS: The results indicate that pregnant women should not be exposed to high levels of iron particles or welding fumes.

Minimum ingested iron cut-off triggering serious iron toxicity in children.

BACKGROUND: Iron intoxication can occur accidentally in children or intentionally by adolescents as a suicide attempt. They usually present with various symptoms including vomiting and diarrhea. Clinical studies in this field has been reported different doses of ingested elemental iron that caused serious toxicity, but none of these studies determined the minimum cut-off of ingested iron that triggered the risk of severe toxicity. The aim of this study was therefore to investigate the demographic features of iron intoxication in Turkish children and to determine the lowest cut-off of ingested elemental iron triggering serious intoxication and the need for prompt management. METHODS: This retrospective study investigated 83 Turkish patients with accidental and intentional iron poisoning. RESULTS: Of the 83 cases of acute iron intoxication, accidental iron consumption was more common than intentional use. Fifty-three patients ingested a median toxic dose of elemental iron of 40.0 mg/kg (IQR, 33.5 mg/kg). The median serum iron concentration in the first 6 h of ingestion was 150 µg/dL (IQR, 282 µg/dL). Twenty patients were given deferoxamine, whereas 63 patients were given supportive treatment. CONCLUSION: The cut-off of ingested elemental iron that triggered serious toxicity and the need for deferoxamine in children <18 years of age was 28 mg/kg.

Iron and manganese-related CNS toxicity: mechanisms, diagnosis and treatment.

INTRODUCTION: Iron (Fe) and manganese (Mn) are essential nutrients for humans. They act as cofactors for a variety of enzymes. In the central nervous system (CNS), these two metals are involved in diverse neurological activities. Dyshomeostasis may interfere with the critical enzymatic activities, hence altering the neurophysiological status and resulting in neurological diseases. Areas covered: In this review, the authors cover the molecular mechanisms of Fe/Mn-induced toxicity and neurological diseases, as well as the diagnosis and potential treatment. Given that both Fe and Mn are abundant in the earth crust, nutritional deficiency is rare. In this review the authors focus on the neurological disorders associated with Mn and Fe overload. Expert commentary: Oxidative stress and mitochondrial dysfunction are the primary molecular mechanism that mediates Fe/Mn-induced neurotoxicity. Although increased Fe or Mn concentrations have been found in brain of patients, it remains controversial whether the elevated metal amounts are the primary cause or secondary consequence of neurological diseases. Currently, treatments are far from satisfactory, although chelation therapy can significantly decrease brain Fe and Mn levels. Studies to determine the primary cause and establish the molecular mechanism of toxicity may help to adapt more comprehensive and satisfactory treatments in the future.

Iron overdose epidemiology, clinical features and iron concentration-effect relationships: the UK experience 2008-2017.

Background: Iron poisoning is potentially serious, but mortality has fallen worldwide since implementation of pack size and packaging restrictions, and changes in iron use during pregnancy. The management of individual cases of overdose remains problematic due to uncertainty about indications for antidote. We examine the epidemiology of iron overdose in hospital cases referred to the UK National Poisons Information Service (NPIS) and evaluate the toxicokinetics of iron in patients ingesting only iron preparations. Methods: Anonymized hospital referral patient data from the NPIS database were collated for the period 1 January 2008 to 31 July 2017. Information was extracted, where recorded, on type of ingestion [iron alone (single), or combined with other agents (mixed)], reported dose, iron salt, timed iron concentrations and symptoms. In single-agent ingestions, the relationships between reported elemental iron dose, early concentrations (4-6 h), and symptoms were evaluated in teenagers and adults (≥13 years) and children (≤12 years) using standard statistical techniques (correlation and unpaired nonparametric comparisons). In those patients with sufficient sample points (three or more), a simple kinetic analysis was conducted. Results: Of 2708 patients with iron overdoses referred by UK hospitals for advice during the 9.7 years study period, 1839 were single-agent ingestions. There were two peaks in age incidence in single-agent exposures; 539/1839 (28.4%) were <6 years (54.1% males) while 675/1839 (36.7%) were between 13 and 20 years (91% females), the latter a substantial excess over the proportion in the totality of hospital referrals to the NPIS in the same period (13-20 years: 23,776/144,268 16.5%; 67.5% female) (p < .0001 overall and for female %). In 475 teenagers and adults and 86 children, with at least one-timed iron concentration available, there was no correlation between stated dose and iron concentration measured 4-6 h post-ingestion. Observed peak iron concentrations were not related to reported symptoms in adults. Initial iron concentrations were significantly higher in 30 patients (25 adults, 5 children) who received desferrioxamine (DFO) compared to those that did not [no DFO: mean 63.8 µmol/L (95% CI 62.1-65.6), median 64; DFO: mean 78.5 µmol/L (95% CI 69.2-87.7), median 78.1; Mann-Whitney p < .0018). No significant differences in symptoms were observed pre-treatment between DFO-treated and untreated groups. No patients died in this cohort. Conclusion: Single-agent iron exposures reported from UK hospitals were most common in children <5 years and young people aged 13-20 years. Poisoning with organ failure was not identified and there were no fatalities. No correlations were observed between reported iron doses and early concentrations, or between iron concentrations and symptoms in this cohort of mild-to-moderate poisoning.

Occupational Metal Exposure and Parkinsonism.

Parkinsonism is comprised of a host of neurological disorders with an underlying clinical feature of movement disorder, which includes many shared features of bradykinesia, tremor, and rigidity. These clinical outcomes occur subsequent to pathological deficits focused on degeneration or dysfunction of the nigrostriatal dopamine system and accompanying pathological inclusions of alpha-synuclein and tau. The heterogeneity of parkinsonism is equally matched with the complex etiology of this syndrome. While a small percentage can be attributed to genetic alterations, the majority arise from an environmental exposure, generally composed of pesticides, industrial compounds, as well as metals. Of these, metals have received significant attention given their propensity to accumulate in the basal ganglia and participate in neurotoxic cascades, through the generation of reactive oxygen species as well as their pathogenic interaction with intracellular targets in the dopamine neuron. The association between metals and parkinsonism is of critical concern to subsets of the population that are occupationally exposed to metals, both through current practices, such as mining, and emerging settings, like E-waste and the manufacture of metal nanoparticles. This review will explore our current understanding of the molecular and pathological targets that mediate metal neurotoxicity and lead to parkinsonism and will highlight areas of critical research interests that need to be addressed.

Neurotoxicity of Metal Mixtures.

Metals are the oldest toxins known to humans. Metals differ from other toxic substances in that they are neither created nor destroyed by humans (Casarett and Doull's, Toxicology: the basic science of poisons, 8th edn. McGraw-Hill, London, 2013). Metals are of great importance in our daily life and their frequent use makes their omnipresence and a constant source of human exposure. Metals such as arsenic [As], lead [Pb], mercury [Hg], aluminum [Al] and cadmium [Cd] do not have any specific role in an organism and can be toxic even at low levels. The Substance Priority List of Agency for Toxic Substances and Disease Registry (ATSDR) ranked substances based on a combination of their frequency, toxicity, and potential for human exposure. In this list, As, Pb, Hg, and Cd occupy the first, second, third, and seventh positions, respectively (ATSDR, Priority list of hazardous substances. U.S. Department of Health and Human Services, Public Health Service, Atlanta, 2016). Besides existing individually, these metals are also (or mainly) found as mixtures in various parts of the ecosystem (Cobbina SJ, Chen Y, Zhou Z, Wub X, Feng W, Wang W, Mao G, Xu H, Zhang Z, Wua X, Yang L, Chemosphere 132:79-86, 2015). Interactions among components of a mixture may change toxicokinetics and toxicodynamics (Spurgeon DJ, Jones OAH, Dorne J-L, Svendsen C, Swain S, Stürzenbaum SR, Sci Total Environ 408:3725-3734, 2010) and may result in greater (synergistic) toxicity (Lister LJ, Svendsen C, Wright J, Hooper HL, Spurgeon DJ, Environ Int 37:663-670, 2011). This is particularly worrisome when the components of the mixture individually attack the same organs. On the other hand, metals such as manganese [Mn], iron [Fe], copper [Cu], and zinc [Zn] are essential metals, and their presence in the body below or above homeostatic levels can also lead to disease states (Annangi B, Bonassi S, Marcos R, Hernández A, Mutat Res 770(Pt A):140-161, 2016). Pb, As, Cd, and Hg can induce Fe, Cu, and Zn dyshomeostasis, potentially triggering neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Additionally, changes in heme synthesis have been associated with neurodegeneration, supported by evidence that a decline in heme levels might explain the age-associated loss of Fe homeostasis (Atamna H, Killile DK, Killile NB, Ames BN, Proc Natl Acad Sci U S A 99(23):14807-14812, 2002).The sources, disposition, transport to the brain, mechanisms of toxicity, and effects in the central nervous system (CNS) and in the hematopoietic system of each one of these metals will be described. More detailed information on Pb, Mn, Al, Hg, Cu, and Zn is available in other chapters. A major focus of the chapter will be on Pb toxicity and its interaction with other metals.

Neurodegeneration Induced by Metals in Caenorhabditis elegans.

Metals are a component of a variety of ecosystems and organisms. They can generally be divided into essential and nonessential metals. The essential metals are involved in physiological processes once the deficiency of these metals has been associated with diseases. Although iron, manganese, copper, and zinc are important for life, it has been evidenced that they are also involved in neuronal damage in many neurodegenerative disorders. Nonessential metals, which are metals without physiological functions, are present in trace or higher levels in living organisms. Occupational, environmental, or deliberate exposures to lead, mercury, aluminum, and cadmium are clearly correlated with the increase of toxicity and varied kinds of pathological situations. Actually, the field of neurotoxicology needs to satisfy two opposing demands: the testing of a growing list of chemicals and resource limitations and ethical concerns associated with testing using traditional mammalian species. Toxicological assays using alternative animal models may relieve some of this pressure by allowing testing of more compounds while reducing expenses and using fewer mammals. The nervous system is by far the more complex system in C. elegans. Almost a third of their cells are neurons (302 neurons versus 959 cells in adult hermaphrodite). It initially underwent extensive development as a model organism in order to study the nervous system, and its neuronal lineage and the complete wiring diagram of its nervous system are stereotyped and fully described. The neurotransmission systems are phylogenetically conserved from nematodes to vertebrates, which allows for findings from C. elegans to be extrapolated and further confirmed in vertebrate systems. Different strains of C. elegans offer a new perspective on neurodegenerative processes. Some genes have been found to be related to neurodegeneration induced by metals. Studying these interactions may be an effective tool to slow neuronal loss and deterioration.

In vitro and in vivo assessment of EDTA-modified silica nano-spheres with supreme capacity of iron capture as a novel antidote agent.

Mesoporous silica nanoparticles having structure of MCM-41 category with amine and EDTA functional groups in the pores were prepared using a co-condensation reaction. The synthetic steps eventuated in the mesoporous silica nanoparticles with spherical sizes lower than 50nm supposed to have high surface area. The nanoparticles' structure and functionality were characterized by FTIR spectroscopy and CHN analysis and the topography were examined by SEM and TEM and hydrodynamic sizes were demonstrated by DLS. The crystallinity and mesoporous pattern were figured out by XRD technique. Then the efficiency of these materials was tested in vitro and in vivo in adsorbing ferrous sulfate which is a supplement normally prescribed in treating iron deficiency and its overdose is potentially lethal, especially in young children. In vivo experiments illustrated that both nanoparticles could efficiently be administrated as an antidote agent against iron overdose, but EDTA-MSN nanoparticles were superior to NH2-MSN nanoparticles.

Iron migration from undamaged and dented juice tinplate cans.

BACKGROUND: Iron migration from tinplate cans to pineapple drink was studied over time using flame atomic absorption spectroscopy, taking into consideration storage temperature, sell-by date and can condition (dented/undamaged). An organoleptic test, at the sell-by date, was also performed. RESULT: Analysis of iron in drinks from tinplate cans, glass and polyethylene terephthalate (PET) bottles was performed up until the sell-by date. For undamaged canned drinks stored at room temperature, iron was found to remain constant at 0.23 ± 0.01 mg L(-1) , from the 24th day until 1 year after production. Iron found in glass and PET bottles also remained constant until the sell-by date, at 0.15 ± 0.04 and 0.12 ± 0.04 mg L(-1) , respectively. However, migration of iron from dented cans was found to be significant. Twelve months after production, iron content in dented cans, stored at room temperature (22 °C) and in a refrigerator chamber (4 °C) was 14.4 ± 1.0 and 5.5 ± 0.4 mg L(-1) , respectively. CONCLUSION: Results showed that for a 35 kg child the intake of three damaged canned drinks may contribute to more than 50% of the iron provisional maximum tolerance daily intake. © 2015 Society of Chemical Industry.

Successful treatment of severe iron intoxication with gastrointestinal decontamination, deferoxamine, and hemodialysis.

Acute iron poisoning is a common and potentially serious problem in the pediatric population. Early recognition and treatment is crucial for a better outcome and to prevent morbidity and mortality. An 18-year-old female, who had accidental ingestion of 50 tablets of ferrous sulfate (100 mg of elemental iron per 335 mg tablet), 100 mg/kg of elemental iron, developed acute gastrointestinal and neurologic signs of toxicity and severe anion gap metabolic acidosis. The patient had received gastrointestinal decontamination, deferoxamine (DFO) infusion, and hemodialysis (HD) resulting in a decrease in serum iron concentration from 2150 to 160 mcg/dL at 24-h post-ingestion and improved mental status. Our cases demonstrate that HD may assist in decreasing serum iron concentration and improving clinical status in patients with massive overdose and life-threatening toxicity.

Geographic patterns of hepatocellular carcinoma mortality with exposure to iron in groundwater in Taiwanese population: an ecological study.

BACKGROUND: Many studies have examined the risk factors for HCC (including hepatitis B virus, hepatitis C virus, aflatoxin, retinol, cigarette smoking, and alcohol consumption). However, data from previous studies on the association between iron exposure, land subsidence, and HCC mortality/incidence were limited, especially in Taiwanese population. We aimed to explore the geographical distribution of HCC mortality rates by township-specific data and to evaluate the association between HCC mortality, land subsidence, and iron levels in groundwater in Taiwan. METHODS: We conducted an ecological study and calculated the HCC age-standardized mortality/incidence rates according to death certificates issued in Taiwan from 1992 to 2001 and incidence data from 1995-1998. The land subsidence dataset before 2005 and iron concentrations in groundwater in 1989 are also involved in this study. Both geographical information systems and Pearson correlation coefficients were used to analyze the relationship between HCC mortality rates, land subsidence, and iron concentrations in groundwater. RESULTS: Township-specific HCC mortality rates are higher in southwestern coastal townships where serious land subsidence and higher township-specific concentrations of iron in groundwater are present. The Pearson correlation coefficients of iron concentrations in groundwater and ASRs of HCC were 0.286 (P = 0.004) in males and 0.192 (P = 0.058) in females for mortality data; the coefficients were 0.375 (P < 0.001) in males and 0.210 (P = 0.038) in females for incidence data. CONCLUSIONS: This study showed that HCC mortality is clustered in southwestern Taiwan and the association with the iron levels in groundwater in Taiwanese population warrant further investigation.

Near fatal iron intoxication managed conservatively.

We report here the case of an infant who presented to the emergency department after unintentional ingestion of almost 130 mg/kg of elemental iron. The infant had evidence of serious toxicity in the form of hypotension, metabolic acidosis and excessive irritability. Her serum iron levels were 360 µg/dl, which was well above the normal range for her age. Despite such high serum levels, the infant made an uneventful recovery with medical management alone and did not require exchange transfusion. We chose to report this case to highlight her uneventful recovery with conservative therapy alone.

Iron autointoxication in a 16-year-old girl: a protective role for hepcidin?

Intentional iron overdose appears to be an increasingly common form of attempted suicide. We present a case of iron overdose in a 16-year-old girl who was found unconscious in her bed and brought to our emergency department. The most remarkable diagnostic findings were the patient's comatose condition, divergent eye position and positive Babinski foot pad reflexes. Laboratory tests showed hyperglycaemia and mild metabolic acidosis. A computed tomography scan of the cerebrum showed no signs of intracerebral haemorrhage or elevated intracerebral pressure. Toxicology screening showed no use of acetaminophen, ethanol or drugs of abuse. The patient was stabilized and monitored on the intensive care ward. When she woke up, she confessed to having taken Fero-Gradumet(®). Retrospectively analysed, the serum iron concentration in the first blood sample (seven hours after ingestion) was 62 µmol/L which corresponds with moderate iron intoxication. The patient received whole bowel irrigation with 2 L polyethyleneglycol solution and de-ironing treatment with intravenous deferoxamine 20 mg/kg in eight hours. She was discharged from the hospital after three days in a good clinical condition. Retrospectively, serum hepcidin concentrations were determined and evaluated in conjunction with serum iron concentrations and the installed treatment. Before medical de-ironing interventions were started, we saw that the serum iron concentration in our patient was already declining. At the same time, we observed a sharp increase in the serum hepcidin concentration. After normalization of serum iron concentrations, hepcidin normalized as well.