Abstract
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.
Introduction
The intentional overdose of iron supplements appears to be an increasingly common form of attempted suicide, especially in young women. 1 We present a case of iron overdose in a 16-year-old girl with coma as a main presenting symptom. The course of the serum iron concentration in this patient is described, including the role of hepcidin in iron regulation.
Case report
A 16-year-old comatose Moroccan girl was brought to the emergency department at our hospital. Her parents revealed that during the day, their daughter had suffered from a headache for which she had asked acetaminophen for. When she went to bed she was pale, and had a blurred speech and instable pose. Several hours later, she was found unconscious in her bed, lying in vomit.
In the emergency department, the patient was treated according to the guidelines of Advanced Pediatric Life Support. The airway was unobstructed. The patient breathed spontaneously with a respiration rate of 40/min and an oxygen saturation of 92%. After oxygen administration via a non-rebreathing mask, the saturation reached 100%. Circulatory parameters were stable with a heart rate of 120/min, blood pressure of 112/69 mmHg, central capillary refill less than three seconds and good peripheral pulsations.
Neurological dysfunction presented as the absence of reaction to vocal or pain stimuli, episodes of vehement physical agitation, divergent eye position and positive Babinski foot pad reflexes on both sides. There was no fever. Further physical examination was not contributory.
Additional examinations were performed to clarify the clinical presentation of this 16-year-old girl. Laboratory tests showed a glucose of 9.4 mmol/L and a mild metabolic acidosis with a pH 7.32 and a base excess 5.2 mmol/L. The complete blood count was normal, as were the liver and renal function tests. No abnormal results were found in urine and liquor examination. A computed tomography scan of the cerebrum showed no signs of intracerebral haemorrhage or elevated intracerebral pressure. Toxicology screening excluded the use of acetaminophen, ethanol, cannabis, amphetamine, metamphetamine, opiates, cocaine, benzodiazepines, methadone and gamma hydroxybutyric acid.
The patient was stabilized and admitted to the intensive care ward. She woke up spontaneously after 12 h and confessed that she took approximately 30 tablets of Fero-Gradumet® (Teofarma Srl, Valle Salimbene (PV), Italy), containing 105 mg Fe2+ per tablet, resulting in a total intake of circa 52 mg/kg Fe2+. 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. 2
We started whole bowel irrigation with 2 L polyethyleneglycol solution to remove unabsorbed iron from the gastrointestinal tract. De-ironing treatment consisted of intravenous deferoxamine 20 mg/kg in eight hours. An abdominal X-ray was made to evaluate for radiopaque tablets, which were not detected. Vital parameters were monitored as well as the serum iron concentration and renal and liver function parameters. Hepcidin concentrations were determined retrospectively by surface-enhanced laser desorption/ionization-time of flight-mass spectometry using stable isotope-labelled hepcidine as an internal standard. 3
The course of the iron and hepcidin serum concentrations is shown in Figure 1. The arrow in Figure 1 points at the time deferoxamine was started. The serum ferritin concentration was 19 μg/L in the first blood sample and increased to a maximum concentration of 73 μg/L, 38 h after ingestion. An overview of iron, ferritin, transferrin and hepcidin values is shown in Table 1. No signs of multiorgan failure were seen before or after starting de-ironing therapy. Our patient left the hospital after three days, in a good clinical condition.
Serum concentrations of iron and hepcidin. The arrow points at the time of starting de-ironing therapy
Serum concentrations of iron, transferrin, ferritin and hepcidin
Discussion
Ingestion of an iron overdose leads to a potentially fatal condition. 4 Iron overdose is considered a leading cause of poisoning-related injury and death in young children. 5 Systemic toxicity may occur following ingestion of more than 60 mg elemental iron per kg body weight. 6 The percentage of children who die after an unintentional iron overdose varies between 8% and 25%. 7
The best modality for decreasing morbidity and mortality of iron overdose is primary prevention. 8 Many hospital admissions with iron poisoning could be prevented by keeping iron supplements safely out of reach of children. 9
The risk of iron overdose in young children is almost doubled when their mother is pregnant. Pregnant women commonly receive iron suppletion therapy. Since the medication has a candy-like appearance, is often kept within the reach of children and is considered harmless by many parents, 10 this may pose a hazard for young children. Children whose mother gave birth to a sibling had an almost four-fold increased risk of iron poisoning in the first month postpartum. 9
Not only unintentional iron overdose is a health-care problem, but intentional iron overdose in attempted suicide is as well, as described in this case report.
A classical iron poisoning occurs in five clinical phases. 11 These five stages are the gastrointestinal stage, the quiescent stage, shock, hepatotoxicity and the stage with gut obstruction. There is a potential for considerable variability and overlap in time in these five phases and not all patients manifest this ‘textbook’ presentation.
The gastrointestinal stage occurs immediately after ingestion (30 min to six hours postingestion). Complaints like epigastric pain, nausea, vomiting and diarrhoea are common and the result of the toxicity of iron on the gastrointestinal mucosa. As a result of vasodilation and intravascular volume loss, hypotension and hypovolemic shock can occur, leading directly to the third phase.
In the classical presentation, there is a quiescent phase several hours postingestion (2–8 h postingestion). In this latent phase, there is a transition between the resolution of gastrointestinal symptoms and the appearance of systemic toxicity.
Several hours after ingestion, the shock phase can become manifest. Because of inadequate perfusion and cellular toxicity, multiorgan failure develops. Symptoms such as hypotension, tachycardia, seizures, coma, worsening metabolic acidosis, renal failure, hepatic dysfunction, coagulopathy and myocardial depression may occur (2–48 h postingestion). Subsequently, hepatotoxicity can develop (12–24 h postingestion). The gut obstruction phase is caused by stricture formation when mucosal injury is healing. This occurs 1–7 weeks after ingestion of the iron overdose. 11
The presentation of our patient did not appear to us immediately as iron intoxication. The severe dysfunction of the central nervous system without further signs of shock or multiorgan failure make this case an atypical presentation of iron intoxication.
The textbook classifications for severity of iron intoxication did not seem to have a good correlation with clinical reality in this case. Our patient was comatose for 12 h, but based on the iron serum concentration and the number of ingested tablets, this case would be classified as moderate intoxication. These findings confirm that iron serum concentrations do not correlate with the actual clinical severity. 12
Iron poisoning occurs when the plasma iron concentration exceeds the total iron-binding capacity, resulting in free circulating iron in the body. Normal absorption of dietary iron involves an energy-dependent transport system that is carrier-mediated. This process is saturable allowing up to 5 mg iron to be absorbed daily. Depending on the iron preparation ingested, an iron overdose may overwhelm this normal transport system by passive adsorption. 13 In intoxication, peak plasma iron concentrations occur 2–4 h postingestion. 14
The relatively low initial iron serum concentration in our patient might be due to the fact that she had ingested Fero-Gradumet, a slow-release preparation. Moreover, the first ferritin concentration of 19 μmol/L suggests that the patient's iron stores were rather limited. A fast tissue uptake of iron from the circulation may therefore have contributed to the blunt response of serum iron.
The main marker for severity of iron toxicity remains as the clinical presentation. After studies in rats, a hypothesis was postulated that serum hepcidin concentrations might contribute to estimate the amount of iron absorption. 12 These rat studies showed elevated concentrations of serum hepcidin and a higher concentration of hepcidin messenger RNA after administration of toxic doses of iron.12,15
Hepcidin is the main iron-regulatory hormone, first described in 2000. 16 Hepcidin causes internalization and degradation of the ferroportin iron channels. Iron transfer into blood from the duodenum, from macrophages and from iron-storing hepatocytes is hereby decreased. Hepcidin is regulated by a feedback loop of iron concentrations. Our case report is the first report of iron autointoxication presenting the course of serum iron concentrations as well as serum hepcidin. Figure 1 shows a rapid increase of the hepcidin concentration, first measured seven hours after ingestion. From earlier studies, it is known that hepcidin response to iron starts within several hours after intake. 16 The hepcidin concentration drops as soon as the iron serum concentration decreases. This concurs with the short half-life of this protein, which is predominantly cleared by the kidneys. 16 One would expect the hepcidin concentration to remain elevated for a longer period in moderate intoxication as occurred in our patient. 15 However, this can be explained by the enhanced elimination of iron by complexation with deferoxamine and the aforementioned rapid tissue uptake of iron from the circulation.
Although the response of hepcidine to increased iron concentrations is rather fast, a clear role in the diagnosis or treatment of iron intoxication is equivocal. Determination of hepcidin is currently limited to specialized laboratories and quite expensive. Moreover, reference values for hepcidin are skewed which impedes the interpretation of individual results.
In addition, the kinetics of hepcidin may be influenced by concurrent inflammation and/or liver disease.
On the other hand, there is a sharp decrease of hepcidin in the presented case within 48 h of intoxication. This may be a clear sign of effectively installed therapy. Moreover, it suggests that the excess storage of iron in liver and macrophages, if present at all, is very limited, thereby reducing possible tissue damage. Together with the results from animal studies, these data are in favour of the use of hepcidin in iron intoxication. 12
Whether hepcidin reduces iron absorption in the case of iron intoxication is a subject for discussion. As mentioned before, hepcidin can diminish the physiological iron uptake by blocking the ferroportin channels in the duodenum and jejunum. In case of acute iron overload, the normal iron transport system may become overwhelmed. Hepcidin cannot influence this passive iron absorption. This probably implies that a protective role of hepcidine depends on both the amount of iron ingested and the preparation used. Our patient ingested the slow-release preparation of Fero-Gramudet and already showed a decrease of serum iron concentrations before therapy was installed. As this concurred with a rise in hepcidine, this might suggest a protective action of hepcidine in the presented case. Whether this also applies in case of excessive ingestion of more rapidly absorbed iron preparations is disputable.
Conclusion
We presented the first case report of iron autointoxication with a presentation of the course of serum iron concentrations as well as serum hepcidin concentrations. Before medical de-ironing interventions were started, the serum iron concentration in our patient was already declining. At the same time, we saw an increase of the serum hepcidin concentration, suggesting a regulating role of this hormone in acute iron intoxication by the slow-release preparation Fero-Gradumet.
Declarations
Footnotes
Acknowledgements:
Not applicable.