Background:Cardiac troponin is the preferred biomarker of myocardial injury. High-sensitivity troponin assays allow measurement of very low levels of troponin with excellent precision. After the introduction of a high-sensitivity troponin I assay the laboratory began to receive enquiries from clinicians about clinically discordant elevated troponin I results. This led to a systematic investigation and characterisation of the cause.Methods:Routine clinical samples were measured by the Architect High Sensitive Troponin-I (hsTnI) and the VITROS Troponin I ES assays (VitrosTnI). Results that were elevated according to the Architect but not the VITROS assay (Group 1) or results elevated by both assays but disproportionately higher on the Architect (Group 2) were re-analysed for hsTnI after re-centrifugation, multiple dilutions, incubation with heterophilic blocking reagents, polyethylene glycol (PEG) precipitation, and Protein A/G/L treatment. Sephacryl S-300 HR gel filtration chromatography (GFC) was performed on selected specimens.Results:A high molecular weight complex containing immunoreactive troponin I and immunoglobulin (macrotroponin I) was identified in 5% of patients with elevated hsTnI. Patients with both macrotroponin and myocardial injury had higher and longer elevation of hsTnI compared with VitrosTnI with peaks of both macrotroponin and free troponin I-C complex on GFC.Conclusions:Circulating macrotroponin I (macroTnI) causes elevated hsTnI results with the Architect High Sensitive Troponin-I assay with the potential to be clinically misleading. The assay involved in this investigation may not be the only assay affected by macrotroponin. It is important for laboratories and clinicians to be aware of and develop processes to identify and manage specimens with elevated results due to macrotroponin.

Background: Miller syndrome (post-axial acrofacial dystosis) arises from gene mutations for the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH).Nonetheless, despite demonstrated loss of enzyme activity dihydroorotate (DHO) has not been shown to accumulate, but paradoxically urine orotate has been reported to be raised, confusing the metabolic diagnosis. Methods:We analysed plasma and urine from a 4-year-old male Miller syndrome patient. DHODH mutations were determined by PCR and Sanger sequencing.Analysis of DHO and orotic acid (OA) in urine, plasma and blood-spot cards was performed using liquid chromatography-tandem mass spectrometry. In vitro stability of DHO in distilled water and control urine was assessed for up to 60 hours. The patient received a 3-month trial of oral uridine for behavioural problems. Results:The patient had early liver complications that are atypical of Miller syndrome. DHODH genotyping demonstrated compound-heterozygosity for frameshift and missense mutations. DHO was grossly raised in urine and plasma, and was detectable in dried spots of blood and plasma. OA was raised in urine but undetectable in plasma. DHO did not spontaneously degrade to OA. Uridine therapy did not appear to resolve behavioural problems during treatment, but it lowered plasma DHO. Conclusion:This case with grossly raised plasma DHO represents the first biochemical confirmation of functional DHODH deficiency. DHO was also easily detectable in dried plasma and blood spots. We concluded that DHO oxidation to OA must occur enzymatically during renal secretion. This case resolved the biochemical conundrum in previous reports of Miller syndrome patients, and opened the possibility of rapid biochemical screening.

Cardiac troponin I and T are the preferred biomarkers for assessing myocardial injury, and the timing of troponin testing is fundamental to its clinical utility. There are arguments for and against the use of troponin testing in the community, and the stance that general practitioners should never order a troponin test can be considered an oversimplification. GPs have a generally sufficient understanding of the test for use in primary care, and have a better understanding of false-negative troponin test results than false-positive results. We suggest that hospitalisation, rather than troponin testing, should be the default option for patients with symptoms suggestive of acute coronary syndrome. A single troponin test is reasonable in primary care to exclude the possibility of acute myocardial infarction in asymptomatic low-risk patients whose symptoms resolved at least 12 hours prior. GPs should factor in the complex logistics of troponin testing in the community before ordering a troponin test: results need to be accurate and timely, and might be obtained at a time of day when it is difficult to contact the doctor or the patient.

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Extreme hyperferritinaemia: further considerationsIn their case report, Sami et al. 1 state that very high ferritin concentrations (greater than 10,000 mg/L) have only been described in adult Still's disease, multiple blood transfusions and severe acute hepatocellular damage. It may be of interest to the authors that such marked hyperferritinaemia has also been documented in patients with the human immunodeficiency virus (HIV) complicated by superinfection with a range of opportunistic organisms, particularly disseminated histoplasmosis. 2 We would also like to emphasize that haemophagocytic syndromes, such as haemophagocytic lymphohistiocytosis (HLH), may also produce ferritin concentrations of this magnitude. 3,4 A variety of drugs, infections and rheumatological diseases, including but not exclusively adult Still's disease, may precipitate a haemophagocytic process, 5 or it may be a primary disorder. The diagnosis of HLH relies on the patient satisfying sufficient criteria, of which serum ferritin is a part. 6 As an aside, it appears that haemophagocytosis is associated with lower glycosylation of circulating ferritin, 7 a feature that may extend to other circulation proteins, notably transferrin, 8 possibly due to liver involvement by the pathological process. As an illustrative example, a recent case from our laboratory of a five-year-old girl with HLH secondary to Epstein-Barr virus (EBV) infection demonstrated a serum ferritin concentration of 29,600 mg/L at diagnosis and detectable serum asialotransferrin on isoelectric focusing.A review of all ferritin results greater than 10,000 mg/L from our laboratory network in the past year found 35 results from 30 patients (0.06% of all ferritin requests). Most patients had received multiple transfusions for a variety of reasons (14 cases) or had severe acute hepatocellular damage (9 cases); however, there were four cases of HLH: two adult, both fatal, and two paediatric, both secondary to EBV infection. Three cases of high ferritin were not clearly explained.