"Macro transcobalamin causing raised vitamin B12: Case-based laboratory investigation".

Determination of plasma vitamin B12 (B12) is a frequently requested laboratory analysis, mainly employed to establish B12 deficiency. However, an increased level of B12 is a common unexpected finding that may be related to an increased concentration of one of the B12 binding proteins, haptocorrin or transcobalamin. This paper describes the extensive laboratory evaluation of a patient with an elevated level of plasma B12 with various well-established assays. Initial studies suggested the presence of a macromolecule consisting of haptocorrin bound B12. Specific determinations of the B12-binding proteins revealed normal amounts of haptocorrin but a markedly increase in both total and B12 saturated transcobalamin (holo-TC). The results are in accord with the presence of macro-transcobalamin. These experiments reveal that determination of the nature of the B12-macromolecules is troublesome due to differences in assays applied to measure these proteins. In addition, this publication creates awareness of macro-holo-TC as a cause of an unexplained increased B12 level.

Twenty Years of Ferroportin Disease: A Review or An Update of Published Clinical, Biochemical, Molecular, and Functional Features.

Iron overloading disorders linked to mutations in ferroportin have diverse phenotypes in vivo, and the effects of mutations on ferroportin in vitro range from loss of function (LOF) to gain of function (GOF) with hepcidin resistance. We reviewed 359 patients with 60 ferroportin variants. Overall, macrophage iron overload and low/normal transferrin saturation (TSAT) segregated with mutations that caused LOF, while GOF mutations were linked to high TSAT and parenchymal iron accumulation. However, the pathogenicity of individual variants is difficult to establish due to the lack of sufficiently reported data, large inter-assay variability of functional studies, and the uncertainty associated with the performance of available in silico prediction models. Since the phenotypes of hepcidin-resistant GOF variants are indistinguishable from the other types of hereditary hemochromatosis (HH), these variants may be categorized as ferroportin-associated HH, while the entity ferroportin disease may be confined to patients with LOF variants. To further improve the management of ferroportin disease, we advocate for a global registry, with standardized clinical analysis and validation of the functional tests preferably performed in human-derived enterocytic and macrophagic cell lines. Moreover, studies are warranted to unravel the definite structure of ferroportin and the indispensable residues that are essential for functionality.

Vasculitis in Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia: A Report of Two Cases.

There is a clear association between myelodysplastic syndrome (MDS)/chronic myelomonocytic leukemia (CMML) and autoimmune manifestations such as vasculitis. It is not clear if autoimmune manifestations in myelodysplastic syndrome are a cause or consequence. We describe two patients with polyarteritis nodosa and large vessel vasculitis, as presenting symptom of a myelodysplastic syndrome with excess blasts type 2 and chronic myelomonocytic leukemia respectively. Immunosuppressive treatment resulted in amelioration of the vasculitis with improvement of the myelodysplastic features in the first patient and rapid evolution to acute myeloid leukemia in the other patient. The association between MDS/CMML and autoimmune manifestations, such as vasculitis, emphasizes the role of autoimmunity in the clinical features and even pathogenesis of MDS/CMML.

No increased mortality risk in older persons with unexplained anaemia.

BACKGROUND: in older persons, anaemia is associated with a number of unfavourable outcomes. In approximately 30% of older persons with anaemia, the cause of the anaemia is unexplained. We assessed the clinical differences between subjects with explained and unexplained anaemia and investigated whether these subjects have different mortality patterns compared with subjects without anaemia. DESIGN: observational prospective follow-up study. SETTING: the Leiden 85-plus study. PARTICIPANTS: four hundred and ninety-one persons aged 86 years. METHODS: the study population was divided in three groups: (i) no anaemia (reference group, n=377), (ii) explained anaemia (iron deficiency, folate deficiency, vitamin B12 deficiency, signs of myelodysplastic syndrome or renal failure, n=74) and (iii) unexplained anaemia, (n=40). Mortality risks were estimated with Cox-proportional hazard models. RESULTS: haemoglobin levels were significantly lower in subjects with explained anaemia than in subjects with unexplained anaemia (P<0.01). An increased risk for mortality was observed in subjects with explained anaemia [HR: 1.93 (95% CI: 1.47-2.52), P<0.001], but not in subjects with unexplained anaemia [HR: 1.19 (95% CI: 0.85-1.69), P=0.31]. Adjusted analyses (sex, co-morbidity, MMSE, institutionalised and smoking) did not change the observed associations for both explained and unexplained anaemic subjects. CONCLUSION: older subjects with unexplained anaemia had similar survival compared with non-anaemic subjects. Increased mortality risks were observed in subjects with explained anaemia compared with non-anaemic subjects.

[The diagnostic value of NT-proBNP in heart failure: in depth analysis]. / De diagnostische waarde van NT-proBNP bij hartfalen.

A 77-year-old man with dyspnoea was suspected to have a decompensatio cordis by the general practitioner. A diuretic was prescribed. Additional radiological and laboratory investigation (e.g. natriuretic peptides and D-dimers) showed pulmonary embolism instead of heart failure. A second patient, a woman aged 79 years, with a history of leukaemic mantle cell lymphoma, was treated with poly-chemotherapy (R-CHOP), after which remission was achieved. Four years later the lymphoma recurred and R-CHOP treatment was started. However this was without success, after which R-CHOP treatment was repeated. Subsequently the patient developed dyspnoea and pneumonia. Following additional radiological and laboratory investigation (e.g. natriuretic peptides) the patient was finally diagnosed with doxorubicin-induced heart failure. Based upon these case studies, the role of brain-natriuretic peptides in the differential diagnostic work-up of dyspnoea is highlighted. Test performance, correlation with disease, monitoring, prognostics, differential diagnostic power, reference values and pitfalls of brain natriuretic peptides are discussed.

Introduction of a new cobalamin (vitamin B12) assay: lessons from a flawed validation study.

BACKGROUND: Plasma vitamin B12 [cobalamin (Cbl)] concentrations are usually measured as a screening marker for vitamin B12 deficiency. Siemens Healthcare Diagnostics has introduced Cbl assays for various platforms, i.e., the immulite (IML) 2000 and 2500. In our laboratories, regular validation studies for the IML 2500 were conducted and showed acceptable quality specifications. After the introduction of the IML 2500 Cbl assay, clinicians in the department of internal medicine reported an increased frequency of patients with Cbl-concentrations less than 148 pmol/L. METHODS: In order to investigate this claim from the clinicians, we retrospectively analyzed the internal and external quality control (QC) of the Cbl assay. In addition, the monthly patient means for the Cbl assay were analyzed both before and after the introduction of the new Cbl assay. RESULTS: No abnormalities were found in the internal and external QCs. However, the monthly patient means for the Cbl assay showed a statistically significant decrease in cobalamin concentrations. Siemens acknowledged the problems and formulated a new Cbl assay, which was subsequently validated in our laboratories and showed equivocal Cbl results when compared to the IML 2000 Cbl assay. CONCLUSIONS: We report a flawed validation study conducted by the manufacturer that resulted in an undetected analytical problem in the IML 2500 Cbl assay, its subsequent introduction on the market, the final recognition of the poor performance of the assay by our clinicians, and the eventual resolution by the manufacturer. Hence, it emphasizes the utmost importance for thorough comparison between assays over the entire measurement range, even when both assays are produced by the same manufacturer.

Simple and safe exclusion of pulmonary embolism in outpatients using quantitative D-dimer and Wells' simplified decision rule.

A safe and effective management strategy is pivotal in excluding pulmonary embolism (PE). The combination of Wells' simplified dichotomous clinical decision rule and D-dimer test is non-invasive and could be highly efficient, though its safety has not been widely studied. We evaluated safety and efficiency of this combination in excluding PE. Wells clinical decision rule was performed in 941 consecutive patients with suspected PE and, if patients had a score