Zinc protoporphyrin levels in COVID-19 are indicative of iron deficiency and potential predictor of disease severity.

BACKGROUND: Coronavirus disease (COVID-19) has a severe impact on all aspects of patient care. Among the numerous biomarkers of potential validity for diagnostic and clinical management of COVID-19 are biomarkers at the interface of iron metabolism and inflammation. METHODS: The follow-up study included 54 hospitalized patients with laboratory-confirmed COVID-19 with a moderate and severe/critical form of the disease. Iron deficiency specific biomarkers such as iron, ferritin, transferrin receptor, hepcidin, and zinc protoporphyrin (ZnPP) as well as relevant markers of inflammation were evaluated twice: in the first five days when the patient was admitted to the hospital and during five to 15 days; and their validity to diagnose iron deficiency was further assessed. The regression and Receiver Operating Characteristics (ROC) analyses were performed to evaluate the prognosis and determine the probability for predicting the severity of the disease in the first five days of COVID-19. RESULTS: Based on hemoglobin values, anemia was observed in 21 of 54 patients. Of all iron deficiency anemia-related markers, only ZnPP was significantly elevated (P<0.001) in the anemic group. When patients were grouped according to the severity of disease, slight differences in hemoglobin or other anemia-related parameters could be observed. However, the levels of ZnPP were significantly increased in the severely ill group of patients. The ratio of ZnPP to lymphocyte count (ZnPP/L) had a discrimination power stronger than the neutrophil to lymphocyte count ratio (N/L) to determine disease severity. Additionally, only two markers were independently associated with the severity of COVID-19 in logistic regression analysis; D-dimer (OR (5.606)(95% CI 1.019-30.867)) and ZnPP/L ratio (OR (74.313) (95% CI 1.081-5108.103)). CONCLUSIONS: For the first time ZnPP in COVID-19 patients were reported in this study. Among all iron-related markers tested, ZnPP was the only one that was associated with anemia as based on hemoglobin. The increase in ZnPP might indicate that the underlying cause of anemia in COVID-19 patients is not only due to the inflammation but also of nutritional origin. Additionally, the ZnPP/L ratio might be a valid prognostic marker for the severity of COVID-19.

Do Extremely Low Gestational Age Neonates Regulate Iron Absorption via Hepcidin?

OBJECTIVES: To evaluate whether extremely preterm infants regulate iron status via hepcidin. STUDY DESIGN: In this retrospective analysis of infants from the Preterm Epo Neuroprotection (PENUT) Trial, urine hepcidin (Uhep) normalized to creatinine (Uhep/UCr) was evaluated among infants randomized to erythropoietin (Epo) or placebo. RESULTS: The correlation (r) between Uhep/UCr and serum markers of iron status (ferritin and zinc protoporphyrin-to-heme ratio [ZnPP/H]) and iron dose was assessed. A total of 243 urine samples from 76 infants born at 24-276/7 weeks gestation were analyzed. The median Uhep/UCr concentration was 0.3, 1.3, 0.4, and 0.1 ng/mg at baseline, 2 weeks, 4 weeks, and 12 weeks, respectively, in placebo-treated infants. The median Uhep/UCr value in Epo-treated infants were not significantly different, with the exception of the value at the 2-week time point (median Uhep/UCr, 0.1 ng/mg; P < .001). A significant association was seen between Uhep/UCr and ferritin at 2 weeks (r = 0.63; P < .001) and at 4 weeks (r = 0.41; P = .01) and between Uhep/UCr and ZnPP/H at 2 weeks (r = -0.49; P = .002). CONCLUSIONS: Uhep/UCr values correlate with serum iron markers. Uhep/UCr values vary over time and are affected by treatment with Epo, suggesting that extremely preterm neonates can regulate hepcidin and therefore their iron status. Uhep is suppressed in extremely preterm neonates, particularly those treated with Epo.

Timing of iron deficiency and recognition memory in infancy.

Objective: To determine the relationship between iron deficiency (or iron-deficient, ID) and neural correlates of recognition memory depending on ID timing (gestation vs. infancy) and infant age at testing (9 vs. 18 months).Study design: Event-related potentials (ERP) were used in a visual recognition memory task (mother vs. stranger face) to compare healthy term infants according to iron status at birth and 9 months. Fetal-neonatal ID was defined as cord serum ferritin < 75 µg/l or zinc protoporphrin/heme ratio > 118 µmol/mol, postnatal ID as ≥ 2 abnormal iron measures at 9 months with normal cord-blood iron status, and iron-sufficient as not ID at birth or 9 months. Recognition of mother faces was measured by negative component (Nc) and late slow wave (LSW). These ERP components reflect attention and memory updating processes, respectively.Results: All groups showed differences in Nc amplitude elicited by mother and stranger faces at 9 months. At 18 months, only postnatal ID and iron-sufficient groups showed condition differences in Nc amplitude. However, the 2 groups were different in the involved brain regions. For LSW, only the 2 ID groups showed condition differences in amplitude at 9 months. At 18 months, condition differences were not observed in any group.Conclusions: This study indicates that the timing of ID in early life (fetal-neonatal vs. postnatal) modulates the impact of ID on recognition memory. Such impact also varies depending on the age of infants at testing (9 vs. 18 months).

Hepcidin and Iron Deficiency in Women One Year after Sleeve Gastrectomy: A Prospective Cohort Study.

Iron deficiency with or without anemia, needing continuous iron supplementation, is very common in obese patients, particularly those requiring bariatric surgery. The aim of this study was to address the impact of weight loss on the rescue of iron balance in patients who underwent sleeve gastrectomy (SG), a procedure that preserves the duodenum, the main site of iron absorption. The cohort included 88 obese women; sampling of blood and duodenal biopsies of 35 patients were performed before and one year after SG. An analysis of the 35 patients consisted in evaluating iron homeostasis including hepcidin, markers of erythroid iron deficiency (soluble transferrin receptor (sTfR) and erythrocyte protoporphyrin (PPIX)), expression of duodenal iron transporters (DMT1 and ferroportin) and inflammatory markers. After surgery, sTfR and PPIX were decreased. Serum hepcidin levels were increased despite the significant reduction in inflammation. DMT1 abundance was negatively correlated with higher level of serum hepcidin. Ferroportin abundance was not modified. This study shed a new light in effective iron recovery pathways after SG involving suppression of inflammation, improvement of iron absorption, iron supply and efficiency of erythropoiesis, and finally beneficial control of iron homeostasis by hepcidin. Thus, recommendations for iron supplementation of patients after SG should take into account these new parameters of iron status assessment.

Porphyrin accumulation in humans with common dysfunctional variants of ABCG2, a porphyrin transporter: potential association with acquired photosensitivity.

Photosensitivity is a skin reaction disorder mediated by phototoxic and/or photoallergic mechanisms. The accumulation of porphyrins is generally considered to induce phototoxicity. ATP-binding cassette subfamily G member 2 (ABCG2) has been identified as a transporter of porphyrins and its common variants-p.Gln126Ter (rs72552713) and p.Gln141Lys (rs2231142)-reportedly decrease the function of porphyrin transport in vitro; however, the physiological importance of ABCG2 as a porphyrin transporter remains to be fully elucidated. We herein investigated whether ABCG2 dysfunction could lead to porphyrin accumulation and photosensitivity in Japanese subjects, and found it to be significantly correlated with erythrocyte protoporphyrin levels (P = 0.012). This appears to be the first clinical finding of ABCG2 dysfunction-associated protoporphyrin accumulation in humans. We divided the patients into a chronic actinic dermatosis (CAD) group and a non-CAD group. CAD was diagnosed based on the criteria of reduced minimal erythema doses to ultraviolet B (UVB) and/or ultraviolet A (UVA). The non-CAD group was composed of patients who exhibited normal reactions to UVB and UVA on phototesting, but had histories of recurrent erythema/papules on sun-exposed areas. Estimated ABCG2 function according to ABCG2 genotypes in the non-CAD group was significantly lower than in the general Japanese population (P = 0.045). In contrast, no difference was found in ABCG2 function between the CAD group and the general population, suggesting that ABCG2 dysfunction might be a genetic factor in non-CAD patients with clinical photosensitivity. In this context, genetic dysfunction of ABCG2 might be an overlooked pathological etiology of "photosensitivity of unknown cause."

Evaluación biológica de la exposición laboral al plomo / Biological assessment of the work-related exposure to lead

Introducción: El plomo, por su amplio uso causa una gran contaminación ambiental y problemas de salud en muchas partes del mundo. La Organización Mundial de la Salud incluyó el plomo dentro de una lista de diez productos químicos causantes de graves efectos sobre la salud. Objetivo: Evaluar los niveles de plomo en sangre y de protoporfirina libre eritrocitaria en un grupo de trabajadores expuestos a plomo inorgánico. Métodos: Estudio descriptivo de corte transversal donde se evaluaron 776 casos que acudieron a los laboratorios del Instituto Nacional de Salud de los Trabajadores en el año 2018, provenientes de diferentes sectores industriales. Se les realizó la determinación de plomo en sangre a 288 y la de protoporfirina a 488, según métodos establecidos en el laboratorio. Los datos obtenidos fueron procesados utilizando Microsoft Excel® y el paquete estadístico Statgraphics Centurion XVI.II. Resultados: El 92 por ciento de los pacientes fue del sexo masculino. La concentración de plomo en sangre osciló entre 5 µg/dL y 89 µg/dL para un promedio en hombres de 24 µg/dL ± 21 µg/dL y en las mujeres de 11 µg/dL ± 9 µg/dL. Para la protoporfirina, esta fluctuó entre 21 µg/dL y 274 µg/dL, con un promedio de 47 µg/dL ± 22 µg/dL en hombres y 66 µg/dL ± 32 µg/dL en las mujeres. El 8 por ciento de los casos evaluados tuvo valores de plomo en sangre mayores de 60 µg/dL y para la protoporfirina el 5 por ciento de los casos presentaron valores por encima de 85 μg/dL. Conclusiones: Algunos casos evaluados presentaron niveles elevados de plomo que superan los límites permitidos, lo que pone en evidencia la necesidad de reforzar las medidas de protección aplicadas a los trabajadores y la importancia de detectar precozmente el problema en el ámbito laboral, antes de que aparezcan repercusiones derivadas de una intoxicación por plomo(AU)

Introduction: Lead, due to its large use, causes a major environmental pollution and health problems in many places around the world. The World Health Organization included lead in a list of ten chemical products causing severe effects in health. Objective: To assess lead levels in blood and free-erythtocyte protoporphyrin (FEP) levels in groups of workers exposed to inorganic lead. Methods: Descriptive. cross-sectional study where 776 cases coming from different industrial sectors were assessed in the laboratories of the National Institute of Workers Health in the year 2018. It was conducted to 288 of the cases a test to determine if there was lead in blood and a test for FEP to 488 cases, according to the methods established in the laboratory. The data collected were processed using Microsoft Excel® and the statistical program called Statgraphics Centurion XVI.II. Results: 92 percent of the patients were males. Lead concentration in blood ranged from 5 µg/dL and 89 µg/dL, for an average in men of 24 µg/dL ± 21 µg/dL, and in women of 11 µg/dL ± µg/dL. FEP concentration swung from 21 µg/dL to 274 µg/dL, with an average of 47 µg/dL ± 22 µg/dL in men, and 66 µg/dL ± 32 µg/dL in women. 8 percent of the assessed cases presented values of lead in blood higher than 60 µg/dL and for FEP, 5 percent of the cases presented values higher than 85 µg/dL. Conclusions: Some of the assessed cases presented high levels of lead which exceed the permitted levels; so, this demonstrates the need of reinforzing the protection measures applied to the workers and the importance of early detecting this problem in work-related environments prior to the onset of repercutions derived from lead poisoning(AU)

Zinc-protoporphyrin determination by HPLC with fluorescence detection as a biomarker of lead effect in artisanal pottery workers.

Lead (Pb) exposure compromises heme synthesis by inhibiting ferrochelatase, forming zinc-protoporphyrin (ZnPP). This study aims to validate a method for the determination of ZnPP by HPLC with fluorescence detection and apply this method to evaluate the extent of Pb exposure of artisanal pottery workers. Extraction procedures were tested using both nonacid and acid liquid-liquid extraction. The former presented a better chromatogram and recovery results. The validated method yielded a good resolution of ZnPP and its free form peaks with acceptable precision and accuracy. Total run time was 15 min and ZnPP peak retention time was 5.6 min. We applied this method to evaluate 39 potters (90% male), mean age 40 years (9-80). The medians (ranges) of blood lead, ZnPP and hemoglobin were 16.0 µg/dl (2.2-71.5), 12.6 µg/dl (4.6-279.8) and 15.1 g/dl (11.0-17.8), respectively. Significant differences were observed for blood lead according to gender, age range (>40 years), direct handling of lead oxide and years of occupation. Significantly higher levels of ZnPP were observed in male potters involved with lead glazing activity. The validated method was shown to be simple with one-step nonacid extraction, good sensitivity, reproducibility and accuracy. Our data shows that these laborers are dangerously exposed to Pb, reflecting the effect on the heme synthesis.

Potential Antioxidant Activity of Calcium and Selected Oxidative Stress Markers in Lead- and Cadmium-Exposed Workers.

Occupational lead (Pb) and cadmium (Cd) exposure occurs during processing and casting of nonferrous metals such as zinc. In contrast to Pb and Cd, Ca is essential for living organisms due to its important role in a multitude of functions, from cell signaling to bone growth. Pb and Cd exposure affects calcium metabolism in various ways. The aim of this study was to investigate the blood levels of Pb, Cd, and Ca and the levels of selected oxidative stress biomarkers in workers exposed to Pb and Cd. Population groups included 264 male employees in a lead-zinc smelter. The study population was divided into two subgroups based on the median of Ca serum level (2.42 mmol/l): the low-Ca-level group (L-Ca group) and the high-Ca-level group (H-Ca group). Ca level was significantly higher in the H-Ca group than in the L-Ca group due to the study design (by 26%). The level of zinc protoporphyrin (ZPP) was significantly higher in the L-Ca group than in the H-Ca group by 13%, while the blood lead levels (PbB) were similar in the examined groups. The level of cadmium (CdB) was significantly higher in the L-Ca group than in the H-Ca group by 33%. From oxidative stress markers in serum, only the levels of malondialdehyde (MDA) and ceruloplasmin (CER) were significantly higher in the L-Ca group than in the H-Ca group, by 12% and 4%, respectively. The correlation analysis showed negative correlations between Ca level and the levels of PbB, ZPP, CdB, and MDA. The presented results indicate that Ca level modulates the serum concentration of Cd and has an impact on Pb-induced impairment of heme synthesis. The higher Ca levels may lead to a decrease in the concentration of lipid peroxidation products. Moreover, serum calcium level seems to be able to modify the level of acute-phase proteins. Obtained results suggest that higher Ca level may be useful in reducing Cd level in occupationally exposed workers.

Light-provoked skin symptoms on the hands of erythropoietic protoporphyria patients related to personal dosimeter measurements, skin symptoms, light protection and priming.

Erythropoietic protoporphyria (EPP) is characterised by accumulation of protoporphyrin IX (PpIX) in erythrocytes. Upon illumination PpIX is released to the skin. Activation of the photoactive substance PpIX causes painful skin symptoms. This study aimed to objectively quantify individual light exposure of EPP patients in their everyday lives through spring and summer. We further aimed to establish the associations between daily symptoms and light exposure dose to photoprimed and non-photoprimed skin, use of gloves, and erythrocyte PpIX concentration. 14 Danish EPP patients participated from April through June, the period when symptoms are most frequent. Light exposure was measured using personal electronic dosimeters with sensor sensitivity comparable to the absorption spectrum of PpIX, measuring the biological effect of the light in this disease. Concurrently participants reported symptoms and use of protective gloves in a diary. Patients had a blood sample analysed for erythrocyte PpIX. The median patient was exposed to an average daily PpIX-weighted light dose of 3.8 J/cm2 corresponding to approximately 15 min in the midday sun during summer in Denmark. The median patient reported symptoms on 29% and wore gloves on 11% of study days. There was a significant positive correlation between erythrocyte PpIX concentration and percentage of days wearing gloves (r = 0.65, p = 0.011), and a significant negative correlation between erythrocyte PpIX concentration and mean daily light dose on days not wearing gloves (r = -0.53, p = 0.049). Photosensitivity was strongly dependent on photopriming.

Examination of the relationship between iron status and cognitive function among healthy young women with and without a recent history of blood donation.

BACKGROUND: With growing awareness of the prevalence of nonanemic iron deficiency among blood donors, there is a need to explore the extent of potential negative consequences. This study examined the relationship between various measures of iron status, blood donation history, and neuropsychological and psychosocial functioning in healthy young women. STUDY DESIGN AND METHODS: Using a cross-sectional design, 160 female undergraduates completed neuropsychology tests and measures of sleep, fatigue, quality of life, and depression before providing a blood sample. Correlational analyses examined the relationship between iron status (ferritin, iron, hemoglobin, and zinc protoporphyrin) and cognitive and psychosocial functioning. Performance on these measures was also examined as a function of recent blood donation history (zero, one, more than one donation in the past year). RESULTS: Iron status (low ferritin, iron, or hemoglobin or high zinc protoporphyrin) was not associated with poorer performance on the cognitive tasks. Further, participants who reported donating once in the previous year performed better, rather than worse, than those with no recent donation history on several measures of executive function, even when controlling for ferritin levels. Although there was some evidence of greater fatigue among those who had donated more than once in the past year, this effect was not accounted for by ferritin levels. CONCLUSION: The present findings are consistent with prior evidence that nonanemic iron deficiency is not associated with cognitive impairment or psychosocial dysfunction in healthy young females. Because these results are based on cross-sectional evidence, further study using longitudinal research is needed to confirm these findings.

Delayed iron does not alter cognition or behavior among children with severe malaria and iron deficiency.

BACKGROUND: Malaria and iron deficiency (ID) in childhood are both associated with cognitive and behavioral dysfunction. The current standard of care for children with malaria and ID is concurrent antimalarial and iron therapy. Delaying iron therapy until inflammation subsides could increase iron absorption but also impair cognition. METHODS: In this study, Ugandan children 18 months to 5 years old with cerebral malaria (CM, n = 79), severe malarial anemia (SMA, n = 77), or community children (CC, n = 83) were enrolled and tested for ID. Children with ID were randomized to immediate vs. 28-day delayed iron therapy. Cognitive and neurobehavioral outcomes were assessed at baseline and 6 and 12 months (primary endpoint) after enrollment. RESULTS: All children with CM or SMA and 35 CC had ID (zinc protoporphyrin concentration ≥80 µmol/mol heme). No significant differences were seen at 12-month follow-up in overall cognitive ability, attention, associative memory, or behavioral outcomes between immediate and delayed iron treatment (mean difference (standard error of mean) ranged from -0.2 (0.39) to 0.98 (0.5), all P ≥ 0.06). CONCLUSIONS: Children with CM or SMA and ID who received immediate vs. delayed iron therapy had similar cognitive and neurobehavioral outcomes at 12-month follow-up. IMPACT: The optimal time to provide iron therapy in children with severe malaria is not known. The present study shows that delay of iron treatment to 28 days after the malaria episode, does not lead to worse cognitive or behavioral outcomes at 12-month follow-up. The study contributes new data to the ongoing discussion of how best to treat ID in children with severe malaria.

Screening for iron deficiency in surgical patients based on noninvasive zinc protoporphyrin measurements.

BACKGROUND: Approximately every third surgical patient is anemic. The most common form, iron deficiency anemia, results from persisting iron-deficient erythropoiesis (IDE). Zinc protoporphyrin (ZnPP) is a promising parameter for diagnosing IDE, hitherto requiring blood drawing and laboratory workup. STUDY DESIGN AND METHODS: Noninvasive ZnPP (ZnPP-NI) measurements are compared to ZnPP reference determination of the ZnPP/heme ratio by high-performance liquid chromatography (ZnPP-HPLC) and the analytical performance in detecting IDE is evaluated against traditional iron status parameters (ferritin, transferrin saturation [TSAT], soluble transferrin receptor-ferritin index [sTfR-F], soluble transferrin receptor [sTfR]), likewise measured in blood. The study was conducted at the University Hospitals of Frankfurt and Zurich. RESULTS: Limits of agreement between ZnPP-NI and ZnPP-HPLC measurements for 584 cardiac and noncardiac surgical patients equaled 19.7 µmol/mol heme (95% confidence interval, 18.0-21.3; acceptance criteria, 23.2 µmol/mol heme; absolute bias, 0 µmol/mol heme). Analytical performance for detecting IDE (inferred from area under the curve receiver operating characteristics) of parameters measured in blood was: ZnPP-HPLC (0.95), sTfR (0.92), sTfR-F (0.89), TSAT (0.87), and ferritin (0.67). Noninvasively measured ZnPP-NI yielded results of 0.90. CONCLUSION: ZnPP-NI appears well suited for an initial IDE screening, informing on the state of erythropoiesis at the point of care without blood drawing and laboratory analysis. Comparison with a multiparameter IDE test revealed that ZnPP-NI values of 40 µmol/mol heme or less allows exclusion of IDE, whereas for 65 µmol/mol heme or greater, IDE is very likely if other causes of increased values are excluded. In these cases (77% of our patients) ZnPP-NI may suffice for a diagnosis, while values in between require analyses of additional iron status parameters.

Results of a pilot study of isoniazid in patients with erythropoietic protoporphyria.

Erythropoietic protoporphyria (EPP), the most common porphyria of childhood and the third most common porphyria of adulthood, is characterized clinically by painful, non-blistering cutaneous photosensitivity. Two distinct inheritance patterns involving mutations affecting genes that encode enzymes of the heme biosynthetic pathway underlie the clinical phenotype. Aminolevulinic acid synthase 2 (ALAS2), the rate limiting enzyme of the heme pathway in the erythron, is a therapeutic target in EPP because inhibiting enzyme function would reduce downstream production of protoporphyrin IX (PPIX), preventing accumulation of the toxic molecule and thereby ameliorating symptoms. Isoniazid (INH) is widely used for treatment of latent and active M. tuberculosis (TB). Sideroblastic anemia is observed in some patients taking INH, and studies have shown that this process is a consequence of inhibition of ALAS2 by INH. Based on these observations, we postulated that INH might have therapeutic activity in patients with EPP. We challenged this hypothesis in a murine model of EPP and showed that, after 4 weeks of treatment with INH, both plasma PPIX and hepatic PPIX were significantly reduced. Next, we tested the effect of INH on patients with EPP. After eight weeks, no significant difference in plasma or red cell PPIX was observed among the 15 patients enrolled in the study. These results demonstrate that while INH can lower PPIX in an animal model of EPP, the standard dose used to treat TB is insufficient to affect levels in humans.

Non-invasive measurement of erythrocyte zinc protoporphyrin in children.

BACKGROUND: Reliable screening for iron deficiency (ID) has required a blood sample and cost-intensive laboratory measurements. A novel method to non-invasively measure erythrocyte zinc protoporphyrin (ZnPP), an established marker for ID, is evaluated in children. METHODS: ZnPP was determined non-invasively by fluorescence measurements on the wet vermillion of the lower lip in 99 hospitalized children aged 9 months to 5 years. For comparison, conventional ID parameters and ZnPP were determined from blood samples. RESULTS: The non-invasively measured ZnPP values had limits of agreement (LoA) of 14 µmol ZnPP/mol heme (95% confidence interval: 9-20) compared to fluorescence measurements directly in blood. Repeated high-performance liquid chromatography reference determinations had comparable LoA of 14 µmol ZnPP/mol heme (9-17). Non-invasive ZnPP measurements had sensitivity and specificity of 67% (39-88%) and 97% (91-99%), and negative and positive predictive value of 94% (90-97%) and 80% (55-93%), for detecting ID as defined by the soluble transferrin receptor (sTfR). In groups with more severe ID as defined by serum ferritin and sTfR, higher ZnPP values were found, with the highest ZnPP values for the group with ID anemia. CONCLUSION: Non-invasive ZnPP measurements are reliably feasible in children. The simple and fast method has the potential to enable wide-spread screening for ID.

ECG conduction disturbances and ryanodine receptor expression levels in occupational lead exposure workers.

OBJECTIVES: A significant number of researches have evidenced that occupational lead (Pb) exposure increased risks of cardiovascular disease. However, evidences about the potential effects of Pb on the cardiac conduction system are sparse and inconclusive. Besides, ryanodine receptors (RyRs) induced dysfunction of cardiac excitation contraction coupling which is considered to be one of the mechanisms in cardiovascular diseases. Therefore, we examined the association between occupational Pb exposure and ECG conduction abnormalities, as well as RyRs in Pb-induced ECG abnormalities. METHODS: We investigated 529 Pb smelter workers, and measured blood lead (BPb), zinc protoporphyrin (ZPP), ECG outcomes and RyR expression levels. Based on BPb levels, the workers were divided into three groups: the BPb not elevated group, the BPb elevated group and the Pb poisoning group. Descriptive and multivariable analyses were performed. RESULTS: Compared with the BPb not elevated group, the Pb poisoning group had a higher incidence of high QRS voltage, and a lower level of RyR1 gene expression (p<0.05). Further unconditional multivariable logistic regression analyses showed that high QRS voltage was positively related to BPb (OR=1.045, 95% CI 1.014 to 1.078) and inversely associated with RyR1 expression (OR=0.042, 95% CI 0.002 to 0.980) after adjusting for potential confounders. In addition, multiple linear regression analyses showed that the QTc interval was positively associated with ZPP (ß=0.299, 95% CI 0.130 to 0.468) after adjusting for potential confounders. CONCLUSIONS: Our study provided evidences that occupational exposure to Pb may be associated with worse ECG outcomes (high QRS voltage), which might be related to decreased levels of RyR1.

[Lead and mercury exposure in populations on the banks of the Bogotá River: a multi-method study]. / Exposición a plomo y mercurio en poblaciones de la ribera del río Bogotá: estudio multi-método.

OBJECTIVES: This study sought to understand the health problems associated with the presence of lead and mercury in the water of the Bogotá River. MATERIALS AND METHODS: A mixed methods study was conducted using interviews, surveys and measurements of zinc protoporphyrin (ZPP) and mercury in blood from 172 individuals. Variables associated with the highest concentrations were identified, as well as the attributes of the cases with increased exposure by means of a qualitative comparative analysis. RESULTS: Interviews reported that river pollution is associated with diseases, although direct exposure to water is rare. River water is widely used for irrigation of crops that are sold in other municipalities. Communities with greater exposure to river water are Tocaima and Girardot. The highest levels of ZPP were observed among those living in these municipalities, did activities at home and performed non-work activities using metals. Increased ZPP levels were associated with depression, nasal bleeding and loss of appetite. The highest concentrations of mercury were found in the inhabitants of Girardot, and were associated with sweating, disorientation, nausea and diarrhea. CONCLUSION: Low levels of lead and mercury were observed in the study population, although there are specific cases with high social vulnerability that require special attention.

OBJETIVOS: Este estudio buscó comprender la problemática sanitaria asociada con la presencia de plomo y mercurio en el agua del río Bogotá. MATERIALES Y MÉTODOS: Se realizó un estudio mixto con entrevistas, encuesta y mediciones de zinc protoporfirina (ZPP) y mercurio en sangre a 172 individuos. Se identificaron variables asociadas con las mayores concentraciones, y mediante análisis comparativo cualitativo los atributos de los casos con mayor exposición. RESULTADOS: Las entrevistas reportaron que la contaminación del río se asocia con enfermedades, pese a que la exposición directa al agua no es frecuente. El agua del río es usada ampliamente para riego de cultivos que se venden en otros municipios. Las comunidades con mayor exposición al agua del río son de Tocaima y Girardot. Los mayores niveles de ZPP se observaron entre quienes vivían en estos municipios, con ocupación hogar y que realizaban actividades extralaborales con metales. Los niveles elevados de ZPP se asociaron con depresión, sangrado nasal y pérdida del apetito. Las mayores concentraciones de mercurio se presentaron entre habitantes de Girardot. Estas se asociaron con sudoración, desorientación, náuseas y diarrea. CONCLUSIÓN: Se presentaron bajos niveles de plomo y mercurio en la población estudiada, aunque hay casos específicos con alta vulnerabilidad social que requieren atención especial.

Erythropoietic Protoporphyria-related Hepatopathy Successfully Treated with Phlebotomy.

A 27-year-old man bearing an erythropoietic protoporphyria (EPP)-associated ferrochelatase (FECH) mutation was admitted to our hospital for general malaise and marked elevation of the serum levels of hepatobiliary enzymes and bilirubin. Initial treatment with plasma exchange did not reduce the blood protoporphyrin or serum liver enzyme levels, so phlebotomy was started. Surprisingly, weekly phlebotomy normalized the serum levels of liver enzymes, accompanied by a marked reduction in the blood protoporphyrin levels. The clinical course of this case strongly suggests that phlebotomy may be a suitable treatment option for EPP-related hepatopathy.

Optimizing diagnostic biomarkers of iron deficiency anemia in community-dwelling Indian women and preschool children.

The detection of iron deficiency anemia is challenged by the paucity of diagnostic tests demonstrating high sensitivity and specificity. Using two biomarkers, zinc-protoporphyrin/heme and hepcidin, we established the diagnostic cut-off values for iron deficiency anemia in preschool children and women. We randomly selected non-anemic individuals (n=190; women=90, children=100) and individuals with iron deficiency anemia (n=200; women=100, children=100) from a preexisting cohort of healthy preschool children and their mothers. The diagnostic performance of these biomarkers was estimated by analyzing receiver operating characteristic curves. Diagnostic cut-offs with a high predictive value for iron deficiency anemia were selected. Median zinc-protoporphyrin/heme and hepcidin values in non-anemic children were 49 µmol/mol heme and 42 ng/mL, respectively, and in non-anemic women these values were 66 µmol/mol heme and 17.7ng/mL, respectively. Children and women with iron deficiency anemia had higher zinc-protoporphyrin/heme ratios (children=151 µmol/mol heme and women=155 µmol/mol heme) and lower hepcidin levels (children=1.2ng/mL and women=0.6ng/mL). A zinc-protoporphyrin/heme ratio cut-off >90 µmole/mole heme in children and >107 µmole/mole heme in women was associated with a high diagnostic likelihood for iron deficiency anemia (children, likelihood ratio=20.2: women, likelihood ratio=10.8). Hepcidin cut-off values of ≤6.8ng/mL in children and ≤4.5ng/mL in women were associated with a high diagnostic likelihood for iron deficiency anemia (children, likelihood ratio=14.3: women, likelihood ratio=16.2). The reference ranges and cut-off values identified in this study provide clinicians with guidance for applying these tests to detect iron deficiency anemia. Erythrocyte zinc-protoporphyrin/heme ratio is a valid point-of-care biomarker to diagnose iron deficiency anemia.

Early detection of colorectal adenocarcinoma: a clinical decision support tool based on plasma porphyrin accumulation and risk factors.

BACKGROUND: An increase in naturally-occurring porphyrins has been described in the blood of subjects bearing different kinds of tumors, including colorectal, and this is probably related to a systemic alteration of heme metabolism induced by tumor cells. The aim of our study was to develop an artificial neural network (ANN) classifier for early detection of colorectal adenocarcinoma based on plasma porphyrin accumulation and risk factors. METHODS: We measured the endogenous fluorescence of blood plasma in 100 colorectal adenocarcinoma patients and 112 controls using a conventional spectrofluorometer. Height, weight, personal and family medical history, use of alcohol, red meat, vegetables and tobacco were all recorded. An ANN model was built up from demographic data and from the integral of the fluorescence emission peak in the range 610-650 nm. We used the Receiver Operating Characteristic (ROC) curve to assess performance in distinguishing colorectal adenocarcinoma patients and controls. A liquid chromatography-high resolution mass spectrometry (LC-HRMS) analytical method was employed to identify the agents responsible for native fluorescence. RESULTS: The fluorescence analysis indicated that the integral of the fluorescence emission peak in the range 610-650 nm was significantly higher in colorectal adenocarcinoma patients than controls (p < 0.0001) and was weakly correlated with the TNM staging (Spearman's rho = 0.224, p = 0.011). LC-HRMS measurements showed that the agents responsible for the fluorescence emission were mainly protoporphyrin-IX (PpIX) and coproporphyrin-I (CpI). The overall accuracy of our ANN model was 88% (87% sensitivity and 90% specificity) with an area under the ROC curve of 0.83. CONCLUSIONS: These results confirm that tumor cells accumulate a diagnostic level of endogenous porphyrin compounds and suggest that plasma porphyrin concentrations, indirectly measured through fluorescence analysis, may be useful, together with risk factors, as a clinical decision support tool for the early detection of colorectal adenocarcinoma. Our future efforts will be aimed at examining how plasma porphyrin accumulation correlates with survival and response to therapy.

The effect of occupational chronic lead exposure on the complete blood count and the levels of selected hematopoietic cytokines.

Associations among lead exposure, blood morphology, and cytokines influencing hematopoiesis are still inconclusive. Therefore, the objective of the present study was to demonstrate whether workers chronically exposed to lead demonstrate changes in complete blood count (CBC) parameters associated with altered levels of selected cytokines influencing hematopoiesis. The study covered 80 male subjects employed in the zinc-lead works in Miasteczko Slaskie. The subjects were divided into two groups: control group (24 healthy administration workers without a history of occupational exposure to lead compounds) and lead exposed group (56 subjects exposed to lead compounds in their work environment). The values of HTC, MCV, MCH, RDW-CV, PDW, and LMR were significantly lower in the exposed group than in the controls by 3%, 5%, 3%, 4%, 15%, and 47%, respectively. However, the levels of MCHC and MPV were higher in the exposed group than in the controls by 3% and 11%, respectively. Analogically, the values of MXD and MXD% were also significantly higher by 118% and 70%, respectively. The concentration of IL-7 was significantly higher in the exposed group compared to the controls by 143%. In this study, chronic lead exposure in the occupational setting at levels <50 µg/dl does not affect RBC count and hemoglobin level but decreases MCV and hematocrit. Similarly, chronic lead toxicity does not affect WBC count but alters proportions of different types of leukocytes with significant increase of MXD count associated with elevated level of IL-7. Oppositely to a short-term lead exposure, chronic lead exposure elevates MPV and does not alter PLT count.