Review

Authors: Pierre Brissot, Antonello Pietrangelo, Paul C Adams...

Haemochromatosis is defined as systemic iron overload of genetic origin, caused by a reduction in the concentration of the iron regulatory hormone hepcidin, or a reduction in hepcidin-ferroportin binding. Hepcidin regulates the activity of ferroportin, which is the only identified cellular iron exporter. The most common form of haemochromatosis is due to homozygous mutations (specifically, the C282Y mutation) in HFE, which encodes hereditary haemochromatosis protein. Non-HFE forms of haemochromatosis due to mutations in HAMP, HJV or TFR2 are much rarer. Mutations in SLC40A1 (also known as FPN1; encoding ferroportin) that prevent hepcidin-ferroportin binding also cause haemochromatosis. Cellular iron excess in HFE and non-HFE forms of haemochromatosis is caused by increased concentrations of plasma iron, which can lead to the accumulation of iron in parenchymal cells, particularly hepatocytes, pancreatic cells and cardiomyocytes. Diagnosis is noninvasive and includes clinical examination, assessment of plasma iron parameters, imaging and genetic testing. The mainstay therapy is phlebotomy, although iron chelation can be used in some patients. Hepcidin supplementation might be an innovative future approach.

Topics: Cation Transport Proteins; Chelation Therapy; Hemochromatosis; Humans; Iron; Magnetic Resonance Imaging; Mass Screening; Phlebotomy; Polymorphism, Genetic; Quality of Life; Ferroportin

PubMed: 29620054
DOI: 10.1038/nrdp.2018.16

Review

Authors: Herbert L Muncie, James Campbell

The thalassemias are a group of inherited hematologic disorders caused by defects in the synthesis of one or more of the hemoglobin chains. Alpha thalassemia is caused by reduced or absent synthesis of alpha globin chains, and beta thalassemia is caused by reduced or absent synthesis of beta globin chains. Imbalances of globin chains cause hemolysis and impair erythropoiesis. Silent carriers of alpha thalassemia and persons with alpha or beta thalassemia trait are asymptomatic and require no treatment. Alpha thalassemia intermedia, or hemoglobin H disease, causes hemolytic anemia. Alpha thalassemia major with hemoglobin Bart's usually results in fatal hydrops fetalis. Beta thalassemia major causes hemolytic anemia, poor growth, and skeletal abnormalities during infancy. Affected children will require regular lifelong blood transfusions. Beta thalassemia intermedia is less severe than beta thalassemia major and may require episodic blood transfusions. Transfusion-dependent patients will develop iron overload and require chelation therapy to remove the excess iron. Bone marrow transplants can be curative for some children with beta thalassemia major. Persons with thalassemia should be referred for preconception genetic counseling, and persons with alpha thalassemia trait should consider chorionic villus sampling to diagnose infants with hemoglobin Bart's, which increases the risk of toxemia and postpartum bleeding. Persons with the thalassemia trait have a normal life expectancy. Persons with beta thalassemia major often die from cardiac complications of iron overload by 30 years of age.

Topics: Blood Transfusion; Bone Marrow Transplantation; Chelation Therapy; Erythrocyte Indices; Erythropoiesis; Hemoglobins; Humans; alpha-Thalassemia; beta-Thalassemia

PubMed: 19678601
DOI: No ID Found

Authors: Antoine N Saliba, Khaled M Musallam, Ali T Taher...

The intricate interplay of anemia and iron overload under the pathophysiological umbrella of ineffective erythropoiesis in non-transfusion-dependent β-thalassemia (NTDT) results in a complex variety of clinical phenotypes that are challenging to diagnose and manage. In this article, we use a clinical framework rooted in pathophysiology to present 4 common scenarios of patients with NTDT. Starting from practical considerations in the diagnosis of NTDT, we delineate our strategy for the longitudinal care of patients who exhibit different constellations of symptoms and complications. We highlight the use of transfusion therapy and novel agents, such as luspatercept, in the patient with anemia-related complications. We also describe our approach to chelation therapy in the patient with iron overload. Although tackling every specific complication of NTDT is beyond the scope of this article, we touch on the management of the various morbidities and multisystem manifestations of the disease.

Topics: Humans; beta-Thalassemia; Iron Chelating Agents; Thalassemia; Iron Overload; Chelation Therapy

PubMed: 37478396
DOI: 10.1182/blood.2023020683

Review

Authors: Ashraf T Soliman, Vincenzo De Sanctis, Mohamed Yassin...

Anaemia is a global public health problem affecting both developing and developed countries with major consequences for human health as well as social and economic development. It occurs at all stages of the life cycle, but is more prevalent in pregnant women and young children. Iron deficiency anaemia (IDA) impairs thyroid metabolism in animals and human and may negatively affect growth and develpment of children. On the other hand both overt and subclinical hypothyroidism are associated with anemia and adding iron to thyroxine therapy improves both conditions compared to thyroxine therapy alone. In addition patients with chronic hemolytic anemia requiring repeated blood transfusion have high prevalence of hypothalamic-pituitary thyroid axis. Both primary hypothyroidism and central hypothyroidism occur in these patients with increasing prevalence with age, severity of the anemia and higher ferritin concentration denoting poor chelation.  Proper blood transfusion and intensive chelation appears to prevent deterioration of thyroid function and in many cases can reverse thyroid pathology. Physicians treating these forms of anemia should be aware of thyroid disorders in these patients for early screening, prevention and proper management of any thyroid dysfunction.

Topics: Anemia, Iron-Deficiency; Anemia, Sickle Cell; Animals; Blood Transfusion; Chelation Therapy; Dietary Supplements; Humans; Hypothyroidism; Iron; beta-Thalassemia

PubMed: 28467346
DOI: 10.23750/abm.v88i1.6048

Review

Authors: Laura Mayans

Asymptomatic lead poisoning has become more common in children. Blood lead levels of less than 5 µg per dL are associated with impairments in neurocognitive and behavioral development that are irreversible. Risk factors for lead poisoning include age younger than five years, low socioeconomic status, living in housing built before 1978, and use of imported food, medicines, and pottery. The U.S. Preventive Services Task Force released a recommendation in 2019 citing insufficient evidence to assess the balance of benefits and harms of universal screening for elevated blood lead levels in asymptomatic children and pregnant women. Local risk factors can be substantial, and the Centers for Disease Control and Prevention (CDC) recommends that states and cities formulate their own targeted screening guidelines. In the absence of local guidance, the CDC recommends screening all Medicaid-eligible children at 12 months and again at 24 months, or at least once between 36 and 72 months if not previously screened. The CDC also recommends universal screening in areas where more than 27% of the housing was built before 1950, or where at least 12% of children 12 to 36 months of age have blood lead levels greater than 10 µg per dL. Life-threatening lead levels are treated with chelation therapy, and lower levels should prompt case management and environmental investigations to identify and remove the source of exposure. Primary prevention strategies are essential to eliminate the harmful effects of lead on child development.

Topics: Chelation Therapy; Child; Child, Preschool; Housing; Humans; Infant; Lead Poisoning; Mass Screening; Risk Factors; Socioeconomic Factors; United States

PubMed: 31259498
DOI: No ID Found

Review

Authors: L Bensefa-Colas, P Andujar, A Descatha...

Mercury is a widespread heavy metal with potential severe impacts on human health. Exposure conditions to mercury and profile of toxicity among humans depend on the chemical forms of the mercury: elemental or metallic mercury, inorganic or organic mercury compounds. This article aims to reviewing and synthesizing the main knowledge of the mercury toxicity and its organic compounds that clinicians should know. Acute inhalation of metallic or inorganic mercury vapours mainly induces pulmonary diseases, whereas chronic inhalation rather induces neurological or renal disorders (encephalopathy and interstitial or glomerular nephritis). Methylmercury poisonings from intoxicated food occurred among some populations resulting in neurological disorders and developmental troubles for children exposed in utero. Treatment using chelating agents is recommended in case of symptomatic acute mercury intoxication; sometimes it improves the clinical effects of chronic mercury poisoning. Although it is currently rare to encounter situations of severe intoxication, efforts remain necessary to decrease the mercury concentration in the environment and to reduce risk on human health due to low level exposure (dental amalgam, fish contamination by organic mercury compounds…). In case of occupational exposure to mercury and its compounds, some disorders could be compensated in France. Clinicians should work with toxicologists for the diagnosis and treatment of mercury intoxication.

Topics: Chelation Therapy; Environmental Exposure; Gastric Lavage; Humans; Mercury; Mercury Poisoning

PubMed: 20579784
DOI: 10.1016/j.revmed.2009.08.024

Review

Authors: Robin A Bernhoft

Mercury is a toxic heavy metal which is widely dispersed in nature. Most human exposure results from fish consumption or dental amalgam. Mercury occurs in several chemical forms, with complex pharmacokinetics. Mercury is capable of inducing a wide range of clinical presentations. Diagnosis of mercury toxicity can be challenging but can be obtained with reasonable reliability. Effective therapies for clinical toxicity have been described.

Topics: Chelating Agents; Chelation Therapy; Environmental Exposure; Humans; Mercury; Mercury Poisoning; Treatment Outcome; Unithiol

PubMed: 22235210
DOI: 10.1155/2012/460508

Review

Authors: Rachael F Grace, Wilma Barcellini

Pyruvate kinase deficiency (PKD) is an autosomal-recessive enzyme defect of the glycolytic pathway that causes congenital nonspherocytic hemolytic anemia. The diagnosis and management of patients with PKD can be challenging due to difficulties in the diagnostic evaluation and the heterogeneity of clinical manifestations, ranging from fetal hydrops and symptomatic anemia requiring lifelong transfusions to fully compensated hemolysis. Current treatment approaches are supportive and include transfusions, splenectomy, and chelation. Complications, including iron overload, bilirubin gallstones, extramedullary hematopoiesis, pulmonary hypertension, and thrombosis, are related to the chronic hemolytic anemia and its current management and can occur at any age. Disease-modifying therapies in clinical development may decrease symptoms and findings associated with chronic hemolysis and avoid the complications associated with current treatment approaches. As these disease-directed therapies are approved for clinical use, clinicians will need to define the types of symptoms and findings that determine the optimal patients and timing for initiating these therapies. In this article, we highlight disease manifestations, monitoring approaches, strategies for managing complications, and novel therapies in development.

Topics: Adolescent; Adult; Anemia, Hemolytic, Congenital Nonspherocytic; Blood Transfusion; Chelation Therapy; Child; Child, Preschool; Cholelithiasis; Clinical Trials as Topic; Disease Management; Female; Fetal Diseases; Genetic Therapy; Genotype; Hematopoietic Stem Cell Transplantation; Humans; Infant; Infant, Newborn; Iron Chelating Agents; Iron Overload; Jaundice, Neonatal; Male; Mutation; Pregnancy; Prevalence; Pyruvate Kinase; Pyruvate Metabolism, Inborn Errors; Splenectomy; Splenomegaly

PubMed: 32702739
DOI: 10.1182/blood.2019000945

Authors: Charles A McKay

Topics: Biomarkers; Chelating Agents; Chelation Therapy; Environmental Exposure; Heavy Metal Poisoning; Heavy Metal Poisoning, Nervous System; Humans; Inappropriate Prescribing; Metals, Heavy; Poisoning; Practice Patterns, Physicians'; Predictive Value of Tests; Treatment Outcome

PubMed: 24248425
DOI: 10.1007/s13181-013-0346-3

Authors: Paavani S Reddy, Margaret Locke, Sherif M Badawy...

INTRODUCTION

Iron chelation therapy (ICT) is essential to prevent complications of iron overload in patients with transfusion-dependent thalassaemia. However, there is currently no standard for how to best measure adherence to ICT, nor what level of adherence necessitates concern for poor outcomes, especially in paediatric patients. The objectives of this review are to identify rates of adherence to ICT, predictors of adherence, methods of measurement, and adherence-related health outcomes in children and adolescents.

METHODS

This review covers the literature published between 1980 and 2020 on ICT in thalassaemia that assessed adherence or compliance. Included studies reflect original research. The preferred reporting items of systematic reviews and meta-analyses (PRISMA) guidelines were followed for reporting results, and the findings were critically appraised with the Oxford Centre for Evidence-based Medicine criteria.

RESULTS

Of the 543 articles, 37 met the inclusion criteria. The most common methods of assessing adherence included patient self-report ( = 15/36, 41.7%), and pill count ( = 15/36, 41.7%), followed by subcutaneous medication monitoring (5/36, 13.8%) and prescription refills ( = 4/36, 11.1%). Study sizes ranged from 7 to 1115 participants. Studies reported adherence either in "categories" with different levels of adherence ( = 29) or "quantitatively" as a percentage of medication taken out of those prescribed ( = 7). Quantitatively, the percentage of adherence varied from 57% to 98.4% with a median of 89.5%. Five studies focussed on interventions, four of which were designed to improve adherence. Studies varied in sample size and methods of assessment, which prohibited performing a meta-analysis.

CONCLUSIONS

Due to a lack of clinical consensus on how adherence is defined, it is difficult to compare adherence to ICT in different studies. Future studies should be aimed at creating guidelines for assessing adherence and identifying suboptimal adherence. These future efforts will be crucial in informing evidence-based interventions to improve adherence and health outcomes in thalassaemia patients.Key messagesPredictive factors associated with ICT adherence in the paediatric population include age, social perception of ICT, social support, and side effects/discomfort.Increased adherence in the paediatric population is associated with decreased serum ferritin and improved cardiac, hepatic, and endocrine outcomes.Inadequate adherence to ICT is associated with increased lifetime health costs.There are few studies that focussed on interventions to increase adherence in the paediatric population, and the studies that do exist all focussed on different types of interventions; successful interventions focussed on consistent, long-term engagement with patients.

Topics: Adolescent; Chelation Therapy; Child; Humans; Iron; Iron Overload; Patient Compliance; Thalassemia

PubMed: 35103514
DOI: 10.1080/07853890.2022.2028894