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Etiological investigation of hyperferritinemia includes a full clinical examination, with the measurement of waist circumference, and simple biological tests including transferrin saturation. The classification between hyperferritinemia without iron overload (inflammation, excessive alcohol intake, cytolysis, L-ferritin mutation) or with iron overload is then relatively easy. Dysmetabolic iron overload syndrome is the most common iron overload disease and is defined by an unexplained serum ferritin level elevation associated with various metabolic syndrome criteria and mild hepatic iron content increase assessed by magnetic resonance imaging. Bloodlettings are often poorly tolerated without clear benefit. Type 1 genetic hemochromatosis (homozygous C282Y mutation on the HFE gene) leads to iron accumulation through an increase of dietary iron absorption due to hypohepcidinemia. More than 95% of hemochromatosis are type 1 hemochromatosis but the phenotypic expression is highly variable. Elastography is recommended to identify advanced hepatic fibrosis when serum ferritin exceeds 1000μg/L. Life expectancy is normal when bloodlettings are started early. Ferroportin gene mutation is an autosomal dominant disease with generally moderate iron overload. Chelators are used in iron overload associated with anaemia (myelodysplastic syndromes or transfusion-dependent thalassemia). Chelation is initiated when hepatic iron content exceeds 120μmol/g. Deferasirox is often used as first-line therapy, but deferiprone may be of interest despite haematological toxicity (neutropenia). Deferoxamine (parenteral route) is the treatment of choice for severe iron overload or emergency conditions., (Copyright © 2023 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Pure red cell aplasia (PRCA) is a rare anemia characterised by profound reticulocytopenia caused by a marked reduction in bone marrow erythroblasts, without abnormalities in other blood lineages. Blackfan-Diamond anemia is an inherited ribosomopathy responsible for a hereditary form of PRCA. Acquired PRCA are separated in primary and secondary forms, including Parvovirus B19 infection, thymoma, lymphoproliferative disorders, autoimmune diseases (lupus) and drug-induced PRCA. The pathophysiology of PRCA is not fully understood and involves both humoral and T lymphocyte autoreactive cells. In Parvovirus B19-related PRCA, treatment is based on polyvalent immunoglobulins. Thymectomy for thymoma is mandatory but results in prolonged remission in a limited number of cases. The therapeutic strategy is based on expert opinion: corticosteroids in monotherapy provide few sustained responses. The choice of an additional immunosuppressant drug is guided by the presence of an underlying disease. In most cases, cyclosporine A is the first choice providing the best response rate but requires a concentration monitoring (150 to 250 ng/mL). The second choice is cyclophosphamide in large granular lymphocyte leukaemia. Sirolimus (mTOR inhibitor) seems to be a promising option especially in refractory cases. Transfusion independence is the main objective. If the patient receives numerous red blood cell transfusions (> 20 packs), iron overload assessment is crucial to initiate an iron chelation. A retrospective and prospective national cohort (EPIC-F) has been set up and is now available to include each case of PRCA to improve the knowledge of this disease and to optimize the therapeutic strategy., (Copyright © 2022 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Tryptase is the most abundant endopeptidase released by mast cells degranulation, involved in many pro and anti-inflammatory processes. Normal serum tryptase range is 0-11.4 μg/L. Tryptase is a useful diagnostic tool for anaphylaxis, systemic mastocytosis (SM) and mast cell activation syndrome (MCAS), where specific threshold values must be used. SM diagnosis criteria include evidence of dense mast cell infiltrate either in the bone marrow or the affected organ (such as skin), presence of KIT D816V mutation and elevated serum tryptase level (>20 μg/L). In SM, tryptase level is correlated with the burden of mast cells in bone marrow. MCAS should be considered in case of severe and recurrent typical clinical signs of systemic mast cell activation involving at least two organs, associated with an increase in serum tryptase level of 20% + 2 μg/L from the individual's baseline. Anaphylaxis is the most severe among hypersensitivity reactions. A clonal mast cell disorder is a central question in anaphylaxis and appropriate explorations should be conducted in these patients. Triggers for anaphylactic reactions vary significantly in the general population and in patients with MS or MCAS. Finally, physicians must be aware of the many pathological and physiological situations that affect tryptase levels., (Copyright © 2020. Published by Elsevier Masson SAS.)

Aceruloplasminemia is a rare iron-overload disease that should be better known by physicians. It is an autosomal recessive disorder due to mutations in ceruloplasmin gene causing systemic iron overload, including cerebral and liver parenchyma. The impairment of ferroxidase ceruloplasmin activity leads to intracellular iron retention leading aceruloplasminemia symptoms. Neurologic manifestations include cognitive impairment, ataxia, extrapyramidal syndrome, abnormal movements, and psychiatric-like syndromes. Physicians should search for aceruloplasminemia in several situations with high ferritin levels: microcytic anaemia, diabetes mellitus, neurological and psychiatric disorders. Diagnosis approach is based on the study of transferrin saturation and hepatic iron content evaluated by magnetic resonance imaging of the liver. Ceruloplasmin dosage is required in case of low transferrin saturation and high hepatic iron content and genetic testing is mandatory in case of serum ceruloplasmin defect. Neurological manifestations occur in the sixties decade and leads to disability. Iron chelators are widely used. Despite their efficacy on systemic and cerebral iron overload, iron chelators tolerance is poor. Early initiation of iron chelation therapy might prevent or slowdown neurodegeneration, highlighting the need for an early diagnosis but their clinical efficacy remains uncertain., (Copyright © 2020. Published by Elsevier Masson SAS.)