A 64-year-old African American male with a history of hypertension and type II diabetes mellitus presented with unexplained upper lip lacerations after several frequent episodes of hemoptysis. Following the upper lip lacerations were several weeks of intermittent unknown episodic fevers. The patient, challenged by impaired mobility, exhibited an array of symptoms, including severe upper lip pain with lacerations and white patches on the tongue. Laboratory findings indicated thrombocytopenia and anemia, with positive tests for both influenza A and B. Despite completing Tamiflu, the patient experienced recurrent fevers. Imaging revealed gastrointestinal abnormalities, leading to the initiation of nystatin and a multi-antibiotic regimen without significant fever resolution. A subsequent tongue biopsy revealed verruca lesions, and acyclovir was initiated. Despite this, the patient developed lip and facial blisters. Negative results from cytomegalovirus (CMV) deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) prompted a shift in focus to managing persistent fevers, ultimately controlled with naproxen but without discoverable cause. This case underscores the diagnostic challenge posed by unexplained fevers in an elderly patient with oral manifestations. The protracted course and evolving symptoms emphasize the intricacies of managing such cases, highlighting the need for continued investigation and collaboration across medical disciplines in navigating complex clinical scenarios.

The use of erythropoiesis-stimulating agents (ESAs) reduces the need for recurrent blood transfusions in patients with advanced kidney disease. Rarely, allergic reactions to recombinant human erythropoietin can develop, complicating anemia management due to cross-reactivity between these agents. We report the use of an outpatient desensitization protocol, which was successfully completed in an adult patient who developed a maculopapular rash as a form of delayed-type hypersensitivity reaction (DTH) to epoetin-alfa (EPO) use, followed by successful re-introduction of EPO and continued tolerance.

Anemia of chronic diseases is a condition, that accompanies several chronic conditions, that have inflammation as an underlying cause. The article covers current concepts of pathogenesis, evaluation and treatment of this type of anemia. The new perspectives in the development of investigational methods and treatment are discussed. The new methods of iron deficiency assessment in patients with systemic inflammation are discussed separately.
Анемия хронических заболеваний – это состояние, которое сопровождает ряд заболеваний, в патогенезе которых важную роль играет системное воспаление. В статье представлены последние сведения о патогенезе, принципах диагностики и перспективах лечения этого вида анемий. Отдельно обсуждаются методы выявления дефицита железа на фоне системного воспаления.

Tuberculosis (TB) is an airborne illness that induces systemic inflammation. It often affects the lungs causing cough, fever, and chest pain. A commonly associated comorbid condition in TB is anemia. This review article has summarized various studies with an aim to gain a better understanding of pathogenesis and the role of cytokines that contribute to the development of anemia in TB. The study has gathered risk factors that enhance the likelihood of TB patients acquiring anemia. It has reviewed therapeutic modalities such as antitubercular therapy and iron therapy in an attempt to find which of them are effective in reducing the severity of anemia. This review article has also emphasized the importance of measuring hepcidin and ferritin and has touched upon the investigations that can be easily implemented.

Multicentric Castleman\'s disease (MCD) is a rare lymphoproliferative disorder with aggressive systemic presentation and poor prognosis. Here, we present a case of MCD in a 37-year-old Asian American woman with a past medical history of the polycystic ovarian syndrome (PCOS), human papilloma virus (HPV), herpes simplex virus-1 (HSV-1), iron deficiency, and vitamin B12 deficiency-related anemia. The patient underwent surgical resection with good recovery. Hemoglobin and erythrocyte sedimentation rate (ESR) normalized after surgical resection. Although the influence of risk factors such as human immunodeficiency virus (HIV) or human herpesvirus-8 (HHV-8) infections on MCD relapse are not well understood, patient education on MCD risk factors is important, as they may place the patient at greater risk for recurrence. MCD should be considered in patients with chronic inflammation and a mass on imaging.

Hematological status may predict HIV disease progression and mortality among adults initiating highly active antiretroviral therapy (HAART).
We aimed to examine the relation of anemia and iron status at HAART initiation with survival and morbidity outcomes.
We conducted a case-cohort study of 570 HIV-infected adults initiating HAART who were enrolled in a trial of multivitamins in Tanzania. Hemoglobin, serum ferritin, and hepcidin concentrations were assessed at HAART initiation and participants were followed up monthly. We adjusted serum ferritin for inflammation using a regression correction method to characterize hematological status. Cox proportional hazards models were used to estimate HRs for mortality and incident clinical outcomes.
We found an 83% prevalence of anemia, 15% prevalence of iron deficiency anemia, and 66% prevalence of anemia of chronic diseases (ACD). The prevalence of elevated iron was 33% and 19% had iron deficiency (ID). After multivariate adjustment, severe anemia (HR: 2.57; 95% CI: 1.49, 4.45) and ACD (HR: 4.71; 95% CI: 2.91, 7.62) were associated with increased risk of mortality as compared with nonanemic participants. In addition, both ID (HR: 2.65; 95% CI: 1.08, 7.78) and elevated iron (HR: 2.83; 95% CI: 2.10, 3.82) were associated with increased risk of mortality as compared with normal iron concentrations. Severe anemia and elevated iron concentrations were associated with incident wasting and >10% weight loss (P values <0.05).
Anemia and both ID and elevated iron were associated with increased mortality among HIV-infected adults initiating HAART. Safety and efficacy studies including anemia etiology, timing of HAART initiation, and dose of iron supplementation among HIV patients appear warranted.This trial was registered at clinicaltrials.gov as NCT00383669.

In case of erythropoiesis, body iron needs to increase to enable the production of new red blood cells. In the 1950s, the observation of an increased digestive iron absorption in the case of phlebotomies had led to propose the existence of an \"erythroid factor\", which regulate the availability of iron for erythropoiesis in this situation. The factor regulating iron stores has been identified in 2000 to be hepcidin. Recently, in 2014, a new factor was discovered, which regulates iron metabolism, independently of iron stores and responds to the increased requirements for iron after stimulation of erythropoiesis by erythropoietin. This factor has been referred to as erythroferrone. Thus, the regulation of iron stores depends on hepcidin, while the adaptation mechanisms of iron availability in case of anemia, are mediated by an erythroid factor that could be erythroferrone. This review summarizes the current knowledge on the role of erythroferrone in iron metabolism, starting from experimental results, obtained mainly on mouse models, and related to iron overload in β-thalassemia, iron disturbances during anemia of chronic diseases and chronic renal failure. These results will have to be compared with those obtained in humans, as soon as a reliable assay for human erythroferrone is available. From a clinical point of view, erythroferrone could become a useful biological marker of iron metabolism and a therapeutic target.

Heparins are efficient inhibitors of hepcidin expression even in vivo, where they induce an increase of systemic iron availability. Heparins seem to act by interfering with BMP6 signaling pathways that control the expression of liver hepcidin, causing the suppression of SMAD1/5/8 phosphorylation. The anti-hepcidin activity persists also when the heparin anticoagulant property is abolished or reduced by chemical reactions of oxidation/reduction (glycol-split, Gs-Heparins) or by high sulfation (SS-Heparins), but the structural characteristics needed to optimize this inhibitory activity have not been studied in detail. To this aim we analyzed three different heparins (Mucosal Heparin, the Glycol split RO-82, the partially desulfated glycol-split RO-68 and the oversulfated SSLMWH) and separated them in fractions of molecular weight in the range 4-16 kD. Since the distribution of the negative charges in heparins contributes to the activity, we produced 2-O- and 6-O-desulfated heparins. These derivatives were analyzed for the capacity to inhibit hepcidin expression in hepatic HepG2 cells and in mice. The two approaches produced consistent results and showed that the anti-hepcidin activity strongly decreases with molecular weight below 7 kD, with high N-acetylation and after 2-O and 6-O desulfation. The high sulfation and high molecular weight properties for efficient anti-hepcidin activity suggest that heparin is involved in multiple binding sites.

Hepcidin is a peptide hormone that controls systemic iron availability and is upregulated by iron and inflammation. Heparins have been shown to be efficient hepcidin inhibitors both in vitro and in vivo, even when their anticoagulant activity has been abolished by chemical reactions of oxidation/reduction (glycol-split). We analyzed a modified heparin type, characterized by a high, almost saturated, sulfation degree and low molecular weight. It inhibited hepcidin expression in hepatic HepG2 cells, and when used in mice, it readily suppressed liver hepcidin mRNA and serum hepcidin, with a significant decrease of spleen iron. This occurred also in inflammation-model, LPS-treated animals, and after heparin chronic 10-day treatments. The heparin had low/absent anticoagulant activity, as tested for factor-Xa and -IIA, APTT and anti Xa. It reduced triglyceride levels in the mice. This heparin acts faster and is more potent than the glycol split-heparins, probably because of its smaller molecular weight and higher sulfation degree. This modified heparin has potential applications for the treatment of diseases with high hepcidin levels.

The discovery of hepcidin clarified the basic mechanism of the control of systemic iron homeostasis. Hepcidin is mainly produced by the liver as a propeptide and processed by furin into the mature active peptide. Hepcidin binds ferroportin, the only cellular iron exporter, causing the internalization and degradation of both. Thus hepcidin blocks iron export from the key cells for dietary iron absorption (enterocytes), recycling of hemoglobin iron (the macrophages) and the release of storage iron from hepatocytes, resulting in the reduction of systemic iron availability. The BMP/HJV/SMAD pathway is the major regulator of hepcidin expression that responds to iron status. Also inflammation stimulates hepcidin via the IL6/STAT3 pathway with a support of an active BMP/HJV/SMAD pathway. In some pathological conditions hepcidin level is inadequately elevated and reduces iron availability in the body, resulting in anemia. These conditions occur in the genetic iron refractory iron deficiency anemia and the common anemia of chronic disease (ACD) or anemia of inflammation. Currently, there is no definite treatment for ACD. Erythropoiesis-stimulating agents and intravenous iron have been proposed in some cases but they are scarcely effective and may have adverse effects. Alternative approaches aimed to a pharmacological control of hepcidin expression have been attempted, targeting different regulatory steps. They include hepcidin sequestering agents (antibodies, anticalins, and aptamers), inhibitors of BMP/SMAD or of IL6/STAT3 pathway or of hepcidin transduction (siRNA/shRNA) or ferroportin stabilizers. In this review we summarized the biochemical interactions of the proteins involved in the BMP/HJV/SMAD pathway and its natural inhibitors, the murine and rat models with high hepcidin levels currently available and finally the progresses in the development of hepcidin antagonists, with particular attention to the role of heparins and heparin sulfate proteoglycans in hepcidin expression and modulation of the BMP6/SMAD pathway.