Secondary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory condition caused by the hyperactivation of macrophages and T-cells, triggered by infection, malignancy, or underlying rheumatological conditions. It rarely presents as a first manifestation of a rheumatological condition. Macrophage activation syndrome (MAS) is secondary HLH associated with underlying hematological conditions. Here, we present a case of a previously healthy 29-year-old female who was admitted with fever, rash, and pancytopenia, found to have HLH, and a workup revealed underlying systemic lupus erythematosus (SLE). She was successfully treated with dexamethasone, etoposide, and belimumab, with complete recovery of her symptoms. This case highlights the importance of a thorough evaluation of rheumatological conditions in all patients with HLH despite their previous medical history and the use of belimumab for SLE.

Cytokine storm syndrome (CSS) is a severe life-threatening condition characterized by a clinical phenotype of overwhelming systemic inflammation, hyperferritinemia, hemodynamic instability, and multiple organ failure (MOF), and, if untreated, it can potentially lead to death. The hallmark of CSS is an uncontrolled and dysfunctional immune response involving the continual activation and expansion of lymphocytes and macrophages, which secrete large amounts of cytokines, causing a cytokine storm. Many clinical features of CSS can be explained by the effects of pro-inflammatory cytokines, such as interferon (IFN)-γ, tumor necrosis factor (TNF), interleukin (IL)-1, IL-6, and IL-18 [1-7]. These cytokines are elevated in most patients with CSS as well as in animal models of CSS [8, 9]. A constellation of symptoms, signs, and laboratory abnormalities occurs that depends on the severity of the syndrome, the underlying predisposing conditions, and the triggering agent.

In 1979, it became recognized in the literature that what we call hemophagocytic lymphohistiocytosis (HLH) was a nonmalignant disease of histiocytes. Subsequently a familial form and a secondary form of HLH were differentiated. When HLH is secondary to an autoimmune disease, rheumatologists refer to this entity as macrophage activation syndrome (MAS) to differentiate it from HLH itself. Although the first cases of MAS likely appeared in the literature in the 1970s, it was not until 1985 that the term activated macrophages was used to describe patients with systemic juvenile idiopathic arthritis (sJIA) complicated by MAS and the term macrophage activation syndrome first appeared in the title of a paper in 1993.MAS is one of the many types of secondary HLH and should not be confused with primary HLH. Experience has taught that MAS secondary to different autoimmune diseases is not equal. In the 30 years since initial description in patients with sJIA, the clinical spectrum, diseases associated with MAS, therapy, and understanding the pathogenesis have all made significant gains. The diagnostic/classification criteria for MAS secondary to sJIA, SLE, RA, and KD differ based on the different laboratory abnormalities associated with each (Ahn et al., J Rheumatol 44:996-1003, 2017; Han et al., Ann Rheum Dis 75:e44, 2016; Ravelli et al., Ann Rheum Dis 75:481-489, 2016; Borgia et al., Arthritis Rheumatol 70:616-624, 2018). These examples include the thrombocytosis associated with sJIA, a chronic generalized activation of the immune system, leading to elevations of fibrinogen and sIL-2R, low platelet count associated with SLE, and more acute inflammation associated with KD. Therefore, individual diagnostic criteria are required, and they all differ from the diagnostic criteria for HLH, which are based on a previously non-activated immune system (Ahn et al., J Rheumatol 44:996-1003, 2017; Han et al., Ann Rheum Dis 75:e44, 2016; Ravelli et al., Ann Rheum Dis 75:481-489, 2016; Borgia et al., Arthritis Rheumatol 70:616-624, 2018; Henter et al., Pediatr Blood Cancer 48:124-131, 2007). This helps to explain why the HLH diagnostic criteria do not perform well in MAS.The initial treatment remains high-dose steroids and IVIG followed by the use of a calcineurin inhibitor for resistant cases. IVIG can be used if there is a concern about malignancy to wait for appropriate investigations or with steroids. Interluekin-1 inhibition is now the next therapy if there is a failure to respond to steroids and calcineurin inhibitors. Advances in understanding the mechanisms leading to MAS, which has been greatly aided by the use of mouse models of MAS and advances in genome sequencing, offer a bright future for more specific therapies. More recent therapies are directed to specific cytokines involved in the pathogenesis of MAS and can lead to decreases in the morbidity and mortality associated with MAS. These include therapies directed to inhibiting the JAK/STAT pathway and/or specific cytokines, interleukin-18 and gamma interferon, which are currently being studied in MAS. These more specific therapies may obviate the need for nonspecific immunosuppressive therapies including high-dose prolonged steroids, calcineurin inhibitors, and etoposide.

UNASSIGNED: Hemophagocytic syndrome or hemophagocytic lymphohistiocytosis (HL) is an immune hyperactivation of multifactorial etiology, characterized by excessive activation of lymphocytes and macrophages, as well as numerous pro-inflammatory cytokines. It has a non-specific and highly variable clinical presentation, with splenomegaly being one of the clinical manifestations. Due to its nature, it can manifest during childhood or adult life, which is why it is a disease of diagnostic and therapeutic complexity.
UNASSIGNED: 38-year-old male patient without comorbidities, who presented with abdominal pain, choluria, fever > 38 °C and diaphoresis of more than 10 days of evolution. A bone marrow aspirate was performed as part of the diagnostic approach with data compatible with hemophagocytosis and cytopenias. The immunosuppressive management did not show the expected response, which is why an open splenectomy was performed as the last therapeutic option with adequate hematological control. A documentary review of the disease was carried out, and of the therapeutic options, emphasizing surgical management in case of refractoriness to medical treatment.
UNASSIGNED: Splenectomy increases the overall survival rate and the time free of HL progression, even though there are still no studies to determine with certainty the ideal time to perform a splenectomy in patients with pancytopenia without splenomegaly who suffer from hemophagocytic syndrome.
UNASSIGNED: el síndrome hemofagocítico o linfohistiocitosis hemofagocítica (LH) es una hiperactivación inmune de etiología multifactorial, caracterizada por activación excesiva de linfocitos y macrófagos, así como por numerosas citocinas proinflamatorias. Tiene una presentación clínica poco específica y muy variable, y la esplenomegalia es una de las manifestaciones clínicas. Debido a su naturaleza puede manifestarse durante la infancia o la vida adulta, por lo que es una enfermedad de complejidad diagnóstica y terapéutica.
UNASSIGNED: paciente del sexo masculino de 38 años sin comorbilidades, quien presentó dolor abdominal, coluria, fiebre > 38 °C y diaforesis de más de 10 días de evolución. Se le hizo aspirado de médula ósea como parte del abordaje diagnóstico con datos compatibles con hemofagocitosis y citopenias. El manejo inmunosupresor no mostró la respuesta esperada, por lo que se hizo esplenectomía abierta como última opción terapéutica con adecuado control hematológico. Se hizo una revisión documental de la enfermedad y de las opciones terapéuticas con énfasis en el manejo quirúrgico en caso de refractariedad al tratamiento médico.
UNASSIGNED: la esplenectomía aumenta la tasa de supervivencia general y el tiempo libre de progresión de la LH, aunque no hay todavía estudios para determinar con certeza el tiempo ideal para hacer una esplenectomía en pacientes con pancitopenia sin esplenomegalia que padezcan síndrome hemofagocítico.

OBJECTIVE: The aim of this study was to assess the role of elevated serum ferritin levels in the onset, pathological progression and prognosis of nonalcoholic fatty liver disease. Nonalcoholic fatty liver disease has been rapidly increasing worldwide. Despite extensive research on the pathogenesis of nonalcoholic fatty liver disease, a lack of sufficient clinical research on the relationship between nonalcoholic fatty liver disease and serum ferritin levels remains.
METHODS: We analysed 968 patients with type 2 diabetes mellitus who underwent liver ultrasound examination and had their serum ferritin levels measured. The presence of nonalcoholic fatty liver disease and advanced liver fibrosis was determined through abdominal ultrasound examination and the nonalcoholic fatty liver disease fibrosis score.
RESULTS: Compared to that in the non-nonalcoholic fatty liver disease group, the presence of hyperferritinemia was significantly more common in the nonalcoholic fatty liver disease group (83.3 vs. 56.3%, p=0.005). When patients with nonalcoholic fatty liver disease were stratified by the nonalcoholic fatty liver disease fibrosis score, those with advanced liver fibrosis exhibited a higher prevalence of hyperferritinemia (56.3, 78.9, and 88.9% for none, simple steatosis, and advanced fibrosis, respectively; p for trend=0.002). In multivariate logistic regression, liver fibrosis was independently associated with hyperferritinemia (odds ratio [OR] 1.45; 95% confidence interval [CI] 1.18-2.02; p=0.014), and this association remained significant in male patients after adjusting for other risk factors (OR 2.66; 95% CI 1.43-5.48; p=0.026).
CONCLUSIONS: Identifying nonalcoholic fatty liver disease patients at a risk of developing nonalcoholic steatohepatitis and advanced fibrosis is crucial for implementing timely interventions and improving patient outcomes. This study highlights the potential utility of serum ferritin levels as a serum biomarker for identifying nonalcoholic steatohepatitis patients and those at a risk of late-stage fibrosis, particularly in male patients with nonalcoholic fatty liver disease.

BACKGROUND: The main genetic cause of iron overload is haemochromatosis (HC). In recent years, the study of non-HFE genes (HFE2, HJV, HAMP, TRF2, SLC40A1, and BMP6) has become relevant thanks to next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) techniques. Our objectives were to estimate the prevalence of both HFE (C282Y/HY63D variants) and non-HFE variants attending a tertiary hospital in Aragón, to predict the effect of the variants on the protein, and to establish a genotype-phenotype correlation evaluating with the clinical context.
METHODS: Retrospective descriptive study from 2006 to 2020 of patients attended at genetic consultation in a reference hospital for HC in Aragon. We calculated prevalence of HFE and non-HFE variants. We analysed non-HFE genes (HFE2, HJV, HAMP, TRF2, SLC40A1, and BMP6), used bioinformatics tools, consulted different databases and measured clinical parameters (laboratory and imaging).
RESULTS: The prevalence of C282Y homozygous was 5.95% respect the total of cases and 0.025% respect our population. The prevalence of non-HFE HC variants was 1.94% respect the total of cases and 0.008% respect our population. We found 27 variants in non-HFE genes and 4 in HFE gene, of which 6 were classified as variant of uncertain clinical significance (VUS), or likely pathogenic or pathogenic according to the ACMG classification criteria.
CONCLUSIONS: Our prevalence results are as expected, and similar to those obtained by other studies. Although some of the genetic findings explain the clinical symptoms of some of our patients, we remain have a high number of patients without a clear molecular diagnosis.

Ferritin (Ftn), a globular protein, sequesters 4500 atoms of iron per molecule. Elevated serum Ftn levels (hyperferritinemia) is an indicator of iron homeostasis disorders. We present the results of an observational study involving 17 patients with hyperferritinemia unrelated to hereditary hemochromatosis (HH). All participants received treatment with 200 mg of bovine lactoferrin (bLf) once (n = 14) or twice (n = 3) a day before meals. The patients, treated with 200 mg/day of bLf, exhibited a significant increase in red blood cells (+10%, p < 0.001), hemoglobin (+4%, p < 0.001), and hematocrit (+15%, p = 0.004), accompanied by a significant reduction in serum Ftn levels (-52%, p < 0.001), C-reactive protein (CRP) (-85.0%, p < 0.001), and D-dimers (-19%, p < 0.001). Among the three patients treated with 400 mg/day of bLf, two had effects similar to those of patients bLf-treated with 200 mg/day and one experienced a strong reduction of Ftn, CRP, and erythrocyte sedimentation rate (from -97% to -75%). The decrease in serum Ftn levels due to bLf treatment was largely independent of gender (p = 0.78), age (p = 0.66), baseline symptoms (p = 0.20), and concomitant acute (p = 0.34) and chronic (p = 0.53) infections. Although this observational pilot study yields positive effects in patients with hyperferritinemia unrelated to HH treated with bLf, a larger sample size is needed for conclusive results.

High ferritin is an important and sensitive biomarker for hemophagocytic lymphohistiocytosis (HLH), a diverse and deadly group of cytokine storm syndromes. Early action to prevent immunopathology in HLH often includes empiric immunomodulation, which can complicate etiologic work-up and prevent collection of early/pre-treatment research samples. To address this, we instituted an alert system where serum ferritin > 1000ng/mL triggered real-time chart review, assessment of whether the value reflected \"inflammatory hyperferritnemia (IHF)\", and biobanking of remnant samples from consenting IHF patients. We extracted relevant clinical data; periodically measured serum total IL-18, IL-18 binding protein (IL-18BP), and CXCL9; retrospectively classified patients by etiology into infectious, rheumatic, or immune dysregulation; and subjected a subgroup of samples to a 96-analyte biomarker screen. 180 patients were identified, 30.5% of which had IHF. Maximum ferritin levels were significantly higher in patients with IHF than with either hemoglobinopathy or transplant, and highly elevated total IL-18 levels were distinctive to patients with Stills Disease and/or Macrophage Activation Syndrome (MAS). Multi-analyte analysis showed elevation in proteins associated with cytotoxic lymphocytes in all IHF samples when compared to healthy controls and depression of proteins such as ANGPT1 and VEGFR2 in samples from hyperferritinemic sepsis patients relative to non-sepsis controls. This single-center, real-time IFH screen proved feasible and efficient, validated prior observations about the specificity of IL-18, enabled early sample collection from a complex population, suggested a unique vascular biomarker signature in hyperferritinemic sepsis, and expanded our understanding of IHF heterogeneity.

暂无摘要。

UNASSIGNED: Serum ferritin (SF) is clinically found to be elevated in many disease conditions, and our research examines serum ferritin in patients with acute kidney injury (AKI) and its implication on the risk of short-term mortality in AKI.
UNASSIGNED: Data were extracted from the Medical Information Mart for Intensive Care IV 2.2 (MIMIC-IV 2.2) database. Adult patients with AKI who had serum ferritin tested on the first day of ICU admission were included. The primary outcome was 28-day mortality. Kaplan-Meier survival curves and Cox proportional hazards models were used to test the relationship between SF and clinical outcomes. Subgroup analyses based on the Cox model were further conducted.
UNASSIGNED: Kaplan-Meier survival curves showed that a higher SF value was significantly associated with an enhanced risk of 28-day mortality, 90-day mortality, ICU mortality and hospital mortality (log-rank test: p < 0.001 for all clinical outcomes). In multivariate Cox regression analysis, high level of SF with mortality was significantly positive in all four outcome events (all p < 0.001). This result remains robust after adjusting for all variables. Subgroup analysis of SF with 28-day mortality based on Cox model-4 showed that high level of SF was associated with high risk of 28-day mortality in patients regardless of the presence or absence of sepsis (p for interaction = 0.730). Positive correlations of SF and 28-day mortality were confirmed in all other subgroups (p for interaction>0.05).
UNASSIGNED: High level of SF is an independent prognostic predictor of 28-day mortality in patients with AKI.