Non-invasive methods for iron overload evaluation in dysmetabolic patients

IntroductionAlthough hyperferritinemia may reflect the inflammatory status of patients with non-alcoholic fatty liver disease (NAFLD), approximately 33% of hyperferritinemia cases reflect real hepatic iron overload.AimTo evaluate a non-invasive method for assessing mild iron overload in patients with NAFLD using 3T magnetic resonance imaging (MRI) relaxometry, serum hepcidin, and the expression of ferritin subunits.MethodsThis cross-sectional study assessed patients with biopsy-proven NAFLD. MRI relaxometry was performed using a 3T scanner in all patients, and the results were compared with iron content determined by liver biopsy. Ferritin, hepcidin, and ferritin subunits were assessed and classified according to ferritin levels and to siderosis identified by liver biopsy.ResultsA total of 67 patients with NAFLD were included in the study. MRI revealed mild iron overload in all patients (sensitivity, 73.5%; specificity, 70%). For mild (grade 1) siderosis, the transverse relaxation rate (R₂*) threshold was 58.9 s^?1 and the mean value was 72.5 s^?1 (SD, 33.9), while for grades 2/3 it was 88.2 s^?1 (SD, 31.9) (p < 0.001). The hepcidin threshold for siderosis was > 30.2 ng/mL (sensitivity, 87%; specificity, 82%). Ferritin H and ferritin L subunits were expressed similarly in patients with NAFLD, regardless of siderosis. There were no significant differences in laboratory test results between the groups, including glucose parameters and liver function tests.ConclusionsMRI relaxometry and serum hepcidin accurately assessed mild iron overload in patients with dysmetabolic iron overload syndrome.     

Relation between iron content of serum ferritin and clinical status factors extracted by factor analysis in patients with hyperferritinemia

OBJECTIVES: The aims of this study were to develop a new technique for determination of iron content of serum ferritin (ICF, micromol Fe/mg protein) and to investigate relations between ICF and clinical status in patients with hyperferritinemia. METHODS: ICF values were determined by a combination of immunoprecipitation of ferritin and direct colorimetric iron assay. One hundred fifty patients with hyperferritinemia were screened. Factor analysis of the results of 11 laboratory tests was applied to extract factors representing the clinical status of patients. Relations between the extracted factors and the ICF values or serum ferritin concentrations were assessed. RESULTS: Within-run coefficients of variation (CVs) of the ICF assay were <==5.7%. The mean ICF value of 150 patients was 0.423 micromol/mg (SD, 0.211 micromol/mg). Three factors representing clinical status were identified: inflammation, tissue cell damage, and body iron status. Serum ferritin level correlated with all three factors. In contrast, ICF correlated significantly only with the factor representing tissue cell damage (r = 0.293, p = 0.001), and this correlation was independent of inflammation and iron status (p = 0.008). CONCLUSIONS: ICF changes in response to tissue cell damage independent of inflammatory and body iron statuses, whereas serum ferritin changes in response to all three pathologic statuses.     

显著高铁蛋白血症与噬血细胞性淋巴组织细胞增多症的相互关系

目的: 探讨显著高铁蛋白血症(marked hyperferritinemia,MHF)与噬血细胞性淋巴组织细胞增多症(hemophagocytic lymphohistiocytosis,HLH)患者的临床特征以及相关性。方法: 回顾性收集北京大学人民医院2017年1月至2018年9月急诊及住院的MHF患者的临床资料,包括患者一般资料,症状体征,血常规、生化、出凝血检测、血清铁蛋白检查,以及自然杀伤(natural killer, NK)细胞活性、可溶性白介素(interleukin, IL)-2受体、骨髓检查等。按是否诊断为HLH分为HLH组和非HLH组,按随访3个月结局分为死亡组与存活组,分别对各组进行比较分析。结果: 123例MHF患者平均年龄为(44.2±17.4)岁,男女比例为1.3 ∶1;常见病因为血液肿瘤、风湿免疫性疾病、铁超载、HLH。随着铁蛋白水平升高,HLH患者比例增加,铁蛋白在10 000~19 999、20 000~29 999、30 000~39 999、40 000~49 999、50 000 μg/L以上时,HLH占比分别为28.8%、40.0%、54.5%、50.0%、50.0%。HLH共46例(37.4%), 继发于肿瘤15例、风湿免疫性疾病14例、感染性疾病2例,不明原因15例。HLH组与非HLH组比较,两组间在年龄、性别、发热、意识障碍、初始铁蛋白、最高铁蛋白、血细胞改变、谷丙转氨酶(alanine aminotransferase, ALT)、谷草转氨酶(aspartate aminotransferase, AST)、总胆红素(total bilirubin,TBIL)、直接胆红素(direct bilirubin DBIL)、甘油三酯(triglyceride, TG)方面差异无统计学意义(P>0.05), 出凝血检测除纤维蛋白原(fibrinogen, Fib)外,差异也无统计学意义(P>0.05),在死亡率方面两组间差异无统计学意义(P>0.05);而在肝、脾、淋巴结肿大,白蛋白(albumin, ALB),Fib方面两组间差异有统计学意义(P<0.05)。死亡组与存活组比较,两组间在年龄,性别,发热,肝、脾、淋巴结肿大,初始铁蛋白,最高铁蛋白,中性粒细胞(neutrophil, Neu),血红蛋白(hemoglobin, Hb),ALT,AST,ALB,TG方面差异无统计学意义(P>0.05),出凝血检测除凝血酶原时间(prothrombin time, PT)外,两组间差异无统计学意义(P>0.05), HLH所占比例两组间差异也无统计学意义(P>0.05),而在意识障碍、血小板计数(platelet, PLT)、PT、TBIL、DBIL方面两组间差异有统计学意义(P<0.05)。结论: 随着铁蛋白水平升高,HLH患者的比例随之增加,但是MHF对于HLH诊断不具有特异性。     

Successful rescue of acute liver failure and hemophagocytic lymphohistiocytosis following varicella infection: A case report and review of literature

Herein we report a case of acute liver failure (ALF) and hemophagocytic lymphohistiocytosis (HLH) induced by varicella infection, successfully rescued by a combination therapy of acyclovir, supportive care, and immunosuppression with dexamethasone and etoposide. A previously healthy 16-year-old boy presented with generalized rash, fever, severe abdominal pain, and abnormal liver function within 4 d. Chickenpox was suspected, and acyclovir and intravenous immunoglobulin were started on admission. However, the patient’s condition deteriorated overnight with soaring transaminases, severe coagulopathy and encephalopathy. On the fourth day of admission, pancytopenia emerged, accompanied by hypofibrinogenemia and hyperferritinemia. The patient was diagnosed with ALF. He also met the diagnostic criteria of HLH according to the HLH-2004 guideline. Polymerase chain reaction (PCR) amplifications of varicella-zoster virus (VZV) were positive, confirming that VZV was a causative trigger for ALF and HLH. In view of the devastating immune activation in HLH, immunosuppression therapy with dexamethasone and etoposide was administered, in addition to high dose acyclovir. The patient’s symptoms improved dramatically and he finally made a full recovery. To our knowledge, this is only the second report of a successful rescue of ALF associated with HLH, without resorting to liver transplantation. The first case was reported in a neonate infected by herpes simplex virus-1. However, survival data in older children and adults are lacking, most of whom died or underwent liver transplantation. Our report emphasizes the clinical vigilance for the possible presence of HLH, and the necessity of extensive investigation for underlying etiologies in patients presenting with indeterminate ALF. Early initiation of specific therapy targeting the underlying etiology, and watchful immunosuppression such as dexamethasone and etoposide, together with supportive therapy, are of crucial importance in this life-threatening disorder.     

Zinc protoporphyrin,a useful parameter to address hyperferritinemia

Zinc protoporphyrin (ZPP) is produced instead of heme as soon as iron support to erythropoiesis becomes insufficient. In iron deficiency the intra-erythrocytic ZPP concentration is increased. The aim of this study was to investigate whether ZPP is influenced by increased iron levels in hereditary hemochromatosis (HE) and is useful in the clarification of hyperferritinemia. Twenty HE patients and 160 patients with hyperferritinemic caused by anemia of chronic disorders, liver diseases, transfusional iron overload and hematologic or solid malignancies were enrolled. ZPP was measured using the Aviv front-face hematofluorometer (normal ≤ 40 μmol/mol heme). In HE, ZPP was significantly lower (median, 20 μmol/mol heme; p = 0.0005) compared to our historical control group. At diagnosis, 15 (75%) HE patients had ZPP values ≤25 μmol/mol heme. After phlebotomy, ZPP remained unchanged (median, 23 μmol/mol heme), although the initially high ferritin concentration decreased to normal. ZPP values in the other hyperferritinemic groups were significantly higher compared to HE and control groups. In contrast to HE, ZPP values ≤25 μmol/mol heme were only observed in 11% of cases with non-transfusional hyperferritinemia. The diagnostic accuracy of a ZPP ≤25 μmol/mol heme to detect HE in non-transfused hyperferritinemic patients was 87%, with a sensitivity of 75% and a specificity of 89%. Showing significantly lower values in HE, ZPP seems to be a useful parameter in distinguishing HE from other hyperferritinemic disorders as those conditions are generally accompanied by an increased ZPP.     

Incidence,Risk Factors,and Outcomes of Hyperferritinemia after Pediatric Cardiac Surgery with Cardiopulmonary Bypass: A Retrospective Study

Objective: Serum ferritin has been identified as a prognostic marker in patients with a variety of diseases. In the present study we aim to determine the prevalence of risk factors and outcomes for hyperferritinemia in children undergoing cardiac surgery with cardiopulmonary bypass for congenital heart defects. Methods: The serum ferritin levels of 457 children between the ages of twentyeight days and three years undergoing cardiopulmonary bypass surgery between June 1, 2017 and June 1, 2018 were analyzed. The prevalence of early postoperative hyperferritinemia was investigated; hyperferritinemia was defined as a ferritin level ≥250 ng/ml. Multivariable regression models including candidate risk factors were constructed to determine the independent predictors of serum ferritin levels post-bypass, analyzed as continuous variables (linear regression) and categorized variables (logistic regression). Multivariable logistic regression was applied to assess the relationship between postoperative hyperferritinemia and a composite of in-hospital mortality, acute kidney injury, extracorporeal life support, prolonged postoperative hospital length of stay and prolonged postoperative mechanical ventilation. Results: Of the 457 included patients, frequency of post-cardiopulmonary bypass hyperferritinemia was 59/457 (10.9%). In multivariate logistic analyses, age [odds ratio (OR) 0.776/90 days], maximum cardiopulmonary bypass flow [OR 1.031/(1 ml/kg)], cardiopulmonary bypass duration (OR 1.095/10 mins) and preoperative hemoglobin [OR 1.207/(10 g/L)] were significantly associated with early postoperative day 1 hyperferritinemia. After risk adjustment, hyperferritinemia was independently associated with the composite outcome (OR 6.373; 95%CI 2.863~14.184, p < 0.001), and improved model discrimination, (AUC 0.868; 95%CI 0.821∼0.916) compared with basic clinical prediction alone (AUC 0.840; 95%CI, 0.790∼0.890; △AUC = 0.0279, p = 0.0218). Conclusion: In this study, we found early postoperative hyperferritinemia was relatively common in pediatric patients after cardiopulmonary bypass. The occurrence of hyperferritinemia may help identify a population at risk of unfavorable in-hospital outcome.     

Maladie de Gaucher de type 1 simulant une thrombopénie immunologique : intérêt de l’hyperferritinémie et de l’hypergammaglobulinémie dans le bilan d’une thrombopénie isolée

IntroductionGaucher disease type 1 is a rare genetic disease. It can cause thrombocytopenia. Current guidelines do not support bone marrow examination in front of isolated thrombocytopenia if no evidence suggests malignant hemopathy. This strategy aiming at sparing unnecessary investigations makes such rare diseases more difficult to diagnose.Case reportA 31-year-old woman was diagnosed with immune thrombocytopenia according to current guidelines. She presented later with mild splenomegaly. Bone marrow aspirate smears showed Gaucher cells. Gaucher disease was then confirmed. Looking backward, initial biological clues (hyperferritinemia, hypergammaglobulinemia) should have enabled to consider the diagnosis.ConclusionGaucher disease type 1 can be responsible for apparently isolated thrombocytopenia. The disease must be looked for if the thrombocytopenia is associated with unexplained hypergammaglobulinemia or hyperferritinemia. Diagnosing immune thrombocytopenia without bone marrow sample requires to systematically pay attention to any clinical or biological abnormality, not to ignore rare differential diagnoses.     

A case of paraneoplastic syndrome mimicking adult-onset Still’s disease

A 49-year-old woman was admitted to our hospital because of fever of unknown origin. The patient had long-lasting spiking fever, hepatosplenomegaly, pleural effusion, and skin rash. Laboratory tests showed marked leukocytosis and an extremely high serum ferritin level (240000ng/ml) accompanied by disseminated intravascular coagulation and hemophagocytic syndrome. Most of the patients features were compatible with a diagnosis of adult-onset Stills disease (AOSD), the rash, however, was not a typical rheumatoid rash but multiforme erythema. Biopsy of a breast nodule revealed breast cancer, leading us to a diagnosis of paraneoplastic syndrome mimicking AOSD. Although this is a rare disorder, cases resembling the present one have been reported, indicating the importance of including paraneoplastic syndrome in the differential diagnosis of AOSD.