Pathogenesis of hypofibrinogenemia in familial hemophagocytic lymphohistiocytosis

In order to investigate the cause of hypofibrinogenemia in familial hemophagocytic lymphohistiocytosis (FHL), formalin-fixed and paraffin-embedded tissue sections of the spleen obtained at autopsy were examined by using immunohistochemical methods for the presence of fibrinogen antigens, and such antigens were detected in approximately 10% of the histiocytes in a diffuse staining pattern. This finding indicates uptake of fibrin and/or fibrinogen molecules by activated histiocytes and suggests that hypofibrinogenemia of FHL is caused by the direct action of activated histiocytes on factor X through Mac-1 receptors, subsequent activation of the common pathway of the coagulation protease cascade, and uptake of fibrin and/or fibrinogen molecules by such cells.     

儿童EB病毒相关噬血细胞综合征的分子生物学机制和诊疗研究进展

EB病毒相关噬血细胞综合征起病凶险,进展迅速,预后差,未经治疗者病死率高.其具体发病机制目前尚不完全清楚,可能与SH2D1A基因突变和EBV潜在膜蛋白1有关.诊断首先需符合噬血细胞性淋巴组织细胞增多症诊断标准,并存在EB病毒感染证据,同时排除原发性噬血.治疗上首选联合化疗,若化疗效果不佳,可行造血干细胞移植和单克隆抗体治疗.     

Difficulties in the diagnosis of familial hemophagocytic lymphohistiocytosis

Familial hemophagocytic lymphohistiocytosis (FHL) is characterized by proliferation and non-malignant activation of histiocytes and T lymphocytes in the reticuloendothelial system. Diagnostic guidelines include fever, splenomegaly, cytopenia, hypertriglyceridemia and/or hypofibrinogenemia with hemophagocytosis in the bone marrow, spleen or lymph nodes. In many patients diagnosis is difficult due to the lack of diagnostic criteria, hemophagocytosis, variability of clinical presentation, spontaneous improvement and the absence of a specific marker of the disease. When there is strong clinical suspicion of FHL, chemotherapy and immunosuppressor treatment should be started early to achieve complete cure and should be followed by hematopoietic stem cell transplantation. We present the case of a 2-month-old girl who presented fever, anemia and thrombocytopenia, enlarged liver and spleen, hyperferritinemia, hypertriglyceridemia, and hypertransaminasemia without the finding of hemophagocytosis in bone marrow. Two of the girl's relatives had died of fulminant hepatic failure of unknown etiology. The patient improved spontaneously but presented reactivation of the disease 3 weeks later and died after splenic biopsy.     

Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis

We retrospectively studied the incidence of familial hemophagocytic lymphohistiocytosis (FHL) in children during the 16-year period 1971-86. First, all departments of pediatrics, pathology, and infectious diseases were enquired for children with FHL or disorders resembling FHL. Secondly, the causes of death of all children who died during the study period in Sweden (n = 19,542) were also investigated. Files and histological specimens were further studied in selected children. By using a set of inclusion/exclusion criteria, we found 32 children with FHL. The incidence was 1.2/1,000,000 children per year. One child per 50,000 live borns developed FHL during this period. The sex ratio was close to 1:1. Prominent early clinical signs were fever (91%), splenomegaly (84%), hepatomegaly (90%), rash (43%), and lymph node enlargement (42%). Neurological symptoms, which developed in 47%, could totally dominate the clinical picture and develop prior to other symptoms and signs. Common laboratory findings were pancytopenia, hypertriglyceridemia, hypofibrinogenemia, elevated serum transaminases, hyperbilirubinemia, hyponatremia, hypoalbuminemia, and a moderate spinal fluid pleocytosis. Chest X-ray often revealed mostly discrete pulmonary infiltrates. FHL is an underdiagnosed disease and in only 11/32 children was diagnosis made during their lifetime. It is important to be aware of the disorder as potential therapy now exists.     

Lipoprotein alterations and plasma lipoprotein lipase reduction in familial hemophagocytic lymphohistiocytosis.

Serum lipid abnormalities are common in familial hemophagocytic lymphohistocytosis (FHL), a disorder also characterized by fever, hepatosplenomegaly, pancytopenia and a prominent lymphohistiocytic accumulation in the mononuclear phagocyte system. The lipoprotein pattern in nine children with FHL was studied with a quantitative method measuring cholesterol and triglycerides in each major class of lipoproteins. Triglycerides were markedly elevated during active FHL in serum, very low density lipoproteins, and low density lipoproteins. Cholesterol was increased in very low density lipoproteins whereas both triglycerides and cholesterol were extremely low in high density lipoproteins. These lipoprotein abnormalities, reversible on successful therapy, are compatible with a depressed lipolytic activity. Post-heparin levels of lipoprotein lipase and hepatic lipase in plasma were studied in four children and found to be markedly low during active FHL. We suggest that inflammatory cytokines, which may strongly suppress lipoprotein lipase activity, can be important mediators in the pathophysiology of FHL and that they may participate in the development of the lipid abnormalities.     

Sensorineural hearing loss in a case of familial hemophagocytic lymphohistiocytosis

Severe sensorineural hearing loss (bilateral >80 dB) was diagnosed in a case of familial hemophagocytic lymphohistiocytosis (FHL). The female patient developed HLH at 3 months of age and underwent allogeneic cord blood transplantation at 11 months of age following 7 months of immuno-chemotherapy. The type 2 FHL patient had a homozygous perforin gene mutation of 1090-1091delCT, and was noted to have hearing loss at 3.5 years of age. Retrospective evaluation did not clarify the exact causes of hearing loss. Reports on Kawasaki disease, suggesting a correlation between severe inflammatory status in infancy and the development of sensorineural hearing loss, may shed some light on this rare complication in this case of FHL. Considering the markedly improved prognosis of FHL due to recent advances made in the molecular diagnosis and in the management including allogeneic hematopoietic stem cell transplantation, auditor by screening might be warranted for surviving FHL patients.     

家族性噬血细胞性淋巴组织细胞增生症分子遗传学及诊疗研究进展

噬血细胞性淋巴组织细胞增生症（HLH）是一组以淋巴细胞、组织细胞增生伴噬血细胞增多而引起多脏器浸润及全血细胞减少为特征的综合征,多威胁生命。HLH分为原发性（又称家族性）和继发性HLH。家族性HLH发病年龄常见于婴幼儿,多与遗传基因的缺陷有关。本文在分子遗传学基础上主要对PRF1、UNC13D、STX11和STXBP2等9种家族性HLH相关基因最近研究进展进行整理,并总结了家族性HLH诊疗方法,以增强对该病的认识与了解。     

Rare coincidence of familial central core disease and hemophagocytic lymphohistiocytosis

Central core disease is a congenital myopathy caused by mutations in RYR1. A 6‐year‐old girl was admitted due to difficulty in running and climbing stairs. Another 13 members through the four generations had similar symptoms, indicating autosomal dominant inheritance. Muscle biopsy showed the characteristic central cores in predominant type 1 fibers. She later developed hemophagocytic lymphohistiocytosis. Mutation analysis identified c.14582G>A in RYR1, and c.1693delG and c.2954 + 5G>A in UNC13D. To our knowledge, this is the first case of a patient with central core disease, carrying a RYR1 mutation in a Korean large family, who had concurrent familial hemophagocytic lymphohistiocytosis.     

儿童噬血细胞淋巴组织细胞增生症23例临床分析

目的 研究HLH-2004方案诊断和治疗噬血细胞淋巴组织细胞增生症(HLH)患儿的效果和预后,分析HLH的相关病因.方法 23例(男14例,女9例)HLH患儿,平均年龄3.8岁,其中12例≤2岁.按HLH-2004诊断标准和治疗方案进行诊断和治疗,并进行可能病因的检查和分析其相关病因.结果 相关病因未明组13例(56.5%),病毒感染相关组5例(21.7%);这二组中有4例未治疗的患儿在诊断后2周内死亡,14例使用HLH-2004方案治疗,仅1例治疗过程中死于消化道出血合并深部霉菌感染,其余13例早期均能获得缓解,4例中途退出治疗并死于复发,9例完成治疗后随访1.5～2年无复发.淋巴瘤相关组3例(13.1%),其中2例为间变性大细胞性淋巴瘤(ALCL),开始使用淋巴瘤方案(COP)治疗,病情未获缓解,加用HLH-2004方案治疗获得快速缓解,再继续按淋巴瘤的化疗方案治疗.其他相关组2例(8.69%),其中系统性红斑狼疮(SLE)和坏死性淋巴结炎(HNL)各1例,均使用肾上腺皮质激素治疗后前者存活,后者死亡.3例诊断后未治疗的患儿全部死亡.结论 HLH-2004诊断标准有较强的诊断可行性.所有HLH患儿对HLH-21304方案免疫一化疗有较好的治疗反应,可获得快速缓解,依托泊苷很可能是关键药物.部分HLH与病毒感染、淋巴瘤、SLE和HNL相关,半数以上病因未明.     

Clonal dissemination of T-lymphocytes in scid mice from familial hemophagocytic lymphohistiocytosis

BACKGROUND: Although familial hemophagocytic lymphohistiocytosis (FHL) has been considered a disorder of T-cell dysfunction, there is no evidence of the clonal origin of T-cells in this disease. PROCEDURE: We engrafted mononuclear cells (MNCs) from five FHL patients into scid mice and examined the infiltration of human cells in mouse organs. The characterization of human cells that infiltrated in the mouse organs was then performed. RESULTS: A diffuse infiltration of human lymphoid cells was detected in scid mice treated with 1 x 10(6) MNCs from one of the five patients. These cells were positive for HLA-DR and CD3, but negative for CD4, CD8, CD20, and CD68, suggesting the infiltration of double negative (DN) T-cells. The MNCs from the other four patients induced murine lymphoma-like disease; T-cell lymphoma in one and lymphoma of unknown origin in three. The characterization of these human DN T-cells was performed. The analysis of the Vbeta repertoire showed no preferential usage of the Vbeta family in MNCs, while the dominant expression of Vbeta13 was detected in T-cells infiltrating in the spleen and lung. A Jbeta analysis showed the restricted usage of Jbeta1.2 for Vbeta13 in these cells, and the clonality of Vbeta13-Jbeta1.2 fragment was confirmed by a single-strand confirmation polymorphism analysis. The analysis of the Valpha repertoire showed that Valpha24 was exclusively used in these DN T-cells, but no usage of JalphaQ for Valpha24 was observed. CONCLUSIONS: A clonal expansion of T-cells was induced in scid mice by the engraftment of MNCs from an FHL patient. The infiltration of DN alphabeta T-cells bearing invariant Valpha24 T-cell receptor in mouse organs may provide a useful clue to the pathogenesis of FHL. In the patients whose MNCs induced murine lymphoma-like disease, some cytokines or unknown factors that stimulate the growth and the tumorigenicity of murine lymphocytes might be produced by the MNCs engrafted in scid mice. Further study is needed to confirm the validity of our experimental approach and the findings observed in scid mice by using more FHL samples.     

小儿EB病毒相关噬血细胞综合征3例报告及文献复习

EB病毒相关噬血细胞综合征 (EBV -AHS)是EB病毒感染诱发组织细胞异常增生并大量吞噬血细胞而引起的一系列临床综合征。其临床特点主要表现为高热、肝脾淋巴结肿大、全血细胞减少和肝功能异常 ,其显著的特征是骨髓涂片或组织中出现体积较大的噬血组织细胞 ,并吞噬血细胞。该文报告 3例并结合文献对本病的发病机制、临床表现、诊断及治疗进行复习。     

EB病毒感染相关噬血细胞综合征的诊治研究进展

噬血细胞综合征(hemophagocytic syndrome,HS)是一组病因及发病机制复杂.组织病理表现以良性组织细胞增生活化,伴随噬血细胞现象的一类综合征.HS分为原发性和继发性两大类,原发性是指家族遗传相关的免疫缺陷状态,继发性指后天获得所致,其中以EB病毒感染相关最为常见.EB病毒感染相关HS的病情进展快,病死率高,现就该病的诊治进展作一概述.