Hemophagocytic Lymphohistiocytosis (HLH) PDF

Hemophagocytic Supervised by : Dr. Mohammed Haseb lymphohistiocytosis Presented by : Dr.Zainab Raad  Histiocyte is a term for tissue macrophages. ❖ The histiocytoses include diseases arising from all cells of the mononuclear phagocytic system, with diseases characterized by p...

Hemophagocytic Supervised by : Dr. Mohammed Haseb lymphohistiocytosis Presented by : Dr.Zainab Raad  Histiocyte is a term for tissue macrophages. ❖ The histiocytoses include diseases arising from all cells of the mononuclear phagocytic system, with diseases characterized by presumed lineage and biology into dendritic cell (DC) disorders, macrophage-related disorders, and malignant histiocytic disorders. ❖ The distinction among these diseases is based on clinical characteristics and histopathologic staining for unique surface markers.  Reactive Histiocyes The cell shape is somewhat irregular with a shaggy contour. A single nucleolus can be seen in each histiocyte.  Hemophagocytic lymphohistiocytosis (HLH) ❖ HLH is quite distinct from the clonal myeloid neoplastic “histiocytic disorders” and characterized by dysfunction of T cells, activated macrophages, and pathologic in ammation. (HLH is Syndrome of pathologic immune activation.) Hemophagocytosis describes the characteristic histopathologic nding of macrophages engul ng erythrocytes or other hematopoietic cells that can be found in marrow, lymph nodes, spleen or liver biopsies. fl fi fi It is classically divided into two types: (1) primary or familial HLH. (2) secondary HLH. ❖ Familial forms: affecting neonates and infants occur in 1 in 50,000 live births. familial form is an autosomal recessive disease without a well-de ned genetic defect. Recently, several defects in genes have been reported in patients with familial (HLH) including mutations in the genes for perforin (PRF1), Munc13-4 (UNC13D) and syntaxin 11 (STX11). Males and females are equally affected. fi ❖ secondary(acquired) HLH: (commonly known as macrophage activation syndrome) usually associated with Che ́ diak–Higashi syndrome, Griscelli syndrome and X-linked lymphoproliferative syndrome, infectious diseases, autoin ammatory and autoimmune diseases, malignancy, immunosuppression, hematopoietic stem cell transplantation, organ transplantation, HIV infection, metabolic diseases. fl Pathophysiology: ❖ HLH represents a hyperin ammatory uncontrolled immune response triggered by various stimuli. Much has been learned about the pathogenesis of genetic HLH, whereas the mechanisms leading to acquired HLH are still poorly understood. ❖ Both familial and acquired forms of HLH are commonly precipitated by viral (particularly Epstein–Barr virus and other herpes viruses), bacterial, fungal and protozoan infections, occurring frequently in an immunocompromised host. fl Genetics of HLH: the majority of genetic syndromes causing HLH shared features of impaired cytotoxic NK and T-cell function, including mutations in PRF1 (encoding perforin), UNC13D (encoding MUNC13-4), STXBP2 (encoding syntaxin binding protein 2), STX11 (encoding syntaxin 11), and RAB27A (encoding Rab27a).These gene defects prevented the normal sequence of perforin being produced, packaged, and secreted from NK cells and cytotoxic T cells upon activation by target cells, leading to pore formation in the target cell membrane, and granzyme injection leading to apoptosis of target cells. Immunologic Defects: Inherited defects in genes that regulate the function of NK cells and cytotoxic T cells have been described in HLH. HLH results from the pathologic activation of T cells and macrophages, which subsequently produce proin ammatory cytokines, IFNγ, TNF-α, IL-6, IL-10, IL-12, and soluble IL-2 receptor α (soluble CD25). Hypercytokinemia generated by activated T cells and macrophages results in multiorgan dysfunction that can rapidly lead to death. fl Pathogenesis of HLH. The macrophages become active and see uncontrolled proliferation through various mechanisms. This causes them to release a variety of pro-in ammatory cytokines which are involved in the further ampli cation effects of HLH. Of note, we can mention INF-γ, IL-1 and IL-6, which are known pro-in ammatory cytokines. Moreover, through IL-12 and IL-18, macrophages also have an effect on cytotoxic T-lymphocytes, activating them and creating a vicious cycle. fi fl fl  ❖ Elevated ferritin is expected in HLH because destruction of red blood cells results in the release of iron into the serum. Additionally, histiocytes increase ferritin production secondary to increased levels of heme-oxygenase due to the in ammatory cytokines. ❖ Hypertriglyceridemia is also expected in HLH, because TNF-α and IFN-γ inhibit lipoprotein lipase activity, which decreases the breakdown of triglycerides for uptake and storage by tissues. ❖ Plasmin will also be elevated due to histiocyte secretion of plasminogen activator, leading to brin breakdown, which decreases brinogen1 and increases D-dimer.2 ❖ Elevated CD25 marks activated lymphocytes, and is the alpha subunit of the interleukin 2 receptor (IL-2R). fi fi fl CLINICAL FEATURES: ❖ HLH is dif cult to diagnose because the presenting signs and symptoms of HLH overlap with other conditions in critically ill patients, making the identi cation of this syndrome challenging ❖ The main symptoms associated with HLH include: prolonged high fever. hepatosplenomegaly. Other clinical ndings include neurological symptoms (such as seizures, meningismus, decreased level of consciousness), rash, pulmonary dysfunction, and lymphadenopathy and clinical features related to Hepatitis. CNS symptoms mimicking encephalitis are also seen. fi fi fi Diagnostic Guidelines for HLH: Diagnosis of HLH can be established by either molecular means or by meeting clinical and laboratory criteria. Molecular diagnosis: primary HLH can be diagnosed by clinical ndings, although genetic testing alone is suf cient. Genetic testing is also commonly used for siblings and to con rm a suspected diagnosis. or The patient ful lls at least 5 of the following 8 diagnostic criteria: 1. Fever 2. Splenomegaly fi fi fi fi 3. Cytopenias (affecting ≥2 of 3 cell lineages: i. Hemoglobin level