Hemophagocytic Lymphohistiocytosis (HLH) is a potentially fatal hyperinflammatory disease caused by a hyperactive and dysregulated immune response. This persistent elevation of proinflammatory cytokines ultimately results in end organ dysfunction. Although multiple types of HLH have been described, HLH can be broadly classified into primary and secondary forms. Primary forms of HLH are uncommon, typically occur in children, and are associated with genetic abnormalities. To date, all of the known genetic abnormalities identified in familial HLH lead to defects in proteins involved in the cytolytic secretory pathway. The cytolytic secretory pathway is a critical function of natural killer (NK) and cytotoxic T lymphocytes (CTL), specialized lymphocytes that use perforin to deliver granzymes to kill target cells. Perforin mutations in HLH were first described by Stepp et al in 1999, and in subsequent years, multiple genetic subtypes of HLH have been described. Perforin pathway gene mutations associated with HLH are listed as follows: UNC13D (FHL3), STX (FHL4), and STXBP2 or UNC18B (FLH5). In contrast to genetic types of HLH, secondary forms of HLH typically occur in older individuals, and can be further subcategorized into infection-associated HLH (frequently EBV), malignancy-associated HLH (frequently T-cell neoplasms), and autoimmune- associated HLH. In addition to EBV, multiple infectious etiologies have been associated with HLH including CMV, HHV6, adenovirus, parvovirus, erlichia, bartonella, brucella, viral hemorrhagic fevers, and visceral leishmaniasis. While the pathogenesis of secondary HLH is not entirely clear, there are increasing reports of affected individuals who are heterozygous for mutation or show polymorphisms in familial HLH genes.
HLH can be diagnosed by molecular identification of an HLH-associated mutation. However, in the absence of a disease defining mutation, the diagnosis of HLH requires at least 5 of the following 8 criteria:
The pathologic criteria of HLH deserve special mention. The histological identification of hemphagocytosis is one of the eight diagnostic criteria for HLH. It is important to note that hemophagocytosis can be seen in normal bone marrows, and by itself does not equate to a diagnosis of HLH. In addition, hemophagocytosis can be absent in cases of HLH due to the cylical nature of the disease, and the absence of histologically identifiable hemophagocytosis does not exclude the diagnosis. Assessment of NK-cell function can be measured by specialized laboratory testing such as the 51-cromium release assay release assay in which a patient’s NK cells are loaded with radionucleotide and are stimulated to degranulate.
In summary, HLH is a frequently fatal disease which results from dysregulation of the cytotoxic response causing hypercytokinemia and end organ dysfunction. HLH can be challenging diagnostically given the multiple clinical, laboratory, and pathological criteria. Establishing a timely diagnosis is a major challenge as the symptoms are non-specific and there is a lack of a single gold standard confirmatory test.
Stepp SE, Dufourcq-Lagelouse R, Le Deist F, Bhawan S, Certain S, Mathew PA, Henter JI, Bennett M, Fischer A, de Saint Basile G, Kumar V. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science. 1999 Dec 3;286(5446):1957-9.
Editorial by Mark Stonecypher, MD