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    Drugs & Diseases > Pediatrics: General Medicine

    Lymphohistiocytosis (Hemophagocytic Lymphohistiocytosis) Workup

    Updated: Jun 09, 2020
    • Author: Robert A Schwartz, MD, MPH; Chief Editor: Max J Coppes, MD, PhD, MBA  more...
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    Workup

    Laboratory Studies

    Because natural killer (NK) cell function or activity is decreased in as many as 90% of patients with hemophagocytic lymphohistiocytosis (HLH), it is one of the most useful laboratory tests. NK cell number is usually not diagnostic.

    In addition to pancytopenia, hypofibrinogenemia, and hypertriglyceridemias, other laboratory abnormalities have been linked to HLH. Ferritin has been observed as a marker for hemophagocytic lymphohistiocytosis, with the serum levels paralleling the course of the disease. [41] A retrospective study evaluated the use of a ferritin value of >500 ng/mL in diagnosing HLH in 344 consecutive patients admitted to the medical intensive care unit. The data suggested that a higher cutoff value of ferritin may have improved utility in the diagnosis of secondary hemophagocytic lymphohistiocytosis in the critical care setting. [42]

    Liver damage has also been reported as evidenced by hyperbilirubinemia (see Bilirubin), hypoalbuminemia (see Albumin), and elevated findings on liver function tests including aspartate aminotransferase (AST) and alanine aminotransferase (ALT). [43]

    The presence of a PRF1 gene mutation can be determined based on flow cytometry by staining perforin contained in lymphocytes.

    The finding of a distinctive Th1/Th2 cytokine pattern (significant increase of interferon [IFN]-ƒ× and interleukin-10 [IL-10] with slightly increased or normal level of IL-6) may represent a useful biomarker for the early diagnosis, differential diagnosis, and the monitoring of the disease. [12]

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    Imaging Studies

    No specific imaging patterns are diagnostic of hemophagocytic lymphohistiocytosis.

    Computed tomography (CT) or ultrasonography findings may include ascites, gallbladder wall thickening, increased periportal echogenicity, lymphadenopathy, and pleural effusion.

    Magnetic resonance imaging (MRI) may show central nervous system (CNS) involvement, but the diagnosis is clinical and molecular. [44]

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    Other Tests

    Arico et al proposed an approach to the diagnostic workup of a patient with suspected hemophagocytic lymphohistiocytosis. [11]  A detailed clinical history should be obtained to exclude other associated conditions, such as metabolic disorders or the DiGeorge syndrome. However, if the diagnostic hemophagocytic lymphohistiocytosis criteria are fulfilled, and the findings for associated conditions are negative, initial testing involves perforin expression by NK cells using flow cytometry.

    Patients who lack perforin expression should be analyzed for the PRF1 gene mutation. NK cell activity should also be determined to aid in differentiating between the hemophagocytic lymphohistiocytosis subtypes. Normal activity is suggestive of the reactive form of hemophagocytic lymphohistiocytosis rather than the familial type.

    DNA samples and fresh cells are suggested to be stored in case of need for future use in familial cases for which no genetic defect can be identified.

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    Procedures

    A skin biopsy can be performed for histologic examination. Lymph node biopsy (see the image below), bone marrow biopsy, or liver biopsy may demonstrate the characteristic hemophagocytosis.

    A lymph node biopsy is performed. Note that a mark A lymph node biopsy is performed. Note that a marking pen has been used to outline the node before removal and that a silk suture has been used to provide traction to assist the removal.
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    Histologic Findings

    A skin biopsy can assist in distinguishing this disorder from other systemic and potentially neoplastic diseases, such as Langerhans cell histiocytosis, myofibrosis, extramedullary hematopoiesis, and leukemia cutis. [3, 45] However, skin biopsy findings are usually not diagnostic and only rarely show hemophagocytosis.

    Because hemophagocytosis must be demonstrated in the bone marrow, spleen, or lymph nodes, appropriate specimens should be collected for documentation. [1] Red blood cells are affected more often than white blood cells or platelets.

    Findings in up to two thirds of initial bone marrow aspirates may be nondiagnostic; thus, a negative examination finding may not rule out hemophagocytic lymphohistiocytosis. An additional bone marrow finding includes dyserythropoiesis, which has been observed in the absence of hemophagocytic histiocytes.

    Additional studies, including lymph node biopsy, should be performed, and treatment should not be delayed if all other criteria have been met. [46]

    Although problematic in a patient with a coagulopathy, a liver biopsy demonstrating a picture similar to chronic persistent hepatitis can support the diagnosis, as can the presence of mononuclear cells in the cerebrospinal fluid (CSF).

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