HLH – Adults & Young People
Being told you have Haemophagocytic Lymphohistiocytosis (HLH), can leave you feeling shocked, upset and very isolated. There are so many questions to be answered and so many feelings to deal with, here we try to answer some of the questions you may have.

Doctors and scientists often call it an ‘orphan’ disease because it is so rare. As a result, research into why it happens and how it can best be treated has been limited.

How does HLH affect patients?
Some patients have no symptoms at all and the disease is found ‘by accident’ when they are investigated for something unrelated.
Although it is possible for HLH to affect people in many different ways it is not uncommon for HLH patients to appear well – this can make the diagnosis even harder to take in.

Diagnosis

It is sometimes difficult to establish the diagnosis of Haemophagocytic Lymphohistiocytosis (HLH), and the combination of the physical symptoms and certain laboratory tests is required. (Note: The understanding of the pathology underlying HLH/FHL disease is evolving, and recommended “diagnostic” criteria are likely to be revised in the future.)

HLH can be challenging to diagnose because the initial symptoms may mimic common infections. Symptoms of HLH may include:
• Low or absent NK (natural killer) cell function.
• Prolonged fever.
• Blood cell abnormalities (low white cells, low red cells, low platelets).
• Enlarged spleen.
• Increased triglycerides (fat) or decreased fibrinogen (protein necessary for clotting) in the
blood.
• Increased ferritin (protein that stores iron) in the blood.
• Abnormal bone marrow test with evidence of Haemophagocytosis (ingestion of red or white cells by
histiocytes) but not malignancy or other cause.
• Abnormally high CD25 (also known as sIL2ra) in the blood indicating abnormally increased T-cell
activation.
• Rash
• Enlarged liver /Liver failure
• Enlarged lymph nodes
• Anaemia
• Jaundice
• Hepatitis
• Respiratory issues (coughing, respiratory distress)
• Seizures
• Altered mental functions

The test for low or absent natural killer cell (NK) function has been found useful in making a clinical diagnosis of HLH. This abnormality is found in many patients with FHL, as well as in many cases of secondary disease but rarely in the X-linked forms.

However, it is just one piece of information and should not be used to determine the diagnosis of HLH as primary or secondary. NK function cannot be determined before birth, and it may not be reliably studied until a child is at least 6 weeks of age. FHL is suspected if siblings have been diagnosed with HLH, if symptoms intensify during treatment for HLH, or if symptoms return after therapy has been stopped.

Since it is difficult to tell the difference between secondary HLH and FHL, any case of HLH should be considered for genetic testing to confirm the diagnosis. Since 1999, at least seven defective genes have been identified. Autosomal recessive: PRF1 (perforin), MUNC13-4, STX11 (Syntaxin), STXBP2, and RAB27A. X-linked: SH2D1A, BIRC4.

There are some FHL patients (approximately 30%) with no identified gene defect, so normal genetic test results do not necessarily rule out the diagnosis of FHL. Genetic testing is usually done on blood, although other kinds of tissue samples can be used. Once the genetic cause is known, the parents can quickly be tested to confirm that they are carriers for that specific genetic type of FHL. Other siblings can also be easily tested, even before birth, once the genetic cause of the disorder in the family is known. Even in the event of death, salvaged tissue can be tested to determine if siblings are at risk.

Please be advised that all the information you read here is not a replacement for the advice you will get from your consultant and their team.

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