This document presents a case report of a 41-year-old man admitted with fever, respiratory symptoms, and deranged liver function tests. Further investigations revealed pancytopenia, hyperferritinemia over 11,000 ng/ml, and bone marrow biopsy showing hemophagocytosis, leading to a diagnosis of acquired hemophagocytic lymphohistiocytosis (HLH) secondary to Epstein-Barr virus infection. HLH is a rare but under-recognized hyperinflammatory condition that can cause multi-organ dysfunction resembling sepsis. It requires specific treatment including dexamethasone, cyclosporine A, and etoposide to control the uncontrolled activation of macrophages and lymphocytes driving the hyperinflammatory state. The

1. A Case of
Hyperferritinemia due
to HLH
Michelle Fallon
Antrim Area Hospital

2. Case Summary
History:
 41 year old man admitted to Antrim Area
Hospital in June 2014
 Generally unwell- headache, rigors, sore
throat and unproductive cough
 LRTI 2 weeks previously treated with
amoxicillin
 Noted weight loss of ½ stone past 2 months,
night sweats
 PMHx: Chronic back pain, no medications
 Social Hx: Non-smoker, builder

3. Initial assessment
Examination:
 Pyrexic 40.9 degrees, HR 140, BP 100/50
 RR 30, Sats 90% RA, Chest clear
 Jaundiced, hepato-splenomegaly, tender RUQ
 No meningism or focal neurology
 No lymphadenopathy or rash, throat clear
Initial investigations:
 Hb 133, WCC 2.8, PLT 84, CRP 97, Deranged
LFTs
 U&E/Coagulation profile unremarkable
 ABG compensated metabolic acidosis, Lactate 2.5

4. Clinical course
Initial management
 Admitted to medical ward
 Managed as sepsis/PUO
 Broad spectrum antibiotics/IV fluids
 Multiple Ix sent
Deterioration
 Persistent pyrexia & worsening LFTs
 Increasing oxygen requirements developed respiratory
failure
 CT CAP: Mediastinal hilar lymphadenopathy, bilateral small
pleural effusions, perihilar air space and ground glass
shadowing. Enlarged spleen.
 Referred to ICU for respiratory support

5. ICU management
Differential diagnosis: Haematological malignancy,
atypical CAP/sepsis, PCP, TB, viral hepatitis, HIV, etc
 Required NIV, high oxygen requirements
 Anti-microbial coverage
 Did not require any other organ support
 Hb drop 130 to 70= pancytopenic
 Iron profile: Ferritin > 11,000 ng/ml
 Required transfusion
 Ix of note: LDH 795, EBV 16,000 copies
 Bone marrow biopsy showed
haemophagocytosis

6. Diagnosis: Acquired Haemophagocytic
Lymphohistiocytosis (HLH) secondary to
infection with Epstein Barr Virus

7. Haemophagocytic
Lymphohistiocytosis (HLH)
Why do we need to know about this?
=rare haematological condition!
Causes SIRS/MODS and may resemble
sepsis
Patients may present to ICU
 Likely under diagnosed
 Fatal if not treated
Requires specific treatment

8. Pathophysiology of HLH
 = Not a malignancy
 ‘Hyperinflammatory
state’
 Uncontrolled activation
of histiocytes,
macrophages and T-cells
 Defective NK (absent or
impaired) and cytotoxic
T-cell function
 Elevated pro-inflammatory
cytokines
 Leads to fever, SIRS
and organ
dysfunction/MODS

9. Primary HLH
Familial/genetic HLH
Usually presents in infants < 12 months
old
Sub-classified into FHL 1-5 depending
upon protein abnormality/gene mutation
FHL 2 most common (= perforin mutation)
 Immune deficiency syndromes associated
with HLH= CHS-1, (Chediak-Higashi),GS-
2 (Griscelli Syndrome), XLP
Can still be triggered by infection

10. Secondary HLH
Secondary or ‘acquired’ HLH associated
with:
Viral infections = classically due to EBV,
CMV
 Other infections (bacterial, fungal, etc)
 Malignancies
Rheumatological disorders (Macrophage
activating Syndrome= MAS)
 Immune deficiency disorders

11. Diagnostic Criteria
International Histiocytosis Society
2004. Requires 5 of 8:
1. Fever
2. Splenomegaly
3. Cytopenia
4. Hypertriglyceridemia or
hypofibrinogenemia
5. Haemophagocytosis (on BM
or LN biopsy)
6. Hyperferritinemia
7. Elevated IL-2 (high soluable
interleukin-2-receptors)
8. Decreased NK cell activity
Henter et al (2007)

13. Ferritin
 Hallmark of HLH is
raised ferritin….
 Ferritin is an iron binding
molecule (L&H subunits)
 Cytoplasmic levels of
ferritin regulated by iron
levels but also influenced
by
cytokines/inflammation
 Hepatocytes,
macrophages and
Kupffer cells secrete
ferritin
 Often elevated as an
acute phase reactant

14. Ferritin levels
Serum ferritin considered elevated if above:
 > 200 ng/mL women
 > 300 ng/mL men
Adams (2008) proportion of general
population will have a serum ferritin
between 200-1000 ng/mL

15. Causes of raised ferritin
 Iron overload (haemochromatosis, transfusion, iron
loading anaemia, porphyria)
 Liver disease (acute/chronic)
 Alcohol/Obesity (metabolic syndrome)
 Autoimmune disease (RA, SLE etc)
 HHCS (hereditary hyperferritinemia/cataract
syndrome)
 Still’s disease*
 Antiphospholipid Syndrome*
 Haemophagocytic syndrome/MAS*
 Sepsis/septic shock*
* Associated with very high ferritin levels (Rosario et
al 2013)

16. Critical illness and ferritin
 Raised due to inflammatory process
 Anaemia common (complex)
 Typically in critically ill patients: raised ferritin/
low iron
 Garcia et al (2007) reported that high ferritin
levels were associated with increased
mortality in children with septic shock
 ? Marker of severity of illness
 Rosario et al (2013) proposed
hyperferritinemia involved pathogenesis of
disease rather than just a marker

17. Treatment of HLH
Common regimen: (HLH-2004 protocol)
 Dexamethasone (chemo-immune therapy)
 Cyclosporine A (CSA)
 Etoposide (associated with increased survival in adults with
secondary HLH, especially effective for EBV associated
disease)
Other:
 IVI immunoglobulin (IVIG)
 HSCT (familial/genetic or severe/recurring)
 Plasma exchange
 IT methotrexate (CNS involvement)
 Case reports- monoclonal antibodies

18. Patient progress
 Transferred to haematology ward after 8 days
in ICU
 Commenced Dexamethasone/Ciclosporine
A/Etoposide
 Ferritin levels decreased to 1896
 Received GCSF/blood transfusion
 Clinically improved
 Discharged home (3/52 following admission)
 Re-admission: a month later, severe back
pain, neutropenia, ferritin increased to 4000,
LDH 828. Dexamethasone dose increased.

19. Outcomes
 Retrospective analysis of HLH-94 treatment
protocol: 54% of 249 patients treated
survived. George (2014).
 Higher survival rates for MAS
 Untreated the familial condition is fatal
 Lack of recognition may contribute to higher
mortality
 Lin et al (2011) fall of ferritin levels of less
than 50% associated with increased risk of
death in children treated for HLH

20. Summary
Haemophagocytic Lymphohistiocytosis
(HLH) is rare but under recognized
Can cause SIRS/MODS and mimic sepsis
 May present in critical care
Multiple causes of hyperferritinemia
Markedly elevated levels should prompt
consideration of HLH as a diagnosis

21. References:
 Adams, P. Management of Elevated Serum Ferrtin Levels. Gastroenterology and Hepatology 2008;
4(5): 333-334
 Castillo, L et al. Secondary hemophaocytic lymphohistiocytosis and severe sepsis/systemic
inflammatory response syndrome/multiorgan dysfunction syndrome/macrophage activation syndrome
share common intermediate phenotypes on a spectrum of inflammation. Pediatric Critical Care
Medicine 2009; 10 (3): 387-92
 Demirkol, D et al. Hyperferritinemia in the critically ill child with secondary hemophagocytic
lymphohistiocytosis/sepsis/multiple organ dysfunction syndrome/macrophage activation syndrome:
what is the treatment?. Critical Care 2102; 16:R52
 George, M. Hemophagocytic lymphohistiocystosis: a review of etiologies and management. Journal
of Blood Medicine 2014; 5:69-86
 Grom, A. Macrophage Activating Syndrome: A review of diagnosis, treatment and prognosis . The
Rhuematologist 201
 0Heming, N et al. Iron deficiency in critically ill patients: highlighting the role of hepcidin. Critical Care
2011; 15: 210
 Henter J et al. Histiocyte Society HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic
lymphohystiocytosis. Pediatric Blood Cancer 2007;48(2):124-131
 Lin T et al. Rate of Decline of Ferritin in Patients with HLH as a Prognostic Variable for Mortality.
Paediatric Blood and Cancer 2011; 56(1) 154-155
 Raschke, R et al. Haemophagocytic Lymphohistiocytosis: A Potentially Underrecognized Association
With Systemic Inflammatory Response Syndrome, Severe Sepsis, and Septic Shock in Adults. Chest
2011; 4:140
 Rosario, C et al. The Hyperferritinemic Syndrome: macrophage activating syndrome, Still’s disease,
septic shock and catastophic antiphospholipid syndrome. BMC Medicine 2013; 11:185
 Tothova, Z et al. Haemophagocytic Syndrome and Critical Illness: New Insights into Diagnosis and
Management. J Intensive Care Med 2014 (Epub ahead of print)

22. Questions…?