A Case of Hyperferritinemia due

to HLHMichelle Fallon

Antrim Area Hospital

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

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

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

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

Diagnosis: Acquired Haemophagocytic

Lymphohistiocytosis (HLH) secondary to

infection with Epstein Barr Virus

HaemophagocyticLymphohistiocytosis (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

Pathophysiology of HLH

= Not a malignancy

‘Hyperinflammatorystate’

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

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

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

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 soluableinterleukin-2-receptors)

8. Decreased NK cell activity

Henter et al (2007)

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

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

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)

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

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

Patient progress

Transferred to haematology ward after 8 days in ICU

Commenced Dexamethasone/CiclosporineA/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.

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

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

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 hemophagocyticlymphohistiocytosis/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 hemophagocyticlymphohystiocytosis. 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)

Questions…?