A previously well 24-year-old male presents with fevers, malaise and jaundice. Microbiological cultures are negative, and despite treatment with broad spectrum antibiotics he continues to deteriorate. The following results are obtained:

Parameter

Patient Value

Adult Normal Range

Sodium

129 mmol/L*

135 – 145

Potassium

5.1 mmol/L*

3.5 – 5.0

Chloride

105 mmol/L

95 – 105

Bicarbonate

14.0 mmol/L*

22.0 – 26.0

Urea

16.3 mmol/L*

3.0 – 8.0

Creatinine

659 µmol/L*

45 – 90

Glucose

7.0 mmol/L*

3.5 – 6.0

Magnesium

1.49 mmol/L*

0.75 – 0.95

Albumin

27 g/L*

35 – 50

Protein

45 g/L*

60 – 80

Total bilirubin

148 µmol/L*

< 26

Conjugated bilirubin

143 µmol/L

Aspartate transferase

2250 U/L*

< 35

Alanine transferase

1218 U/L*

< 35

Alkaline phosphatase

43 U/L

30 – 110

g-Glutamyl transferase

68 U/L*

< 40

Ionised calcium

0.97 mmol/L*

1.10 – 1.35

Calcium corrected

1.95 mmol/L*

2.12 – 2.62

Phosphate

1.11 mmol/L

0.80 – 1.50

Creatinine Kinase

500 U/L*

55 – 170

Iron Level

34 µmol/L

6 – 35

Ferritin

181,900 µg/L*

30 – 400

Transferrin

0.6 g/L*

2.0 – 3.6

Ammonia

78 µmol/L*

16 – 60

Parameter

Patient Value

Adult Normal Range

Haemoglobin

132 g/L

120 – 160

White Cell Count

5.2 x 109/L

4.0 – 11.0

Platelet count

24 x 109/L*

150 – 350

Parameter

Patient Value

Adult Normal Range

Prothrombin time

20.0 sec*

12.0 – 16.5

International normalised ratio (INR)

1.8*

0.9 – 1.3

Activated    partial    thromboplastin time (APTT)

77.0 sec*

27.0 – 38.5

Fibrinogen

0.7 g/L*

2.0 – 4.0

D-Dimer

66.0 mg/L*

< 0.5

a) Interpret the abnormalities (30% marks)

b) What is the most likely diagnosis? (10% marks)

c) What are precipitants of this condition? (10% marks)

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College answer

a)

Interpret the abnormalities.

Mild hyponatraemia and hyperkalaemia

AKI: Rise in creatinine out of proportion to rise in urea (ratio urea: creatinine < 100:1) – due to intrinsic renal dysfunction or associated severe liver injury

Reduced bicarbonate and normal anion gap metabolic acidosis Hyperbilirubinaemia – mostly conjugated

Acute hepatocellular liver injury: ratio AST:ALT increased but not quite 2:1 indicative of alcoholic hepatitis (also not supported by only slightly elevated GGT) but suggestive other acute liver injury Other synthetic liver dysfunction: INR 1.8; Ammonia mildly elevated

Mildly elevated CK - ? muscle injury

Severely elevated ferritin with normal iron levels. Normal Hb/ Wcc

Markedly deranged coagulation: severe thrombocytopaenia, low fibrinogen, markedly elevated APTT and severely elevated D-Dimer – Suggestive of DIC type pathology

b)

What is the most likely diagnosis?

Given    the   severity    of   the    elevated    ferritin   and   multiorgan   involvement,              Haemphagocytic lymphohistioctyosis (haemophagocytic syndrome)

c)

What are precipitants of this condition?

Viral infections particularly EBV/CMV/HSV/VZC/Parvovirus Malignancy especially lymphoma and leukaemia Rheumatologic conditions

Discussion

First, let's list the abnormalities, and briefly digress on their meaning: 

  • Hyponatremia
  • Hyperkalemia
  • Acidosis
  • Renal failure (the lower urea suggests that something other than pre-renal failure is responsible)
  • The magnesium is raised
  • Albumin and portein are low
  • The bilirubin is very elevated, and it is mainly conjugated bilirubin
  • The transaminases are elevated, which suggests a noncholestatic cause of the raised bilirubin
  • There is hypocalcemia
  • CK is elevated, but only trivially so
  • The transferrin is low and the iron levels are essentially normal
  • The ammonia is raised, which is not unexpected given the degree of hepatic damage
  • In the haematology, there is substantial thrombocytopenia, but the counts are otherwise normal
  • The coags are deranged, but not spectacularly so.
  • The ferritin level is abominably elevated, to the point that the lab technician would recoil in horror from the analyser, and ring you directly.

So, the only thing this could be is haemophagocytic syndrome. The causes of this rare disease can be found in the review article by Gritta Janka (2008):

Congenital:

  • familial HLH (FHLH)
  • Chediak-Higashi syndrome (CHS 1)
  • Griscelli syndrome (GS 2)
  • X-linked proliferative syndrome (XLP)
  • The UpToDate article has whole pages listing obscure-sounding loci of mutation.

Acquired causes

  • Infectious
    • EBV
    • CMV
    • HIV
    • Leishmania
  • Neoplastic
    • Lymphoma, especially T and NK-cell
  • Autoimmune
    • SLE
    • Kawasaki disease

References

Lee, Mark H., and Robert T. Means. "Extremely elevated serum ferritin levels in a university hospital: associated diseases and clinical significance." The American journal of medicine 98.6 (1995): 566-571.

Hearnshaw, Sarah, Nick Paul Thompson, and Andrew McGill. "The epidemiology of hyperferritinaemia." World journal of gastroenterology 12.36 (2006): 5866. - ! WARNING ! this link will download the whole September issue, with the potential to fatally clog your internet hole.

Janka, Gritta E. "Hemophagocytic syndromes." Blood reviews 21.5 (2007): 245-253.