Question 12.1

The following data refer to a 65-year-old male admitted to ICU with septic shock on a background of active rheumatoid arthritis.

Parameter

Patient Value

Adult Normal Range

Haemoglobin

86 g/L*

125 – 180

Serum ferritin

298 µg/L

15 – 300

Serum iron

7 µmol/L*

9 – 27

Total Iron Binding Capacity (TIBC)

52 µmol/L

47 – 70

Transferrin Saturation (Iron / TIBC x 100)

28%

16 – 40

Erythropoietin level

15 U/L

4 – 28

C-reactive protein (CRP)

321 mg/L*

< 8

a) What abnormality is demonstrated in this patient? Give your reasoning. (20% marks)

b) What is the pathogenesis of these changes?                                               (20% marks)

c) What are the principles of management?                                                      (10% marks)

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College answer

  1. Anaemia of Inflammation demonstrated by:
    • decreased haemoglobin
    • decreased iron
    • normal to high ferritin
    • suppressed erythropoietin
    • elevated CRP.
  1. Inflammation -> cytokines (IL6) -> increased hepcidin -> decreased iron release from bone marrow, decreased iron release from macrophages, decreased absorption of iron -> suppressed erythopoeisis
  1. Control inflammation, no value to iron replacement, no value to the use of erythropoietin.

Discussion

This question is essentially identical to Question 18.1 from the first paper of 2015, except in the older SAQ question (c) reads "what specific treatment strategy would correct the demonstrated abnormality" instead of "what are the principles of management".  These two alternative wordings must surely mean the exact same thing, because  the college answer was identical for both versions of the question.

Anyway: a generic iron studies interpretation rubrik looks like this:

Interpretation of Abnormal Iron Studies
Condition MCV MCHC Serum iron Ferritin Transferrin Transferrin
saturation
TIBC
Iron deficiency anaemia low low low low high <20% high
Anaemia of inflammation (chronic disease) low low low normal low normal low or normal
Acute phase response normal normal low high low low low
Iron overload normal normal high high normal high high

The college answer refers to "Anaemia of Inflammation", a nomenclature which has superseded "anaemia of chronic disease" as  the description of the anaemia which has low serum iron in spite of normal body iron stores (i.e. normal ferritin). This "inflammation" could actually be anything proinflammatory, and so it would be difficult to comment whether the rheumatoid arthritis is more responsible then the sepsis, or vice versa. In either case, the biochemical picture would be more or less the same.

Alternative explanations for these laboratory results could also include the anaemia of decreased erythropoietin release associated with renal failure; but the college specifically gave us RA, sepsis and a raised CRP, clearly aiming the candidates at something inflammatory. Iron studies in anaemia of chronic renal failure tend to demonstrate iron deficiency, i.e. the ferritin is also low, but there is a group in whom there is a "functional" iron deficiency with normal ferritin levels and a failure of iron release from body stores (Babitt & Lyn, 2012). If the inflammatory elements were omitted from the story, this would be a legitimate alternative explanation.

The erythropoietin level is a weird thing to add because it is expensive and not usually a part of the normal panel. The  RPCA Manual lists it as one of the tests "occasionally indicated" to discriminate primary from secondary erythrocytosis. It is not essential to the diagnosis of anaemia.

The mechanism of anaemia of inflammation can be summarised as follows:

  • Decreased iron availability
    • Cytokine release in inflammation (mainly IL-6) stimulates the synthesis of hepcidin, a regulatory molecule which controls the release of iron into the circulation.
    • A high hepcidin level decreases the availability of iron by promoting "iron trapping" within the bone marrow and macrophages. Thus, the iron stores in this form of anaemia are normal, which renders iron infusion pointless.
    • In the absence of circulating iron, erythropoiesis is restricted.
  • Increased erythrocyte phagocytosis
    • Cytokine-activated macrophages destroy red cells at an increased rate
    • This reduces the lifespan of erythrocytes.
  • Decreased erythropoiesis signals
    • Cytokines act directly on the bone marrow to reduce the rate of erythropoiesis, independent of the levels of circulating erythropoietin
    • Occasionally the level of erythropoietin is also suppressed, which is thought to be a cytokine-related effect acting on its renal secretion.

Routine management of such an anaemia is therefore somewhat unexciting:

  • Iron infusion is futile, as the iron stores are essentially intact
  • Erythropoietin supplementation is futile, as the bone marrow won't respond anyway
  • Blood transfusion is what you'd resort to while treating the cause of the inflammation

But let's say that for some reason you've lost interest in treating causes of things. Can we cosmetically make the iron study numbers look better? Turns out that yes, we can. There are several possible treatments for this sort of anaemia which specifically target the mechanism of its pathogenesis:

  • Tocilizumab, a monoclonal antibody against the IL-6 receptor
  • A thus-far unnamed hepcidin-binding monoclonal antibody may soon become available (apparently, in 2014 it was in Phase 2 trials)
  • Heparin reduces hepcidin production, but in prescribing overmuch heparin to the anaemic patient one might be merely exchanging one problem for another.

References

Hawkins, Stephen F., and Quentin A. Hill. "Diagnostic Approach to Anaemia in Critical Care." Haematology in Critical Care: A Practical Handbook (2014): 1-8.

Gross, I. "Laboratory Studies in the Diagnosis of Iron Deficiency, Latent Iron Deficiency and Iron Deficient Erythropoiesis". from http://iron.sabm.org

Pieracci, Fredric M., et al. "A Multicenter, Randomized Clinical Trial of IV Iron Supplementation for Anemia of Traumatic Critical Illness*." Critical care medicine 42.9 (2014): 2048-2057.

Litton, Edward, et al. "The IRONMAN trial: a protocol for a multicentre randomised placebo-controlled trial of intravenous iron in intensive care unit patients with anaemia." Crit Care Resusc 16 (2014): 285-290.

Corwin, Howard L., et al. "Efficacy of recombinant human erythropoietin in critically ill patients: a randomized controlled trial." Jama 288.22 (2002): 2827-2835.

Mesgarpour, Bita, et al. "Safety of off-label erythropoiesis stimulating agents in critically ill patients: a meta-analysis." Intensive care medicine 39.11 (2013): 1896-1908.

Nemeth, Elizabeta, and Tomas Ganz. "Anemia of inflammation." Hematology/Oncology Clinics 28.4 (2014): 671-681.

Babitt, Jodie L., and Herbert Y. Lin. "Mechanisms of anemia in CKD." Journal of the American Society of Nephrology (2012): ASN-2011111078.

Nemeth, Elizabeta, and Tomas Ganz. "Anemia of inflammation." Hematology/Oncology Clinics 28.4 (2014): 671-681.