Labs

The following is the complete blood count (CBC) from the day you see the patient:

WBC (109/L)Hb (g/dL)MCV (fL)MCHC (g/dL)RDW-SDPLT (109/L)
9.310.77027.744.2334

What’s what: WBC, white blood cell count; Hb, hemoglobin; MCV, mean cell volume; MCHC, mean cellular hemoglobin concentration; RDW-SD, red cell distribution width-standard deviation; platelets, PLT; Normal values: WBC 5-10 x 109/L, RBC 4-6 x 1012/L, Hb 12-16 g/dL, Hct 35-47%, MCV 80-100 fL, MCHC 32-36 g/dL, RDW-SD < 45 fL, platelets (PLT) 150-450 x 109/L

The following are two ranges that pay off to memorize! It saves you having to look up the values each time you interpret a complete blood count.

Here is a diagnostic algorithm for anemia. Note that this patient has microcytic anemia.

Fill in the expected serum ferritin level (low, normal or high):

DisorderExpected ferritin level
Iron deficiency anemia
Thalassemia minor
Inflammation

Fill in the expected serum ferritin level (low, normal or high):

DisorderExpected ferritin level
Iron deficiency anemiaLow
Thalassemia minorNormal or slightly elevated
InflammationHigh

The patient’s following are the patient’s iron indices:

Note the very low TSAT, another clue of underlying iron deficiency.

The patient gives a compelling history of iron deficiency anemia with symptoms of pica and restless legs. Iron deficiency is usually associated with a low ferritin. Is it possible to have iron deficiency with a ferritin this elevated?

a
Yes
Iron deficiency with a ferritin this high is very unusual, but it may been seen in cases of ferritin leak from cells or the condition that this patient has (more on this shortly).
b
No

To understand what is going on we need to bite the bullet and consider some basic physiology:

Ferritin production is regulated at two levels:

  • Transcription (DNA –> mRNA)
  • Translation (mRNA –> protein)

In inflammation, cytokines (especially interleukin 6) promote ferritin gene transcription (production of mRNA from DNA).

Iron deficiency, by contrast, leads to a block in ferritin translation (production of protein from mRNA).

When both inflammation and iron deficiency are present, the suppressing effect of iron deficiency on ferritin protein synthesis “wins out” over cytokine-mediated induction of ferritin gene transcription. As result, no matter how powerful the inflammatory stimulus, concomitant iron deficiency typically prevents the ferritin level from exceeding about 100 ng/ml (there are some exceptions, most notably patients with end-stage renal disease on hemodialysis).

Let’s come back to our diagnostic buckets in patients with hyperferritinemia:

Assuming that the patient has iron deficiency, which of the following is/are true?

a
The patient can’t have iron overload and deficiency at the same time.
That’s stating the obvious!
b
She is unlikely to have concomitant inflammation with a ferritin this high.
Even patients with severe inflammation will not increase their ferritin this high in the setting of iron deficiency. Remember, the translational block of ferritin protein production in iron deficiency wins out over cytokine induction of ferritin transcription in inflammation when both conditions are present together.
c
She may have a condition associated with ferritin leak.
Yes, because leak is just a physical disruption of cells. It overrides any sophisticated control mechanisms of ferritin transcription and translation.

Hyperferritinemia associated with cellular leak refers to those situations in which damage to cells, for example hepatocytes or macrophages, leads to physical leakage of ferritin protein from the intracellular space into the blood. In this case, the leaked ferritin can raise the serum ferritin regardless of what is going on at a gene transcription or translation level.

But, cellular leak typically occurs in patients with serious underlying medical conditions, such as acute liver failure or hemophagocytic lymphohistiocytosis (HLH). Your patient is clinically stable and complains only of symptoms of anemia and iron deficiency.

Let’s look at her hemoglobin, mean cell volume and ferritin over time:

DateHb (g/dL)MCV (fL)Ferritin (ng/ml)
Day you see her10.7703789
2 weeks earlier11.570Not done
1 year earlier13.4852889
3 years earlier13.7823325

The patient’s anemia is:

a
Acquired

Correct. The hemoglobin was normal, now it is low.

b
Hereditary

The patient has symptoms of iron deficiency and an acquired microcytic, hypochromic anemia. However, her ferritin is chronically elevated including today when you see her. In the absence of a medical condition associated with ferritin leak from cells, how do you reconcile these findings of suspected iron deficiency + elevated serum ferritin.

  • What’s going on?
  • Should the patient be treated for iron deficiency?
  • What other tests could be done to confirm that the patient is iron deficient?

Let’s begin with the last question first. There is another test for iron deficiency called serum zinc protoporphyrin. The following is a schematic of heme biosynthesis. Normally the last step incorporates iron in protoporphyrin, giving rise to iron protoporphyrin (also called heme). In the absence of iron (i.e., in iron deficiency anemia), zinc is incorporated instead of iron leading to zinc protoporphyrin, which can be assayed in the blood.

Zinc protoporphyrin is a “send out” lab, and takes some time for the results to return. So we will have to make some treatment decisions without this result. However, let’s take a sneak preview of the test result that came back about 2 weeks later:

These results are consistent with a diagnosis of iron deficiency.

The answer to this puzzle is that patient has a condition called hereditary hyperferritinaemia cataract syndrome (HHCS)!

HHCS is a rare autosomal dominant genetic disease first described in 1995 as an autosomal dominant disorder, and characterized by significantly raised serum ferritin and bilateral congenital cataracts. There is no evidence of iron overload, inflammation or malignancy.

Ferritin has an iron responsive element (IRE) in the 5′-untranslated region (5′-UTR). Low iron levels result in binding of inhibitory proteins to the IRE that inhibit translation (and therefore ferritin protein production). Increasing iron levels displace these proteins from the mRNA, allowing translation to proceed.

In HHCS, there is a mutation in the IRE of the L-ferritin gene (there are two types of ferritin: L and H). This leads to:

  • Disruption of the interaction between IRE and IRE-regulatory proteins (IRP).
  • Relief of translational inhibition of L-ferritin.
  • Constitutive expression of L-ferritin and hyperferritinemia.
  • L-ferritin accumulation in the lens of the eye.

The single clinical manifestation of HHCS is early-onset bilateral cataracts.

Post-transcriptional control of ferritin synthesis by the IRP/IRE... |  Download Scientific Diagram
Post-transcriptional control of ferritin synthesis by the IRP/IRE network. Iron depletion activates IRP-1 and -2 for binding to the IRE in the 5′-untranslated region of ferritin mRNA. This IRP-IRE interaction prevents translation of ferritin and eventually decreases ferritin protein levels. IRP, iron-regulatory protein. Source.

How cool is that?!

The patient eventually had DNA sequencing performed to confirm the diagnosis of HHCS at a molecular level. She was found to have a characteristic mutation in the 5′-untranslated region. These are her actual results: