Labs

The following is the patient’s complete blood count (CBC) when you see her in clinic:

WBC (109/L)Hb (g/dL)Hct (%)MCV (fL)PLT (109/L)
6.813.141.793189

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

Here are the results of her iron indices:

Here are the results of her iron indices:

Is the patient iron deficient?

a
Yes
b
No
c
Maybe
See next slide for explanation.

Is the patients low serum ferritin of 24 ng/ml (mg/L) diagnostic of iron deficiency? Let’s look at the data:

Below are recommended serum ferritin cutoffs to determine iron deficiency:

Cross-sectional studies have examined the sensitivity and specificity of serum ferritin concentrations for diagnosing iron deficiency, using iron staining of bone marrow aspirate as the gold standard:

  • In a study of 203 women, SF concentration cutoff of < 30 mg/L resulted in a sensitivity and specificity of 93% and 75%, respectively
  • In a study of 123 patients, SF concentration
    • < 15 mg/L had a sensitivity of 72% and specificity of 96%
    • < 30 mg/L, had a sensitivity of 92% and specificity of 92%
  • In a study of 20 healthy students SF concentration:
    • < 40 mg/L had a sensitivity of 100% and specificity of 92%.
    • <15 mg/L had a sensitivity of 57% and specificity of 100%
  • In a study of 53 healthy students, SF concentration:
    • < 15 mg/L had a sensitivity of 60% and specificity of 100%
    • < 30 mg/L had a sensitivity of 100% and specificity of 89%

Our patient has a ferritin of 24 mg/L. Based on the data above, she has a pretest probability of iron deficiency of about 90%

Here are the results of her iron indices:

The next slide shows a schematic comparing iron homeostasis under normal conditions and in a state of iron overload.

A normal transferrin saturation (TSAT) is 20% to 45%.

Schematic showing transferrin synthesized in the liver and released into the blood circulation (abstractly represented by the whole field in which transferrin is shown). Iron is absorbed by the gastrointestinal tract and is released by tissue macrophages (not shown). Iron does not normally circulate freely, but is bound to transferrin. Each transferrin molecule can bind up to 3 molecules of iron. Normally, only about 30% of the iron-binding sites are occupied. Transferrin delivers iron to developing erythroid precursor cells in the bone marrow.

You review the outside labs and note that just 4 months ago, her transferrin saturation (TSAT) was 60-70% on two occasions, including on a fasting sample. Not knowing anything about the patient, what are the three likeliest causes of such a high TSAT?

Schematic showing transferrin synthesized in the liver and released into the blood circulation. Iron is absorbed by the gastrointestinal tract and is stored in and released by tissue macrophages (upper right). Iron does not normally circulate freely, but is bound to transferrin. Each transferrin molecule can bind up to 3 molecules of iron. Normally, only about 30% of the iron-binding sites are occupied. Transferrin delivers iron to developing erythroid precursor cells in the bone marrow
Schematic showing iron overload state (e.g., hereditary hemochromatosis). Note the increased absorption or iron from the intestines, and the increased release of iron from tissue macrophages into the blood (upper right), owing to an opening of the “floodgates” from reduced hepcidin (gatekeeper) function. As a result, serum iron increases, as does transferrin saturation. Over time, ferritin levels inside cells (especially, macrophages and hepatocytes) increase in order to accommodate storage of the iron. Ferritin is secreted into the circulation at levels proportional to the storage form.

In this case, there is no history of congenital hemolytic anemia (which is associated with ineffective erythropoiesis) or blood transfusion, two causes of iron overload. Therefore you wonder about a diagnosis of hereditary hemochromatosis and you order a genetic screen. The following are the results:

Are these results consistent with a diagnosis of hereditary hemochromatosis?

a
Yes
Either homozygous for C282Y or compound heterozygous for C282Y and H63D qualify for a diagnosis of hereditary hemochromatosis. H63D homozygosity does not.
b
No

Is it possible to have iron deficiency in a patient with hereditary hemochromatosis?

a
Yes
b
No

The patient has hereditary hemochromatosis, symptoms of iron deficiency and a low serum ferritin. These findings support a diagnosis of iron deficiency in the setting of hereditary hemochromatosis, probably secondary to menstrual blood loss. The patient is sufficiently symptomatic that she wishes to try a course of iron. She is administered IV Feraheme 510 mg x 2. Two months later, her iron indices are repeated:

Should the patient receive a phlebotomy at this point?

a
Yes
b
No
Despite the high TSAT, her iron stores are not elevated based on her normal ferritin level. The goal of phlebotomy is to maintain the serum ferritin < 50-100 ng/ml.

Hereditary hemochromatosis is seen more often (and tends to be more severe) in men than women. Some researchers believe that this may be due, in part, to a woman’s monthly blood loss through menstruation. Consequently, iron accumulation is slower in women than men, and the average age of diagnosis for women is approximately 10 years later than in men (usually after menopause).

This case highlights several important points:

  • Even patients with hereditary hemochromatosis may develop iron deficiency from bleeding.
  • The diagnosis of hereditary hemochromatosis may be masked by iron deficiency:
    • In this case, the ferritin was consistently normal.
    • The transferrin saturation (TSAT) may be normal, as seen when the patient was iron deficient.

An isolated elevation of TSAT (normal serum ferritin) is, in fact, a normal finding early on in all patients with hereditary hemochromatosis. This phenomenon is nicely captured in the following letter to British Medical Journal:

BMJ 2011;342:c7251

The following are labs from another patient, in this case a 21 year-old woman, that demonstrate an increased transferrin saturation (TSAT) prior to any increase in serum ferritin:

Hereditary hemochromatosis (HH) genetic screen:

Explaining an early elevation of transferrin saturation (TSAT) in the absence of elevated ferritin:

Whether early or late in the course of hereditary hemochromatosis, the hepcidin-controlled floodgates are wide open, promoting entry of iron into the circulation from the intestine and from storage pools (primarily in macrophages). This leads to excess iron in the blood and an elevated transferrin saturation as we saw in our original patient after her iron deficiency was treated. However, early on there is no demonstrable increase in storage iron (the serum ferritin is normal).
Later in the course of the condition, there is progressive accumulation of storage iron, which is reflected by an increase in tissue iron (stored as ferritin) and a parallel, proportional increase in serum ferritin.

Let’s consider transferrin saturation (TSAT) in more detail:

  • The transferrin saturation is the ratio of the serum iron concentration and the total iron binding capacity (TIBC) expressed as a percentage.
  • Approximately 2% of the adult US population has transferrin saturation levels greater than 55%.
  • Reported to have a sensitivity of greater than 90% for hemochromatosis.
  • Transferrin saturation is often elevated in young adults with hemochromatosis before the development of iron overload or a rise in ferritin concentration.
  • A common threshold used in screening studies is >45% in women and >50% in men.
  • There is considerable diurnal variations in TSAT:
    • Serum transferring is usually steady with no significant short-term fluctuations.
    • However, serum iron usually fluctuates diurnally and changes acutely depending on dietary iron intake.
    • Some, but not all, authorities recommend a fasting morning sample as a means to overcome this variability.
  • Transferrin is a negative acute protein. Inflammation results in lower TIBC but also lower serum iron, so the net TSAT is often reduced.
  • Transferrin is produced by the liver. Thus, TIBC is often reduced in cirrhosis. The serum iron may be normal or high leading to elevated TSAT.