Mr. J is a 55-year-old man who presents with a 6-month history of progressive fatigue and a 3-month history of "legs that hop all over the place when I am sitting in the evening or trying to get to sleep." He was last seen by another primary care provider about 2 years ago and was told he was in good health. His daily medications include a multivitamin and a full-strength aspirin. Currently, he denies any new life stress other than sleep disturbance.

A review of his systems is noncontributory with the exception of intermittent upper gastrointestinal upset, or "heartburn" he attributes largely to dietary indiscretion. He denies the presence of melena or frank blood in stool. He does not smoke and drinks one to two beers on two occasions in an average week. He is not physically active and works as an accountant. On physical examination, findings show his body mass index at 34 kg/m2 and blood pressure at 152/98. The rest of his physical examination is within normal limits. Using a validated scale, Mr. J's report of involuntary leg movement meets diagnostic criteria for restless leg syndrome (RLS).

Findings

Upon laboratory diagnosis, the following findings were noted: (See Table: "Laboratory Studies").

These laboratory findings are consistent with iron deficiency anemia (IDA) with the exception of a normal serum iron. Therefore, how did Mr. J develop an IDA? Why is his serum iron within normal limits while other laboratory indicators point to a diagnosis of IDA? Is his new report of RLS associated with this anemia?

IDA

Worldwide, iron deficiency is the most common reason for anemia. Men and postmenopausal women require 1 mg of iron each day. During reproductive years, women require 1.5 to 3 mg per day of iron, in part because of the monthly loss of RBCs with menses. In each of these circumstances, iron requirements are achievable with a well-balanced diet. Because an estimated 8 years of poor iron intake is needed in adults before IDA occurs, diet is rarely its origin. Rather, chronic blood loss causing a wasting of the RBCs' recyclable iron is the most common cause.

Occult gastrointestinal blood loss-such as from an oozing erosive gastritis or gastrointestinal malignancy-is a common cause of IDA, as is excessive menstrual flow. One mL of packed RBCs contains 1 mg of iron, so even losses of 2 to 3 mL of blood through the gastrointestinal tract can lead to iron deficiency.1,2 In Mr. J's case, fecal occult blood tests were positive in three samples from three different stools. Upper and lower gastrointestinal endoscopy revealed an erosive gastritis, which likely was the source of his anemia. Helicobacter pylori testing was negative. His lower gastrointestinal tract was normal.

Diagnosis

Microcytosis is usually seen in patients with impaired hemoglobin synthesis. In addition, because hemoglobin gives RBCs their characteristic red color, smallness and pallor go together. Thus, a microcytic cell will also be hypochromic (low mean hemoglobin concentration).

RDW reflects the degree of variation in RBC size. This measurement is elevated when RBCs are of varying sizes, which implies that cells were synthesized under different conditions. In IDA, normocytic cells produced before iron depletion will continue to circulate until their 90- to 120-day lifespan ends. The new, smaller, iron-deficient cells containing less hemoglobin are produced, and the RDW increases (above 15%) as a result of this cell size variation. This finding is often described as anisocytosis in RBC morphologic studies.1,2

In IDA, the order of the changes in laboratory markers is as follows:

* ferritin (decreases as iron stores are depleted)

* iron in marrow (absent as marrow stores are exhausted)

* serum iron (decreases as less iron is available to circulate)

* RDW (increases as new cells are smaller than older cells, one of the earliest IDA markers)

* TIBC (increases as more iron binding sites open)

* hemoglobin and hematocrit (decreases as fewer RBCs are produced, a later IDA marker)

* RBC indices (becomes altered as smaller, paler cells are produced, a later IDA marker).1,2

Mr. J's serum iron was not consistent with the IDA diagnosis. Upon futher questions, Mr. J reported that he had, in response to his fatigue, changed his usual multivitamin to a product with iron and was taking up to three tablets per day. Since serum iron is essentially a drug level measurement, ingestion of any iron supplement within 24 hours of the test creates a normal or increased level in the presence of IDA.3

Treatment

IDA therapy involves both iron replacement and treatment of the underlying cause. With Mr. J, treatment of the erosive gastritis included discontinuation of the daily aspirin therapy and initiation of a proton pump inhibitor to facilitate gastric healing. Oral iron therapy was also prescribed. Other health issues, including obesity and hypertension, were also addressed.

RLS is a common condition. Primary RLS is considered an idiopathic central nervous system disorder that evokes milder symptoms earlier in life that worsen in middle age.4,5 Mr. J had not displayed RLS symptoms until recently; his history is more consistent with secondary RLS.

Iron deficiency is one of the most commonly reported causes of RLS with symptoms usually resolving themselves once the underlying condition is treated.4,5 After approximately 6 weeks of iron therapy, Mr. J reported a significant improvement in his RLS symptoms. Within 6 months, his anemia was corrected, ferritin stores were normalized, and his RLS symptoms and fatigue were resolved.

References