Older Woman With Increased Fatigue

RONALD RUBIN, MD—Series Editor
Temple University

Dr Rubin is professor of medicine at Temple University School of Medicine and chief of clinical hematology in the department of medicine at Temple University Hospital, both in Philadelphia.



What's The "Take Home"?

An 80-year-old woman is brought to the office because her daughter thinks she has not been displaying her usual “vim, vigor, and energy” in recent months. Up until now she has enjoyed excellent health; she takes only low doses of a thiazide diuretic for mild essential hypertension and a statin for hypercholesterolemia.


Previous blood tests showed random glucose levels between 95 and 120 mg/dL. Specific current symptoms are vague, but she seems to be more easily fatigued with usual activity than previously and has been declining opportunities for family activities, which drew her daughter’s attention. During a review of systems, the patient reports occasional tingling in her feet. Her appetite seems good, but she has lost 10 lb in the past 6 months.


The patient appears healthy. She has no pallor of her conjunctivae or abnormalities in her mouth and tongue. Heart rate is 88 beats per minute, and she has a mild grade II flow murmur, which is audible over the precordium. The remainder of the examination is normal, including a mental and neurological evaluation.


A random blood glucose measurement shows a level of 101 mg/dL. Hemoglobin level is 10.8 g/dL with a mean corpuscular volume of 108 µm3 and normal white blood cell and platelet counts. A serum vitamin B12 level is 240 pg/mL; serum folate is normal; homocysteine is 24 µmol/L; and methylmalonic acid (MMA) is 1111 nmol/L.


A. Begin daily oral supplementation of vitamin B12 immediately with biochemical follow-up in 3 months

B. Have family members administer vitamin B12 intramuscularly every month.

C. Administer 2 injections of 1000 µg of vitamin B12 and reevaluate clinically and biochemically (metabolically) in 6 to 8 weeks.

D. Test for evidence of malabsorption, such as intrinsic factor and gastrin measurements.



Correct Answer: A

With the aging of the population, cobalamin (vitamin B12) deficiency has become more common and important. Newer testing paradigms are available that can help distinguish true tissue B12 deficiency—an important condition with serious hematologic and neurologic morbidity—from the more common but less clinically important “dietary” deficiency and borderline low B12 levels encountered by routine laboratory testing. In any evaluation, three major issues must be addressed1:

• Is the patient truly B12 deficient?

• Does a malabsorptive mechanism exist that is causing this deficiency?

• What constitutes the most rational therapeutic and monitoring strategy?


The first issue—is the patient truly B12 deficient—has been nicely resolved by the excellent evaluation reported with this case. Even now, serum vitamin B12 levels are not as accurate as would be hoped to make the diagnosis.1,2 Although a reading of less than 200 pg/mL has a reasonably high accuracy of true B12 deficiency,1 values in the low range of 200 to 300 pg/mL can be deceptive, especially in the geriatric population.1,3

Thus, a paradigm has ensued that utilizes changes in the metabolites that occur with true tissue B12 deficiency—namely, elevations of homocysteine to more than 25 µmol/L and MMA to levels higher than 1000 nmol/L as corroborative for tissue B12 deficiency.1 In fact, MMA levels are currently thought to be the most sensitive and specific assays to diagnose B12 deficiency.1,3

This patient exhibits a classic set of clinical findings, including a macrocytic anemia and subtle neurologic findings; has a B12 level in the lower range; and has positive secondary test results for specific metabolic accumulations. All of the above confirm that there is true B12 deficiency here.


The next question that needs always to be answered in the author’s opinion, as well as that of excellent literature,1,2 is whether or not there is true malabsorptive pathophysiology involved in the deficiency rather than the very common “food malabsorption,” dietary type of low B12 levels so common in elderly patients but far less common as a cause of true, clinically important tissue B12 deficiency. Examples of true malabsorptive B12 deficiency include classic autoimmune pernicious anemia, in which autoantibodies to gastric parietal cells result in their absence and the subsequent absence of the intrinsic factor required for B12 absorption.2 Other examples include the ever more common gastric surgeries for obesity as well as ileum disease and/or resection as with inflammatory bowel disease.

The importance of this differentiation in causation is that most authorities would choose lifelong parenteral B12 therapy rather than any oral B12 scheme when absorption is in question.1 In such instances, essentially no B12 can be absorbed by the oral route. In this patient, choice D (malabsorption testing) is thus an indicated and effective management strategy. Alternatively, starting an oral regimen prior to determining whether or not true malabsorption is present (choice A) is premature at best and is the least effective maneuver offered; therefore, it is the correct answer to the question posed here.


Finally, what is the most rational treatment and monitoring approach in B12 deficiency? As discussed above, when true malabsorption is demonstrated, parenteral B12 therapy should be given. Intramuscular injections are well tolerated by the patient and guarantee delivery of B12 into the body. An excellent technique that lowers cost even below that of oral supplementation is to instruct family members in administration of the injections, which can be given at home every 1 to 2 months (choice B). In this era of frequent insulin doses and the use of home parenteral anticoagulants such as low molecular weight heparins, convenient home B12 administration as described should be offered in most situations.

Choice C relates to cases in which the diagnosis remains in question—a therapeutic trial. In B12 deficiency this is very easy to do and, in fact, the literature offers such a trial as an alternative to malabsorption testing and even metabolic confirmation.1 Does the anemia and macrocytosis correct (this requires a 6- to 8-week period)? Does the neuropathy resolve and if metabolic testing was used to confirm the diagnosis, did it normalize (this takes only about 2 weeks or so)? If these occur, then the diagnosis is secure and the efficacy of therapy is proven.


On the initial follow-up visit, vitamin B12 1000 µg was given intramuscularly and the patient’s family was instructed in administering further injections. She received a total of 4 injections and was seen 6 weeks later when her hemoglobin level was 12.9 g/dL and her homocysteine and MMA levels had normalized. Both she and her family commented on the return of her usual energy. The tingling had resolved as well. An intrinsic factor antibody level was elevated. ■


1. Carmel R. How I treat cobalamin (vitamin B12) deficiency. Blood. 2008;112:2214-2222.

2. Toh BH, van Driel IR, Gleeson PA. Mechanisms of disease: pernicious anemia. N Engl J Med. 1997;337:1441-1448.

3. Tangney CC, Aggarwal NT, Li H, et al. Vitamin B12, cognition and brain MRI measures. Neurology. 2011;77:1276-1282.