Intramedullary hemolysis with a markedly elevated LDH can be seen in severe vitamin B 12 deficiency, which has many causes, but one cause in particular warrants consideration in this case: pernicious anemia. Pernicious anemia has an overall prevalence of about 0.1%, but is more common in older adults, and is estimated to be present in 2% to 3% of adults aged > 65 years. 2 Prevalence is also increased in patients with other autoimmune diseases such as vitiligo and hypothyroidism, which our patient has. 3 The pathophysiology of pernicious anemia relates to either autoimmune gastric parietal cell destruction and/or the development of antibodies against intrinsic factor, which is required for absorption of vitamin B 12. Early disease may present with macrocytosis and a normal hemoglobin initially, but anemia develops over time if left untreated. When the primary cause of pernicious anemia is gastric parietal cell destruction, there is also an associated lack of stomach acid production (achlorhydria) with resulting poor micronutrient absorption; specifically, vitamin D, vitamin C, and iron. Hence, 30% of patients diagnosed with pernicious anemia have concurrent iron deficiency, which may counteract macrocytosis and result in a normal mean corpuscular volume. 4 Some medications are also poorly absorbed in achlorhydric states, such as levothyroxine, and treatment doses need to be increased, which could explain his markedly elevated TSH despite presumed medication adherence.
Vitamin B 12 is essential for both the peripheral and central nervous systems. Longstanding severe B 12 deficiency can explain all of his neurological and neurocognitive changes. The most common neurologic findings in B 12 deficiency are symmetric paresthesias or numbness and gait problems. The sensory neuropathy affects the lower extremities more commonly than the upper. Untreated, patients can develop progressive weakness, ataxia, and orthostatic hypotension with syncope, as well as neuropsychiatric changes including depression or mood impairment, cognitive slowing, forgetfulness, and dementia.
Dr. Ulin:
Dr. Orlander, which pieces of objective data are most important in forming your differential diagnosis, and what tests would you obtain next?
Dr. Orlander:
The 3 most salient laboratory tests to me are a complete blood count, with all cell lines impacted but the hemoglobin and hematocrit most dramatically impacted, reticulocyte count of 0.8%, which is inappropriately low and hence suggests a hypoproliferative anemia, and the elevated LDH > 5000 IU/L.
Since my suspected diagnosis is pernicious anemia, I would obtain a blood smear looking for hypersegmented neutrophils, > 1 white blood cells with 5 lobes, or 1 with 6 lobes, which should clinch the diagnosis. Methylmalonic acid (MMA) levels are the most sensitive test for B 12 deficiency, so I would also obtain that. Finally, I would check a B 12 level, since in a patient with pernicious anemia, I would expect the level to be < 200 pg/mL.
Dr. Ulin:
Before we reveal the results of the patient’s additional workup, how do you approach interpreting B 12 levels?
Dr. Orlander:
Measuring B12 can sometimes be problematic: the normal range is considered 200 to 900 pg/mL, but patients with measured low-normal levels in the range of 200 to 400 pg/mL can actually be physiologically deficient. There are also several common causes of falsely low and falsely high B 12 levels in the absence of B 12 deficiency. Hence, for patients with mild symptoms that could be due to B 12 deficiency, many clinicians choose to just treat with B 12 supplementation, deeming it safer to treat than miss an early diagnosis. B 12 is involved in hydrogen transfer to convert MMA into succinyl-CoA and hence true vitamin B 12 deficiency causes an increase in MMA.