Vitamin B12 deficiency results in neuropsychiatric, hematologic, gynecologic, cardiovascular, and cutaneous manifestations. It is seen most commonly in the elderly, malabsorption diseases (>60% of all cases), vegans, and vegetarians. Manifestations of pernicious anemia may be similar to Addison disease and may lead to a misdiagnosis. Herein, we report two cases of vitamin B12 deficiency in which clinical features shared many similarities with Addison disease. Both patients presented with progressive darkening of hands and postural hypotension that reversed with replenishment of vitamin B12. Vitamin B12 deficiency should be considered in patients presenting with skin lesions especially with other coexisting autoimmune diseases.
Vitamin B12 is a water soluble vitamin, present in various forms: cyanocobalamin (vitamin B12), hydroxocobalamin (vitamin B12a), aquacobalamin (vitamin B12b), nitritocobalamin (vitamin B12c), 59-deoxyadenosylcobalamin (coenzyme B12), and methylcobalamin (methyl B12). Its deficiency is a major health issue and a major diagnostic challenge; its presentation varies from being asymptomatic to affecting multiple organ systems. Some of the better studied and better known manifestations are hematologic such as macrocytic anemia, pancytopenia and neurological, such as orthostatic hypotension, paraesthesias, and abnormal gait [
A 40-year-old African American woman with history of myasthenia gravis, Hashimoto’s thyroiditis stable on thyroxine replacement, and childhood asthma was seen in the outpatient clinic for numerous complaints including fatigue, multiple syncopal episodes, and diffuse darkening of the palms of both hands for the past 3 to 4 months. There was no rash or dermatitis preceding the onset of hyperpigmentation.
She is a nonvegetarian and reports occasional alcohol use but no smoking or illicit drugs. She has a family history of type 2 diabetes mellitus, heart disease, hypertension, autoimmune disorders, and hypothyroidism.
Physical examination showed a well-developed woman in no distress. Her blood pressure was 113/88 sitting, 105/76 standing, temperature of 37° Celsius, pulse of 92 (sitting), 112 beats/minute (standing), and respiratory rate of 16 breaths/minute. She had pale mucus membranes. The respiratory, cardiovascular, neurological, and abdominal examinations were unremarkable. Axillary and pubic hairs was intact. Her extremities showed diffuse hyperpigmented, nonpruritic, and macular lesions on the palms and soles bilaterally (Figure
Pertinent laboratory studies were as noted in Table
Summary of patient’s laboratory results.
Investigation | Pretreatment | Posttreatment | Reference range* |
---|---|---|---|
Hemoglobin (gm/dL) | 10.9 | 10.8 | 12–16 gm/dL |
Hematocrit % | 31.6 | 31.1 | 43.3%–46.6% |
Mean corpuscular volume: MCV (fL) | 113 | 86.4 | 80–100 fL |
Serum vitamin B12 (pg/mL) | 67 | 412 | 200–950 pg/mL |
Thyroid-stimulating hormone: TSH (milli-int units/L) | 1.36 | 0.4–4.0 mIU/L | |
Free thyroxine (microgm/dL) | 1.47 | 0.7–2.0 mcg/dL | |
Plasma morning cortisol (microgm/dL) | 7.1 | ||
Post-adrenocorticotropic hormone (ACTH) plasma cortisol (microgm/dL) | 27.3 | Normal > 18 |
The patient was started on 1,000
A 65-year-old African American woman was rushed to the hospital by ambulance following an episode of syncope at a community supermarket. She regained consciousness within a few minutes. There was no tongue biting, urinary incontinence, or postictal confusion. She reported some premonitory symptoms of warmth and sweating and gave a history of light-headedness, weakness, and fatigue over the last 2 weeks. She denied palpitations, chest pain, shortness of breath, fever, dizziness, or visual changes. She denied headache or weakness.
Over the last couple of months, she had multiple episodes of fall but no loss of consciousness. The falls were increasing in frequency over the last 2 weeks. She lived alone and had a history of hypertension for almost thirteen years for which she was noncompliant with her medications. She did not smoke, drink alcohol, or use any illicit drugs. Her mother had hypertension and died at the age of 80 years from heart disease.
On examination, her temperature was 37°C, the respiratory rate was 24 breaths per minute, and blood pressure while supine was 89/52 mm Hg, with a heart rate of 52 beats per minute; on standing, her blood pressure fell to 69/40 mm Hg, with a heart rate of 74 beats per minute. Her blood glucose level was 120 mg per deciliter. Oxygen saturation was 100 percent on 2 liters of oxygen via nasal cannula.
Physical evaluation showed no signs of head trauma. Her respiratory, cardiovascular, and abdominal examinations were unremarkable. Neurological examination showed decreased sensation to light touch in a stocking and glove distribution. Upper limb reflexes were brisk and lower limb reflexes were absent. Vibratory sensation and position sense were decreased in both upper and lower limbs. An extensor plantar response was noted bilaterally and Romberg’s test was positive. There was hyperpigmentation of both palms with dark discoloration of the nails (Figure
Contrast computed tomography (CT) of the head showed no obvious lesion. An electrocardiogram revealed sinus bradycardia at a rate of 50 beats per minute with no ST or T wave changes. A 24-hour holter monitoring was performed which revealed sinus bradycardia without other arrhythmias.
Her laboratory studies were as shown in Table
Summary of patient’s laboratory results.
Investigation | Patient value (pretreatment) | Reference range* |
---|---|---|
Hemoglobin | 10.5 gm/mL | 12–16 gm/dL |
Hematocrit | 30.4 | 43.3%–46.6% |
MCV | 121 fL | 80–100 fL |
Platelet |
|
177–406 Th/cm |
Total white count |
|
|
Peripheral smear | Macrocytosis | — |
Serum vitamin B12 | 55 pg/mL | 200–950 pg/mL |
Serum folate | ||
Plasma morning cortisol mcg/mL | 10.24 | |
Post-ACTH plasma cortisol | 41.11 | Normal > 18 |
Serum alcohol levels were undetectable and urine toxicology was negative. Esophagogastro-dudodenoscopy was performed and the gastric biopsy was suggestive of chronic atrophy of the body and fundus. The endoscopic findings were further reinforced by high serum levels of antibodies to intrinsic factor and gastric parietal cells confirming malabsorption of vitamin B12 due to lack of intrinsic factor. Thus, the diagnosis of pernicious anemia was established.
The patient was started on intramuscular injection of vitamin B12 (1,000
Studies show a prevalence of cobalamin deficiency around 20% (ranging from 5 to 60% depending on parameters for cobalamin) in industrialized nations [
In pernicious anemia, the gastric parietal cells are targeted by the autoimmune process. Hence, the production of intrinsic factor is affected leading to defective absorption of vitamin B12.
The effects of vitamin B12 deficiency on the hematologic, nervous, and gastrointestinal systems are well studied. It has been implicated as a cause of orthostatic hypotension [
Historically, Thomas Addison described pernicious anemia and Addison’s disease. There is a debate about whether Thomas Addison himself mistakenly reported both clinical entities in his 1855 monograph on adrenal disease [
The dermatologic manifestations, first described in 1944 by Dr Bramwell Cook [
An understanding of the enzymatic reactions dependent on vitamin B12 helps appreciate the mechanisms involved in the development of neurological complications. Two principal enzymatic reactions require vitamin B12 as a key cofactor: the mitochondrial conversion of methylmalonyl-CoA to succinyl-CoA and the cytoplasmic methyl transfer reaction that converts homocysteine to methionine. The latter reaction is accompanied by the conversion of methyltetrahydrofolate to tetrahydrofolate, a precursor for purine and pyrimidine synthesis. The interruption of this step due to vitamin B12 deficiency leads to impaired synthesis of DNA and a megaloblastic maturation pattern of hematopoietic cells [
Methionine is converted to S-adenosylmethionine (SAM) which methylates neurotransmitters and phospholipids [
Our cases highlight the fact that the clinical presentation of vitamin B12 deficiency may be similar to Addison disease and patients can present with primarily cutaneous symptoms that improved dramatically with vitamin B12 replacement. Very few other cases to our knowledge have had similar presentations. This is to emphasize that early recognition of mucocutaneous symptoms may aid to prevent severe irreversible neurological complications in the future [
Vitamin B12 deficiency may be more common than generally thought and is most likely under-diagnosed due to varied and unusual presentations. It may be worthwhile to consider vitamin B12 deficiency and determine serum B12 level in all the patients with symptoms suggestive of Addison disease such as hyperpigmentation and orthostatic hypotension. Early diagnosis can limit morbidity and inappropriate workups. Hyperpigmentation associated with vitamin B12 deficiency is completely reversible with treatment.
The authors declare no conflict of interests.