Check these studies out! I printed a few copies for my medical practice Abstract
Although cobalamin (vitamin B12) deficiency was described over a century ago, it is still difficult to establish the correct diagnosis and prescribe the right treatment. Symptoms related to vitamin B12 deficiency may be diverse and vary from neurologic to psychiatric. A number of individuals with vitamin B12 deficiency may present with the classic megaloblastic anemia.
In clinical practice, many cases of vitamin B12 deficiency are overlooked or sometimes even misdiagnosed. In this review, we describe the heterogeneous disease spectrum of patients with vitamin B12 deficiency in whom the diagnosis was either based on low serum B12 levels, elevated biomarkers like methylmalonic acid and/or homocysteine, or the improvement of clinical symptoms after the institution of parenteral vitamin B12 therapy. We discuss the possible clinical signs and symptoms of patients with B12 deficiency and the various pitfalls of diagnosis and treatment.
Abbreviations and Acronyms: CoA, coenzyme A; holoTC, holotranscobalamin; IF, intrinsic factor; IM, intramuscularly; MMA, methylmalonic acid
Several scientific articles and textbooks have described the clinical presentation of patients with cobalamin (vitamin B12) deficiency.1, 2 After the classic presentation of Addison-Biermer disease with megaloblastic anemia, many generations of doctors have been educated with the view that vitamin B12 deficiency exclusively presents itself with this type of anemia. Additional cases have been reported in which neurologic abnormalities were the main presenting symptom, with subacute combined degeneration of the spinal cord as one of the most feared manifestations,3 often leading to permanent disability. Lindenbaum et al4 reported a large series of 40 patients who had neurologic symptoms or psychiatric disorders caused by vitamin B12 deficiency but who had no anemia or macrocytosis. Psychiatric symptoms may vary from depression to mania, psychosis, and occasionally suicidal thoughts (Supplemental Table 1, available online at mcpiqojournal.org).5 The reason why some patients mainly present with megaloblastic anemia and others with neurologic symptoms remains unknown.
Laboratory investigations with the establishment of low serum B12 levels and elevated levels of methylmalonic acid (MMA) are the cornerstone of diagnostics, but normal levels of serum B12 and MMA do not exclude symptomatic B12 deficiency. In clinical practice, many cases of B12 deficiency are overlooked or sometimes even misdiagnosed because of misconceptions and misbeliefs among health care professionals. We have summarized the most frequently encountered misconceptions and misbeliefs regarding vitamin B12 deficiency in Table 1.
Patient D
Patient D is a 33-year-old woman with a history of fatigue, inertia, indolence, paresthesia in her hands and feet, difficulties concentrating, problems with remembering things, and word finding disturbances. An acquaintance mentioned to her the possibility of vitamin B12 deficiency. Her primary care physician ordered a serum vitamin B12 measurement, which was 190 pmol/L, and subsequently advised her to start hydroxocobalamin injections. Her MMA and homocysteine levels were unfortunately not measured. After 5 weeks of treatment, her symptoms had decreased considerably. Her physician then ordered repeated serum vitamin B12 measurement, which revealed a value of more than 1476 pmol/L. Subsequently, the physician became concerned about possible vitamin B12 intoxication and asked the patient to stop treatment. Five to 6 weeks later, her symptoms had increased substantially. She was referred to our clinic for evaluation. Her main question was why this successful treatment was stopped. Hydroxocobalamin injections were restarted, in a frequency of twice weekly, which resulted in a gradual improvement of her symptoms. This case illustrates the difficulties of an incomplete diagnostic work-up and also the dangers of measuring serum vitamin B12 levels during parenteral administration. Hydroxocobalamin is not toxic, and successful treatment should not be stopped. Usually, the period between injections can be prolonged when all symptoms have disappeared.
Patient A
Patient A is a 55-year-old woman admitted to the psychiatry department of our hospital because of depression. In addition to symptoms related to her depression, she reported pain in the lower legs, paresthesia and numbness in the feet, and difficulty walking. Her history included Graves disease, for which she had undergone thyroidectomy several years earlier and was subsequently prescribed levothyroxine. We were invited for consultation because of slightly elevated free thyroxine levels. The patient had no symptoms suggestive of thyrotoxicosis. On examination, she had signs of severe peripheral neuropathy of the lower legs (absent reflexes, superficial and deep sensation) and several skin lesions compatible with vitiligo. Laboratory studies (also summarized in Supplemental Table 2, available online at mcpiqojournal.org) (reference ranges provided parenthetically) revealed a hemoglobin level of 7.0 mmol/L (>7.5 mmol/L) and mean corpuscular volume of 105 fl (85-98 fl). Her serum vitamin B12 level was 51 pmol/L (145-450 pmol/L). These findings prompted the diagnosis of pernicious anemia caused by vitamin B12 deficiency, and hydroxocobalamin injections were initiated immediately. Within 3 to 4 weeks, the patient reported that her symptoms gradually lessened, and her walking capacity improved. Additional laboratory tests revealed the presence of antibodies against parietal cells and intrinsic factor (IF). Six weeks later, the attending psychiatric resident ordered an additional serum vitamin B12 measurement. Because the serum vitamin B12 level was greater than 1476 pmol/L, hydroxocobalamin injections were stopped after consultation with an internal medicine resident. The patient was discharged home 3 months later, but no follow-up appointment at our outpatient clinic was made. The discharge letter did not mention the diagnosis of pernicious anemia, nor the treatment with hydroxocobalamin injections. This exclusion went unnoticed until 8 months later, when we realized she was lost to follow-up and invited her for a follow-up visit. She presented at our outpatient clinic shortly thereafter and reported a severe increase of her symptoms. One month earlier, her primary care physician had ordered measurement of her serum vitamin B12 level, which was 251 pmol/L; he did not restart treatment because he was unaware of the earlier findings. We strongly advised the patient to recommence hydroxocobalamin injections, which she continued twice weekly for the following 2 years. Gradually, her symptoms abated. Two years later, there were still bouts of pain, numbness, and paresthesia, but she was able to walk supported only by a walking stick. This case is a clear example of pernicious anemia in the constellation of a polyglandular autoimmune syndrome. Unwarranted cessation of therapy may lead to severe worsening of neurologic abnormalities and irreversible damage.
Patient B
Patient B is a 17-year-old girl who had a 2-year history of fatigue, sleepiness, numbness in her hands, dizziness, exertional dyspnea, and problems with concentrating and finding the correct words while in conversations. Table 2 summarizes her most important symptoms. Because her mother had presented with symptomatic vitamin B12 deficiency 6 months earlier, she was tested as well. Clinical examination did not reveal major abnormalities. Laboratory examination yielded a total serum vitamin B12 level of 112 pmol/L, with an intermediate level of holotranscobalamin (holoTC) of 54 pmol/L (40-125 pmol/L) and a low total haptocorrin concentration of 162 pmol/L (203-596 pmol/L). Her MMA value was 178 nmol/L (<300 pmol/L), homocysteine level was 11 pmol/L (<10 pmol/L), and folate concentration was 19 nmol/L (10-36 nmol/L). Antibodies against parietal cells, IF, and transglutaminase/gliadin were absent. Because of our clinical suspicion of vitamin B12 deficiency, she was treated with hydroxocobalamin, 1000-μg injections twice weekly, with a beneficial effect on her symptoms (Table 2). As can be appraised from her symptom list, many improved considerably or resolved completely. This case illustrates the clear clinical syndrome of vitamin B12 deficiency despite intermediate holoTC and normal MMA levels.
Patient E
Patient E is a 68-year-old woman who was treated by a hematologist in another hospital for a period of 3 years because of macrocytic anemia (hemoglobin, 7.5 pmol/L; mean corpuscular volume, 110 fl). There was no history of alcohol abuse. Extensive evaluation revealed no other abnormalities, and her serum vitamin B12 value was 301 pmol/L. She had already been treated for several years with levothyroxine because of primary hypothyroidism. Myelodysplastic syndrome was diagnosed by bone marrow aspiration, and she received blood transfusions twice. In 2017, she experienced progressive pains in her legs and almost completely lost the feeling in her feet; she was not able to walk outside her house anymore. Even walking in her home was extremely difficult and painful. Additional laboratory examinations did not reveal any new abnormalities. She was admitted to the neurology department in another hospital and found to have severe polyneuropathy. Magnetic resonance imaging of the spinal cord showed symmetric bilateral high signal within the dorsal columns, suggestive of subacute combined degeneration of the cord; magnetic resonance imaging of the brain revealed minimal white matter lesions. Again, her serum vitamin B12 level was normal, as were thiamine, pyridoxine, and folate values. No signs or laboratory abnormalities consistent with connective tissue disease or other causes of polyneuropathy were found. Biochemical and microbiological evaluation of cerebrospinal fluid revealed no abnormalities. After 2 weeks of observation, her doctors decided to initiate hydroxocobalamin treatment. Two days later, results of additional testing were returned: her MMA level was 37,000 nmol/L, and her homocysteine value was 165 μmol/L. These findings confirmed the existence of severe vitamin B12 deficiency. Additional testing yielded a high titer of antibodies against IF and parietal cells. Because of uncertainty about the diagnosis, she was referred to our outpatient clinic 2 months later. No additional clues arose from history or physical examination. Repeated examination of the bone marrow specimen did not confirm a diagnosis of myelodysplastic syndrome and showed only a slight increase of erythropoiesis. The most likely diagnosis was Addison-Biermer disease and interference in the vitamin B12 assay by the IF autoantibodies. No serum samples were left to test this hypothesis. Six months after diagnosis and initiation of high-dose hydroxocobalamin treatment, the patient still had considerable neurologic damage, loss of sensations in her feet and legs, and inability to walk without the use of a rollator walker. The anemia has resolved completely. This case is a classic example of how the assay for serum vitamin B12 can be wrong because of interference of the assay by IF autoantibodies.
Discussion
We have described the disease spectrum of a number of patients who attended our outpatient clinic with possible vitamin B12 deficiency in whom the diagnosis was either based on low serum vitamin B12 levels, elevated biomarkers like MMA and/or homocysteine, or the improvement of clinical symptoms after the institution of parenteral vitamin B12 therapy. Altogether, these cases show the considerable heterogeneity of vitamin B12 deficiency. Not all cases were easy to recognize or diagnose. The most prevalent symptoms of vitamin B12 deficiency are neurologic, such as paresthesia in hands and feet, muscle cramps, dizziness, cognitive disturbances, ataxia, and erectile dysfunction, as well as fatigue, psychiatric symptoms like depression, and macrocytic anemia.1, 2, 7, 8, 9, 10 However, there is evidence that in the Western world as well as China, less than 20% of people with demonstrable low serum vitamin B12 levels have macrocytic anemia.11, 12, 13, 14 Although the demonstration of low serum vitamin B12 levels is considered diagnostic, there is a poor correlation between these levels and symptoms,8, 9, 15 and even people with vitamin B12 levels below 140 pmol/L may not have symptoms.16 This factor sheds a different light on the discussion regarding appropriate cutoff levels for serum vitamin B12 and related parameters. Some investigators suggest that it is necessary to establish different reference cutoffs according to age and the applied analytic method.17 However, serum vitamin B12 tests also may fail because many people with symptoms related to cobalamin deficiency may have serum vitamin B12 levels above the lower reference level of 140 pmol/L.18, 19 Although several factors may be of influence, in a considerable number of cases this issue can be caused by the earlier use of oral supplementation with multivitamins or high-dose oral vitamin B12 preparations.20 It has been reported that even a dose of 10 μg/d can increase vitamin B12 levels to more than 200 pmol/L in elderly individuals (>65 years).21 Oral supplementation may increase the serum vitamin B12 level but often not enough to replenish the vitamin B12 levels in the tissues21 unless very high doses (1000-2000 μg/d) are used.
And there were more cases!
I will be interested to hear my doctor's opinions on this when I see him I will keep you posted
Some help needed please.
Results MMA & Homocysteine
