Duthie SJ, McMillan P.
Uracil misincorporation in human DNA detected using single cell gel electrophoresis.
Carcinogenesis. 1997 Sep;18(9):1709-14. doi: 10.1093/carcin/18.9.1709.
Abstract/Text
Poor folate status may be important in the aetiology of several epithelial cell malignancies including cancer of the uterine cervix. Folic acid is essential in the synthesis of purine nucleotides and the pyrimidine nucleoside thymidine and it is probable that imbalances in these DNA precursors negatively effect DNA stability and may ultimately lead to malignant transformation. The development of a modified 'comet assay' using the bacterial DNA repair enzyme uracil DNA glycosylase, to detect misincorporated uracil in human DNA is reported here. The effect of perturbing folic acid and deoxyuridine levels on uracil misincorporation in normal human lymphocytes and cultured human tumour cells was investigated using this assay. HeLa cells and peripheral human lymphocytes incubated as agarose-embedded nucleoids, with 1 unit of uracil DNA glycosylase per microg of DNA, contained low levels of uracil in their DNA. Both HeLa cells and stimulated human lymphocytes cultured in folate-deficient medium were growth arrested. Incubating human lymphocytes in folate-deficient medium significantly increased the level of uracil detected compared with control cells. HeLa cells showed an increase in non-specific DNA damage (strand breaks). Deoxyuridine (100 microM) significantly increased the level of uracil detected in the DNA of both folate-deficient and control HeLa cells. It appears that this modified comet assay specifically detects misincorporated uracil in single human cells. It should, therefore, prove valuable in determining the role of folic acid status in DNA instability and cancer.
Tran PN, Tran MH.
Cobalamin deficiency presenting with thrombotic microangiopathy (TMA) features: A systematic review.
Transfus Apher Sci. 2018 Feb;57(1):102-106. doi: 10.1016/j.transci.2018.01.003. Epub 2018 Jan 11.
Abstract/Text
INTRODUCTION: Cobalamin deficiency may result in hematologic characteristics similar to thrombotic microangiopathy (TMA). To facilitate diagnosis, we reviewed reported cases of acquired cobalamin deficiency presenting with TMA features (c.def-TMA).
METHODS: A literature search identified reports of c.def-TMA. Deficiency was defined as B12 levels of <118 pmol/L. Corrected reticulocyte counts and reticulocyte production indexes were calculated. Clinical features were presented as proportion abnormal and results summarized as medians and interquartile ranges (IQR).
RESULTS: Patient level data was extracted from 41 identified cases. Median age (years) was 43 (30-55) with 21/41 (51%) being female. Cobalamin deficiency was noted in 35/40 (87.5%) but fold increases in MMA and HC were 30 and 6, respectively. The etiology was pernicious anemia in 28/41 (68%) cases. Anemia was both universal and severe, with hemoglobin levels of 55 g/L (4.7-6.6). Hypersegmented neutrophils were noted in 23/37 (62%), schistocytes in 29/38 (76%) and median LDH levels 3981 U/L (2004-5467). The RPI was <3.0% in all patients. Thrombocytopenia occurred in 33/41 (80.5%) with a median platelet count of 91 × 109/L (42-112). Plasma infusion or exchange was initiated in 14/41 (34%) with associated complications in 2 cases.
CONCLUSION: Reticulocytopenia (RPI of <3.0%) was a universal finding that aids in differentiating c.def-TMA from other causes of hemolysis. C.def-TMA was associated with severe anemia, generally mild-moderate thrombocytopenia, and significant elevations in LDH.
Copyright © 2018 Elsevier Ltd. All rights reserved.
Karlsson FA, Burman P, Lööf L, Mårdh S.
Major parietal cell antigen in autoimmune gastritis with pernicious anemia is the acid-producing H+,K+-adenosine triphosphatase of the stomach.
J Clin Invest. 1988 Feb;81(2):475-9. doi: 10.1172/JCI113344.
Abstract/Text
In autoimmune gastritis antibodies against a membrane-bound parietal cell antigen of previously unknown function are present in the sera of patients. In this study, a vesicular membrane preparation of porcine gastric mucosa cells was found to be a potent antigenic source. This preparation blocked greater than 90% of antibody binding to a lysate of gastric mucosa cells. The membrane fraction contained H+,K+-ATPase (EC 3.6.1.36) as the major protein, which in sodium dodecyl sulfate-polyacrylamide gel electrophoresis migrated with a weight of 92 kD. After reduction and alkylation, this component was resolved into two bands of similar staining intensity (92 and 88 kD). Immunoblotting analysis showed that sera of patients recognized antigen with pattern identical to the major protein of the vesicular membranes. Protein A-Sepharose beads preincubated with immunoglobulins of five individual patient (but not control) sera were all found to reduce both the H+,K+-ATPase activity and the amount of parietal cell antigen of a preparation of vesicular membranes solubilized in n-octylglucoside. Taken together, the results of this study indicate that the major parietal cell antigen is identical to the acid-producing enzyme, H+,K+-ATPase, of the parietal cell.
Yang DT, Cook RJ.
Spurious elevations of vitamin B12 with pernicious anemia.
N Engl J Med. 2012 May 3;366(18):1742-3. doi: 10.1056/NEJMc1201655.
Abstract/Text
Carmel R, Agrawal YP.
Failures of cobalamin assays in pernicious anemia.
N Engl J Med. 2012 Jul 26;367(4):385-6. doi: 10.1056/NEJMc1204070.
Abstract/Text
Spivak JL.
Masked megaloblastic anemia.
Arch Intern Med. 1982 Nov;142(12):2111-4.
Abstract/Text
In six patients, eight episodes of anemia associated with folic acid or vitamin B12 deficiency were unaccompanied by macrocytosis. Six of the eight episodes of anemia were complicated by illnesses of an inflammatory or infectious nature, two patients had iron deficiency, two appeared to have a thalassemia trait, and one had severe renal failure. In five of the eight episodes, erythropoiesis was not megaloblastic and there was insufficient anisocytosis or poikilocytosis to suggest an underlying vitamin deficiency state. Hypersegmented neutrophils were observed in all episodes, but a neutrophil lobe average of greater than 3.5 lobes per cell was observed only once, and in one patient, less than 5% of the circulating neutrophils were hypersegmented. Giant metamyelocytes, however, were present in the marrow in all of the episodes and provided an important clue to the presence of the vitamin deficiency state.
Carmel R, Spencer CA.
Clinical and subclinical thyroid disorders associated with pernicious anemia. Observations on abnormal thyroid-stimulating hormone levels and on a possible association of blood group O with hyperthyroidism.
Arch Intern Med. 1982 Aug;142(8):1465-9.
Abstract/Text
of 162 patients with pernicious anemia whom we studies, 24.1% had clinical thyroid disease; 11.7% were hypothyroid and 8.6% were hyperthyroid. When abnormal serum thyroid-stimulating hormone (TSH) levels were also considered, thyroid disorders existed in 48.3% of 143 patients. Increased or decreased TSH levels as the sole dysfunction occurred in 14.7% and 6.3% of cases, respectively, and were often associated with thyroid antibodies. The high TSH group fits the picture of subclinical hypothyroidism. The nature of the low TSH group remains to be defined. We conclude that TSH screening in patients with pernicious anemia uncovers frequent abnormalities, which are superimposed on a higher coincidence of overt thyroid disease than previously described. Interestingly, also, eight of nine hyperthyroid patients and all seven patients with low TSH levels had blood type O, contrasting significantly with hypothyroid subjects, who more often had blood type A, and with patients without thyroid disorders.
Carmel R.
Malabsorption of food cobalamin.
Baillieres Clin Haematol. 1995 Sep;8(3):639-55. doi: 10.1016/s0950-3536(05)80224-0.
Abstract/Text
Food-cobalamin malabsorption is marked by the inability to release cobalamin from food, which therefore cannot be taken up by intrinsic factor for absorption. The defect is not detectable by classical clinical tests like the Schilling test which are all based on the absorption of free, crystalline cobalamin. Tests of food-cobalamin absorption have been devised, the most popular ones using cobalamin bound to eggs or to chicken serum. The disparity between the abnormal results of these tests and the normal results with the Schilling test defines the disorder of food-cobalamin malabsorption. Release of cobalamin from food requires acid and pepsin, and most food-cobalamin malabsorptive states can be traced to gastric defects. However, other mechanisms may also play a role. The malabsorption is limited to food cobalamin and any free cobalamin, presumably including recycled biliary cobalamin, will be absorbed normally, which may explain its frequently insidious nature. The effect on cobalamin status covers a broad spectrum. At one extreme, some individuals, perhaps in the earliest stages, have normal cobalamin status, while at the other extreme may be found deficiency every bit as severe as in the most florid case of pernicious anaemia. Most often, however, the deficiency is mild, frequently marked by only a low serum cobalamin level, mild evidence of metabolic insufficiency and, sometimes, minimal clinical sequelae. Moreover, in some cases the gastric defect progresses and intrinsic factor secretion is affected, thus transforming into classical pernicious anaemia; this is not inevitable, however, and probably occurs in only a minority of patients. The course of food-cobalamin malabsorption is therefore a varied one. Nevertheless, it may be the most common cause of subtle or mild cobalamin deficiency and it is also sometimes associated with severe deficiency. Its identification and treatment need to be considered more widely in the clinical setting.
Bauman WA, Shaw S, Jayatilleke E, Spungen AM, Herbert V.
Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin.
Diabetes Care. 2000 Sep;23(9):1227-31. doi: 10.2337/diacare.23.9.1227.
Abstract/Text
OBJECTIVE: Of patients who are prescribed metformin, 10-30% have evidence of reduced vitamin B12 absorption. B12-intrinsic factor complex uptake by ileal cell surface receptors is known to be a process dependent on calcium availability Metformin affects calcium-dependent membrane action. The objective of this study was to determine the magnitude and mechanism of the reduction in serum vitamin B12 after metformin administration.
RESEARCH DESIGN AND METHODS: A comparative study design was employed using 2 groups (metformin and control). A total of 21 patients with type 2 diabetes received sulfonylurea therapy; 14 of these 21 patients were switched to metformin. Monthly serum total vitamin B12 measurements and holotranscobalamin (holoTCII) (B12-TCII) were performed. After 3 months of metformin therapy, oral calcium supplementation was administered.
RESULTS: Serial serum vitamin B12 determinations revealed a similar decline in vitamin B12 and holoTCII. Oral calcium supplementation reversed the metformin-induced serum holoTCII depression.
CONCLUSIONS: Patients receiving metformin have diminished B12 absorption and low serum total vitamin B12 and TCII-B12 levels because of a calcium-dependent ileal membrane antagonism, an effect reversed with supplemental calcium.
Force RW, Nahata MC.
Effect of histamine H2-receptor antagonists on vitamin B12 absorption.
Ann Pharmacother. 1992 Oct;26(10):1283-6. doi: 10.1177/106002809202601018.
Abstract/Text
OBJECTIVE: To discuss the potential of histamine H2-receptor antagonists (H2RAs) to cause malabsorption of vitamin B12 (cyanocobalamin).
DATA SOURCES: Pertinent literature was identified via a MEDLINE search. Journals and references cited in published articles also were used as data sources.
STUDY SELECTION: Studies evaluating the effect of H2RAs on vitamin B12 absorption were reviewed.
DATA SYNTHESIS: H2RAs decrease acid secretion by the gastric parietal cells. Gastric acid and pepsin produced by these cells are required for the cleavage of vitamin B12 from dietary sources. Intrinsic factor (IF), also produced by gastric parietal cells, is required for vitamin B12 absorption from the gastrointestinal tract. Although H2RAs have not conclusively been shown to decrease IF secretion, studies have demonstrated a significant reduction in food-bound vitamin B12 absorption secondary to decreased acid secretion in patients taking these drugs.
CONCLUSIONS: H2RAs have the potential to cause vitamin B12 deficiency. This may be important in patients with inadequate stores of vitamin B12 (e.g., poor diet), particularly those receiving H2RA therapy continuously for more than two years. Healthcare providers should be aware of this potential adverse effect.
Saltzman JR, Kemp JA, Golner BB, Pedrosa MC, Dallal GE, Russell RM.
Effect of hypochlorhydria due to omeprazole treatment or atrophic gastritis on protein-bound vitamin B12 absorption.
J Am Coll Nutr. 1994 Dec;13(6):584-91. doi: 10.1080/07315724.1994.10718452.
Abstract/Text
OBJECTIVE: To investigate the effects of hypochlorhydria and acidic drink ingestion on protein-bound vitamin B12 absorption in elderly subjects.
METHODS: Absorption of protein-bound vitamin B12 was examined in elderly normal subjects (n = 8), and in hypochlorhydric subjects due to omeprazole treatment (n = 8) or with atrophic gastritis (n = 3). Subjects underwent absorption tests of protein-bound vitamin B12 ingested with water, cranberry juice and 0.1 N hydrochloric acid.
RESULTS: Protein-bound vitamin B12 absorption was lower in the omeprazole-treated group (0.50%) compared to the normal group (1.21%; p < 0.001). With cranberry juice ingestion, the omeprazole-treated group showed an increase in absorbed protein-bound vitamin B12 (p = 0.025). With dilute hydrochloric acid ingestion, there was a further increase in vitamin B12 absorption (p < 0.001).
CONCLUSION: Omeprazole causes protein-bound vitamin B12 malabsorption, and ingestion of an acidic drink improves protein-bound vitamin B12 absorption.
Schenk BE, Festen HP, Kuipers EJ, Klinkenberg-Knol EC, Meuwissen SG.
Effect of short- and long-term treatment with omeprazole on the absorption and serum levels of cobalamin.
Aliment Pharmacol Ther. 1996 Aug;10(4):541-5. doi: 10.1046/j.1365-2036.1996.27169000.x.
Abstract/Text
AIMS: To evaluate absorption of protein-bound and unbound cyanocobalamin before and during treatment with omeprazole, and cobalamin levels in patients on long-term treatment with omeprazole.
METHODS: In eight former duodenal ulcer patients absorption of unbound and protein-bound cobalamin was determined by measuring 24-h urinary excretion of unbound 58Co-cyancobalamin or protein-bound 57Co-cyanocobalamin during a modified Schilling test. Tests were performed before and during treatment with 20 mg and 40 mg omeprazole daily for 9 days. Serum cobalamin levels were assessed in 25 patients with gastro-oesophageal reflux disease (GERD) before and during long-term maintenance therapy with omeprazole. Mean treatment duration was 56 months (range 36-81 months).
RESULTS: Urinary excretion of unbound cobalamin was unchanged with both dosages of omeprazole. Excretion of 57Co-cyanocobalamin, however, decreased significantly during treatment with both 20 mg omeprazole (mean +/- S.E.M.: 1.31 +/- 0.20 vs. 0.54 +/- 0.17%; P < 0.02) and 40 mg omeprazole (1.25 +/- 0.26 vs. 0.29 +/- 0.06%; P < 0.02). Mean serum cobalamin levels (+/- S.E.M.) before and during therapy with omeprazole in GERD patients were 298 +/- 27 and 261 +/- 16 pg/mL (normal range 180-900 pg/mL), respectively (P = N.S.).
CONCLUSIONS: Absorption of protein-bound, but not unbound, cyanocobalamin is decreased when measured by a modified Schilling test during treatment with omeprazole. However, no change in serum cobalamin levels was observed in patients with GERD after treatment with omeprazole for up to 7 years.
Chapman LE, Darling AL, Brown JE.
Association between metformin and vitamin B12 deficiency in patients with type 2 diabetes: A systematic review and meta-analysis.
Diabetes Metab. 2016 Nov;42(5):316-327. doi: 10.1016/j.diabet.2016.03.008. Epub 2016 Apr 26.
Abstract/Text
AIM: Metformin is the most widely used oral hypoglycaemic drug, but it may lower B12 status, which could have important clinical implications. We undertook a systematic review and meta-analysis of the relationship between metformin use and vitamin B12 deficiency in persons with type 2 diabetes.
METHODS: Electronic database searches were undertaken (1st January 1957-1st July 2013) using the Cochrane library, Scopus, CINAHL, Grey literature databases, Pub Med Central, NICE Clinical Guidelines UK, and ongoing clinical trials. Included studies were of any study design, with data from patients with type 2 diabetes of any age or gender, taking any dose or duration of metformin. Planned primary outcomes were serum vitamin B12 levels, % prevalence or incidence of vitamin B12 deficiency and risk of vitamin B12 deficiency.
RESULTS: Twenty-six papers were included in the review. Ten out of 17 observational studies showed statistically significantly lower levels of vitamin B12 in patients on metformin than not on metformin. Meta-analysis performed on four trials demonstrated a statistically significant overall mean B12 reducing effect of metformin of 57pmol/L [WMD (fixed)=-0.57 (95% CI: -35 to -79pmol/L)] after 6weeks to 3months of use.
CONCLUSION: The evidence from this review demonstrates an association between metformin usage and lower levels of vitamin B12 by 57pmol/L, which leads to frank deficiency or borderline status in some patients with type 2 diabetes. This suggests that it is prudent to monitor B12 levels in these patients who are at increased risk of deficiency.
Copyright © 2016 Elsevier Masson SAS. All rights reserved.
Gilligan MA.
Metformin and vitamin B12 deficiency.
Arch Intern Med. 2002 Feb 25;162(4):484-5. doi: 10.1001/archinte.162.4.484.
Abstract/Text
Andrès E, Noel E, Goichot B.
Metformin-associated vitamin B12 deficiency.
Arch Intern Med. 2002 Oct 28;162(19):2251-2. doi: 10.1001/archinte.162.19.2251-a.
Abstract/Text
SCHWARTZ SO, KAPLAN SR, ARMSTRONG BE.
The long-term evaluation of folic acid in the treatment of pernicious anemia.
J Lab Clin Med. 1950 Jun;35(6):894-8.
Abstract/Text
Savage DG, Lindenbaum J.
Neurological complications of acquired cobalamin deficiency: clinical aspects.
Baillieres Clin Haematol. 1995 Sep;8(3):657-78. doi: 10.1016/s0950-3536(05)80225-2.
Abstract/Text
Neuropsychiatric syndromes occur in about 40% of Cbl-deficient patients and are characterized by progressive and variable damage to the spinal cord, peripheral nerves and cerebrum. The first abnormality is usually sensory impairment, most often presenting as distal and symmetrical paraesthesiae of the lower limbs and frequently associated with ataxia. Almost all patients demonstrate loss of vibratory sensation, often in association with diminished proprioception and cutaneous sensation and a Romberg sign. Corticospinal tract involvement is common in more advanced cases, with abnormal reflexes, motor impairment and, ultimately, spastic paraparesis. A minority of patients exhibit mental or psychiatric disturbances or autonomic signs, but these rarely if ever occur in the absence of other neurological changes. Because N2O inactivates Cbl, abuse of the gas may lead to typical Cbl neuropathy. Haematological changes are minimal and serum Cbl levels and Schilling tests normal in most patients. The severity of neurological abnormalities prior to treatment correlates with the duration of symptoms and the haemoglobin level. Initial severity, symptom duration and initial haemoglobin also correlate with residual neurological damage after Cbl therapy. The inverse correlation between severity of anaemia and neurological damage is not understood. Diagnosis of Cbl neuropathy can usually be made in the presence of the typical neuropsychiatric abnormalities, a low serum Cbl level and evidence of megaloblastic haemopoiesis. In some patients serum MMA and HCYS determinations or a therapeutic trial may be required. A neurological response usually occurs within the first 3 months, although further improvement may occur with time. Patients with advanced disease may be left with major residual disability. Therefore early diagnosis is critical. Pharmacological doses of folic acid reverse the haematological abnormalities of Cbl deficiency. This may allow neuropathy to develop or progress and make recognition of deficiency more difficult. There is no clear evidence that folic acid therapy precipitates or exacerbates Cbl neuropathy. Haematological improvement may occur in a fraction of patients receiving small doses of folate, but the data are inadequate to predict the danger of low levels of folate supplementation in the general population.
Eussen SJ, de Groot LC, Clarke R, Schneede J, Ueland PM, Hoefnagels WH, van Staveren WA.
Oral cyanocobalamin supplementation in older people with vitamin B12 deficiency: a dose-finding trial.
Arch Intern Med. 2005 May 23;165(10):1167-72. doi: 10.1001/archinte.165.10.1167.
Abstract/Text
BACKGROUND: Supplementation with high doses of oral cobalamin is as effective as cobalamin administered by intramuscular injection to correct plasma markers of vitamin B(12) deficiency, but the effects of lower oral doses of cobalamin on such markers are uncertain.
METHODS: We conducted a randomized, parallel-group, double-blind, dose-finding trial to determine the lowest oral dose of cyanocobalamin required to normalize biochemical markers of vitamin B(12) deficiency in older people with mild vitamin B(12) deficiency, defined as a serum vitamin B(12) level of 100 to 300 pmol/L (135-406 pg/mL) and a methylmalonic acid level of 0.26 mumol/L or greater. We assessed the effects of daily oral doses of 2.5, 100, 250, 500, and 1000 mug of cyanocobalamin administered for 16 weeks on biochemical markers of vitamin B(12) deficiency in 120 people. The main outcome measure was the dose of oral cyanocobalamin that produced 80% to 90% of the estimated maximal reduction in the plasma methylmalonic acid concentration.
RESULTS: Supplementation with cyanocobalamin in daily oral doses of 2.5, 100, 250, 500, and 1000 mug was associated with mean reductions in plasma methylmalonic acid concentrations of 16%, 16%, 23%, 33%, and 33%, respectively. Daily doses of 647 to 1032 mug of cyanocobalamin were associated with 80% to 90% of the estimated maximum reduction in the plasma methylmalonic acid concentration.
CONCLUSION: The lowest dose of oral cyanocobalamin required to normalize mild vitamin B(12) deficiency is more than 200 times greater than the recommended dietary allowance, which is approximately 3 mug daily.
Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J.
Effective treatment of cobalamin deficiency with oral cobalamin.
Blood. 1998 Aug 15;92(4):1191-8.
Abstract/Text
Because cobalamin deficiency is routinely treated with parenteral cobalamin, we investigated the efficacy of oral therapy. We randomly assigned 38 newly diagnosed cobalamin deficient patients to receive cyanocobalamin as either 1 mg intramuscularly on days 1, 3, 7, 10, 14, 21, 30, 60, and 90 or 2 mg orally on a daily basis for 120 days. Therapeutic effectiveness was evaluated by measuring hematologic and neurologic improvement and changes in serum levels of cobalamin (normal, 200 to 900 pg/mL) methylmalonic acid (normal, 73 to 271 nmol/L), and homocysteine (normal, 5.1 to 13.9 micromol/L). Five patients were subsequently found to have folate deficiency, which left 18 evaluable patients in the oral group and 15 in the parenteral group. Correction of hematologic and neurologic abnormalities was prompt and indistinguishable between the 2 groups. The mean pretreatment values for serum cobalamin, methylmalonic acid, and homocysteine were, respectively, 93 pg/mL, 3,850 nmol/L, and 37. 2 micromol/L in the oral group and 95 pg/mL, 3,630 nmol/L, and 40.0 micromol/L in the parenteral therapy group. After 4 months of therapy, the respective mean values were 1,005 pg/mL, 169 nmol/L, and 10.6 micromol/L in the oral group and 325 pg/mL, 265 nmol/L, and 12.2 micromol/L in the parenteral group. The higher serum cobalamin and lower serum methylmalonic acid levels at 4 months posttreatment in the oral group versus the parenteral group were significant, with P < .0005 and P < .05, respectively. In cobalamin deficiency, 2 mg of cyanocobalamin administered orally on a daily basis was as effective as 1 mg administered intramuscularly on a monthly basis and may be superior.
Copyright 1998 by The American Society of Hematology.
Bolaman Z, Kadikoylu G, Yukselen V, Yavasoglu I, Barutca S, Senturk T.
Oral versus intramuscular cobalamin treatment in megaloblastic anemia: a single-center, prospective, randomized, open-label study.
Clin Ther. 2003 Dec;25(12):3124-34. doi: 10.1016/s0149-2918(03)90096-8.
Abstract/Text
BACKGROUND: Cobalamin (vitamin B12) deficiency, the most common cause of megaloblastic anemia, is treated with intramuscular (IM) cobalamin. It has been suggested by some investigators that oral (p.o.) cobalamin treatment may be as effective in the treatment of this condition, with the advantages of ease of administration and lower cost.
OBJECTIVE: This study assessed the effects and cost of p.o. versus i.m. cobalamin treatment in patients with megaloblastic anemia due to cobalamin deficiency.
METHODS: This was a 90-day, prospective, randomized, open-label study conducted at the Division of Hematology, Department of Internal Medicine, Adnan Menderes University Research and Practice Hospital (Aydin, Turkey). Patients aged > or =16 years with megaloblastic anemia due to cobalamin deficiency were randomized to receive 1000-microg cobalamin p.o. once daily for 10 days (p.o. group) or 1000-microg cobalamin i.m. once daily for 10 days (i.m. group). After 10 days, both treatments were administered once a week for 4 weeks, and after that, once a month for life. Patients were assessed for the presence of reticulocytosis between treatment days 5 and 10 until it was detected. Therapeutic effectiveness was assessed by measuring hematologic parameters on days 0, 10, 30, and 90 and serum vitamin B12 concentration on days 0 and 90. The Mini-Mental State Examination was used before and after the B12 therapy for cognitive function assessment and 125-Hz diapozone was used for vibration threshold testing. Neurologic sensory assessment, including soft-touch and pinprick examinations, was used to identify neuropathy at baseline and study end. Tolerability was assessed using laboratory tests and patient interview. Cost was assessed using the cost of the study drug and of the injection.
RESULTS: Sixty patients completed the study 26 in the p.o. group (16 men, 10 women; mean [SD] age, 60 [15] years) and 34 in the i.m. group (17 men, 17 women; mean [SD] age, 64 [10] years). Reticulocytosis was observed in all patients. In the p.o. group, at days 30 and 90, all hematologic parameters changed significantly versus day 0 (mean hemoglobin levels increased [both P<0.001]; mean corpuscular volume decreased [both P<0.001]; mean white blood cell count increased [day 30, P<0.01; day 90, P<0.001]; and mean platelet count increased [both P<0.001]). The mean serum vitamin B12 concentration increased significantly from day 0 to 90 (P<0.001). These hematologic parameters and the recovery patterns were similar between the 2 groups. Neurologic findings included sensitive peripheral neuropathy in 9 patients (15.0%), alteration of cognitive function (loss of memory, impaired concentration) in 7 patients (11.7%), and loss of sense of vibration in 5 patients (8.3%). Neurologic improvement was detected in 7 of 9 patients (77.8%) in the p.o. group and 9 of 12 patients (75.0%) in the i.m. group at day 30.
CONCLUSIONS: In this study of patients with megaloblastic anemia due to cobalamin deficiency, p.o. cobalamin treatment was as effective as i.m. cobalamin treatment. P.o. treatment also was better tolerated and less expensive compared with IM treatment. However, because of the small sample size and the short term of this study, further long-term studies are needed to determine the efficacy of p.o. cobalamin treatment.
Kokkola A, Sjöblom SM, Haapiainen R, Sipponen P, Puolakkainen P, Järvinen H.
The risk of gastric carcinoma and carcinoid tumours in patients with pernicious anaemia. A prospective follow-up study.
Scand J Gastroenterol. 1998 Jan;33(1):88-92. doi: 10.1080/00365529850166266.
Abstract/Text
BACKGROUND: This endoscopic follow-up study was undertaken to evaluate the risk of gastric cancer (GC) and carcinoids in patients with pernicious anaemia (PA) and to analyse whether early detection of GC could be provided by regular endoscopic follow-up.
METHODS: Screening gastroscopy was performed in 71 patients with pernicious anaemia, and thereafter they were followed up with gastroscopies at 3-year intervals for a mean time of 5.8 years. Standardized incidence ratios (SIR) were calculated, the expected number being based on incidence rates in the whole Finnish population.
RESULTS: Two GCs were found during the follow-up period; one of these patients was asymptomatic and the other had abdominal symptoms. The SIR was 5.0 (95% confidence interval, 0.6-18). Eight carcinoids were detected, and all but one were removed endoscopically, and no metastases were found. The patients who had carcinoid tumours were younger at the diagnosis of PA than those who did not develop carcinoids (mean, 40 versus 55 years). Additionally, the patients with carcinoids had longer duration of PA (mean, 11 versus 5 years).
CONCLUSIONS: During the follow-up period the risk of GC was increased. The risk of gastric carcinoids seems to be very high in patients with pernicious anaemia when compared with a normal population, but they are mostly relatively benign tumours. Regular routine gastroscopic follow-up is not indicated in patients with pernicious anaemia.
