Vitamin B12 Malabsorption Due to a Biologically Inert Intrinsic Factor

Abstract Sixteen patients (from Bombay) with severe vitamin B12 malabsorption due to intrinsic factor deficiency, presenting as subacute combined degeneration of the cord (7), tropical sprue (3), anemia (2), thyrotoxicosis (2), diabetes mellitus (1), and pain in the abdomen (1), are reported. The difficulties of establishing a definite diagnosis of pernicious anemia in Indian population are described. The lower incidence of circulating intrinsic factor antibody (IFA) in Indian patients with histamine-fast achlorhydria and poor vitamin B12 absorption is emphasized. The necessity of separating atrophic gastritis, with severely impaired vitamm B12 absorption, from pernicious anemia on the basis of absence or presence of IFA in serum and/or gastric juice cannot be overemphasized.

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The functional cobalamin (vitamin B12)–intrinsic factor receptor is a novel complex of cubilin and amnionless

Blood ◽

10.1182/blood-2003-08-2852 ◽

2004 ◽

Vol 103 (5) ◽

pp. 1573-1579 ◽

Cited By ~ 188

Author(s):

John C. Fyfe ◽

Mette Madsen ◽

Peter Højrup ◽

Erik I. Christensen ◽

Stephan M. Tanner ◽

...

Keyword(s):

Vitamin B12 ◽

Autosomal Recessive ◽

Megaloblastic Anemia ◽

Intrinsic Factor ◽

Gel Filtration ◽

Autosomal Recessive Disorder ◽

Lysosomal Degradation ◽

Amino Terminal ◽

Genes Encoding ◽

Vitamin B12 Malabsorption

Abstract Imerslund-Gräsbeck syndrome (I-GS, megaloblastic anemia 1) is an autosomal recessive disorder characterized by intestinal cobalamin (vitamin B12) malabsorption and proteinuria. I-GS–causing mutations are found in either of 2 genes encoding the epithelial proteins: cubilin and amnionless (AMN). Cubilin recognizes intrinsic factor (IF)–cobalamin and various other proteins to be endocytosed in the intestine and kidney, respectively, whereas the function of AMN is unknown. Here we show that cubilin and AMN colocalize in the endocytic apparatus of polarized epithelial cells and copurify as a tight complex during IF-cobalamin affinity and nondenaturing gel filtration chromatography. In transfected cells expressing either AMN or a truncated IF-cobalamin–binding cubilin construct, neither protein alone conferred ligand endocytosis. In cubilin transfectants, cubilin accumulated in early biosynthetic compartments. However, in cells cotransfected with AMN and the cubilin construct, cubilin trafficked to the cell surface and endosomes, and the cells exhibited IF-cobalamin endocytosis and lysosomal degradation of IF. These data indicate that cubilin and AMN are subunits of a novel cubilin/AMN (cubam) complex, where AMN binds to the amino-terminal third of cubilin and directs subcellular localization and endocytosis of cubilin with its ligand. Therefore, mutations affecting either of the 2 proteins may abrogate function of the cubam complex and cause IG-S.

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A Case Report of Pernicious Anemia and Recurrent Aphthous Stomatitis

The Journal of Contemporary Dental Practice ◽

10.5005/jcdp-10-2-83 ◽

2009 ◽

Vol 10 (2) ◽

pp. 83-89 ◽

Cited By ~ 2

Author(s):

Ricardo Alves Mesquita ◽

Bruna Gonçalves Garcia ◽

Marcelo Ferreira Pinto Cardoso ◽

Omar de Faria ◽

Ricardo Santiago Gomez

Keyword(s):

Folic Acid ◽

Case Report ◽

Vitamin B12 ◽

Pernicious Anemia ◽

Systemic Disease ◽

Intrinsic Factor ◽

Serum Vitamin ◽

Recurrent Aphthous Stomatitis ◽

Aphthous Stomatitis ◽

Vitamin B12 Malabsorption

Abstract Aim The aim of this report is to present the management of a patient with pernicious anemia afflicted with recurrent aphthous stomatitis (RAS). Background RAS is one of the most common lesions of the oral mucosa. Although the exact etiology of RAS is still unknown different hematinic deficiencies have been proposed. Case Report Painful recurrent ulcers covered with a grayish pseudomembrane surrounded by an erythematous margin were identified on the tongue and in the buccal mucosa of a 71-year-old woman. The patient also presented with depapilation of the tongue. The clinical diagnosis was RAS. Laboratory tests including a hemogram were ordered to determine existing levels of folic acid, iron, ferritin, and vitamins B2, B6, and B12. Levels of serum vitamin B12 and serum hemoglobin were low. The laboratory investigation also showed a medium corpuscular volume of 104.1 fl. A gastroduodenoscopy revealed no macroscopic abnormality. A gastric biopsy showed mucosal atrophy in the gastric corpus with evidence of intestinal metaplasia. Antibodies against an intrinsic factor were negative. The diagnosis pernicious anemia was made, with RAS caused by vitamin B12 malabsorption. Treatment consisted of the administration of 1.0 ml of hydroxocolabamin intramuscularly twice weekly over four weeks followed by 1.0 ml once weekly for four weeks. Clinical resolution was observed after two months. Summary The association of RAS with vitamin B12 malabsorption is a rare event. However, along with conventional RAS clinical management, iron, folic acid, vitamin B deficiencies, and nutritional intolerance must be considered. Evaluation of the predisposing factors is imperative in treating patients with RAS including vitamin B12 malabsorption. Clinical Significance Determination of the levels of vitamin B12 should be the basis for replacement therapy. Such therapy can be considered a benefit to the patients with RAS as its etiology remains unclear. Clinicians must be alert to the possibility this lesion could be a signal of systemic disease. Citation Garcia BG, Cardoso MFP, Faria O, Gomez RS, Mesquita RA. A Case Report of Pernicious Anemia and Recurrent Aphthous Stomatitis. J Contemp Dent Pract 2009 March; (10)2:083-089.

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Competition Between Bacteria and Intrinsic Factor for Vitamin B12: Implications for Vitamin B12 Malabsorption in Intestinal Bacterial Overgrowth

Gastroenterology ◽

10.1016/s0016-5085(72)80177-x ◽

1972 ◽

Vol 62 (2) ◽

pp. 255-260 ◽

Cited By ~ 38

Author(s):

R.A. Giannella ◽

S.A. Broitman ◽

N. Zamcheck

Keyword(s):

Vitamin B12 ◽

Intrinsic Factor ◽

Bacterial Overgrowth ◽

Intestinal Bacterial Overgrowth ◽

Vitamin B12 Malabsorption

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Bioavailability of Vitamin B12

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000041 ◽

2010 ◽

Vol 80 (45) ◽

pp. 330-335 ◽

Cited By ~ 28

Author(s):

Lindsay Helen Allen

Keyword(s):

Vitamin B12 ◽

Vitamin B12 Deficiency ◽

The Elderly ◽

Radioactive Isotopes ◽

Animal Source Foods ◽

Dietary Requirements ◽

In Vivo Labeling ◽

B12 Deficiency ◽

Vitamin B12 Malabsorption

Vitamin B12 deficiency is common in people of all ages who consume a low intake of animal-source foods, including populations in developing countries. It is also prevalent among the elderly, even in wealthier countries, due to their malabsorption of B12 from food. Several methods have been applied to diagnose vitamin B12 malabsorption, including Schillings test, which is now used rarely, but these do not quantify percent bioavailability. Most of the information on B12 bioavailability from foods was collected 40 to 50 years ago, using radioactive isotopes of cobalt to label the corrinoid ring. The data are sparse, and the level of radioactivity required for in vivo labeling of animal tissues can be prohibitive. A newer method under development uses a low dose of radioactivity as 14C-labeled B12, with measurement of the isotope excreted in urine and feces by accelerator mass spectrometry. This test has revealed that the unabsorbed vitamin is degraded in the intestine. The percent bioavailability is inversely proportional to the dose consumed due to saturation of the active absorption process, even within the range of usual intake from foods. This has important implications for the assessment and interpretation of bioavailability values, setting dietary requirements, and interpreting relationships between intake and status of the vitamin.

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Cubilin, the Intrinsic Factor-Vitamin B12 Receptor in Development and Disease

Current Medicinal Chemistry ◽

10.2174/0929867325666181008143945 ◽

2020 ◽

Vol 27 (19) ◽

pp. 3123-3150 ◽

Cited By ~ 2

Author(s):

Renata Kozyraki ◽

Olivier Cases

Keyword(s):

Vitamin B12 ◽

Cancer Progression ◽

Intrinsic Factor ◽

Basic Research ◽

Toxic Substances ◽

Human Pathology ◽

Peripheral Membrane Protein ◽

Epidermal Growth ◽

Fgf8 Signaling

Gp280/Intrinsic factor-vitamin B12 receptor/Cubilin (CUBN) is a large endocytic receptor serving multiple functions in vitamin B12 homeostasis, renal reabsorption of protein or toxic substances including albumin, vitamin D-binding protein or cadmium. Cubilin is a peripheral membrane protein consisting of 8 Epidermal Growth Factor (EGF)-like repeats and 27 CUB (defined as Complement C1r/C1s, Uegf, BMP1) domains. This structurally unique protein interacts with at least two molecular partners, Amnionless (AMN) and Lrp2/Megalin. AMN is involved in appropriate plasma membrane transport of Cubilin whereas Lrp2 is essential for efficient internalization of Cubilin and its ligands. Observations gleaned from animal models with Cubn deficiency or human diseases demonstrate the importance of this protein. In this review addressed to basic research and medical scientists, we summarize currently available data on Cubilin and its implication in renal and intestinal biology. We also discuss the role of Cubilin as a modulator of Fgf8 signaling during embryonic development and propose that the Cubilin-Fgf8 interaction may be relevant in human pathology, including in cancer progression, heart or neural tube defects. We finally provide experimental elements suggesting that some aspects of Cubilin physiology might be relevant in drug design.

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Divalent cations and vitamin B12 uptake by intestinal brush-border membrane vesicles

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1980.239.6.g452 ◽

1980 ◽

Vol 239 (6) ◽

pp. G452-G456

Author(s):

R. C. Beesley ◽

C. D. Bacheller

Keyword(s):

Vitamin B12 ◽

Brush Border ◽

Brush Border Membrane ◽

Divalent Cations ◽

Intrinsic Factor ◽

Membrane Vesicles ◽

Brush Border Membrane Vesicles ◽

Tetraacetic Acid ◽

Intestinal Brush Border Membrane ◽

Intestinal Brush Border

Brush-border membrane vesicles from hamster intestine were employed to investigate uptake (binding) of vitamin B12 (B12). Ileal vesicles took up 25 times more B12 than did jejunal vesicles. Uptake of B12 by ileal vesicles was dependent on intrinsic factor (IF) and required Ca2+. Increasing the Ca2+ concentration caused an increase in uptake of B12 reaching a maximum at approximately 8 mM Ca2+. At high Ca2+ concentrations, 6–8 mM, Mg2+ had little effect on uptake of B12. At low Ca2+ concentrations, up to 2 mM, Mg2+ stimulated B12 uptake. Mg2+, Mn2+, and, to a lesser extent, Sr2+ stimulated Ca2+-dependent B12 uptake, but Zn2+, Ba2+, Na+, K+, and La3+ did not. B12 was apparently not metabolized and was bound as IF-B12 complex, which could be removed with (ethylenedinitrilo)tetraacetic acid (EDTA). Our results suggest that two types of divalent cation reactive sites are involved in binding of IF-B12. One is Ca2+ specific. The other is less specific reacting with Mg2+, Mn2+, Sr2+, and perhaps Ca2+ itself, thereby stimulating Ca2+-dependent binding of IF-B12 to its ileal receptor.

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