Hereditary intrinsic factor deficiency in China caused by a novel mutation in the intrinsic factor gene-a case report.

BACKGROUND: Hereditary intrinsic factor deficiency is a rare disease characterized by cobalamin deficiency with the lack of gastric intrinsic factor because of gastric intrinsic factor (GIF) mutations. Patients usually present with cobalamin deficiency without gastroscopy abnormality and intrinsic factor antibodies. CASE PRESENTATION: A Chinese patient presented with recurrent severe anemia since age 2 with low cobalamin level and a mild elevation of indirect bilirubin. The hemoglobin level normalized each time after intramuscular vitamin B12 injection. Gene test verified a c.776delA frame shift mutation in exon 6 combined with c.585C > A nonsense early termination mutation in exon 5 of GIF which result in the dysfunction of gastric intrinsic factor protein. The hereditary intrinsic factor deficiency in literature was further reviewed and the ancestry of different mutation sites were discussed. CONCLUSIONS: A novel compound heterozygous mutation of GIF in a Chinese patient of hereditary intrinsic factor deficiency was reported. It was the first identified mutation of GIF in East-Asia and may indicate a new ancestry.

Autoimmune Gastritis.

CONTEXT.­: Autoimmune gastritis (AG) is a corpus-restricted chronic atrophic gastritis associated with intrinsic factor deficiency, either with or without pernicious anemia. Autoimmune gastritis is a microscopic disease because patients present with no or vague symptoms, and clinicians rarely find endoscopic changes. Autoimmune gastritis only becomes a clinical disease when pathologists diagnose it in gastric biopsies performed for a variety of clinical indications. Unfamiliarity with this disease can result in misdiagnosis of patients, and thus inadequate patient management. OBJECTIVE.­: To review the pathogenesis, clinical features, diagnostic criteria, differential diagnoses, sequelae, and surveillance recommendations for AG. DATA SOURCES.­: The sources of the study include a review of the pertinent literature for AG. CONCLUSIONS.­: Autoimmune gastritis is an important disease characterized by a loss of oxyntic mucosa and presence of metaplastic epithelium and enterochromaffin-like cell hyperplasia. Awareness and proper diagnosis are critical to prevent mismanagement of patients.

Anemia perniciosa. Del pasado al presente / Pernicious anemia. From past to present

Actualmente, la anemia perniciosa es la causa más frecuente de déficit de vitamina B12 en los países occidentales. La lesión histológica sobre la que se sustenta es la gastritis crónica atrófica autoinmune. La destrucción de las células parietales provoca un déficit de factor intrínseco, proteína fundamental para que la vitamina B12 se absorba en el íleon terminal. Los avances que se han producido en las dos últimas décadas han reabierto el debate sobre una enfermedad que parecía olvidada por su aparente simplicidad. El nuevo papel del H. pylori, el valor de los anticuerpos anticélula parietal y antifactor intrínseco, la verdadera utilidad de los niveles séricos de vitamina B12, el riesgo de adenocarcinoma y carcinoides gástricos o el tratamiento con vitamina B12 oral, son algunos de los temas de actualidad que se analizan en profundidad en esta revisión (AU)

Pernicious anemia is currently the most common cause of vitamin B12 deficiency in Western countries. The histological lesion upon which this condition is based is autoimmune chronic atrophic gastritis. The destruction of parietal cells causes a deficiency in intrinsic factor, an essential protein for vitamin B12 absorption in the terminal ileum. Advances in the last two decades have reopened the debate on a disease that seemed to have been forgotten due to its apparent simplicity. The new role of H. pylori, the value of parietal cell antibodies and intrinsic factor antibodies, the true usefulness of serum vitamin B12 levels, the risk of adenocarcinoma and gastric carcinoids and oral vitamin B12 treatment are just some of the current issues analyzed in depth in this review (AU)

Vitamin B12-dependent taurine synthesis regulates growth and bone mass.

Both maternal and offspring-derived factors contribute to lifelong growth and bone mass accrual, although the specific role of maternal deficiencies in the growth and bone mass of offspring is poorly understood. In the present study, we have shown that vitamin B12 (B12) deficiency in a murine genetic model results in severe postweaning growth retardation and osteoporosis, and the severity and time of onset of this phenotype in the offspring depends on the maternal genotype. Using integrated physiological and metabolomic analysis, we determined that B12 deficiency in the offspring decreases liver taurine production and associates with abrogation of a growth hormone/insulin-like growth factor 1 (GH/IGF1) axis. Taurine increased GH-dependent IGF1 synthesis in the liver, which subsequently enhanced osteoblast function, and in B12-deficient offspring, oral administration of taurine rescued their growth retardation and osteoporosis phenotypes. These results identify B12 as an essential vitamin that positively regulates postweaning growth and bone formation through taurine synthesis and suggests potential therapies to increase bone mass.

Frequency of intrinsic factor antibody in megaloblastic anaemia.

OBJECTIVE: To evaluate the presence of intrinsic factor antibody in vitamin B12 deficient patients. STUDY DESIGN: Cross-sectional, observational study. PLACE AND DURATION OF STUDY: Fauji Foundation Hospital, Foundation University Medical College and Armed Forces Institute of Pathology, Rawalpindi, from January 2011 to June 2012. METHODOLOGY: A total of 120 patients of megaloblastic anaemia were selected on the basis of low serum vitamin B12 level. The intrinsic factor antibody tests were performed by ELISA method. The patients were considered positive or negative on the basis of presence or absence of intrinsic factor antibody respectively. The data was analyzed by using SPSS version 14. RESULTS: Pernicious anaemia with intrinsic factor deficiency was found in 13.3% in 120 vitamin B12 deficient patients. The mean age of patients of pernicious anaemia was 41.5 years, with a male to female ratio of 1:2.5. It was relatively more common in older age (17% in age more than 60 years) as compared to other age groups. CONCLUSION: Frequency of pernicious anaemia in megaloblastic anaemia was 13.3%. The male to female ratio was 1:2.5 and it was relatively more common in age group of more than 60 years.

Gastric intrinsic factor deficiency with combined GIF heterozygous mutations and FUT2 secretor variant.

Several genome-wide association studies (GWAS) have identified a strong association between serum vitamin B12 and fucosyltransferase 2 (FUT2), a gene associated with susceptibility to Helicobacter pylori infection. Hazra et al. conducted a meta-analysis of three GWAS and found three additional loci in MUT, CUBN and TCN1. Other GWAS conducted in Italy and China confirmed the association for FUT2 gene. Alpha-2-fucosyltransferase (FUT2) catalyzes fucose addition to form H-type antigens in exocrine secretions. FUT2 non-secretor variant produces no secretion of H-type antigens and is associated with high-plasma vitamin B12 levels. This association was explained by the influence of FUT2 on H. pylori, which is a risk factor of gastritis, a main cause of vitamin B12 impaired absorption. However, we recently showed that H. pylori serology had no influence on FUT2 association with vitamin B12, in a large sample population, suggesting the involvement of an alternative mechanism. GIF is another gene associated with plasma levels of vitamin B12 and gastric intrinsic factor (GIF) is a fucosylated protein needed for B12 absorption. Inherited GIF deficiency produces B12 deficiency unrelated with gastritis. We report 2 families with heterozygous GIF mutation, 290T>C, M97T, with decreased binding affinity of GIF for vitamin B12 and one family with heterozygous GIF mutation 435_437delGAA, K145_N146delinsN and no B12 binding activity of mutated GIF. All cases with vitamin B12 deficit carried the FUT2 rs601338 secretor variant. Ulex europeus binding to GIF was influenced by FUT2 genotypes and GIF concentration was lower, in gastric juice from control subjects with the secretor genotype. GIF290C allele was reported in 5 European cases and no Africans among 1282 ambulatory subjects and was associated with low plasma vitamin B12 and anaemia in the single case bearing the FUT2 secretor variant. We concluded that FUT2 secretor variant worsens B12 status in cases with heterozygous GIF mutations by impairing GIF secretion, independently from H. pylori-related gastritis.

Do all the patients with gastric parietal cell antibodies have pernicious anemia?

OBJECTIVE: This study evaluated whether all the patients with serum gastric parietal cell antibody (GPCA) positivity had pernicious anemia (PA). MATERIALS AND METHODS: The blood hemoglobin (Hb), iron, and vitamin B12 concentrations, and mean corpuscular volume (MCV) in 124 GPCA-positive patients were measured and compared with the corresponding data in 124 age- and sex-matched healthy controls. PA was defined by World Health Organization (WHO) as having an Hb concentration < 13 g dl(-1) for men and < 12 g dl(-1) for women, an MCV ≥ 100 fl, and a serum vitamin B12 level < 200 pg ml(-1) . RESULTS: We found that 20, 25, and 20 GPCA-positive patients had deficiencies of Hb (men < 13 g dl(-1) , women < 12 g dl(-1) ), iron (<60 µg dl(-1) ), and vitamin B12 (<200 pg ml(-1) ), respectively. Moreover, 16 GPCA-positive patients had abnormally high MCV (≥ 100 fl). GPCA-positive patients had a significantly higher frequency of Hb, iron, or vitamin B12 deficiency and of abnormally high MCV (all P-values < 0.001) than healthy controls. However, only 12.9% of 124 GPCA-positive patients were diagnosed as having PA by the WHO definition. CONCLUSION: Only 12.9% of GPCA-positive patients are discovered to have PA by the WHO definition.

Pernicious anemia in Chinese: a study of 181 patients in a Hong Kong hospital.

To study the clinical and hematologic features of pernicious anemia in Chinese, we describe 181 Chinese with megaloblastic anemia and low serum cobalamin, in association with either classic Schilling test results (82 patients) or the presence of serum antibody to intrinsic factor (99 patients), encountered in a regional hospital in Hong Kong from May 1994 to May 2005. The median age was 75 years (range, 32-95 yr) and the male to female ratio was 1:1.5. The chief presenting feature was anemia, and fewer than 10% of patients presented predominantly with neurologic deficit. Gastric biopsies of 109 patients showed glandular atrophy in 73, endocrine cell hyperplasia in 5, polyps in 14, adenocarcinoma in 1, and chronic gastritis in the rest. Gastric adenocarcinoma occurred in 1.7% of patients after a median follow-up of 35 months (range, 0.5-132 mo). Diabetes mellitus occurred in 24% of patients and thyroid disease in 7%. No specific ABO blood group was associated with pernicious anemia. Serum antibody to intrinsic factor (73%) occurred more frequently than serum antibody to gastric parietal cell (65%) (p=0.353). The frequency of serum antibody to gastric parietal cell was higher in male (78%) than in female patients (53%) (p=0.018). Pernicious anemia is a major cause of megaloblastic anemia in Chinese.

Nonradioactive vitamin B12 absorption test evaluated in controls and in patients with inherited malabsorption of vitamin B12.

BACKGROUND: Current tests for evaluation of vitamin B(12) absorption are problematic because they involve the use of radioactively labeled vitamin B(12). We describe a vitamin B(12) absorption test that circumvents this problem. METHODS: We measured cobalamin or transcobalamin saturated with cobalamin (holo-TC) 24 h after three 9-microg doses of vitamin B(12) given orally at 6-h intervals. We studied 17 patients with inherited malabsorption of vitamin B(12) attributable to Imerslund-Grasbeck syndrome (n = 13) or intrinsic factor deficiency (n = 4), their obligate heterozygous biological parents (n = 19), and healthy controls (n = 44). RESULTS: In the patients, the median (range) change of holo-TC after the B(12) load was not significant [1 (-42 to 5) pmol/L], nor was the change of cobalamin [-3 (-32 to 22) pmol/L], consistent with a lack of measurable active or passive absorption. In controls, however, the median (range) increases of holo-TC and cobalamin were 26 (-6 to 63) pmol/L and 41 (-37 to 109) pmol/L, respectively. Similarly, the parents showed increases of 23 (-2 to 47) pmol/L and 27 (-15 to 94) pmol/L. The mean areas under the ROC curves (95% confidence intervals) were 0.97 (0.93-1.0) for holo-TC and 0.87 (0.79-0.94) for cobalamin, distinguishing patients from controls. At a cutoff of 6 pmol/L for holo-TC, the diagnostic sensitivity (95% confidence interval) was 100 (81-100)%, and the diagnostic specificity was 92 (82-97)%. CONCLUSION: Measurement of holo-TC after administration of vitamin B(12) is a promising approach for evaluating vitamin B(12) absorption.

Identification of a 4-base deletion in the gene in inherited intrinsic factor deficiency.

A 4-base deletion has been identified in the coding region of the gene for gastric intrinsic factor (IF) in an 11-year-old girl with severe anemia and cobalamin (Cbl) deficiency. The bone marrow showed frank megaloblastic morphology, and the Schilling test indicated a failure to absorb Cbl that was corrected by coadministration of IF. Pentagastrin administration induced acid secretion, but the gastric juice lacked IF as determined by CbI binding, by fractionation of protein-bound CbI, and by immunoprecipitation with anti-IF antiserum. Individual exons were amplified by the polymerase chain reaction by using primers to the flanking intronic regions, and the nucleotide sequence analysis identified a 4-base deletion (c183_186delGAAT) spanning positions 104 to 107 in exon 2, resulting in premature termination of translation. This mutation also eliminates a site for Bst XI endonuclease and introduces a site for BsaBI for identifying this deletion in hereditary IF deficiency.

A genetic polymorphism in the coding region of the gastric intrinsic factor gene (GIF) is associated with congenital intrinsic factor deficiency.

Congenital intrinsic factor (IF) deficiency is a disorder characterized by megaloblastic anemia due to the absence of gastric IF (GIF, GenBank NM_005142) and GIF antibodies, with probable autosomal recessive inheritance. Most of the reported patients are isolated cases without genetic studies of the parents or siblings. Complete exonic sequences were determined from the PCR products generated from genomic DNA of five affected individuals. All probands had the identical variant (g.68A>G) in the second position of the fifth codon in the coding sequence of the gene that introduces a restriction enzyme site for Msp I and predicts a change in the mature protein from glutamine(5) (CAG) to arginine(5) (CGG). Three subjects were homozygous for this base exchange and two subjects were heterozygous, one of which was apparently a compound heterozygote at positions 1 and 2 of the fifth codon ([g.67C>G] + [g.68A>G]). The other patient, heterozygous for position 2, had one heterozygous unaffected parent. Most parents were heterozygous for this base exchange, confirming the pattern of autosomal recessive inheritance for congenital IF deficiency. cDNA encoding GIF was mutated at base pair g.68 (A>G) and expressed in COS-7 cells. The apparent size, secretion rate, and sensitivity to pepsin hydrolysis of the expressed IF were similar to native IF. The allelic frequency of g.68A>G was 0.067 and 0.038 in two control populations. This sequence aberration is not the cause of the phenotype, but is associated with the genotype of congenital IF deficiency and could serve as a marker for inheritance of this disorder.

Folate and Vitamin B(12) deficiency presenting as pancytopenia in pregnancy: a case report and review of the literature.

We present a case of extreme pancytopenia in a 27-year-old pregnant woman. The initial picture was compatible with a severe hematological problem in the category of aplastic anemia, paroxysmal nocturnal hemoglobinuria or even acute leukemia. The further biochemical investigations revealed, however, a folate deficiency. Nowadays this is a very rare cause of pancytopenia. Next to this she also had a Vitamin B(12) deficiency due to intrinsic factor failure. The recent literature is discussed.

[Severe polyneuropathy after using nitrous oxide as an anesthetic. A preventable disease?]. / Polineuropatía grave tras utilización de óxido nitroso como anestésico. Una patología prevenible?

INTRODUCTION: Nitrous oxide is a commonly used anaesthetic agent. One complication of this is due to its capacity to inactivate cobalamin. Therefore, in patients with poor reserves of vitamin B12, neurological and hematological alterations may be induced after a short period of exposure to nitrous oxide. CLINICAL CASE: A 69 year old man was anesthetized for three hours with 50% nitrous oxide during a surgical operation. Two weeks later he complained of severe mixed, mainly sensory polyneuropathy and was unable to walk. On diagnostic studies, vitamin B12 levels were found to be 18 pg/ml. The Shilling test confirmed that there was lack of intrinsic factor. In the preoperative studies a striking increase in motor conduction velocity was observed. Neurophysiological studies showed that there was mixed polyneuropathy, predominantly axonal. After starting treatment with hydroxycobalamin there was marked improvement and the patient became able to walk unaided. CONCLUSION: Since nitrous oxide may cause serious neurological alterations in patients with subclinical deficits of cobalamin, which may not always be accompanied by hematological changes, we consider the need for determination of plasma levels of vitamin B12 and if possible, of methylmalonic acid and homocysteine in elderly patients who are to have general anesthetics involving nitrous oxide.

Cellular import of cobalamin (Vitamin B-12).

Recent studies have isolated and characterized human gastric intrinsic factor (IF) and transcobalamin II (TC II) genes, whose products mediate the import of cobalamin (Cbl; Vitamin B-12) across cellular plasma membranes. Analyses of cDNA and genomic clones of IF and TC II have provided some important insights into their sites of expression, structure and function. IF and TC II genes contain the same number, size and position of exons, and four of their eight intron-exon boundaries are identical. In addition, they share high homology in certain regions that are localized to different exons, indicating that IF and TC II may have evolved from a common ancestral gene. Both IF and TC II mediate transmembrane transport of Cbl via their respective receptors that function as oligomers in the plasma membrane. IF-mediated import of Cbl is limited to the apical membranes of epithelial cells; it occurs via a multipurpose receptor recently termed "cubilin," and the imported Cbl is usually exported out of these cells bound to endogenous TC II. On the other hand, TC II-mediated Cbl import occurs in all cells, including epithelial cells via a specific receptor, and the Cbl imported is usually retained, converted to its coenzyme forms, methyl-Cbl and 5'-deoxyadenosyl-Cbl, and utilized.

Congenital intrinsic factor deficiency in a Spanish patient.

Vitamin B-12 deficiency was diagnosed in a 26-year-old man. Examinations performed to determine the etiology of the deficiency showed a vitamin B-12 malabsorption in the Schilling test which was corrected by adding intrinsic factor (IF) as well as normal gastric mucosa and acid secretion, although IF in gastric juice was absent. Family study showed normal serum vitamin B-12 levels in the parents, who are first cousins, and siblings. A gastric examination in the father and the sister showed decreased IF secretion, indicating heterozygosity for the disorder.