Periconceptual consumption of folic acid has been shown to decrease the incidence of neural tube defects. The strategy of universal fortification of staple foodstuffs with folic acid presents the possibility of life-long exposure to unmetabolized folic acid. Chief among the risks of exposure to folic acid in the circulation is that of masking the diagnosis of cobalamin deficiency in pernicious anemia and the progression of neurologic disease. Other effects are unknown. For instance, the effect of in vivo chronic exposure of adult and fetal cells to the synthetic form of the vitamin has never been investigated at the population level. This study examined the acute appearance of unmetabolized folic acid in serum in response to the consumption of some fortified foodstuffs by young and elderly volunteers. Subjects on a 5-d regimen of fortified ready-to-eat-cereal and bread in addition to their normal diet had a threshold intake of 266 micrograms folic acid per meal at which unaltered folic acid appeared in the serum. Subjects given folic acid in either isotonic saline, milk, or white bread also had a threshold>> 200 micrograms. From patterns of food consumption in the United States, the implementation of flour fortification at 1.4 mg/kg is unlikely to lead to folic acid appearance in serum, assuming that consumption is spread throughout the day. Increasing this level of fortification, however, as has been advocated by some agencies, may result in the repeated appearance of folic acid in serum over many years, particularly in consumers in nontargeted populations of large amounts of fortified foods. The "safe level of intake" of 1 mg folate/d set by the US Food and Drug Administration may cause a serum folic acid effect. Furthermore, a repeated serum folic acid response is likely to be found in many women complying with the advice to take 400 micrograms folic acid/d to prevent the occurrence of neural tube defects.

OBJECTIVE

The enteropathy associated with common variable immunodeficiency (CVID) is poorly characterized, and its possible relationships with well-defined causes of enteropathy, such as celiac sprue (CS), remain debated. We aimed to assess the clinical and histopathological features of the enteropathy associated with CVID.

METHODS

The medical files of 50 CVID patients with gastrointestinal symptoms were analyzed retrospectively. Histological, phenotypic, and molecular analysis of intestinal endoscopic specimens was centrally performed.

RESULTS

Chronic diarrhea was the most frequent gastrointestinal symptom (92%), and biological evidence of malabsorption was observed in 54% of patients. Chronic gastritis associated or not with pernicious anemia and microscopic colitis were the most frequently observed histopathological features in gastric and colonic mucosa, respectively. Small-bowel biopsies available in 41 patients showed moderate increase in intestinal intraepithelial lymphocytes in 31 patients (75.6%) and villous atrophy in 21 patients (51%). Distinctive features from CS were a profound depletion in plasma cells and follicular lymphoid hyperplasia. Presence of peripheral blood CD8+ hyperlymphocytosis was predictive of intestinal intraepithelial hyperlymphocytosis. Intravenous (i.v.) immunoglobulin (Ig) therapy had no effect on enteropathy-related symptoms. Gluten-free diet improved only two out of 12 patients with villous atrophy, whereas all patients (7/7) responded to steroid therapy.

CONCLUSIONS

Several distinctive features differentiate CVID enteropathy from other causes of enteropathy including CS. Replacement i.v. Ig therapy is insufficient to improve gastrointestinal symptoms. Steroids are effective in reducing inflammation and restoring mucosal architecture.

OBJECTIVE

To provide information regarding the use of folic acid in combination with a multivitamin supplement for the prevention of neural tube defects and other congenital anomalies, so that physicians, midwives, nurses, and other health care workers can assist in the education of women in the pre-conception phase of their health care. OPTION: Supplementation with folic acid and vitamins is problematic, since 50% of pregnancies are unplanned, and women's health status may not be optimal when they conceive.

RESULTS

Folic acid in combination with a multivitamin supplement has been associated with a decrease in specific birth defects.

METHODS

Medline, PubMed, and Cochrane Database were searched for relevant English language articles published between 1985 and 2007. The previous Society of Obstetricians and Gynaecologists of Canada (SOGC) Policy Statement of November 1993 and statements from the American College of Obstetrics and Gynecology and Canadian College of Medical Geneticists were also reviewed in developing this clinical practice guideline.

METHODS

The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care.

RESULTS

Promoting the use of folic acid and a multivitamin supplement among women of reproductive age will reduce the incidence of birth defects. The costs are those of daily vitamin supplementation and eating a healthy diet.

CONCLUSIONS

1. Women in the reproductive age group should be advised about the benefits of folic acid in addition to a multivitamin supplement during wellness visits (birth control renewal, Pap testing, yearly examination) especially if pregnancy is contemplated. (III-A) 2. Women should be advised to maintain a healthy diet, as recommended in Eating Well With Canada's Food Guide (Health Canada). Foods containing excellent to good sources of folic acid are fortified grains, spinach, lentils, chick peas, asparagus, broccoli, peas, Brussels sprouts, corn, and oranges. However, it is unlikely that diet alone can provide levels similar to folate-multivitamin supplementation. (III-A) 3. Women taking a multivitamin containing folic acid should be advised not to take more than one daily dose of vitamin supplement, as indicated on the product label. (II-2-A) 4. Folic acid and multivitamin supplements should be widely available without financial or other barriers for women planning pregnancy to ensure the extra level of supplementation. (III-B) 5. Folic acid 5 mg supplementation will not mask vitamin B12 deficiency (pernicious anemia), and investigations (examination or laboratory) are not required prior to initiating supplementation. (II-2-A) 6. The recommended strategy to prevent recurrence of a congenital anomaly (anencephaly, myelomeningocele, meningocele, oral facial cleft, structural heart disease, limb defect, urinary tract anomaly, hydrocephalus) that has been reported to have a decreased incidence following preconception / first trimester folic acid +/- multivitamin oral supplementation is planned pregnancy +/- supplementation compliance. A folate-supplemented diet with additional daily supplementation of multivitamins with 5 mg folic acid should begin at least three months before conception and continue until 10 to 12 weeks post conception. From 12 weeks post-conception and continuing throughout pregnancy and the postpartum period (4-6 weeks or as long as breastfeeding continues), supplementation should consist of a multivitamin with folic acid (0.4-1.0 mg). (I-A) 7. The recommended strategy(ies) for primary prevention or to decrease the incidence of fetal congenital anomalies will include a number of options or treatment approaches depending on patient age, ethnicity, compliance, and genetic congenital anomaly risk status. OPTION A: Patients with no personal health risks, planned pregnancy, and good compliance require a good diet of folate-rich foods and daily supplementation with a multivitamin with folic acid (0.4-1.0 mg) for at least two to three months before conception and throughout pregnancy and the postpartum period (4-6 weeks and as long as breastfeeding continues). (II-2-A) OPTION B: Patients with health risks, including epilepsy, insulin dependent diabetes, obesity with BMI >35 kg/m2, family history of neural tube defect, belonging to a high-risk ethnic group (e.g., Sikh) require increased dietary intake of folate-rich foods and daily supplementation, with multivitamins with 5 mg folic acid, beginning at least three months before conception and continuing until 10 to 12 weeks post conception. From 12 weeks post-conception and continuing throughout pregnancy and the postpartum period (4-6 weeks or as long as breastfeeding continues), supplementation should consist of a multivitamin with folic acid (0.4-1.0 mg). (II-2-A) OPTION C: Patients who have a history of poor compliance with medications and additional lifestyle issues of variable diet, no consistent birth control, and possible teratogenic substance use (alcohol, tobacco, recreational non-prescription drugs) require counselling about the prevention of birth defects and health problems with folic acid and multivitamin supplementation. The higher dose folic acid strategy (5 mg) with multivitamin should be used, as it may obtain a more adequate serum red blood cell folate level with irregular vitamin / folic acid intake but with a minimal additional health risk. (III-B) 8. The Canadian Federal Government could consider an evaluation process for the benefit/risk of increasing the level of national folic acid flour fortification to 300 mg/100 g (present level 140 mg/100 g). (III-B) 9. The Canadian Federal Government could consider an evaluation process for the benefit/risk of additional flour fortification with multivitamins other than folic acid. (III-B) 10. The Society of Obstetricians and Gynaecologists of Canada will explore the possibility of a Canadian Consensus conference on the use of folic acid and multivitamins for the primary prevention of specific congenital anomalies. The conference would include Health Canada/Congenital Anomalies Surveillance, Canadian College of Medical Geneticists, Canadian Paediatric Society, Motherisk, and pharmaceutical industry representatives.

RESULTS

This is a revision of a previous guideline and information from other consensus reviews from medical and government publications has been used.

BACKGROUND

The Society of Obstetricians and Gynaecologists of Canada.

Available evidence suggests that fracture prediction with bone densitometry may improve when used on people at high risk of osteoporotic fractures. The objectives of this literature review were: (1) to identify risk factors for fracture that are associated with the development of a low bone mass for both men and women; (2) to describe and assess the relationship between these factors and the risk of fracture; and (3) to classify them according to the strength of their association with fracture incidence. Studies were identified from MEDLINE (1982-1997), HealthSTAR (1975-1997) and The Cochrane Library (1997) databases. Pre-stated inclusion criteria (original analytic studies assessing risk factors for osteoporotic fractures in men and women) and methodologic quality were assessed by two independent investigators. Information on the study design and analysis, characteristics of participants, exposure (risk factor) and outcome measures (relative risk and odds ratios for fracture incidence), control for potential confounding factors and risk estimates was extracted using a standardized protocol. Qualitative and meta-analytic techniques were used for data synthesis. As a result, risk factors were classified into three groups according to their strength of association with fracture: high risk (RR>> or = 2), moderate risk (1 < RR < 2) and no risk or protective (RR < or = 1). Of approximately 80 risk factors identified from 94 cohort and 72 case-control studies, 15% were classified in the high-risk group, including low body weight, loss of weight, physical inactivity, the consumption of corticosteroids or anticonvulsants, primary hyperparathyroidism, diabetes mellitus type 1, anorexia nervosa, gastrectomy, pernicious anemia, and aging >> 70-80 years). Eighteen percent and 8% of risk factors were classified in the moderate and no risk group respectively, whereas 60% showed either a lack of scientific evidence confirming their association with fracture or contradictory results. An efficient strategy for bone densitometry provision may thus be its selective use in those individuals who present with several strong or moderate risk factors for fracture related to bone mass loss.

Using a constant perfusion technique, sodium and bicarbonate absorption was studied in human subjects. The following observations were made on sodium absorption from saline solution: (a) the rate of sodium absorption is markedly influenced by bulk water flow, (b) when net water flow is zero, sodium absorption is zero if there are no concentration gradients between plasma and lumen that favor net NaCl diffusion; and (c) the PD between abraded skin and jejunal lumen is near zero when saline is perfused and does not change with partial substitution of sulfate or bicarbonate for chloride. Based on these observations, we conclude that sodium absorption from saline is entirely passive in the human jejunum. On the other hand, in the presence of bicarbonate sodium is absorbed actively against electrochemical gradients. The mechanism of the link between bicarbonate and sodium absorption was studied in normal subjects and in 11 patients with pernicious anemia; the latter were chosen because they do not secrete gastric acid which can react with bicarbonate in the jejunal lumen. We observed that bicarbonate absorption (a) occurs against steep electrochemical gradients, (b) does not generate a potential difference between abraded skin and jejunal lumen, (c) is inhibited by acetazolamide, and (d) generates a high CO2 tension in jejunal fluid. These observations suggest that bicarbonate absorption is mediated by active hydrogen secretion, rather than by bicarbonate ion transport per se, and that the link between sodium and bicarbonate transport is best explained by a sodium-hydrogen exchange process.

OBJECTIVE

In the era of genome-wide association studies, familial risks are used to estimate disease heritability and the likelihood of candidate-gene identification. This study was undertaken to estimate associations of rheumatoid arthritis (RA) with any of 33 autoimmune diseases and related conditions among parents and offspring, singleton siblings, twins, and spouses.

METHODS

The Multigeneration Register in Sweden was used as a reliable source of information on Swedish families throughout the last century. Data on autoimmune diseases in individual family members were obtained through linkage to the Hospital Discharge Register. The standardized incidence ratio (SIR) was calculated as a measure of the relative risk of RA in family members of patients with RA or any of 33 other autoimmune diseases or related conditions, as compared with the relative risk of RA in those lacking an affected family member.

RESULTS

Among a total of 447,704 patients, 47,361 were diagnosed as having RA. The SIRs for RA were 3.02 in offspring of affected parents, 4.64 in siblings, 9.31 in multiplex families, 6.48 in twins, and 1.17 in spouses. Significant associations with the familial risk of RA in offspring according to parental proband were observed for ankylosing spondylitis (SIR 2.96), localized scleroderma (SIR 2.40), Sjögren's syndrome (SIR 2.25), systemic lupus erythematosus (SIR 2.13), systemic sclerosis (SIR 1.65), Hashimoto thyroiditis/hypothyroidism (SIR 1.54), pernicious anemia (SIR 1.53), sarcoidosis (SIR 1.40), psoriasis (SIR 1.36), Wegener's granulomatosis (SIR 1.34), and asthma or polymyalgia rheumatica (SIR 1.32).

CONCLUSIONS

This is the first study to compare the familial risks of RA in relation to a large number of autoimmune diseases and related conditions using data from a single population. The high discordant familial risks in this population suggest that there is extensive genetic sharing between RA and the associated diseases.

Pernicious anemia is a common cause of megaloblastic anemia throughout the world and especially in persons of European or African descent. Dietary deficiency of vitamin B12 due to vegetarianism is increasing and causes hyperhomocysteinemia. The breast-fed infant of a vitamin B12-deficient mother is at risk for severe developmental abnormalities, growth failure, and anemia. Elevated methylmalonic acid and/or total homocysteine are sensitive indicators of vitamin B12-deficient diets and correlate with clinical abnormalities. Dietary vitamin B12 deficiency is a severe problem in the Indian subcontinent, Mexico, Central and South America, and selected areas in Africa. Dietary vitamin B12 deficiency is not prevalent in Asia, except in vegetarians. Areas for research include intermittent vitamin B12 supplement dosing and better measurements of the bioavailability of B12 in fermented vegetarian foods and algae.

Polyglandular autoimmune syndrome (PAS) has been well characterised and the accepted criteria for diagnosis are the presence of at least two of the three major components: hypoparathyroidism (HPT), candidiasis, and adrenal insufficiency (AI). HPT may, however, be the only manifestation of the syndrome. Iranian Jews, having a high rate of consanguinity, appear to be a community in which PAS type I is frequent. We report on 19 families of patients with HPT from the Iranian Jewish community assuming that they are in fact affected with PAS type I. In the 19 families, 23 patients were affected, including 11 males and 12 females. All the patients but one had HPT (96%), and most were diagnosed by the age of 20 years (91%). AI was diagnosed in five of our patients; in all cases but one it appeared after HPT. Mild oral candidiasis was present in four patients and six of the patients (three males and three females) had hypogonadism. Other features of the syndrome found in some of our patients were pernicious anaemia, hypothyroidism, and alopecia. The disease is autosomal recessive and the calculated prevalence among the Iranian Jews is 1:6500 to 1:9000. The disease is also found with a very high incidence among Finns. A comparison of the symptoms between the two groups showed clinical differences including the relative rarity of candidiasis and absence of keratopathy among the Iranian Jews.

The incidence of gastric cancer is decreasing and lies between 10 and 15 new cases per 100,000 population per year in most Western countries. Peak age is between 60 and 80 years. While distal gastric cancers account for the overall decrease in gastric cancer, tumors in the proximal stomach (cardia and esophagogastric junction) are on the rise. Recognized risk factors for gastric cancer are infection with Helicobacter pylori, dietary factors (e.g. high intake of salt-preserved foods), smoking, pernicious anemia and a history of partial gastrectomy.

Severe vitamin B(12) deficiency produces a cluster of neurological symptoms in infants, including irritability, failure to thrive, apathy, anorexia, and developmental regression, which respond remarkably rapidly to supplementation. The underlying mechanisms may involve delayed myelination or demyelination of nerves; alteration in the S-adenosylmethionine:S-adenosylhomocysteine ratio; imbalance of neurotrophic and neurotoxic cytokines; and/or accumulation of lactate in brain cells. This review summarizes the current knowledge concerning infantile vitamin B(12) deficiency, including a pooled analysis of case studies of infants born to mothers with untreated pernicious anemia or a strict vegetarian lifestyle and a discussion of the mechanisms that may underlie the manifestations of deficiency.

A simplified microbiological assay for determining the folate content of red cells is described. As in previously reported methods Lactobacillus casei is used as test organism but two modifications are introduced. First, haemolysis is carried out in water containing 1 g.% of ascorbic acid; secondly, haemolysates are not incubated before the assay. Using this assay, recovery of pteroylglutamic acid added in two different concentrations to five different whole blood samples was 97.0 +/- 1.9 S.E. % and 106.1 +/- 4.7 S.E. % respectively. The coefficient of variation of the assay was between 11.2 and 15.0%. Haemolysates were best stored deep frozen, showing no significant loss of L. casei activity for three to five months at -20 degrees C. On the other hand, non-haemolysed blood samples were best stored at 4 degrees C. when there was no loss of activity for seven to 10 days. Experiments confirmed that plasma is necessary for the maximum release of red cell L. casei activity, and showed that only small amounts of plasma are necessary; folate- and B(12)-deficient plasma released slightly lower L. casei activities from red cells than did normal plasma. The red cell folate levels of 40 healthy normal subjects ranged from 160 to 640 mmug. per ml. of packed red cells. One hundred and twenty patients with subnormal serum folate levels due to idiopathic steatorrhoea, nutritional folate deficiency and Crohn's disease, partial gastrectomy, myelosclerosis, and polycythaemia vera were studied. Red cell folate levels were subnormal (range from 7 to 143 mmug. per ml.) in 40 patients with megaloblastic anaemia, the lowest levels occurring in the most anaemic patients. Subnormal red cell folate levels also occurred in 23 (29%) of the 80 non-anaemic patients. There was a good correlation between red cell folate level and severity of folate deficiency assessed by polymorph nuclear lobe counts, and, in the non-anaemic patients bone marrow morphology. It is concluded that, in the absence of B(12) deficiency, the red cell folate level is a precise guide to the severity of folate deficiency. Patients with serum folate levels less than 3.0 mmug. per ml. almost always had megaloblastic anaemia or obvious morphological changes of folate deficiency. In patients with borderline serum folate levels (3.0-5.9 mmug. per ml.) haematological changes varied widely. The degree of change correlated with the red cell folate level in these patients. The formiminoglutamic acid (Figlu) test was positive (range 20-660 mg. excreted in eight hours) in all 30 patients with megaloblastic anaemia due to folate deficiency tested and also in 17 (31%) of 54 non-anaemic patients who were folate deficient. The amount of Figlu excreted paralleled the red cell folate level in both the anaemic and non-anaemic, folate-deficient patients tested. Figlu excretion, like the red cell folate level, appeared to be a satisfactory index of tissue folate stores. In 46 patients with pernicious anaemia, the red cell folate levels ranged from 26 to 396 mmug. per ml., 29 (63%) of them having subnormal levels. The ratio of mean red cell to mean serum folate level, 13.0:1, was lower than that of normal subjects. As in folate deficiency the patients with the lowest haemoglobin concentrations had the lowest red cell folate levels. Figlu was positively excreted in 10 (59%) of 17 patients with pernicious anaemia tested, being particularly increased in those with low red cell folate levels. Reticulocytes of patients with pernicious anaemia on treatment and with haemolytic anaemia were shown to have higher folate levels than their corresponding mature cells. It is concluded that reticulocytes in general have relatively high folate levels.

Pepsinogen I and pepsinogen II were purified from gastric mucosa and used to develop a radioimmunoassay for pepsinogen II and an improved radioimmunoassay for pepsinogen I. Each immunochemically homogeneous preparation contained only its characteristic components by radioelectophoretic analysis, and migrated as a singly band in polyacrylamide gel. The mean (+/- SD) level of serum pepsinogen II in 42 healthy control subjects was 10,8 +/- 3.8 ng/ml, significantly less (p less than 0.001) than the level of pepsinogen I, which was 62.9 +/- 22.2 ng/ml. The correlation between serum pepsinogen I and pepsinogen II was highly significant (r = 0.700, p less than 0.001) in these subjects. In 20 patients with pernicious anemia the mean serum pepsinogen II level was 10.6 +/- 2.5 ng/ml, not different from normal, but significantly higher (p less than 0.001) than the level of pepsinogen I which was 5.9 +/- 4.7 ng/ml. IN 10 patients with total gastrectomy, serum pepsinogen I was 3.9 +/- 3.1 ng/ml and serum pepsinogen II was 3.2 +/- 3.1 ng/ml; both values were significantly lower (p less than 0.001) than the corresponding levels in pernicious anemia. The predominance of pepsinogen I in the serum of healthy control subjects suggests that either the gastric chief cell normally releases more pepsinogen I than pepsinogen II into the circulation or that pepsinogen I has longer metabolic clearance rate than pepsinogen II. The marked decrease in serum pepsinogen I in patients with pernicious anemia is best explained by a loss of gastric chief cells due to severe atropic gastritis of te fundic glands. The normal distribution of serum pepsinogen II levels in these patients may reflect an increased number of pyloric glands due to pyloric gland metaplasia of the proximal stomach.

To determine if levels of serum total homocysteine are elevated in patients with either cobalamin or folate deficiency, we utilized a new capillary gas chromatographic-mass spectrometric technique to measure total homocysteine in the serum of 78 patients with clinically confirmed cobalamin deficiency and 19 patients with clinically confirmed folate deficiency. Values ranged from 11 to 476 mumol/liter in the cobalamin-deficient patients and 77 of the 78 patients had values above the normal range of 7-22 mumol/liter as determined for 50 normal blood donors. In the cobalamin-deficient patients, serum total homocysteine was positively correlated with serum folate, mean corpuscular volume, serum lactate dehydrogenase, serum methylmalonic acid, and the degree of neurologic involvement, and inversely correlated with platelets and hematocrit. In the folate-deficient patients, values for serum total homocysteine ranged from 17 to 185 mumol/liter and 18 of the 19 patients had values above the normal range. Some patients with pernicious anemia who were intermittently treated with cyanocobalamin were found to have elevated serum levels of total homocysteine while they were free of hematologic and neurologic abnormalities. The measurement of serum total homocysteine will help define the incidence of cobalamin deficiency and folate deficiency in various patient populations.

We describe a personal series of 60 cases of parkinsonism with onset under the age of 40 years. Known causes for early onset of secondary parkinsonism, such as Wilson's disease or encephalitis, were excluded in every case. Two groups were identified: those with onset after the age of 21 in whom no hereditary factors could be ascertained (56 cases), and those with onset before 21 years all of whom had familial parkinsonism. In neither group have we found any association with prematurely grey hair, hypertension, diabetes, pernicious anaemia, or thyroid disorder. Among their families, we have not found any association with diabetes, pernicious anaemia, or thyroid disorder. We propose that cases of apparent idiopathic Parkinson's disease beginning between age 21-40 years should be called "young onset Parkinson's disease." Twenty percent of such patients in our series had at least one first- or second-degree relative in the same or antecedent generations with parkinsonism, but only 1.5% of their relatives at risk had parkinsonism, which is similar to the prevalence in the general population. Ten percent of these patients had at least one relative with essential tremor, but only 1.6% of their relatives at risk had tremor, which again was similar to the prevalence in the population in general. These patients with young onset Parkinson's disease responded well to levodopa therapy. However, dyskinesias and response fluctuations occurred early and frequently. The prevalence of dyskinesias and response fluctuations was strongly correlated with the duration of levodopa treatment, but not with the duration (or probably the severity) of the disease before levodopa therapy was commenced. The involuntary movements often were severe and frequently were diphasic. Despite long disease duration, the incidence of dementia in young onset patients aged less than 65 years was negligible. We believe that most, if not all, patients in this group have degenerative Lewy body idiopathic Parkinson's disease, representing the lower end of a skewed deviation for age of onset of this disease. We have so far failed to identify any additional environmental factor which may have accelerated disease onset in these patients. In contrast, cases of parkinsonism beginning before age 21 years were invariably familial. We proposed that they should be called "juvenile parkinsonism." All affected relatives with parkinsonism also had young disease onset, and all but one were siblings. None of four such patients seen by us has demented, and computed tomography (CT) scan has been normal in all four. We believe that most such patients have some form of genetically determined secondary parkinsonism.

OBJECTIVE

To investigate the prevalence of Helicobacter pylori associated chronic gastritis in patients with gastric cancer.

METHODS

Serum IgG antibodies for H pylori were determined in 54 consecutive patients with gastric carcinoma. The prevalence of H pylori in gastric mucosa was also examined histologically (modified Giemsa) in 32 patients from whom adequate biopsy specimens of the antrum and corpus were available. Thirty five patients with gastrointestinal tumours outside the stomach and 48 with non-gastrointestinal malignancies served as controls.

RESULTS

Of the 54 patients, 38 (70%) had H pylori antibodies (IgG) in their serum (three additional patients had H pylori antibodies IgA, class specific but not IgG specific). This prevalence was significantly higher (p less than 0.05) than that (49%) in the 35 controls. No differences in prevalence of H pylori antibodies were found between gastric cancer cases of intestinal (IGCA) or diffuse (DGCA) type, both these types showing H pylori antibodies (IgG) in 71% of the patients. In the subgroup of 32 subjects, five patients had normal gastric mucosa and four showed corpus limited atrophy ("pernicious anaemia type" atrophy of type A). All of these nine patients had no evidence of current or previous H pylori infection in serum (no IgG antibodies) or in tissue sections (negative Giemsa staining). The remaining 23 patients had antral or pangastritis, and all had evidence of current or previous H pylori infection.

CONCLUSIONS

H pylori associated chronic gastritis was the associated disease in 75% of the patients with gastric cancer occurring equally often in both IGCA and DGCA groups. About 25% of cases seem to have a normal stomach or severe corpus limited atrophy, neither of which showed evidence of concomitant H pylori infection.

Autoimmune conditions are associated with an elevated risk of lymphoproliferative malignancies, but few studies have investigated the risk of myeloid malignancies. From the US Surveillance Epidemiology and End Results (SEER)-Medicare database, 13 486 myeloid malignancy patients (aged 67+ years) and 160 086 population-based controls were selected. Logistic regression models adjusted for gender, age, race, calendar year and number of physician claims were used to estimate odds ratios (ORs) for myeloid malignancies in relation to autoimmune conditions. Multiple comparisons were controlled for using the Bonferroni correction (P<0.0005). Autoimmune conditions, overall, were associated with an increased risk of acute myeloid leukaemia (AML) (OR 1.29) and myelodysplastic syndrome (MDS, OR 1.50). Specifically, AML was associated with rheumatoid arthritis (OR 1.28), systemic lupus erythematosus (OR 1.92), polymyalgia rheumatica (OR 1.73), autoimmune haemolytic anaemia (OR 3.74), systemic vasculitis (OR 6.23), ulcerative colitis (OR 1.72) and pernicious anaemia (OR 1.57). Myelodysplastic syndrome was associated with rheumatoid arthritis (OR1.52) and pernicious anaemia (OR 2.38). Overall, autoimmune conditions were not associated with chronic myeloid leukaemia (OR 1.09) or chronic myeloproliferative disorders (OR 1.15). Medications used to treat autoimmune conditions, shared genetic predisposition and/or direct infiltration of bone marrow by autoimmune conditions, could explain these excess risks of myeloid malignancies.

BACKGROUND

Elevated risk of cancers of the stomach, colon, and buccal cavity, as well as of lymphoma and leukemia, have been reported for patients with pernicious anemia in case reports and hospital-based and cross-sectional studies.

METHODS

A cohort of 2021 men and 2496 women living in the Uppsala health care region in Sweden, discharged with a hospital diagnosis of pernicious anemia from 1965 to 1983, was followed for 20 years for subsequent risk of cancer.

RESULTS

A total of 553 cancers were diagnosed among these patients, significantly more than expected based on cancer standardized incidence rates (SIRs) in the general population (SIR = 1.4; 95% confidence interval [CI], 1.2-1.5). Most prominent were excesses for cancer of the stomach (SIR = 2.9; 95% CI, 2.4-3.5), esophagus (SIR = 3.2; 95% CI, 1.8-5.2), and pancreas (SIR = 1.7; 95% CI, 1.2-2.4) among men and women; myeloid leukemia among men (SIR = 4.4; 95% CI, 1.8-5.2); and multiple myeloma among women (SIR = 2.5; 95% CI, 1.1-4.9). An excess of gastric carcinoid tumors also was evident in this cohort. The risk of stomach cancer was highest in the first year after diagnosis of pernicious anemia (SIR = 7.4; 95% CI, 5.3-10.1), but an increased risk persisted throughout the follow-up period. The risk of esophageal cancer also remained elevated throughout the study period, although the risk of pancreatic cancer dropped off after 5 years.

CONCLUSIONS

This study confirms the excess risk of gastric carcinoma and carcinoid tumors associated with pernicious anemia, and suggests that the susceptibility state may extend to esophageal and other cancers.

Polyglandular autoimmune syndromes (PAS) are rare polyendocrinopathies characterized by the failure of several endocrine glands as well as nonendocrine organs, caused by an immune-mediated destruction of endocrine tissues. This article summarizes extensive clinical, epidemiological, serological, and genetic data of a large collective of patients with PAS (n = 360). Since 1988, more than 15,000 adult patients with endocrine diseases have been screened at the endocrine center of the Mainz University, and 151 of 360 patients with PAS have regularly been followed. Type 1 diabetes, Graves' disease, Hashimoto thyroiditis, Addison's disease, vitiligo, alopecia, hypogonadism, and pernicious anemia were observed in 61%, 33%, 33%, 19%, 20%, 6%, 5%, and 5%, respectively. The most common disease combination was type 1 diabetes and autoimmune thyroid disease. In most patients, type 1 diabetes was the first manifestation of PAS (48%). The longest time intervals between manifestations of the first and second immune endocrinopathies occurred between type 1 diabetes and thyroid disease (13.3 +/- 11.8 yr) and between vitiligo and thyroid disease (16.3 +/- 13.3 yr), but a shorter time interval was observed between Addison's and thyroid diseases. Of the 471 patients with type 1 diabetes screened, 83 (17.6%) were positive for PAS. Subsequently, sera of 126 patients with PAS, 287 with type 1 diabetes, and 303 matched controls were compared for human leukocyte antigens. Patients with PAS had significantly higher frequencies of the human leukocyte antigens A24, A31, B8, B51, B62, DR3, and DR4 (relative risk, 2.35, 2.74, 2.47, 7.17, 2.22, 1.94, and 2.46) vs. controls, and for A31, B15, B52, B55, DR2, DR11, and DR13 (relative risk, 2.51, 7.96, 3.99, 5.36, 4.46, 2.89, and 3.26) vs. type 1 diabetes patients without PAS. In conclusion, patients with autoimmune endocrine disease should be followed on a regular basis. In subjects at risk for PAS, functional screening every 3 yr is warranted. If clinical disease is present, serological measurement of organ-specific antibodies should follow.

Simultaneous 24-hour intragastric acidity and plasma gastrin concentrations were measured in 12 duodenal ulcer patients before and on the twenty-eighth day of treatment with either ranitidine 150 mg b.d. or omeprazole 20 mg o.m. Median integrated 24-hour intragastric acidity was decreased significantly from 1148 to 490 and 36 mmol.hour litre-1 during treatment with ranitidine and omeprazole, respectively, whilst median intragastric 24-hour plasma gastrin was raised significantly from 328 to 799 and 1519 pmol.hour litre-1 respectively. When the results of all 48 experiments were considered together, there was a significant inverse correlation between the 24-hour integrated values for intragastric acidity and plasma gastrin concentration. Both drugs caused a significant elevation of plasma gastrin throughout the 24 hours, although ranitidine had no effect on intragastric acidity from 1900 to 2200 hours. When compared with similar profiles of acidity and gastrin in pernicious-anaemia patients, the modest elevations of plasma gastrin observed in this study suggest that neither drug will be associated with clinically relevant enterochromaffin-like cell proliferation in duodenal ulcer patients.