Pernicious anemia associated with cryptogenic cirrhosis: Two case reports and a literature review.

RATIONALE: Pernicious anemia (PA) is an autoimmune gastritis that results from the destruction of gastric parietal cells and the associated lack of an intrinsic factor to bind ingested vitamin B12. While an association between PA and various liver diseases has been rarely reported, reports of associated diseases include primary biliary cholangitis, autoimmune hepatitis, and Interferon-treated hepatitis C. We present 2 cases of PA associated with cryptogenic cirrhosis (CC), which has not been previously reported in the literature. PATIENT CONCERNS: A 42-year-old man presented with fatigue, pallor, and sustained abdominal distension that had persisted for 15 days. An 87-year-old man was admitted to the hospital for an unsteady gait and loss of appetite that had persisted for 20 days. DIAGNOSES: Symptoms, laboratory tests, and imaging findings for both patients were indicative of PA and CC.Both had neurological and psychiatric symptoms during hospitalization that were ultimately linked to a vitamin B12 deficiency but not hepatic encephalopathy. INTERVENTIONS: Both patients received intramuscular injections of vitamin B12. OUTCOMES: Hemoglobin levels of the 2 patients increased gradually, and their neurological symptoms were alleviated. LESSONS: PA associated with a liver disease is rare, and the underlying mechanism can only now be clarified. We speculate that autoimmune dysfunction and chronic vitamin B12 deficiency caused by PA might be unique causes of liver cirrhosis. Additional investigations are needed to verify these findings.

[Is Schilling test necessary for the etiological diagnosis of B12 insufficiency?].

In the following article a comparative evaluation of the tests used for the causative investigation of vitamin B(12) deficiency is presented. Although Schilling test since 2003 is not available in the market, it is considered the gold standard as a functional test of vitamin B(12) absorption, as it not only has a high specificity for the diagnosis of pernicious anaemia but also examines both gastric and intestinal stage of vitamin B(12) absorption. Consequently restoration of Schilling test in the clinical setting is necessary for the etiological diagnosis of B(12) insufficiency at least until a new and better vitamin B(12) absorption test is approved.

Déficit de cobalamina hereditario juvenil causado por mutaciones en el gen GIF / Hereditary juvenile cobalamin deficiency due to mutations in GIFgene

Los errores congénitos del metabolismo de la cobalamina afectan a su absorción, transporte o metabolismo intracelular. La anemia megaloblástica hereditaria juvenil por déficit de vitamina B12 está causada por una malabsorción de cobalamina. En la anemia perniciosa congénita por déficit de factor intrínseco, y en la anemia megaloblástica 1 por malabsorción de vitamina B12, causada por un defecto en el receptor vitamina B12/factor intrínseco o síndrome de Imerslund-Gräsbeck, existe un déficit de vitamina B12. El diagnóstico diferencial entre estas dos entidades no puede ser completado únicamente mediante la clínica y los datos de laboratorio. Presentamos un paciente español con anemia megaloblástica hereditaria juvenil por déficit de factor intrínseco, heterocigoto compuesto para dos mutaciones distintas en el gen GIF. La identificación de mutaciones causantes de la enfermedad en genes específicos ha mejorado nuestra capacidad de diagnóstico y tratamiento de estas situaciones (AU)

Inborn errors of cobalamin (Cbl) metabolism affect its absorption, transport, as well as its intracellular metabolism. Hereditary juvenile megaloblastic anaemia due to cobalamin deficiency, results from defects in Cbl absorption. There is a lack of vitamin B12 in congenital pernicious anaemia due to intrinsic factor deficiency and megaloblastic anaemia 1 due to selective intestinal malabsorption of vitamin B12 or Imerslund-Gräsbeck syndrome. Differential diagnosis can't be accomplished only by clinical and biochemical findings. We present a patient from Spain with a megaloblastic anaemia due to intrinsic factor deficiency (IFD). The patient is a compound heterozygous in GIF gene for a splice site mutation inherited from his mother and a missense change inherited from his father. The identification of disease-causing mutations in specific genes has improved our ability to diagnose many of these conditions (AU)

Estimated radiation dose to breast feeding infant following maternal administration of 57Co labelled to vitamin B12.

Administration of a radiopharmaceutical may result in a radiation dose to an infant due to ingestion of the radiopharmaceutical secreted in the breast milk. Following a maternal administration of Co labelled to vitamin B12 (cyanocobalamin) as part of a Schilling test an estimate of the absorbed dose to a breast feeding infant was calculated. Milk samples were collected from every feed in the first 24 h, and at approximately 48 and 72 h post-administration. The absorbed dose to the infant's liver (the organ receiving the highest dose) was calculated to be 0.23 mGy. The effective dose to the infant was calculated to be 0.025 mSv, which is considerably lower than the current regulatory limit of 1 mSv. The Administration of Radioactive Substances Advisory Committee advise that the first feed, at approximately 4 h after administration, be discarded. The data show that this was unwarranted, and that the peak concentration of Co in the breast milk occurred at around 24 h.

Prospective evaluation of protein bound vitamin B12 (cobalamin) malabsorption in the elderly using trout flesh labelled in vivo with 57Co-cobalamin.

BACKGROUND: The frequency of dietary protein bound vitamin B12 malabsorption in elderly patients remains controversial. AIMS: To evaluate this malabsorption in elderly hospitalised patients using a modified Schilling test. PATIENTS: Fourteen elderly patients with low B12 blood levels were prospectively selected from 394 hospitalised patients. METHODS: The modified Schilling test was performed with trout labelled in vivo. RESULTS: The test was normal in five healthy elderly subjects, in 7/8 patients with pancreatic insufficiency, and in nine non-elderly patients with antral gastritis. The low decision limit was established at 3.3% (median 4.8%). From the 14 elderly patients with low B12 prospectively selected from 394 hospitalised patients, seven had a real deficiency with anaemia and an increased homocysteine and/or methylmalonate serum level. The modified Schilling test showed malabsorption in five of these patients, including two in which the standard Schilling test was normal, and three in which the standard Schilling test was partially corrected by an intrinsic factor. CONCLUSIONS: Protein bound vitamin B12 malabsorption was detected in at least 0.5% of elderly hospitalised patients, using the labelled trout flesh absorption test.

Cobalamin.

Cobalamin (vitamin B12) is an essential nutrient derived exclusively from bacterial sources. It is an essential cofactor for three known enzymatic reactions. Untreated deficiency, caused by either the autoimmune disease pernicious anemia or nutritional lack, results in a macrocytic anemia and/or subacute combined degeneration of the spinal cord and is eventually fatal. Cobalamin in serum is bound to two proteins, transcobalamin and haptocorrin. The former is responsible for the essential delivery of cobalamin to most tissues. Inadequate tissue availability of cobalamin results in increased concentration of methylmalonic acid and homocyst(e)ine due to inhibition of methylmalonyl-CoA mutase and methionine synthase, respectively. Strict vegetarians have long been known to be at risk of cobalamin deficiency, which develops insidiously over many years. It is now clear that a significant number of the elderly and HIV-positive individuals are also at increased risk of deficiency. Any individual with reduced ability to split cobalamin from food-protein may also become deficient even though intrinsic factor is present. Diagnosis of cobalamin deficiency has frequently relied on total serum cobalamin and the Schilling test. Newer approaches such as analysis of methylmalonic acid, homocyst(e)ine, holotranscobalamin, anti-intrinsic factor antibodies, and serum gastrin may provide more cost-effective testing, as well as identify those with a covert deficiency.

Accuracy of measurement of dual-isotope Schilling test urine samples: a multicenter study [corrected].

UNLABELLED: As a component of our quality assurance program, this multicenter study was performed to characterize the magnitude and types of error present in measurement of typical dual-isotope Schilling test (DIST) urine samples. METHODS: A panel of three simulated DIST urine samples was formulated corresponding to diagnoses of normal excretion, malabsorption and pernicious anemia and was distributed to eight hospitals in our regional area (three novice and five experienced users). Count-rate data and urine volume measurements from each site were analyzed for accuracy against the predicted values and a carefully measured gold standard and were correlated with the methodology and equipment used. RESULTS: Three of 24 results were uninterpretable due to an overly low ratio of intrinsic factor bound to free vitamin B12 excretion (B/F ratio), inconsistent with possible diagnoses. In 20 of 21 interpretable samples, results corresponded to the appropriate diagnoses, with typical values noted in 18 of the cases and slightly atypical yet diagnostic values seen in the remaining two cases. In only one sample did values correspond to an erroneous diagnosis (low normal or partial malabsorption rather than pernicious anemia). The four major discrepancies (test failure or misdiagnosis) were largely attributable to blunders and were limited to two of the three novice sites and to a single experienced site which had grossly inaccurate raw data (background greater than sample counts). CONCLUSION: Quantitation of vitamin B12 excretion in DIST urine samples is a reliable method of evaluation when performed by reasonably experienced and competent clinical laboratories. Improved accuracy may be obtained by increasing the stochastic certainty of the count data and by more careful measurement of the sample and urine volumes.

Detection of protein bound vitamin B12 malabsorption. A case report and review of the literature.

The Schilling test is used to identify the cause of vitamin B12 malabsorption in patients with low serum vitamin B12 levels. The initial step required for vitamin B12 absorption is a process of separation from the protein complexes of food. The crystalline Co-57 vitamin B12 used in the Schilling test does not reproduce this physiologic process. Thus, a crystalline stage I Schilling test may be normal even in the face of cobalamin malabsorption. An adjunctive stage I Schilling test using Co-57 vitamin B12 bound to protein has been developed. The authors describe a patient with protein-bound vitamin B12 malabsorption whose crystalline Co-57 vitamin B12 stage I Schilling test was normal. A subsequent stage I Schilling test using Co-57 vitamin B12 bound to chicken serum revealed significant cobalamin malabsorption. A review of the history and literature of this diagnostic test using protein bound vitamin B12 is also presented.

[Cost-benefit of the Schilling test using cobalt-57]. / Costo-beneficio de la prueba de Schilling con cobalto-57.

Our purpose in the present publication is to determine the cost-benefit relation of the Schilling test used to measure the intestinal absorption of radioactive vitamin B12. The 60Co-B12 urinary excretion Schilling test was first reported in 1953, and five years later it was being performed at the National Institute of Nutrition (INNSZ) in Mexico City. It was performed in its original version until 1969 and from 1970 to 1980, the direct absorption was measured with a whole-body counter. For the last nine years we have used the Schilling test with 57Co labeled cyanocobalamin. From January 1981 through March 1990, 240 of these tests were carried out in 120 patients. The results were tabulated and compared with their clinical diagnosis. We analyzed our laboratory and labor costs. An oral dose of 0.5 micrograms of vitamin B12 labelled with 18.5 Bq of 57Co is taken by the fasting patients and two hours later one mg of standard B12 vitamin is injected. Urine is collected for 48 hours and the radioactivity is measured in a scintillation counter. Three days later the test is repeated with an additional oral dose of intrinsic factor (IF). The total expense is calculated using the following factors: the cost of the imported radioactive vitamin, IF capsules, parenteral B12 vitamin, syringes, equipment use and its depreciation, laboratory material, and salaries for the professional and administrative personnel.(ABSTRACT TRUNCATED AT 250 WORDS)

Diagnosing vitamin B12 deficiency, a common geriatric disorder.

Vitamin B12 deficiency in the elderly is a common disorder associated with an increased morbidity if it goes undetected, as often happens. Its diagnosis can be enhanced if the clinician recognizes the associated clinical features of nonspecific symptoms, glossitis, and dermatologic and neuropsychiatric abnormalities, and realizes the limitations of various tests (serum B12 assay, parietal cell and intrinsic factor antibody, mean corpuscular volume, and Schilling tests). Available data indicate it is sufficient to prescribe replacement B12 injections three or four times a year.

Schilling test: physiologic basis for and use as a diagnostic test.

With the advent of binding assays for vitamin B12 in blood, the Schilling test, which involves administration of radioactive B12 to a patient and subsequent urine collection for 24 to 48 h, fell into disuse in many laboratories. However, the test is still the only way to actually measure whether vitamin B12 is being absorbed through the terminal ilium. By administering radioactive vitamin B12, along with a preparation of intrinsic factor (IF), lack of functional IF may also be demonstrated. The Schilling test requires that attention be paid to a number of parameters, including the amount of radioactive vitamin B12 administered and the completeness of the urine collection. These factors, and others required for correct performance of the test, are discussed in this article.

The use of hydroxocobalamin in the Schilling test.

Hydroxocobalamin and cyanocobalamin have been compared as the 'flushing dose' in the Schilling test. In healthy, haematologically normal subjects excretion of the test dose was greater following a hydroxocobalamin flushing dose than following a cyanocobalamin flushing dose, and to a lesser extent this was also true in patients requiring investigation. There were occasional discrepant results, but in general it appears that, although reference values differ, hydroxocobalamin is a suitable replacement for cyanocobalamin in the Schilling test.

Cobalamin absorption determined by the stool spot test. Reliability in patients with uremia or disorders of the ileum.

A cobalamin absorption test, the stool spot test (SST), which makes use of radioactive cobalamin and a nonabsorbable isotope, 51Cr-trichloride, has been shown to produce reliable results in patients with pernicious anemia and in healthy controls. The reliability of the SST in patients with bowel disorders and in patients with decreased renal function was investigated by comparing with both whole-body counting and the Schilling test. Fourteen patients with bowel disorders and eight patients with uremia joined the trial. The SST correlated highly significantly with the whole-body counting method. However, the precision of the SST was poor in patients with decreased bowel transit time and inferior to that in the uremic patients. In one of two patients with decreased bowel transit time the two isotopes were shown to have different transit times, thus invalidating the test. In patients with uremia the SST was significantly more reliable than the Schilling test. It is concluded that the SST is reliable also in patients with uremia but may not be reliable in patients with intestinal disorders and decreased bowel transit time. In these patients collection of larger stool samples is recommended.

Schilling evaluation of pernicious anemia: current status.

The Schilling examination remains a popular means of evaluating in vivo absorption of vitamin B12. When absorption is abnormally low, the test may be repeated with addition of exogenous intrinsic factor (IF) in order to correct the IF deficiency that characterizes pernicious anemia. A dual-isotope variation provides a means of performing both stages of the test simultaneously, thereby speeding up the test and reducing dependence on complete urine collection. The dual-tracer test depends on no exchange of B12 moieties on the IF molecule. In vitro studies suggest that this exchange does take place, in a manner dependent on time, temperature, and pH. Furthermore, in vivo studies indicate that, when administered simultaneously, the absorption of unbound B12 is elevated, and IF-bound B12 is reduced, in pernicious-anemia patients, relative to the classic two-stage examination. A number of clinical studies indicate significant difficulty in resolving clinical diagnoses with the dual-tracer test. The potential weaknesses of the test discussed herein can be overcome by temporally separating the administration of the two B12 doses and by treating secondary malabsorption where it exists. An algorithm is offered for selecting the most suitable variation of the Schilling test to improve the accuracy of test results and the ease of performance.

Dual isotope Schilling test for measuring absorption of food-bound and free vitamin B12 simultaneously.

A prototype food-bound vitamin B12 (food-B12) absorption test has been developed in which 57Co-B12 was incorporated in vitro into egg yolk (yolk-B12) and served to volunteers in 50-g cooked portions together with toast and coffee for breakfast. Six hours later, 1 mg nonlabeled B12 was given intramuscularly and 24-hour urine was collected for radioactivity measurement. In separate tests, the absorption of yolk-B12 and crystalline 57Co-B12 was equally poor in patients with pernicious anemia. However, in patients with simple gastric achlorhydria and those who had undergone gastric surgery, the assimilation of yolk-B12 was impaired greatly, whereas the absorption of crystalline radio-B12 was normal. Egg yolk labeled with 58Co-B12 was administered together with crystalline 57Co-B12 in a dual isotope test with results similar to those obtained when the tests were prepared separately. This yolk-58Co-B12 test with its ability to detect malabsorption of food-B12 may be considered as an addition to the first part of the Schilling test.