Schilling Test Research Articles

Biochemical tests in the diagnosis of chronic pancreatitis and in the evaluation of pancreatic insufficiency

Chronic pancreatitis (adults) and cystic fibrosis (children) are the most common diseases leading to exocrine pancreatic insufficiency that, when reduced to <5% of normal function, is characterised by steatorrhoea. The pathogenesis of the former condition is outlined, and recent concepts are emphasized. Biochemical tests to detect pancreatic insufficiency and to identify pancreatic disease as the cause of steatorrhea include: serum enzyme tests (lipase, amylase, trypsin); stool chymotrypsin; isotopic tests based upon the assimilation of [ 14C] lipids and starch or excretion of the isotope as breath CO 2, as well as the dual-labelled Schilling test; oral function tests utilising substrates hydrolysed by pancreatic enzymes such as benzoyl tyrosyl- p-aminobebzoic acid and fluorescein dilaurate; and duodenal intubation studies following meal-induced or hormonal stimulation of the pancreas. The rationale for these tests and the cumulative clinical experience of their utility are reviewed. A recommended diagnostic strategy is briefly presented. The role of various biochemical procedures to evaluate the efficacy of pancreatic enzyme replacement therapy is also described.

Cobalamin absorption and serum homocysteine and methylmalonic acid in elderly subjects with low serum cobalamin

We prospectively studied 41 consecutive elderly patients with serum cobalamin (vitamin B12) levels lower than 125 pmol/l. The protein-bound cobalamin absorption test (PBAT) was performed in 34 of them and in 27 selected elderly control patients. The lower decision limit was 0.18% and an abnormal test was detected in only 9 (26%) of the 34 patients with low serum cobalamin level. When the PBAT was compared to the Schilling (Dicopac method) test, a concordant result was found in 80%. Serum methylmalonic acid and/or total homocysteine concentrations were elevated in 75% (26/35) of the patients with low serum cobalamin levels but also in 30% (5/17) of the control patients. Of the 12 and 9 cobalamin-deficient patients with elevated serum levels of methylmalonic acid and homocysteine, normalization after cobalamin therapy was obtained in 11 and 5 respectively. In conclusion, determination of serum metabolites and their response to cobalamin therapy are a sensitive index of significant cobalamin deficiency and a useful means of distinguishing between cobalamin and folate deficiency. The PBAT offers little advantage over the Schilling test in diagnosing cobalamin malabsorption in elderly patients.

Vitamin B12 Deficiency in Patients with Ileocolic Neobladders

The terminal ileum is widely used for reconstruction of the lower urinary tract. Since the terminal ileum exclusively absorbs vitamin B12, removal of ileum from the gastrointestinal tract for use in lower urinary tract reconstruction may predispose patients to vitamin B12 deficiency. In a prospective study serial vitamin B12 levels were obtained postoperatively in 24 patients who underwent cystectomy for malignancy and ileocolic neobladder urinary diversion with a mean followup of 25 months (range 6 to 53). Any patient who had a low vitamin B12 serum level (less than 200pg./ml.) underwent a Schilling test to confirm malabsorptive vitamin B12 deficiency. Six patients (25%) had low serum vitamin B12 levels, of whom 3 (13%) had an abnormal Schilling test. No patient had megaloblastic anemia. One patient with malabsorptive vitamin B12 deficiency had neurological symptoms 53 months postoperatively. We conclude that vitamin B12 deficiency can occur following ileocolic neobladder reconstruction. Patients with true vitamin B12 deficiency should be identified and placed on lifelong parenteral vitamin B12.

Function of terminal ileum in patients with Yersinia-triggered reactive arthritis.

In order to study the function of the intestinal epithelium in the terminal ileum, the Schilling test was performed in 10 patients with Yersinia-triggered reactive arthritis, in 10 patients who had recovered from Yersinia enteritis without complications, and in five patients with rheumatoid arthritis treated with non-steroidal anti-inflammatory agents. The Schilling test indicates absorption of vitamin B12 in the terminal ileum, i.e. the area affected by Yersinia and inflamed in patients with reactive arthritis. The findings obtained demonstrate increased uptake through the epithelium in this area of the intestine in patients with Yersinia-triggered reactive arthritis. There are two possible explanations. First, Yersinia infection may have a long-term effect on the gut mucosa. Secondly, some individuals may, at the level of the terminal ileum, show enhanced absorption of vitamin B12 and/or other substances such as microbes or their components, resulting in increased susceptibility to certain infections.

Myths About Vitamin B12 Deficiency

Neurologic manifestations of vitamin B12 deficiency are protean, including neuropathy, depression, and dementia. We present evidence to dispel confounding myths about vitamin B12 deficiency. Hematologic indices are normal in up to 30% of patients with vitamin B12 deficiency, and results of the Schilling test may be normal in patients with symptoms of deficiency. Isolated neuropathy or myelopathy may occur independently, but often appear concurrently. The neuropathy is primarily axonal and predominantly sensory. Myelopathy is caused by demyelinated areas in posterior and lateral columns. After therapy, recovery from neuropathy is incomplete or may extend for several years. Vitamin B12 replacement should not be withheld from patients with borderline vitamin B12 levels, since the consequences of allowing myelopathy, neuropathy, dementia, and mental disorders to worsen clearly outweigh any disadvantage of therapy.

Development of sustained achlorhydria in a patient with the Zollinger-Ellison syndrome treated with omeprazole

Spontaneous remission of gastric acid hypersecretion in the Zollinger-Ellison syndrome occurs rarely. This study shows the development of gastric secretory mucosal atrophy resulting in achlorhydria and loss of pepsin secretion in a 63-year-old woman with the Zollinger-Ellison syndrome. Reduced secretion began soon after starting treatment with omeprazole, and achlorhydria became complete 6 months later. The patient remains well with normal endoscopy results and is achlorhydric 4 years after the start of treatment and 34 months after stopping omeprazole. She was not colonized with Helicobacter pylori until 36 months after developing achlorhydria. Serum gastrin has increased from 1000 to between 5000 and 12,500 ng/L (pg/mL), was not suppressible by gastric acidification, and was not associated with G-cell hyperplasia. She also has a normal Schilling test and normal immunoglobulins, and lacks antibodies to parietal cells or H+,K+-ATPase. Moderate enterochromaffinlike cell hyperplasia is apparent for the first time on the latest biopsy sample.

Subtle vitamin-B12 deficiency and psychiatry: a largely unnoticed but devastating relationship?

A long list of psychiatrically inclined illnesses or symptoms, especially some cases of mood disorder, dementia, paranoid psychoses, violent behavior and fatigue, have been documented to be caused by vitamin-B12 deficiency, among other causes. The author uses reputably published literature — and extrapolations from it — to show that these conditions are possibly more commonly caused by B12 deficiency than is currently generally accepted, mostly because of a lack of appreciation of the lowest serum-B12 level that is necessary to protect against the cerebral manifestations of this deficiency. After surveying the whole area of psychiatry and nutritional deficiencies in general, the author deals with the role of vitamin-B12 in mood disorders, paranoid psychoses and dementia in more detail. In doing so, he cites some useful conclusions from the literature, including the debunking of several myths about the diagnosis and treatment of brain-B12-deficiency, especially the efficacy of high dose oral treatment and the relative inefficacy of the Schilling's test.

Introduction of a Well-type germanium/lithium semiconductor detector in nuclear medicine

Semi-in-vivo diagnostic procedures in nuclear medicine are commonly carried out using conventional scintillation detectors. Modern semiconductor detectors have rarely been applied in this field until now. A particular example of this group is the Well-type germanium/lithium detector, a semiconductor detector which combines a high energy resolution with a high efficiency for gamma-radiation. The latter, combined with an excellent signal-to-background ratio, allows accurate detection of even very low activities. Patient doses can therefore be reduced considerably, as was demonstrated in erythrocyte survival studies, platelet survival studies and the Schilling test. The effective dose equivalent associated with erythrocyte survival studies, using the recommended 51Cr method, could be reduced from 780 to 2 μSv. The effective dose equivalent in platelet survival studies, using the recommended 111In method, could be reduced from 1400 to 14 μSv. For both procedures, the reliability was demonstrated by the results obtained with healthy controls. In the Schilling test, using 57Co, the effective dose equivalent could be reduced from 54 to 9 μSv. In addition, the high resolution of Ge-detectors enables selective and accurate determination of individual components in mixtures of isotopes. Therefore, with such detectors, low-level double-labeling procedures can be introduced in semi-in-vivo nuclear medicine, thus creating the possibility of studying certain unanswered but clinically relevant questions.

Malabsorption of Vitamin B12 in Pancreatic Insufficiency of the Adult and of the Child

Vitamin B12 can bind two carrier proteins in the digestive tract, haptocorrin (R binder) and intrinsic factor, but only its binding to intrinsic factor allows its absorption. A malabsorption of vitamin B12 is observed in about 30% of adult patients with exocrine pancreatic insufficiency, using the Schilling test. None of the hypotheses that have tried to explain this malabsorption are entirely satisfactory. A failure to degrade haptocorrin can prevent the binding of vitamin B12 to intrinsic factor. It has also been suggested that pancreatic secretion could modify the structure of intrinsic factor, enabling the uptake of the vitamin B12-intrinsic factor complex by the ileum. Other factors can also affect the binding of vitamin B12 to intrinsic factor, such as the gastric pH and bile. The Schilling test is abnormal in nearly all cases of cystic fibrosis. One explanation could be the gastric hyperacidity observed in this disease. Despite the frequency of abnormal Schilling tests, vitamin B12 deficiency is very rare in cases of exocrine pancreatic dysfunction, in adults as well as in children with cystic fibrosis. The assimilation of this vitamin with a tracer included in food instead of the crystalline labeled cobalamin used in the Schilling test remains to be investigated.

Neurologic and Evoked Potential Abnormalities in Subtle Cobalamin Deficiency States, Including Deficiency Without Anemia and With Normal Absorption of Free Cobalamin

The meaning of a low serum cobalamin level when the classic findings of pernicious anemia are lacking is undergoing reevaluation. We therefore studied the neurologic status of 11 patients who had low cobalamin levels without definite hematologic evidence of deficiency. Neurologic evaluation included pattern-shift visual and median and posterior tibial nerve somatosensory evoked potentials. None of the patients had megaloblastic changes in the blood or bone marrow, although 7 of the 11 had subtle cellular cobalamin disturbances demonstrated by an abnormal deoxyuridine suppression test result. Seven patients had normal Schilling test results and 2 had borderline results; however, 2 of the 5 patients tested further had food-cobalamin malabsorption, while a third had prepernicious anemia. The patients displayed a variety of neurologic problems, including dementia, depression, myelopathy, neuropathy, and seizure disorder; 1 patient was neurologically normal by clinical criteria. Evoked potential abnormalities were demonstrable in 8 of the 9 patients with subtle cobalamin deficiency, and in at least 5 cases the disturbance was central. In contrast, both patients whose low serum cobalamin levels were found on evaluation to be spurious had normal evoked potentials. Evoked potential abnormalities improved in the one patient retested after cobalamin therapy. These findings demonstrate that neurologic deficits occur not only in classic cobalamin deficiency but also in subtle or atypical cobalamin deficiency states in which anemia is absent and Schilling test results are normal. Electrophysiologic evidence of neurologic impairment is often present, even in patients without obvious clinical neurologic abnormalities.

Investigation of seemingly pathogen-negative diarrhoea in patients infected with HIV1.

Thirty three consecutive patients infected by human immunodeficiency virus type 1 (HIV1) with persistent diarrhoea which remained undiagnosed after microbiological examination of six stool samples and rectal histology were investigated for malabsorption. All had xylose and Schilling tests, distal duodenal biopsy, comprehensive barium studies, microbiological examination of six further stool samples, and repeat rectal histology. A microbiological or histological diagnosis of infection was made in 12 patients (multiple organisms in three). Cryptosporidia were identified on five occasions, cytomegalovirus on four, Giardia lamblia on two, and herpes simplex, Campylobacter jejuni, Salmonella enteritidis, and Entamoeba histolytica once each. No organism was found when weight loss was less than 5 kg or stool volume less than 400 ml/day (n = 9). Pathogens were identified in nine of 13 patients (69%) with weight loss greater than 10 kg and stool volume more than 800 ml/day. Barium studies were normal except for ileal flocculation in two patients with cryptosporidiosis. Evidence for malabsorption existed in 24 patients--impaired xylose absorption (n = 19) and abnormal Schilling test (n = 21). Of the patients with a severely abnormal Schilling test, a pathogen was identified in 11 (79%) (including all five with cryptosporidia, and two of the patients with only moderate diarrhoea and weight loss). A simple scoring system based on degree of weight loss and Schilling test result may help to identify the HIV positive patient with seemingly pathogen-negative diarrhoea in whom further investigations are likely to show a specific cause.

Prevalence of Intrinsic Factor Antibodies and Vitamin B12 Malabsorption in Older Patients Admitted to a Rehabilitation Hospital

It is possible that the commonly measured serum level of vitamin B12 may miss some cases when used to detect vitamin B12 malabsorption and deficiency in older persons. Serum levels of vitamin B12 and intrinsic factor antibody (IFAB) were determined on 250 consecutive patients over the age of 70 admitted to a rehabilitation hospital. Patients with abnormal results on either test were given the standard Schilling test when possible. Eight patients had documented B12 malabsorption. Of these, five had a low serum B12 level alone and one had a low serum B12 level and a positive IFAB level; however, two patients had positive IFAB and normal serum B12 levels. Serum IFAB level may serve as a useful adjunct to serum B12 level in detecting vitamin B12 malabsorption in older patients.

Low holotranscobalamin II is the earliest serum marker for subnormal vitamin B12 (cobalamin) absorption in patients with AIDS

In AIDS, as previously found in pernicious anemia (PA), the earliest serum marker of subnormal vitamin B12 (cobalamin) absorption, and therefore of negative B12 balance, is low serum holotranscobalamin II (holo-TC II; B12-TC II) despite normal total serum B12 level, normal serum homocysteine, and normal classic (oral free radio-B12) Schilling test. This may be accompanied by subtle and insidious damage to hematopoietic, immunologic, neuropsychiatric, nutritional and alimentary systems, confirmed by correction on therapeutic trial with B12 therapy. Our studies suggest such selective B12 deficiency occurs in about half of the HIV-1 infected, in part due to frequent depression of B12 absorption by HIV-1 attack on the gastric mucosa and/or opportunistic infection attack on the small bowel, and in part due to a telescoping of the continuum of the stages of negative B12 balance in relation to damage to B12 delivery by the infective and/or systemic disease process. In AIDS, when total serum B12 is normal despite tissue depletion of B12, if the classic Schilling test does not reveal subnormal food B12 absorption, the food Schilling test does. We hypothesize that DNA-synthesizing cells of the hematopoietic, immunologic, neurologic and other systems which have surface receptors solely for holo-TC II, and which have low B12 stores, rapidly become dysfunctional due to B12 deficiency when holo-TC II is low, while cells (such as liver cells) which also have surface receptors for holohaptocorrin (B12-haptocorrin) remain B12-replete. We believe this to be another example of the concept of selective nutrient deficiency in one cell line but not another.

Mental Dysfunction and Cobalamin Deficiency

To the Editor .—Carmel 1 has described a series of pernicious anemia cases defined by a low serum cobalamin level and either an abnormal Schilling test result, absence of intrinsic factor, or presence of anti—intrinsic factor antibodies. A number of these cases displayed only neurologic or neuropsychiatric symptoms, with normal hematologic parameters. In another recent study, Lindenbaum et al 2 described similar observations. We agree with these authors and feel that the neuropsychiatric aspects of cobalamin deficiency need to be emphasized. Cobalamin deficiency may present as organic psychosis with neither spinal cord nor hematologic abnormalities. 3,4 We have studied two patients who presented with organic psychosis and low vitamin B 12 levels in the absence of any neurologic or hematologic abnormalities. One patient showed diffuse slowing on electroencephalographic examination and mild cerebral dysfunction on neuropsychologic testing; both the electroencephalographic and the neuropsychiatric test results became normal after vitamin B 12

Mental Dysfunction and Cobalamin Deficiency-Reply

In Reply .—Mental dysfunction can be the presenting symptom of cobalamin deficiency in the absence of any hematologic abnormalities. This has been described by many in the past, yet continues to merit emphasis because of its important clinical implications. The letter by Miller and coworkers provides another such welcome reminder. It is also interesting to note, incidentally, that neither of the patients in the 1983 report by Evans and coworkers 1 had pernicious anemia in its currently accepted gastroenterological definition as cobalamin malabsorption due to lack of intrinsic factor. Both patients had normal Schilling test results. In the light of our 2,3 and others' 4 data, it seems highly likely that their patients' cobalamin deficiency arose from food-cobalamin malabsorption (one of the patients had documented gastric achlorhydria). Thus, physicians must think seriously of cobalamin deficiency in neurologically impaired patients, not only in the face of normal blood cell counts, but

The Value of Urine Creatinine Analysis in the Evaluation of Schilling Tests

We performed a prospective study to assess the clinical value of evaluating the adequacy of 24-hour urine specimens submitted for Schilling tests. A total of 121 specimens were evaluated of which 51 had abnormal vitamin B12 excretion values. Of those 51, there were 23 with apparently inadequate total creatinine content (implying a collection of less than 24 hours). Six of 12 specimens with less than 600 ml had adequate total creatinine content as well as normal vitamin B12 excretion. Compared with evaluation of specimen volume alone, these data support the inexpensive urine creatinine assay as a valuable source of information regarding the adequacy of 24-hour urine collections thereby improving the specificity of the Schilling test.

Dependence on Cyanocobalamin Injections

To the Editor. — I started reading the article by Drs Lawhorne and Ringdahl 1 with interest. By the time I finished, I was angry and depressed enough to write this letter. Throughout the article, there was no mention of how vitamin B 12 deficiency can be scientifically assessed for clinical purposes. Current practice seems to emphasize the art of medicine, and also the economics of medicine under the guise of cost containment, at the expense of science. The workup of a patient with vitamin B 12 problems can be expensive and inconclusive, but it can also be objective and scientific with minimum cost. 2 One does not have to do Schilling or deoxyuridine suppression tests, measure vitamin B 12 levels, perform gastrointestinal series, etc, which are expensive and sometimes uninformative. There are simple tests that every physician orders routinely but perhaps does not look at critically. For example, the

Vitamin B12 Malabsorption in Patients With Acquired Immunodeficiency Syndrome

We have examined 11 patients with the acquired immunodeficiency syndrome (AIDS) for evidence of subclinical vitamin B12 malabsorption. Three subjects (27%) had low levels of vitamin B12. Eight subjects (73%), including these 3 subjects plus 5 others with normal vitamin B12 levels, had abnormal Schilling test results. In addition, 15% of an unselected population of 121 patients with AIDS and 7% of 27 patients without AIDS who were seropositive for human immunodeficiency virus type 1 (HIV-1) had low serum vitamin B12 levels. Stool cultures from the 8 subjects with abnormal Schilling test results revealed no pathogens. Intestinal involvement by Kaposi's sarcoma was found in only 1 patient. Biopsy specimens from 5 of 6 patients with vitamin B12 malabsorption, however, contained mononuclear cells harboring HIV-1, as indicated by in situ hybridization studies. Our observations suggest that vitamin B12 malabsorption is common in patients with AIDS and may be a very early manifestation of infection with HIV-1.

Absence of luminal intrinsic factor after gastric bypass surgery for morbid obesity.

Abnormally low serum cobalamin levels (less than 180 pg/ml) have been observed in 154 of 429 patients (36%) at an average of 22 months (range 3-64 months) after gastric bypass surgery for morbid obesity. Twenty-four patients underwent a Schilling test and retrograde endoscopy of the bypassed gastric segment to determine the presence of intrinsic factor (IF) in gastric aspirates and in mucosal biopsies at 22 +/- 4 months after surgery. Five patients had a normal cobalamin level (405 +/- 44 pg/ml), and gastric juice intrinsic factor was present in three of them (11 +/- 7 ng/ml). Nineteen patients had a low cobalamin level (113 +/- 8 pg/ml), and gastric juice IF was found in only two subjects of this group (10 ng/ml each). Basal gastric juice IF concentration of healthy control subjects was 24 +/- 5 ng/ml. Schilling test results were normal in all five patients of the first group and in only nine patients of the group with cobalamin deficiency after surgery. To assess whether IF was present within the parietal cells of subjects with absent luminal IF, we studied gastric biopsy material of 14 patients using a well-characterized indirect immunoperoxidase method. IF was identified in fundic mucosal biopsy specimens of all 14 patients with absent gastric juice IF. We conclude that cobalamin deficiency occurs in a significant number of patients after gastric bypass and is associated with absence of gastric juice IF. We propose that this abnormality might be caused by inadequate secretion of IF from the bypassed stomach.

Clinical Usefulness of Dual-Label Schilling Test for Pancreatic Exocrine Function

The usefulness of the pancreatic dual-label Schilling test as an indirect test of pancreatic exocrine function was evaluated. This dual-label Schilling test was based on the difference of absorption for [58Co]cobalamin bound to hog R protein and [57Co]cobalamin bound to intrinsic factor. In this study, the test was performed in 7 normal subjects, 5 patients with pancreatectomy, 12 patients with chronic pancreatitis, 10 patients with suspicion of chronic pancreatitis, and 13 patients without chronic pancreatitis. The normal lower limit (mean -2 SD) of excretion ratio for [58Co]/[57Co] in 24-h urine was 0.68. Of the 26 patients on whom endoscopic retrograde pancreatography was performed, none of the 9 patients with normal pancreatogram, 4 of the 9 patients with mild to moderate pancreatitic changes in pancreatogram, and 7 of the 8 patients with advanced pancreatitic changes in pancreatogram showed a positive value lower than the ratio of 0.68 in this test. In 28 patients examined with the direct test of pancreatic secretory capacity, 2 of the 13 patients with normal function, 6 of the 9 patients with mild dysfunction, and 5 of the 6 patients with definite dysfunction were positive in this test. The results of the pancreatic dual-label Schilling test significantly correlated with those of a direct test of pancreatic secretory capacity and the findings of pancreatitic changes in pancreatogram (p less than 0.01, chi 2 test). The ratio for [58Co]/[57Co] correlated (r = 0.73) with the maximal bicarbonate concentration in duodenal juice of the direct test of pancreatic secretory capacity. The impairment of bicarbonate output by the pancreas may adversely affect the transfer of cobalamin from R protein to intrinsic factor. It suggested that the pancreatic dual-label Schilling test is useful for detecting not only patients with severe pancreatic insufficiency but also the relatively early stage of chronic pancreatitis with bicarbonate secretory dysfunction of the pancreas.