Antibody negative coeliac disease presenting in elderly people—an easi
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《英国医生杂志》
1 Royal Hallamshire Hospital, Sheffield S10 2JF, 2 Greystones Medical Centre, Sheffield S11 7BJ
Correspondence to: D S Sanders, Room P39, P Floor, Gastroenterology and Liver Unit, Royal Hallamshire Hospital, Sheffield S10 2JF d.s.sanders28@btopenworld.com
Epidemiological studies screening cohorts of healthy volunteers in the United States of America, the United Kingdom, and other European countries have determined that the prevalence of adult coeliac disease in the general population is in the magnitude of 1 per 100 to 200.1-4
The diagnosing of coeliac disease is often delayed,3-7 perhaps owing to a failure to recognise the protean manifestations of this disease in both primary and secondary care.5-9 Coeliac disease used to be perceived as involving gastrointestinal symptoms suggestive of malabsorption, but this manner of presentation is now described as the classic (typical) form.4 Patients with coeliac disease may have the silent or atypical form (no gastrointestinal symptoms), and the condition may present insidiously—for example, with iron deficiency anaemia, osteoporosis, cryptogenic hypertransaminasaemia, or neurological symptoms.5-10 The increasing recognition of coeliac disease is attributed to the use of new serological assays that have a high sensitivity and specificity.4 Antibody testing, however, is not the absolute method of diagnosis. We present a case of an elderly man presenting with coeliac disease in whom the condition would not have been recognised without a second duodenal biopsy.
Case report
In May 2003 a 79 year old man with longstanding dyspepsia presented to his general practitioner with worsening indigestion, tiredness, and rapid weight loss. Blood tests arranged by the doctor showed a macrocytic anaemia with low concentrations of vitamin B-12 and folate. The patient subsequently had a negative result on endomysial antibody testing. A gastroscopy in June 2003 did not show any macroscopic abnormalities, and routine quadrantic duodenal biopsies were histologically normal. Over the following three months the patient's condition deteriorated. He developed anorexia, with a documented weight loss of 15 kg. For the first time, the patient started to complain of lower gastrointestinal symptoms. Although he did not have an increased frequency in defecation, he noted that the stool had become foul smelling, and he described abdominal bloating and increased flatus. When the patient was seen in a gastroenterology clinic his immunoglobulin concentrations, IgG and IgA gliadin antibodies, endomysial antibodies, and tissue transglutaminase activity were checked. In addition, an urgent colonoscopy yielded a macroscopically normal result. Routine terminal ileal and colonic biopsies were all normal. His blood tests were reviewed: results for endomysial antibodies and IgA gliadin were now positive; IgG gliadin was negative; and transglutaminase activity was 237 (normal range 0-10 units per millilitre). Repeat gastroscopy showed macroscopic features consistent with coeliac disease (figure) and duodenal biopsies showed total villous atrophy. The patient was breathless, had a haemoglobin concentration of 82 g/l, had developed ankle oedema, and had an albumin concentration of 30 (normal range 35-48) g/l. In view of this, in February 2004 he was started on both a gluten-free diet and 30 mg of prednisolone daily. He was also transfused with 2 units of packed cells. Video capsule endoscopy showed virtual pan-atrophy of the small bowel but no evidence of lymphoma.
Endoscopic features of coeliac disease with scalloping and mosaic appearance of small bowel
By August 2004 the patient no longer required prednisolone and subsequently gained 8 kg. He now had few gastrointestinal symptoms, and because of this improvement, he was committed to the gluten-free diet. Results on testing for IgG and IgA gliadin antibodies and endomysial antibodies were negative. Repeat duodenal biopsy showed an almost complete histological resolution except for intraepithelial lymphocytes.
Discussion
Coeliac disease is still incorrectly perceived as being both an uncommon disease and a disease of childhood or infancy. Most cases are adult, however, and occur in people aged 40-60 years.1-5 Patients in this age group may present with coeliac disease in an atypical manner. However, if an elderly patient presents with symptoms and signs suggesting malabsorption, coeliac disease should be part of the differential diagnosis.
In our case, the family doctor had already considered this possibility and arranged a gastroscopy as well as checking the patient's endomysial antibodies. Why were both these investigations negative? Our understanding of coeliac disease has been that histological changes are patchy and more prominent in the proximal small bowel rather than distally; this is thought to be related to the higher gluten load proximally.4 11 However, reports have been published of villous atrophy being initially missed on duodenal biopsy and only subsequently recognised if repeat small bowel biopsies are obtained.4 11 Cases of small bowel villous atrophy evolving over a period of time have also been documented. Initially, all that may be seen on biopsy could be an increase in intraepithelial lymphocytes and in particular an increase in the ratio of gamma to delta T cells (in the presence of positive antibodies).12 13 In our case, both duodenal biopsy specimens were reviewed blindly by an independent gastrointestinal histopathologist. Despite this second assessment, there were still no subtle features of coeliac disease on the initial biopsy.
Although endomysial antibody testing is highly specific (in excess of 90%), this antibody has been reported as being negative in lesser grades of villous atrophy (for example, partial or subtotal villous atrophy).4 14 Although uncommon, antibody negative coeliac disease is also well described.4 15 We repeated the antibody titre (at a dilution of 1 in 20) on the original sample and it was still negative. A recently described alternative explanation is that of masking of endomysial antibody by IgA smooth muscle actin autoantibodies (J Dunne et al, 11th coeliac international symposium, Belfast, 2004). Irrespective of the mechanisms, in clinical terms both these results were initially negative, and we were able to make the diagnosis only when the patient presented with a "coeliac crisis" (the most severe form of coeliac disease, presenting with overt malabsorption).4 Our case is highly unusual because the patient initially had both a negative antibody profile and a normal duodenal biopsy. Perhaps at the earliest stage of presentation the patient had not developed all the immunological features of coeliac disease; this would be supported by the fact that macroscopic abnormalities were only noted at the time of the second endoscopy and video capsule endoscopy. If we had not reconsidered the possibility of coeliac disease (and repeat testing) then we would not have been able to diagnose the condition or treat it appropriately.
Coeliac crisis is a rare condition, usually described as presenting with marked malabsorption and a good response to a gluten-free diet and steroids.4 With the arrival of serology testing for coeliac disease, fewer cases have been described in the literature.
Doctors in both primary and secondary care should always consider the possibility of coeliac disease even in elderly people. Negative serology should not necessarily reassure the clinician. In the presence of a clinically deteriorating patient a duodenal biopsy should be performed.13 Elderly patients following a gluten-free diet will see improvements in their symptoms and be committed to the diet despite their age.16
Editorial by Watson and p 773
Consider duodenal biopsy for elderly patients with overt malabsorption, even if coeliac antibody profile is negative
Contributors: DSS, DPH, MEMcA, and CJA acted as clinical and/or endoscopic investigators. SSC interpreted and reviewed the histological specimens. MH and GW interpreted the immunological data. All authors jointly wrote and revised the manuscript. DSS is the guarantor.
Funding: None.
Competing interests: DSS is an associate medical adviser for Coeliac UK (a national medical charity). This is an honorary post with no financial benefits.
References
West J, Logan RF, Hill PG, Lloyd A, Lewis S, Hubbard R, et al. Seroprevalence, correlates, and characteristics of undetected coeliac disease in England. Gut 2003;52: 960-5.
Bingley PJ, Williams AJ, Norcross AJ, Unsworth DJ, Lock RJ, Ness AR, et al. Undiagnosed coeliac disease at age seven: population based prospective birth cohort study BMJ 2004;328: 322-3.
Fasano A, Berti I, Geraduzzi T, Not T, Colletti RB, Drago S, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States. Arch Intern Med 2003;163: 286-92.
Fasano A, Catassi C. Current approaches to diagnosis and treatment of celiac disease: an evolving spectrum. Gastroenterology 2001;120: 636-51.
Green PHR, Stavropoulos SN, Panagi SG, Goldstein SL, McMahon DJ, Absan H, et al. Characteristics of adult celiac disease in the USA: results of a national survey. Am J Gastroenterol 2001;96: 126-31.
Hin H, Bird G, Fisher P, Mahy N, Jewell D. Coeliac disease in primary care: case finding study. BMJ 1999;318: 164-7.
Johnston SD, Watson RGP, McMillan SA, Sloan J, Love AHG. Coeliac disease detected by screening is not silent—simply unrecognised. Q J Med 1998;91: 853-60.
Sanders DS, Patel D, Stephenson TJ, Milford-Ward A, McCloskey EV, Hadjivassiliou M, et al. A primary care cross-sectional study of undiagnosed adult coeliac disease. Eur J Gastroenterol Hepatol 2003;15: 407-13.
Sanders DS, Carter MJ, Hurlstone DP, Pearce A, Milford Ward A, McAlindon ME, et al. Association of adult coeliac disease with irritable bowel syndrome: a case control study in patients fulfilling the Rome II criteria referred to secondary care. Lancet 2001;358: 1504-8.
Hadjivassiliou M, Gibson A, Davies-Jones GAB, Lobo AJ, Stephenson TJ, Milford-Ward A. Does cryptic gluten sensitivity play a role in neurological illness? Lancet 1996;347: 369-71.
H?roldt BS, McAlindon ME, Stephenson TJ, Hadjivassiliou M, Sanders DS. Making the diagnosis of coeliac disease: is there a role for push enteroscopy? Eur J Gastroenterol Hepatol 2004;16: 1143-6.
Collin P, Helin H, Maki M, Hallstrom O, Karvonen AL. Follow-up of patients positive in reticulin and gliadin antibody tests with normal small-bowel biopsy findings. Scand J Gastroenterol 1993;28: 595-8.
Kaukinen K, Collin P, Holm K, Karvonen AL, Pikkarainen P, Maki M. Small-bowel mucosal inflammation in reticulin or gliadin antibody-positive patients without villous atrophy. Scand J Gastroenterol 1998;33: 944-9.
Rostami K, Kerckhaert J, Tiemessen R, von Blomberg BME, Meijer JWR, Mulder CJJ. Sensitivity of antiendomysium and antigliadin antibodies in untreated celiac disease: disappointing in clinical practice. Am J Gastroenterol 1999;94: 888-94.
Thomas PD, Forbes A, Green J, Howdle P, Long R, Playford R, et al. Guidelines for the investigation of chronic diarrhoea, 2nd edition. Gut 2003;52(suppl 5): v1-15.
Gasbarrini G, Ciccocioppo R, De Vitis I, Corazza GR, Club del Tenue Study Group. Coeliac disease in the elderly. A multicentre Italian study. Gerontology 2001;47: 306-10.(David S Sanders, consultant gastroentero)
Correspondence to: D S Sanders, Room P39, P Floor, Gastroenterology and Liver Unit, Royal Hallamshire Hospital, Sheffield S10 2JF d.s.sanders28@btopenworld.com
Epidemiological studies screening cohorts of healthy volunteers in the United States of America, the United Kingdom, and other European countries have determined that the prevalence of adult coeliac disease in the general population is in the magnitude of 1 per 100 to 200.1-4
The diagnosing of coeliac disease is often delayed,3-7 perhaps owing to a failure to recognise the protean manifestations of this disease in both primary and secondary care.5-9 Coeliac disease used to be perceived as involving gastrointestinal symptoms suggestive of malabsorption, but this manner of presentation is now described as the classic (typical) form.4 Patients with coeliac disease may have the silent or atypical form (no gastrointestinal symptoms), and the condition may present insidiously—for example, with iron deficiency anaemia, osteoporosis, cryptogenic hypertransaminasaemia, or neurological symptoms.5-10 The increasing recognition of coeliac disease is attributed to the use of new serological assays that have a high sensitivity and specificity.4 Antibody testing, however, is not the absolute method of diagnosis. We present a case of an elderly man presenting with coeliac disease in whom the condition would not have been recognised without a second duodenal biopsy.
Case report
In May 2003 a 79 year old man with longstanding dyspepsia presented to his general practitioner with worsening indigestion, tiredness, and rapid weight loss. Blood tests arranged by the doctor showed a macrocytic anaemia with low concentrations of vitamin B-12 and folate. The patient subsequently had a negative result on endomysial antibody testing. A gastroscopy in June 2003 did not show any macroscopic abnormalities, and routine quadrantic duodenal biopsies were histologically normal. Over the following three months the patient's condition deteriorated. He developed anorexia, with a documented weight loss of 15 kg. For the first time, the patient started to complain of lower gastrointestinal symptoms. Although he did not have an increased frequency in defecation, he noted that the stool had become foul smelling, and he described abdominal bloating and increased flatus. When the patient was seen in a gastroenterology clinic his immunoglobulin concentrations, IgG and IgA gliadin antibodies, endomysial antibodies, and tissue transglutaminase activity were checked. In addition, an urgent colonoscopy yielded a macroscopically normal result. Routine terminal ileal and colonic biopsies were all normal. His blood tests were reviewed: results for endomysial antibodies and IgA gliadin were now positive; IgG gliadin was negative; and transglutaminase activity was 237 (normal range 0-10 units per millilitre). Repeat gastroscopy showed macroscopic features consistent with coeliac disease (figure) and duodenal biopsies showed total villous atrophy. The patient was breathless, had a haemoglobin concentration of 82 g/l, had developed ankle oedema, and had an albumin concentration of 30 (normal range 35-48) g/l. In view of this, in February 2004 he was started on both a gluten-free diet and 30 mg of prednisolone daily. He was also transfused with 2 units of packed cells. Video capsule endoscopy showed virtual pan-atrophy of the small bowel but no evidence of lymphoma.
Endoscopic features of coeliac disease with scalloping and mosaic appearance of small bowel
By August 2004 the patient no longer required prednisolone and subsequently gained 8 kg. He now had few gastrointestinal symptoms, and because of this improvement, he was committed to the gluten-free diet. Results on testing for IgG and IgA gliadin antibodies and endomysial antibodies were negative. Repeat duodenal biopsy showed an almost complete histological resolution except for intraepithelial lymphocytes.
Discussion
Coeliac disease is still incorrectly perceived as being both an uncommon disease and a disease of childhood or infancy. Most cases are adult, however, and occur in people aged 40-60 years.1-5 Patients in this age group may present with coeliac disease in an atypical manner. However, if an elderly patient presents with symptoms and signs suggesting malabsorption, coeliac disease should be part of the differential diagnosis.
In our case, the family doctor had already considered this possibility and arranged a gastroscopy as well as checking the patient's endomysial antibodies. Why were both these investigations negative? Our understanding of coeliac disease has been that histological changes are patchy and more prominent in the proximal small bowel rather than distally; this is thought to be related to the higher gluten load proximally.4 11 However, reports have been published of villous atrophy being initially missed on duodenal biopsy and only subsequently recognised if repeat small bowel biopsies are obtained.4 11 Cases of small bowel villous atrophy evolving over a period of time have also been documented. Initially, all that may be seen on biopsy could be an increase in intraepithelial lymphocytes and in particular an increase in the ratio of gamma to delta T cells (in the presence of positive antibodies).12 13 In our case, both duodenal biopsy specimens were reviewed blindly by an independent gastrointestinal histopathologist. Despite this second assessment, there were still no subtle features of coeliac disease on the initial biopsy.
Although endomysial antibody testing is highly specific (in excess of 90%), this antibody has been reported as being negative in lesser grades of villous atrophy (for example, partial or subtotal villous atrophy).4 14 Although uncommon, antibody negative coeliac disease is also well described.4 15 We repeated the antibody titre (at a dilution of 1 in 20) on the original sample and it was still negative. A recently described alternative explanation is that of masking of endomysial antibody by IgA smooth muscle actin autoantibodies (J Dunne et al, 11th coeliac international symposium, Belfast, 2004). Irrespective of the mechanisms, in clinical terms both these results were initially negative, and we were able to make the diagnosis only when the patient presented with a "coeliac crisis" (the most severe form of coeliac disease, presenting with overt malabsorption).4 Our case is highly unusual because the patient initially had both a negative antibody profile and a normal duodenal biopsy. Perhaps at the earliest stage of presentation the patient had not developed all the immunological features of coeliac disease; this would be supported by the fact that macroscopic abnormalities were only noted at the time of the second endoscopy and video capsule endoscopy. If we had not reconsidered the possibility of coeliac disease (and repeat testing) then we would not have been able to diagnose the condition or treat it appropriately.
Coeliac crisis is a rare condition, usually described as presenting with marked malabsorption and a good response to a gluten-free diet and steroids.4 With the arrival of serology testing for coeliac disease, fewer cases have been described in the literature.
Doctors in both primary and secondary care should always consider the possibility of coeliac disease even in elderly people. Negative serology should not necessarily reassure the clinician. In the presence of a clinically deteriorating patient a duodenal biopsy should be performed.13 Elderly patients following a gluten-free diet will see improvements in their symptoms and be committed to the diet despite their age.16
Editorial by Watson and p 773
Consider duodenal biopsy for elderly patients with overt malabsorption, even if coeliac antibody profile is negative
Contributors: DSS, DPH, MEMcA, and CJA acted as clinical and/or endoscopic investigators. SSC interpreted and reviewed the histological specimens. MH and GW interpreted the immunological data. All authors jointly wrote and revised the manuscript. DSS is the guarantor.
Funding: None.
Competing interests: DSS is an associate medical adviser for Coeliac UK (a national medical charity). This is an honorary post with no financial benefits.
References
West J, Logan RF, Hill PG, Lloyd A, Lewis S, Hubbard R, et al. Seroprevalence, correlates, and characteristics of undetected coeliac disease in England. Gut 2003;52: 960-5.
Bingley PJ, Williams AJ, Norcross AJ, Unsworth DJ, Lock RJ, Ness AR, et al. Undiagnosed coeliac disease at age seven: population based prospective birth cohort study BMJ 2004;328: 322-3.
Fasano A, Berti I, Geraduzzi T, Not T, Colletti RB, Drago S, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States. Arch Intern Med 2003;163: 286-92.
Fasano A, Catassi C. Current approaches to diagnosis and treatment of celiac disease: an evolving spectrum. Gastroenterology 2001;120: 636-51.
Green PHR, Stavropoulos SN, Panagi SG, Goldstein SL, McMahon DJ, Absan H, et al. Characteristics of adult celiac disease in the USA: results of a national survey. Am J Gastroenterol 2001;96: 126-31.
Hin H, Bird G, Fisher P, Mahy N, Jewell D. Coeliac disease in primary care: case finding study. BMJ 1999;318: 164-7.
Johnston SD, Watson RGP, McMillan SA, Sloan J, Love AHG. Coeliac disease detected by screening is not silent—simply unrecognised. Q J Med 1998;91: 853-60.
Sanders DS, Patel D, Stephenson TJ, Milford-Ward A, McCloskey EV, Hadjivassiliou M, et al. A primary care cross-sectional study of undiagnosed adult coeliac disease. Eur J Gastroenterol Hepatol 2003;15: 407-13.
Sanders DS, Carter MJ, Hurlstone DP, Pearce A, Milford Ward A, McAlindon ME, et al. Association of adult coeliac disease with irritable bowel syndrome: a case control study in patients fulfilling the Rome II criteria referred to secondary care. Lancet 2001;358: 1504-8.
Hadjivassiliou M, Gibson A, Davies-Jones GAB, Lobo AJ, Stephenson TJ, Milford-Ward A. Does cryptic gluten sensitivity play a role in neurological illness? Lancet 1996;347: 369-71.
H?roldt BS, McAlindon ME, Stephenson TJ, Hadjivassiliou M, Sanders DS. Making the diagnosis of coeliac disease: is there a role for push enteroscopy? Eur J Gastroenterol Hepatol 2004;16: 1143-6.
Collin P, Helin H, Maki M, Hallstrom O, Karvonen AL. Follow-up of patients positive in reticulin and gliadin antibody tests with normal small-bowel biopsy findings. Scand J Gastroenterol 1993;28: 595-8.
Kaukinen K, Collin P, Holm K, Karvonen AL, Pikkarainen P, Maki M. Small-bowel mucosal inflammation in reticulin or gliadin antibody-positive patients without villous atrophy. Scand J Gastroenterol 1998;33: 944-9.
Rostami K, Kerckhaert J, Tiemessen R, von Blomberg BME, Meijer JWR, Mulder CJJ. Sensitivity of antiendomysium and antigliadin antibodies in untreated celiac disease: disappointing in clinical practice. Am J Gastroenterol 1999;94: 888-94.
Thomas PD, Forbes A, Green J, Howdle P, Long R, Playford R, et al. Guidelines for the investigation of chronic diarrhoea, 2nd edition. Gut 2003;52(suppl 5): v1-15.
Gasbarrini G, Ciccocioppo R, De Vitis I, Corazza GR, Club del Tenue Study Group. Coeliac disease in the elderly. A multicentre Italian study. Gerontology 2001;47: 306-10.(David S Sanders, consultant gastroentero)