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Onset of coeliac disease after a spontaneous miscarriage during a holiday in Australia: Coincidence or causal relationship?
‘he
Netherlauds
JOURNAL OF MEDICINE ELSEVIER
Netherlands
Journal
of Medicine
52 (1998)
147-149
Brief report
Onset of coeliac disease after a spontaneous miscarriage during a holiday in Australia: coincidence or causal relationship? A.M. Dondorp a,* , G.H. de Groot b a Department
of Internal
Medicine, Academic Medical Centre, b Department of Internal Medicine, Rode Kruis Received
19 August
1997; revised
8 December
Meibergdreef Ziekenhuis,
9, 1105 AZ Amsterdam, Beuerwijk, Netherlands
1997; accepted
9 December
Netherlands
1997
Abstract Diarrhoea contracted whilst travelling in a (subkropical country often has an infectious cause. However, dietary changes can also be of importance. We describethe caseof a 28-year-old woman, who developed severecoeliac diseaseduring a trip in the Australian outback. The nutritional history revealed that the patient’s diet contained more wheat products during her trip than she was used to in Holland. Moreover, the onset of symptoms coincided with a spontaneous miscarriage of an 8-week-old embryo. This correlation has been described in severalcase reports in the literature. However, the pathophysiologic mechanism behind this correlation is unknown. Some speculative mechanisms are proposed here. Further investigations into this relationship could increase our understanding of the immunopathogenesis of coeliac disease.0 1998 Elsevier ScienceB .V. Keywords:
Coeliac
disease;
Pregnancy;
Traveling
1. Introduction Diarrhoea beginning during an exotic trip can have many causes, most often infectious in origin [l]. The presented case shows an entirely different cause of severe, prolonged diarrhoea. The point of initiation seems to relate to both a holiday trip in the outback of Central Australia, as well as to a spontaneous miscarriage. 2. Case report
The patient, a 28-year-old female, had been well until this episode. She had been travelling with a * Corresponding
author.
0300-2977/98/$19.00 0 1998 Elsevier PII SO300-2977(98)00015-l
Science
B.V.
All rights
reserved
camper in the outback of Central Australia for a week when she had had a spontaneous miscarriage of an g-week-old embryo. She subsequently developed severe diarrhoea. She passed watery to loose stools up to 18 times a day, without mucus or blood. The bowel frequency reduced with starvation. She felt ill, had a poor appetite and was nauseous. She lost 10 kg in 3 weeks. The patient was treated with metronidazole and erythromycin, assuming an infectious cause for her diarrhoea, with no relief of symptoms. She decided to return to Holland where she was admitted to our hospital. Upon physical examination we saw a moderately ill, dehydrated female in poor nutritional state. She weighed 49 kg and was 1.70 m tall. Her temperature was 37.4”C, blood pressure 100/70 mmHg and pulse
148
A.M.
Dondorp,
G.H. de Groat/Netherlands
rate 88/min. The abdomen was Bat with normal peristaltic sounds. There was no abdominal tenderness and the liver and spleen were not enlarged. Rectal and vaginal examination revealed no abnormalities. Laboratory investigations showed an ESR of 2 mm in the first hour while a full blood count did not show any abnormalities. Plasma sodium was 129 mmol/l, potassium 3.3 mmol/l, calcium 2.11 mmol/l and magnesium 0.58 mmol/l with a plasma albumin of 27 g/l (BCP). Total plasma protein was 48 g/l, serum iron was 5 kmol/l with a total iron binding capacity of 25 Fmol/l. Serum folate was 1.3 nmol/l (decreased), vitamin B ,* was 0.16 nmol/l (slightly decreased). Total cholesterol was 2.6 mmol/l, serum triglycerides 1.4 nmol/l. The 25OH vitamin D content was normal with 51 nmol/l. On the day of admission, stool production was 2300 g/24 h. The total fat content of the faeces was 6.4 g/24 h, when the patient was using a non-standardised low-fat diet. Stool sodium was 67 mmol/l, potassium 29 mmol/l, with an osmolality of 310 mOsm/kg; with the formula, osmotic gap = 310 - 2 X (sodium concentration + potassium concentration), the calculated stool osmotic gap was 118 mmol/kg (normal < 50 mmol/kg), consistent with osmotic diarrhoea. Microscopic examination of the stools did not show leucocytes or parasites. There was no occult blood and stool cultures remained negative. To further establish a malabsorption syndrome a D-xylose test was performed which showed no uptake of D-xylose after oral administration. Standardised oral lactate administration did not increase plasma glucose levels. In addition, the results of the Schilling’s test (parts 1 and 2) were severely disturbed. In summary, the patient had severe osmotic diarrhoea with dehydration and weight loss due to malabsorption. Gastroduodenal endoscopy was performed, indicating a slight bulboduodenitis. Microscopic examination of the small bowel biopsies revealed evident villous atrophy without clear crypt hypertrophy. The epithelial lining was flattened and intra-epithelial lymphocytes were detected. No Giardia lambliu were seen. A diagnosis of coeliac disease was suspected and further proven by a high serum concentration of IgA antibodies against gliadine (900 IU) and a fast rever-
Journal
of Medicine
52 (1998)
147-149
sal of all symptoms after the patient started a gluten-free diet. In retrospect, the patient appeared to have had episodes of diarrhoea during childhood. Unconsciously, she had habituated herself to avoid wheat products. Instead of bread, she was used to take dairy products for lunch. As a child, she already avoided pancakes. During her holiday in Australia, however, she grew accustomed to the local diet, containing considerably more wheat products than she was used to. In particular, she ate much more bread and related products.
3. Discussion Coeliac disease is characterised by intestinal malabsorption with characteristic mucosal changes of the small intestines, as described in the present case, and provoked by the ingestion of the ethanol soluble moiety of gluten prevalent in wheat, rye, oats and barley. The morphological changes are reversible after discontinuation of the gluten intake [2,3]. The disease can lead to severe symptoms of osmotic diarrhoea and a malabsorption syndrome as described in this case. The prevalence of coeliac disease in the Netherlands is ca. 16 per 100000 inhabitants; in 63% of cases, the disease only becomes apparent at adult age
[41. Immunological changes are thought to play a central role in the pathogenesis of coeliac disease [2,3]. It is plausible that immunological changes during pregnancy and puerperium have triggered the onset of overt coeliac disease in the present case. There are a few case reports describing an exacerbation of coeliac disease preceded by pregnancy or puerperium [5-71. The pathophysiologic mechanisms behind this relationship is unknown, but could involve upregulation of HLA class II molecules in the intestinal mucosa during pregnancy. Increased expression of HLA class II molecules and aberrant expression on intestinal epithelium has been found in patients with a postpartum autoimmune gastritis, preceding the appearance of an overt atrophic gastric mucosa [8]. Oestrogens may play a role in the upregulation of HLA class II molecules [9]. Increased expression of HLA class II molecules is thought to
A.M. Dondorp,
G.H.
de Groat/Netherlands
be one of the factors involved in the transference of subclinical to overt coeliac disease [lo,1 11. Class II antigens are involved in the presentation of antigens by the antigen presenting cells to antigen specific CD4+ T-lymphocytes in the lamina propria of the small intestine. This leads to an antigen-specific upregulation of interleukin-2 receptors, which can be seen as the first step in the inflammatory response that eventually leads to the mucosal damage in coeliac disease [2]. The importance of these HLA class II molecules is supported by the association of coeliac disease with certain HLA-D haplotypes (HLA-DR3 and HLA-DQW2) encoding these molecules [ 11,121. In addition to these immunological changes, the increased gluten consumption during her holiday in Australia could have been a cofactor in the development of her symptoms. An association between travelling in a tropical country and the onset of coeliac disease has been described previously and seems to be present in the current case as well [13]. Beside the effect of pregnancy and puerperium on the course of coeliac disease, coeliac disease is vice versa associated with an increased incidence of spontaneous miscarriage and stillbirth [14,15]. This increased risk, however, disappears when a gluten-free diet has been started [14]. In conclusion, the presented case shows that diarrhoea beginning during an exotic trip can be due to coeliac disease, and does not always have an infectious origin. Changes in diet, i.e. increased gluten consumption, during such a trip can provoke the onset of coeliac disease. However, a remarkable correlation between the onset of the disease and a spontaneous miscarriage exists in the presented case. Further investigations into this relationship could increase our understanding of the immunopathogenesis of coeliac disease.
Journal
of Medicine
52 (1998)
147-149
149
References [l] Farthing MJG. Travelers’ diarrhoea. Gut 1994;35:1-5. [2] Marsh MN. Gluten, major histocompatibility complex and the small intestine. Gastroenterology 1992;102:330-354. [3] Trier JS. Celiac sprue. New Engl J Med 1991;325:17091719. (review). [4] Jansen Th, Luikens D, Karssen PHZ, Mulder CJJ. Epidemiologie van coeliakie in Nederland. Ned Tijdschr Geneeskd 1994;138:2544-2548. [5] Pauzner R, Rothman P, Schwartz E, Neuman G, Farfel Z. Acute onset of celiac disease in the puerperium. Am J Gastroenterol 1992;87:1037-1039. [6] Erdozan JC, Martin de Argila C, Cerezo E, Lizasoain J, Presa M. Adult celiac disease: reactivation during pregnancy and puerperium. Am J Gastroenterol 1993;88: 1139-l 140. [7] Stewart K, Willoughby JMT. Postnatal presentation of celiac disease. Br Med J 1988;297:1245. [8] Burman P, K%mpe 0, Kraaz W, LdGf L, Smolka A, Karlsson A, Karlsson-Parra A. A study of autoimmune gastritis in the postpartum period and a 5-year follow up. Gastroenterology 1992;103:934-942. [9] Denman AM. Sex hormones, autoimmune diseases, and immune responses. Br Med J 1991;303:2-3. [lo] Ferguson A, Arranz E, O’Mahoni S. Clinical and pathological spectrum of coeliac disease - active, silent, latent, potential. Gut 1993;34:150-151. [ll] Howdle PD, Blair GE. Molecular biology and coeliac disease. Gut 1992;33:573-575. [12] Keuning JJ, Pefia AS, van Leeuwen A, van Hooff JP, van Rood JJ. HLA-DW3 associated with coeliac disease. Lancet 1976;307-i:506-508. [13] Van Bergeijk JD, Mulder CJ, Thies JE. Coeliac disease. Three cases of delayed diagnosis after a sojourn in the tropics. Neth J Med 1993;43(5-6):222-226. [14] Sher KS, Mayberry JF. Female fertility, obstetric and gynaecological history in coeliac disease. A case control study. Digestion 1994;55(4):243-246. [15] Molteni N, Bardella MT, Bianchi PA. Obstetric and gynecological problems in women with untreated celiac sprue. J Clin Gastroenterol 1990:12:37-39.
Netherlauds
JOURNAL OF MEDICINE ELSEVIER
Netherlands
Journal
of Medicine
52 (1998)
147-149
Brief report
Onset of coeliac disease after a spontaneous miscarriage during a holiday in Australia: coincidence or causal relationship? A.M. Dondorp a,* , G.H. de Groot b a Department
of Internal
Medicine, Academic Medical Centre, b Department of Internal Medicine, Rode Kruis Received
19 August
1997; revised
8 December
Meibergdreef Ziekenhuis,
9, 1105 AZ Amsterdam, Beuerwijk, Netherlands
1997; accepted
9 December
Netherlands
1997
Abstract Diarrhoea contracted whilst travelling in a (subkropical country often has an infectious cause. However, dietary changes can also be of importance. We describethe caseof a 28-year-old woman, who developed severecoeliac diseaseduring a trip in the Australian outback. The nutritional history revealed that the patient’s diet contained more wheat products during her trip than she was used to in Holland. Moreover, the onset of symptoms coincided with a spontaneous miscarriage of an 8-week-old embryo. This correlation has been described in severalcase reports in the literature. However, the pathophysiologic mechanism behind this correlation is unknown. Some speculative mechanisms are proposed here. Further investigations into this relationship could increase our understanding of the immunopathogenesis of coeliac disease.0 1998 Elsevier ScienceB .V. Keywords:
Coeliac
disease;
Pregnancy;
Traveling
1. Introduction Diarrhoea beginning during an exotic trip can have many causes, most often infectious in origin [l]. The presented case shows an entirely different cause of severe, prolonged diarrhoea. The point of initiation seems to relate to both a holiday trip in the outback of Central Australia, as well as to a spontaneous miscarriage. 2. Case report
The patient, a 28-year-old female, had been well until this episode. She had been travelling with a * Corresponding
author.
0300-2977/98/$19.00 0 1998 Elsevier PII SO300-2977(98)00015-l
Science
B.V.
All rights
reserved
camper in the outback of Central Australia for a week when she had had a spontaneous miscarriage of an g-week-old embryo. She subsequently developed severe diarrhoea. She passed watery to loose stools up to 18 times a day, without mucus or blood. The bowel frequency reduced with starvation. She felt ill, had a poor appetite and was nauseous. She lost 10 kg in 3 weeks. The patient was treated with metronidazole and erythromycin, assuming an infectious cause for her diarrhoea, with no relief of symptoms. She decided to return to Holland where she was admitted to our hospital. Upon physical examination we saw a moderately ill, dehydrated female in poor nutritional state. She weighed 49 kg and was 1.70 m tall. Her temperature was 37.4”C, blood pressure 100/70 mmHg and pulse
148
A.M.
Dondorp,
G.H. de Groat/Netherlands
rate 88/min. The abdomen was Bat with normal peristaltic sounds. There was no abdominal tenderness and the liver and spleen were not enlarged. Rectal and vaginal examination revealed no abnormalities. Laboratory investigations showed an ESR of 2 mm in the first hour while a full blood count did not show any abnormalities. Plasma sodium was 129 mmol/l, potassium 3.3 mmol/l, calcium 2.11 mmol/l and magnesium 0.58 mmol/l with a plasma albumin of 27 g/l (BCP). Total plasma protein was 48 g/l, serum iron was 5 kmol/l with a total iron binding capacity of 25 Fmol/l. Serum folate was 1.3 nmol/l (decreased), vitamin B ,* was 0.16 nmol/l (slightly decreased). Total cholesterol was 2.6 mmol/l, serum triglycerides 1.4 nmol/l. The 25OH vitamin D content was normal with 51 nmol/l. On the day of admission, stool production was 2300 g/24 h. The total fat content of the faeces was 6.4 g/24 h, when the patient was using a non-standardised low-fat diet. Stool sodium was 67 mmol/l, potassium 29 mmol/l, with an osmolality of 310 mOsm/kg; with the formula, osmotic gap = 310 - 2 X (sodium concentration + potassium concentration), the calculated stool osmotic gap was 118 mmol/kg (normal < 50 mmol/kg), consistent with osmotic diarrhoea. Microscopic examination of the stools did not show leucocytes or parasites. There was no occult blood and stool cultures remained negative. To further establish a malabsorption syndrome a D-xylose test was performed which showed no uptake of D-xylose after oral administration. Standardised oral lactate administration did not increase plasma glucose levels. In addition, the results of the Schilling’s test (parts 1 and 2) were severely disturbed. In summary, the patient had severe osmotic diarrhoea with dehydration and weight loss due to malabsorption. Gastroduodenal endoscopy was performed, indicating a slight bulboduodenitis. Microscopic examination of the small bowel biopsies revealed evident villous atrophy without clear crypt hypertrophy. The epithelial lining was flattened and intra-epithelial lymphocytes were detected. No Giardia lambliu were seen. A diagnosis of coeliac disease was suspected and further proven by a high serum concentration of IgA antibodies against gliadine (900 IU) and a fast rever-
Journal
of Medicine
52 (1998)
147-149
sal of all symptoms after the patient started a gluten-free diet. In retrospect, the patient appeared to have had episodes of diarrhoea during childhood. Unconsciously, she had habituated herself to avoid wheat products. Instead of bread, she was used to take dairy products for lunch. As a child, she already avoided pancakes. During her holiday in Australia, however, she grew accustomed to the local diet, containing considerably more wheat products than she was used to. In particular, she ate much more bread and related products.
3. Discussion Coeliac disease is characterised by intestinal malabsorption with characteristic mucosal changes of the small intestines, as described in the present case, and provoked by the ingestion of the ethanol soluble moiety of gluten prevalent in wheat, rye, oats and barley. The morphological changes are reversible after discontinuation of the gluten intake [2,3]. The disease can lead to severe symptoms of osmotic diarrhoea and a malabsorption syndrome as described in this case. The prevalence of coeliac disease in the Netherlands is ca. 16 per 100000 inhabitants; in 63% of cases, the disease only becomes apparent at adult age
[41. Immunological changes are thought to play a central role in the pathogenesis of coeliac disease [2,3]. It is plausible that immunological changes during pregnancy and puerperium have triggered the onset of overt coeliac disease in the present case. There are a few case reports describing an exacerbation of coeliac disease preceded by pregnancy or puerperium [5-71. The pathophysiologic mechanisms behind this relationship is unknown, but could involve upregulation of HLA class II molecules in the intestinal mucosa during pregnancy. Increased expression of HLA class II molecules and aberrant expression on intestinal epithelium has been found in patients with a postpartum autoimmune gastritis, preceding the appearance of an overt atrophic gastric mucosa [8]. Oestrogens may play a role in the upregulation of HLA class II molecules [9]. Increased expression of HLA class II molecules is thought to
A.M. Dondorp,
G.H.
de Groat/Netherlands
be one of the factors involved in the transference of subclinical to overt coeliac disease [lo,1 11. Class II antigens are involved in the presentation of antigens by the antigen presenting cells to antigen specific CD4+ T-lymphocytes in the lamina propria of the small intestine. This leads to an antigen-specific upregulation of interleukin-2 receptors, which can be seen as the first step in the inflammatory response that eventually leads to the mucosal damage in coeliac disease [2]. The importance of these HLA class II molecules is supported by the association of coeliac disease with certain HLA-D haplotypes (HLA-DR3 and HLA-DQW2) encoding these molecules [ 11,121. In addition to these immunological changes, the increased gluten consumption during her holiday in Australia could have been a cofactor in the development of her symptoms. An association between travelling in a tropical country and the onset of coeliac disease has been described previously and seems to be present in the current case as well [13]. Beside the effect of pregnancy and puerperium on the course of coeliac disease, coeliac disease is vice versa associated with an increased incidence of spontaneous miscarriage and stillbirth [14,15]. This increased risk, however, disappears when a gluten-free diet has been started [14]. In conclusion, the presented case shows that diarrhoea beginning during an exotic trip can be due to coeliac disease, and does not always have an infectious origin. Changes in diet, i.e. increased gluten consumption, during such a trip can provoke the onset of coeliac disease. However, a remarkable correlation between the onset of the disease and a spontaneous miscarriage exists in the presented case. Further investigations into this relationship could increase our understanding of the immunopathogenesis of coeliac disease.
Journal
of Medicine
52 (1998)
147-149
149
References [l] Farthing MJG. Travelers’ diarrhoea. Gut 1994;35:1-5. [2] Marsh MN. Gluten, major histocompatibility complex and the small intestine. Gastroenterology 1992;102:330-354. [3] Trier JS. Celiac sprue. New Engl J Med 1991;325:17091719. (review). [4] Jansen Th, Luikens D, Karssen PHZ, Mulder CJJ. Epidemiologie van coeliakie in Nederland. Ned Tijdschr Geneeskd 1994;138:2544-2548. [5] Pauzner R, Rothman P, Schwartz E, Neuman G, Farfel Z. Acute onset of celiac disease in the puerperium. Am J Gastroenterol 1992;87:1037-1039. [6] Erdozan JC, Martin de Argila C, Cerezo E, Lizasoain J, Presa M. Adult celiac disease: reactivation during pregnancy and puerperium. Am J Gastroenterol 1993;88: 1139-l 140. [7] Stewart K, Willoughby JMT. Postnatal presentation of celiac disease. Br Med J 1988;297:1245. [8] Burman P, K%mpe 0, Kraaz W, LdGf L, Smolka A, Karlsson A, Karlsson-Parra A. A study of autoimmune gastritis in the postpartum period and a 5-year follow up. Gastroenterology 1992;103:934-942. [9] Denman AM. Sex hormones, autoimmune diseases, and immune responses. Br Med J 1991;303:2-3. [lo] Ferguson A, Arranz E, O’Mahoni S. Clinical and pathological spectrum of coeliac disease - active, silent, latent, potential. Gut 1993;34:150-151. [ll] Howdle PD, Blair GE. Molecular biology and coeliac disease. Gut 1992;33:573-575. [12] Keuning JJ, Pefia AS, van Leeuwen A, van Hooff JP, van Rood JJ. HLA-DW3 associated with coeliac disease. Lancet 1976;307-i:506-508. [13] Van Bergeijk JD, Mulder CJ, Thies JE. Coeliac disease. Three cases of delayed diagnosis after a sojourn in the tropics. Neth J Med 1993;43(5-6):222-226. [14] Sher KS, Mayberry JF. Female fertility, obstetric and gynaecological history in coeliac disease. A case control study. Digestion 1994;55(4):243-246. [15] Molteni N, Bardella MT, Bianchi PA. Obstetric and gynecological problems in women with untreated celiac sprue. J Clin Gastroenterol 1990:12:37-39.