Life-threatening onset of coeliac disease: a case report and literature review.

BACKGROUND: Coeliac disease (CD) results from an immune-mediated reaction to gluten in genetically predisposed individuals. In rare cases CD may occur with acute features deferring the diagnosis and exposing these patients to possible life-threatening complications. Herein we present the case of a young woman with a coeliac crisis, that is, a sudden clinical onset characterised by severe electrolyte imbalance due to an unknown (previously unrecognised) CD.
METHODS: This is a case report and literature review revealing that coeliac crisis is under-reported, with a total of 48 adult cases so far published. The diagnosis in our case was established by histopathological analysis of multiple duodenal biopsies. The patient's serum was tested by enzyme-linked immunoassay to detect antitransglutaminase IgA antibodies.
RESULTS: In contrast to cases reported in the literature, with male gender predominance and a mean age of 50±17 years, our patient was a young female case of coeliac crisis. However, like in our patient, a higher incidence of coeliac crisis was associated with the human leucocyte antigen (HLA)-DQ2 haplotype, versus HLA-DQ8, and a severe (Marsh-Oberhüber 3c) duodenal mucosa atrophy. Notably, there is no clear correlation between the antitissue transglutaminase 2 IgA antibody titre and coeliac crisis onset/severity, as confirmed by our case report.
CONCLUSIONS: The present case highlights that CD may manifest quite abruptly with a severe malabsorption syndrome, that is, electrolyte abnormalities and hypoproteinaemia. Our case should alert physicians, in particular those in the emergency setting, that even a typically chronic disorder, such as CD, may show life-threatening complications requiring urgent management. © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Introduction

Coeliac disease (CD) is a multisystemic, immune-mediated illness evoked by gluten ingestion in genetically susceptible individuals.1 The main target organ of the autoimmune reaction against the enzyme tissue transglutaminase (TG2) is the small bowel, where the gluten-related inflammatory cascade causes a progressive mucosal damage leading to severe villous atrophy.1 2 From a clinical standpoint, CD is a multifaceted chronic condition displaying a broad spectrum of intestinal (ranging from mild irritable bowel syndrome-like to severe malabsorption symptoms) and extraintestinal manifestations targeting several tissues and organs (eg, skin, endocrine/exocrine glands, nervous system, joint/muscles). As a result, CD remains a challenging condition to be diagnosed, thus causing a significant delay in establishing the appropriate therapy and increasing related morbidity.3–5

A potentially life-threatening and neglected clinical manifestation of CD is the so-called ‘coeliac crisis’, characterised by acute, massive watery diarrhoea, severe dehydration and metabolic disturbances, leading to neuromuscular weakness, tetanic seizures, cardiac arrhythmias and even sudden death in extreme cases.6–8 This condition is largely under-reported and under-recognised both in children and adults, with a total of 48 adult cases published so far.6–46 In most cases, coeliac crisis develops due to voluntary or inadvertent gluten ingestion in patients with or without an established diagnosis of CD. Only rarely a coeliac crisis heralds the clinical onset of CD, requiring hospitalisation and rapid therapeutic management due to possible occurrence of severe complications with high morbidity and mortality.9–13

Herein we describe the case of a patient admitted to our emergency department for a severe life-threatening coeliac crisis as the first manifestation of a previously unknown CD.

Case report

A 34-year-old woman was admitted to the emergency unit complaining of limb numbness and watery diarrhoea (8–10 bowel movements/day) which started 2 weeks earlier. The patient reported a weight loss of about 10 kg in the last 2 months in the absence of hyporexia. Her clinical history unravelled microcytic anaemia treated with oral iron replacement. Physical examination showed severe weakness of the limbs with a bilaterally positive Trousseau’s sign without cardiorespiratory abnormalities. Vital parameters were within the normal range. The abdomen was flat, without tenderness, while auscultation disclosed increased intestinal sounds. Her ECG showed a sinus rhythm with type 1 atrioventricular block, flat T waves associated with U waves and an elongated QTc interval (570 ms). Laboratory tests revealed severe electrolyte imbalance, with hyponatraemia (133 mmol/L), hypokalaemia (1.6 mmol/L), hypocalcaemia (ionised calcium of 0.9 mmol/L), hypophosphataemia (1.6 mg/dL) and hypomagnesaemia (1.4 mmol/L). Furthermore, the patient had hypochromic microcytic anaemia (haemoglobin of 85 g/L, with a mean cell volume of 68 fL and a mean cell haemoglobin of 20.6 pg), normal platelet count (297×10ˆ9/L), iron (serum iron 18 µg/dL; ferritin 2 ng/mL) and folate deficiency (2 ng/mL), as well as hypoproteinaemia and hypoalbuminaemia (total serum protein 4.4 g/dL; albumin 2.6 g/dL). Due to severe electrolyte imbalance, a conspicuous electrolyte replacement was rapidly administered, leading to a slight improvement in electrocardiographic abnormalities. The patient was then admitted to the internal medicine ward for adequate investigation and treatment. During the hospitalisation, the common causes of infectious diarrhoea were excluded by stool cultures, and the faecal occult blood test resulted negative. Both ultrasound and abdominal X-ray examinations were unremarkable. Liver function tests revealed a slight increase of transaminases, with alanine transaminase and aspartate transaminase values of 47 U/L and 60 U/L (n.v. 5-35 for both parameters), respectively. Based on the lack of fever, normal C reactive protein and the presence of non-bloody, watery diarrhoea, the patient was further evaluated with an upper endoscopy. The examination revealed stigmata of villous atrophy at the duodenal level (figure 1), where biopsies were taken from the bulb and the second portion. Histopathological analysis showed the presence of a severe villous atrophy (Marsh-Oberhüber grade 3c) (figure 2) without any evidence of aberrant intraepithelial lymphocytes.14 Based on the histopathological result, we used enzyme-linked immunoassay to test IgA anti-TG2, which turned to be positive at low titre (23 U/mL, n.v. <10 U/mL). This result was associated with the positivity of IgA antiendomysial antibodies (1:80) revealed by indirect immunofluorescence.47 48 The genetic test showed human leucocyte antigen (HLA)-DQ2 positivity. Therefore, a firm diagnosis of CD was established and the patient started a gluten-free diet (GFD). Due to rapid improvement after gluten withdrawal, a course with steroid treatment was deemed not necessary. Since diarrhoea and paraesthesia showed significant improvement with complete regression in about a week, the patient was discharged in good health.

Figure 1

Representative duodenal endoscopic picture showing decreased mucosal folds carrying a scalloping profile, together with a mosaic pattern and an increased vascular network (arrow), all suggestive of villous atrophy.

Figure 2

Representative microphotograph of the duodenal mucosa showing villous atrophy and crypt hyperplasia with dense inflammatory infiltrate of the lamina propria (Marsh-Oberhüber lesion grade 3c). H&E staining, original magnification 200×.

Discussion and review of the literature

In the vast majority of cases, the natural history of CD is characterised by chronic evolution without acute exacerbations. Conversely, coeliac crisis is burdened by severe acute symptoms such as abdominal pain and distension, massive diarrhoea and weight loss, causing a life-threatening malabsorption syndrome. In most cases, gluten is introduced inadvertently, whereas in some patients with poor compliance to GFD a voluntary ingestion may occur.3 6 7 Only seldom a coeliac crisis can herald the onset of CD,10 as it was in the herein reported case. Among the reported cases described in table 1, there was a greater prevalence of female than male gender (28 vs 20), with a mean age of 50±17 years, which is higher than the age of the present case.9–46 Like in the present case, a higher incidence of coeliac crisis has been reported in patients carrying the HLA-DQ2 haplotype of genetic susceptibility to the disease as compared with those with HLA-DQ8, whereas the biopsy specimens showed signs characteristic of Marsh-Oberhüber 3 (from ‘a’ to ‘c’) mucosal lesions.1 Other common clinical features included weight loss, hypoproteinaemia and electrolyte abnormalities, whereas coagulation abnormalities (ie, prothrombin time elongation) along with markedly reduced platelet count were uncommon. No clear correlation was found between the anti-TG2 IgA antibody titre and coeliac crisis onset/severity, as also supported by our case showing only a twofold increase above the upper normal limit.

Table 1

Synopsis highlighting the main features of adult cases (n=48) with coeliac crisis published so far

Reference	Age	Sex	Weight loss	Favorable evolution with GFD	Diagnosis			HLA	Hb (g/L)	PLT (x109/L)	INR	Hypo-proteinaemia	Electrolyte Abnormalities	LOS (days)	Death
					Biopsy (Marsh grade)	EMA	TG2 (UI/mL)
Ozaslan et al9	75	M	Yes	Yes	N/A	Positive	N/A	N/A	59	97	N/A	Yes	Yes	10	No
	55	F	N/A	Yes	N/A	Positive	N/A	N/A	79	43	N/A	Yes	Yes	8	No
Poudyal et al10	20	M	No	Yes	N/A	N/A	100	DQ8	86	N/A	N/A	No	Yes	N/A	No
Gutiérrez et al11	26	F	N/A	Yes	3c	N/A	23.4	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A
Wolf et al12	36	F	Yes	Yes	3c	N/A	N/A	N/A	<110	N/A	N/A	N/A	Yes	N/A	No
Forrest et al15	43	F	Yes	Yes	3c	N/A	608	N/A	78	<100	2.1	Yes	Yes	107	No
Akbal et al16	52	F	Yes	Yes	N/A	Positive	Positive	N/A	<100	N/A	N/A	Yes	Yes	N/A	No
Al Shammeri et al17	50	F	N/A	Yes	N/A	1/160	15	N/A	N/A	N/A	N/A	N/A	Yes	N/A	No
Atikou et al19	26	F	N/A	Yes	3	Positive	N/A	N/A	N/A	N/A	N/A	No	Yes	N/A	No
Parry and Acharya20	83	M	N/A	Yes	N/A	Positive	6	N/A	N/A	N/A	N/A	N/A	N/A	N/A	No
Magro and Pullicino21	38	M	Yes	Yes	3c	N/A	35.9	N/A	152	N/A	1.6	Yes	Yes	N/A	No
Lindo Ricce et al22	63	F	N/A	No	3c	N/A	45	DQ2	N/A	N/A	N/A	Yes	Yes	30	No
de Almeida Menezes et al25	31	M	Yes	Yes	N/A	N/A	N/A	N/A	N/A	N/A	3.48	Yes	Yes	6	No
Gonzalez et al26	76	M	Yes	Yes	N/A	N/A	N/A	N/A	102	N/A	>10	N/A	Yes	10	No
Da Costa Becker et al27	49	F	Yes	Yes	3c	Positive	Positive	N/A	72	250	>1.5	Yes	Yes	N/A	No
Ferreira et al28	56	M	Yes	Yes	N/A	N/A	N/A	DQ2	<110	N/A	>1.2	No	Yes	7	No
Helvaci et al29	25	F	Yes	Yes	3c	N/A	100	N/A	N/A	N/A	N/A	Yes	Yes	14	No
Chen et al30	24	F	Yes	Yes	3c	N/A	99	N/A	93	N/A	3.2	No	Yes	8	No
Sbai et al31	43	M	Yes	Yes	3c	N/A	19	N/A	N/A	N/A	N/A	No	Yes	5	No
Bul et al32	46	M	Yes	Yes	N/A	N/A	48	N/A	110	N/A	N/A	Yes	No	N/A	No
Tiwari et al33	26	F	N/A	Yes	N/A	N/A	100	N/A	158	N/A	N/A	Yes	Yes	N/A	No
Bou-Abboud et al34	69	M	N/A	Yes	3b	N/A	132	N/A	48	N/A	1.2	Yes	Yes	N/A	No
Yilmaz et al35	75	M	No	Yes	N/A	3+	Positive	N/A	81	180	N/A	Yes	Yes	6	No
	82	F	Yes	N/A	N/A	1+	Positive	N/A	76	156	N/A	Yes	Yes	8	No
Ribeiro do Vale et al36	58	M	Yes	Yes	3c	1/640	142	N/A	116	N/A	1.6	No	Yes	11	No
Mrad et al37	64	F	Yes	Yes	3c	Positive	200	N/A	87	N/A	>1.2	Yes	Yes	N/A	No
Jamma et al38	34	F	Yes	Yes	3b	N/A	113	DQ8	N/A	N/A	N/A	N/A	Yes	7	No
	51	M	Yes	Yes	3c	N/A	200	DQ2	N/A	N/A	N/A	N/A	Yes	11	No
	48	F	Yes	Yes	3b	N/A	0	DQ2	N/A	N/A	N/A	N/A	Yes	4	No
	70	M	Yes	Yes	3	N/A	100	N/A	N/A	N/A	N/A	N/A	Yes	N/A	No
	48	F	Yes	N/A	3	N/A	N/A	DQ2	N/A	N/A	N/A	N/A	Yes	7	No
	68	F	Yes	Yes	3	N/A	6	DQ2	N/A	N/A	N/A	N/A	Yes	5	No
	67	F	Yes	Yes	3c	N/A	250	DQ2	N/A	N/A	N/A	N/A	Yes	8	No
	74	F	Yes	Yes	3c	N/A	24.5	N/A	N/A	N/A	N/A	N/A	No	7	No
	65	M	Yes	Yes	3	N/A	21.3	DQ2	N/A	N/A	N/A	N/A	Yes	10	No
	68	M	Yes	Yes	3b	N/A	117	DQ2	N/A	N/A	N/A	N/A	Yes	11	No
	65	F	Yes	Yes	3c	N/A	22	DQ2	N/A	N/A	N/A	N/A	No	13	No
	49	F	Yes	Yes	3	N/A	83.7	DQ2	N/A	N/A	N/A	N/A	Yes	4	No
Hammami et al39	26	F	Yes	No	N/A	N/A	N/A	N/A	N/A	N/A	N/A	Yes	Yes	7	Yes
Toyoshima et al 40	30	F	Yes	Yes	N/A	1/1280	5	N/A	114	N/A	N/A	Yes	Yes	N/A	No
Kelly et al41	23	F	N/A	Yes	N/A	N/A	33.9	N/A	120	94	N/A	N/A	Yes	21	No
Krishna et al42	67	M	Yes	Yes	3	Negative	4	DQ8	124	160	N/A	Yes	Yes	15	No
Chandan et al43	58	M	Yes	Yes	3c	N/A	200	N/A	47	N/A	N/A	Yes	Yes	N/A	No
Kizilgul et al44	50	M	Yes	Yes	3	158.7	200	N/A	94	N/A	N/A	N/A	Yes	N/A	No
Selen et al45	37	F	Yes	Yes	3	Positive	Positive	N/A	80	N/A	N/A	Yes	Yes	N/A	No
Gupta et al46	30	F	Yes	Yes	3b	N/A	N/A	N/A	<110	N/A	N/A	Yes	Yes	7	No
Present Case	34	F	Yes	Yes	3c	1/80	23	DQ2	85	297	2,52	Yes	Yes	9	No

EMA, antiendomysial antibodies; F, female; GFD, gluten-free diet; Hb, haemoglobin; HLA, human leucocyte antigen; INR, international normalised ratio; LOS, length of stay; M, male; N/A, not applicable; PLT, platelets; TG2, tissue transglutaminase.

Among the major features of this case were the abrupt onset of symptoms, in particular of those related to electrolyte imbalance, and the severity of the clinical picture prompting admission to the emergency department. Further to severe dehydration, the patient presented with neuromuscular weakness, a finding detected in other reports,7 9 13–21 and electrocardiographic abnormalities due to the key role exerted by potassium in regulating cell excitability. Likely, hypocalcaemia and hypomagnesaemia also contributed to worsening cellular excitability. According to previous evidence,6 9–13 hypoproteinaemia with hypalbuminaemia and metabolic acidosis were found in our patient as hallmarks of malabsorption, whereas paraesthesia was likely related to electrolyte imbalance. However, the variety of possible clinical pictures in coeliac crisis should be underlined, ranging from central nervous system involvement with tetraplegia/paraplegia and ataxia,17–19 psychosis22 as well as seizures,23 24 to coagulopathy11 25–27 and acute kidney injury.28 29 In all cases described so far, coeliac crisis required urgent hospitalisation. The milestone treatment is fluid resuscitation with correction of the electrolyte imbalance, which can lead to life-threatening cardiac arrhythmias. Nutritional support is also of paramount importance, and clinicians should take coeliac crisis in mind during differential diagnosis of severe acute diarrhoea with weight loss, as patients’ prognosis can dramatically improve with a simple dietary intervention.

In our case, like in almost all cases described, GFD led to a dramatic improvement in clinical picture. Nutritional management should take into consideration the possible occurrence of a refeeding syndrome, which can be fatal if not recognised and treated properly, as described in one patient with coeliac crisis.39 In less than 20% of cases (8 of 48 cases, 16%), corticosteroids were administered during management.49 However, we decided not to use steroids since their usefulness was recently questioned.38 50 It was reported previously that immunosuppression with corticosteroids and azathioprine for autoimmune hepatitis or prednisone for Bell’s palsy did not prevent the occurrence of coeliac crisis in patients.17 51 Moreover, steroid therapy may increase electrolyte depletion, facilitating the occurrence of refeeding syndrome.22 Finally, despite the acute onset of malabsorption syndrome in adulthood, our case did not show features of complicated CD52 53 (ie, refractory CD), and the clinical picture dramatically improved in a few days with GFD, still the only effective treatment available.54

Conclusion

The present case highlights the possibility that CD may manifest quite abruptly with a severe malabsorption syndrome and related electrolyte abnormalities and hypoproteinaemia. This would imply that even a typically chronic disorder, such as CD, may have an acute onset in a small proportion of patients, which emergency physicians should be aware of. Although rarely encountered in clinical practice, this acute onset of CD requires hospitalisation and immediate treatment (ie, electrolyte replacement and protein correction) in order to avoid life-threatening complications.