Accepted: 28 August 2001Published online: 6 December 2001© Springer-Verlag 2001

Abstract Background: Coeliac dis-ease is a disorder characterised bymalabsorption related to abnormalsmall bowel structure and intoler-ance to gluten. There are several re-ports of an increased risk for malig-nancy in coeliac disease and its rela-tion to gluten-free, reduced gluten,or normal diet. While a normal dietis associated with an excess of can-cer of the mouth, pharynx, oesopha-gus, and also of lymphoma, treat-ment with a gluten-free diet restoresthe cancer risk back to normal. Patient: In the present study, we re-port on a 63-year-old female patientwith a history of coeliac disease fortwenty years who presented withpersistent diarrhoea, weight loss, and

an abdominal mass. Results: Thegastroenterological work-up revealedsmall bowel mucosal atrophy, ab-sence of functional splenic tissue,and evidence for an involution of amesenteric lymph node, termed cavi-tation. Discussion: This triad hasbeen previously described to repres-ent a rare disease entity related tocoeliac disease. We report a two-yearfollow-up and a review of the litera-ture on the pathogenesis, prognosis,and therapeutical implications of thisdisease entity.

Keywords Diarrhoea · Lymph nodecavitation · Coeliac disease · Hyposplenism

Int J Colorectal Dis (2002) 17:192–198DOI 10.1007/s00384-001-0361-8 C A S E R E P O RT

Frank SchmitzKarl-Heinz HerzigEckhard StüberMarkus TiemannAxel Reinecke-LüthgeRolf NitscheUlrich R. Fölsch

On the pathogenesis and clinical course of mesenteric lymph node cavitation and hyposplenism in coeliac disease

Introduction

Coeliac disease (CD) – also termed coeliac sprue andgluten-sensitive enteropathy – is a disorder characterisedby the presence of malabsorption secondary to intestinalvillous atrophy which is reversed by gluten withdrawal.At present, the prevalence of CD is estimated to be0.35–0.5% and appears to be substantially higher inmany populations than previously thought [1, 2, 3]. Onelikely explanation for the lack of epidemiological data isthe great variation of the clinical picture. Individualswith typical villous atrophy and crypt hyperplasia of theintestine may still be free of symptoms. CD is an ente-ropathy affecting mainly the proximal small intestinewhich can be defined as an intolerance in geneticallysusceptible individuals to proteins found in wheat, bar-ley, and rye [4]. Alcohol extraction of gluten proteinfrom wheat yields at least four related glutamine-rich

polypeptides collectively termed gliadin. Significantsteps toward a better understanding of the pathogenesisof CD have been made in the last 4 years. This progressis largely due to the work of Dieterich et al. [5] whoidentified tissue transglutaminase (tTG) as the main ifnot sole endomysial autoantigen, and who further de-fined its role in antigenic potentiation of gliadin in genet-ically susceptible individuals. They ruled out a major di-rect toxic effect of gluten and implicated primarily T cellmediated mechanisms [6, 7].

There is little doubt that patients with CD are at in-creased risk for developing malignancy, particularlylymphoma [8, 9]. There are several reports of an associ-ation between steatorrhoea and intestinal lymphoma[10]. One previous study in 210 patients with CD re-vealed an increased risk for malignant complicationsand a statistically-significant protective effect of a glu-ten-free diet.

F. Schmitz (✉ )Department of Medicine 1, Ruhr-University Bochum, Gudrunstrasse 56,44791 Bochum, Germanye-mail: frank.schmitz@uni-bochum.deTel.: +49-234-5092378Fax: +49-234-5092309

K.-H. Herzig · E. Stüber · R. Nitsche U.R. FölschDepartment of Medicine I, Christian-Albrechts-University of Kiel,Kiel, Germany

M. Tiemann · A. Reinecke-LüthgeDepartment of Pathology, Christian-Albrechts-University of Kiel,Kiel, Germany

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Diagnosis of CD is challenging because of its widespectrum of clinical manifestations. Once the disease hasbeen considered by the clinician, CD is diagnosed bysmall bowel biopsy and a dramatic clinical response to agluten-free diet (GFD). Additionally, serum immuno-globulin A (IgA) autoantibodies to endomysium have asensitivity and specificity for the disease exceeding 90%[11]. A minority of patients fail to respond to glutenwithdrawal primarily or after an initial clinical and histo-logical response. This so-called refractory or unclassifiedCD is a diagnosis of exclusion and appears to representat least one different disease entity; it is associated witha high mortality rate [12].

In the present study, we shall report on a patient witha rare and serious complication of CD which is charac-terised by small bowel mucosal atrophy, splenic atrophy,and an abdominal mass representing an involuted mesen-teric lymph node, a development that has come to betermed ‘cavitation’. We provide the clinical picture andtreatment over a 2-year follow-up period, a review of theliterature, and an outline of the pathogenesis and thera-peutic implications of this rare disease entity.

Case report

A 62-year-old female patient was referred in January 1997 to theDepartment of General Internal Medicine of the University Medi-cal Center of the city of Kiel, Germany, by her family practitioner.She had been complaining of diarrhoea for a period of 6 months.She was having three to four loose bowel movements per day andalso reported a weight loss of 10 kg within the preceding3 months. The stool appearance was described as brown in colourand loose but not foul-smelling nor extremely voluminous.

Past medical history

The patient had been diagnosed as suffering from coeliac diseasein 1980. The diagnosis was based on chronic diarrhoea associatedwith subtotal villous atrophy of the small bowel mucosa and anunequivocal response to a gluten-free diet. The diagnosis was re-evaluated in 1981 as there was a relapse of the malabsorption syn-drome. An infectious aetiology including pathogenic bacteria, pro-

tozoa, and parasites was ruled out as underlying the chronic diar-rhoea. Since upper gastrointestinal (GI) endoscopy once again re-vealed a subtotal villous atrophy in the duodenum, there was,however, considerable suspicion that the patient had not adheredstrictly to the recommended diet. She was reinstructed and encour-aged to adhere to the dietary restrictions.

Due to another episode of diarrhoea and a rosacea-like rash,she was hospitalised again in February 1983. Dermatologists ruledout dermatitis herpetiformis Duhring upon examining a skin biop-sy. The patient admitted that her compliance to adhere to a gluten-free diet was poor. Another instruction by nutrition specialists wasprovided.

The patient was fine until 1991 when she presented with pe-ripheral oedema and diarrhoea. At that time, an abdominal ultra-sound revealed a normal sized spleen. To rule out pancreatic insuf-ficiency as an underlying cause of persistent diarrhoea, faecal chy-motrypsin excretion was measured and found to be decreased. Forthis reason, substitution with pancreatic enzymes was begun andthe stool frequency returned to normal until October 1996.

Gastroenterological work-up in 1997

On examination, she presented with a weight of 50 kg and a heightof 164 cm. Palpation of the abdomen revealed a nontender butfirm mass in the left paraumbilical region with a cranio-caudal di-ameter of approximately 10 cm.

A gastroenterological work-up was initiated (Table 1). Thewhite blood cell count was normal. No human pathogenic bacte-ria, fungi, ova, or parasites could be cultured from several stoolspecimens. The mean stool weight over 3 subsequent days was282 g/day [normal less than 200 g/day] with a lipid excretion of30 g [normal less than 7 g/day] per day. A glucose-H2 breath testwas suggestive of small intestinal bacterial overgrowth. Exocrinepancreatic insufficiency was ruled out by direct pancreatic func-

Table 1 Gastrointestinal function tests

Diagnostic test Value Normal range

Stool weight 282 g/day <200Stool fat 30 g/day <7Glucose-H2 breath test Pathological resultD-Xylose absorption Pathological result

Direct pancreatic function test (secretin-caerulein test)HCO3

– secretion 3.1 mmol/30 min >5.5Lipase secretion 60,880 U/30 min >52,000

Table 2 Laboratory chemistryLaboratory function test January 1997 September 1998

Serum calcium (2.1–2.6 mmol/l) 2.06 1.84Vitamin D (25-OH-cholecalciferol) (25–120 ng/ml) 25Serum albumin (3.5–5.5 g/dl) 3.9 3.4Serum iron (37–145 µg/dl) 37 36Serum β-carotenes (>100 µg/dl) 21Prothrombin time (75–100%) 95 97Haematocrit (37–46%) 38 37Ferritin (15–300 ng/ml) 85IgA-anti-gliadin antibodies NegativeIgA-anti-endomysial antibodies Negative NegativeIgA-anti-tissue transglutaminase NegativeHLA class I B8HLA class II DR3, DQ2

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wards, a multiplex polymerase chain reaction (PCR) was done toamplify the T cell receptor γ gene region as described by Trainoret al. [14]. Only polyclonal rearrangement patterns of the γ chainT cell antigen receptor (TCR) were detected in mucosal lympho-cytes.

Double contrast enteroclysis revealed mucosal flattening with-in the proximal segments of the short bowel (Fig. 2). The abdomi-nal mass was confirmed by ultrasound with a homogeneous andmildly hypoechogenic pattern in comparison with renal cortex tis-sue. The examiner suggested that the mass could be in direct con-tact with the pancreas. The spleen was not visible. The absence ofsplenic tissue was confirmed scintigraphically by single photonemission computed tomography after administration of heat dena-tured 99mTc-labelled erythrocytes, which are sequestered in func-tional splenic tissue.

A CT scan of the abdomen also confirmed the existence of anabdominal tumour and the absence of splenic tissue (Fig. 3). Themass had a diameter of 5×7×8 cm. It appeared encapsulated withpartial capsular calcifications and unrelated to any solid organ. A needle biopsy of the abdominal mass was obtained which re-vealed hyaline-like cell-free material.

The patient’s findings can be summarised as follows:

1. Small intestinal mucosal atrophy2. Intra-abdominal tumour of unknown origin3. Absence of splenic tissue4. Small intestinal bacterial overgrowth

Treatment and follow-up

The patient received nutrition counsel and a gluten-free diet totreat the small bowel mucosal atrophy. Antibiotic therapy for erad-ication of the small bowel bacterial overgrowth consisted of100 mg doxycycline twice daily for 14 days. To minimise the riskof potentially life-threatening pneumococcal infections, a vaccinewas administered [17, 18]. On follow-up visits, the patient report-

Fig. 1A, B Small bowel mucosal biopsy. Small bowel mucosal bi-opsies reveal marked mucosal flattening and crypt hyperplasia (A)and an increased number of intraepithelial lymphocytes (B). H&Estain, magnification 100× (A) and 400× (B)

Fig. 2 Small bowel enteroclysis. This small bowel enteroclysisshows the calcified capsule of the abdominal mass as indicated(arrow). Note the dilatation of the entire visualised small bowelwhich also appears smooth

tion testing using intravenous administration of secretin and caeru-lein as secretagogues. Laboratory findings suggested a malabsorp-tive state as indicated by decreased serum albumin and β-caroteneconcentrations as well as low serum calcium, vitamin D, and ironlevels (Table 2). Serum studies for anti-endomysial antibodies(EMA), IgG, and IgA-antigliadin antibodies and IgA-anti-tTG antibodies were negative. Serum levels for total IgA, IgG, andIgM were repeatedly within normal limits.

Endoscopies of the upper and lower gastrointestinal tract wereperformed and multiple biopsies obtained. Microbiological cul-tures of these biopsies were negative. On microscopy, there wasmarked mucosal flattening and crypt hyperplasia in the duodenalbiopsies and even more pronounced hyperregenerative-atrophicchanges in the proximal jejunum consistent with histopathologicalchanges observed in coeliac disease. The periodic acid-Schiff(PAS) stain revealed no evidence for PAS-positive bacteria withinthe intestinal mucosa. The intraepithelial lymphocyte (IEL) countwas elevated with 42–50 IEL per 100 enterocytes (Fig. 1).

To rule out enteropathy-associated T-cell lymphoma, DNA wasextracted from paraffin embedded tissue of a gastrointestinal biop-sy specimen according to the method of Wan et al. [13]. After-

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ed that she had suffered no diarrhoea since the third day afterstarting antibiotic treatment. She was free of symptoms at 6 and12 months after discharge, and she gained 4 kg of weight. A repeatCT scan showed the abdominal mass to be unchanged.

Discussion

The reported patient’s diagnosis in 1980 of CD wasmade according to commonly accepted criteria, includ-ing IgA-antigliadin antibodies, subtotal villous atrophy,and an optimal response to gluten withdrawal. The pa-tient required several hospitalisations for chronic diar-rhoea after that which were related to intentional or inad-vertent gluten ingestion. Upon work-up in 1997, the pa-tient displayed neither IgA-antigliadin (AGA) nor en-domysial antibodies (EMA). We also tested her serum bythe more objective IgA-anti-tissue transglutaminase en-zyme-linked immuno-sorbent assay, which was also neg-ative. This autoantibody response (EMA, AGA, and tTGnegative) is extremely unlikely in CD, and can only beexplained by IgA deficiency or intestinal T cell lympho-ma. IgA serum levels, however, were repeatedly withinnormal limits. Ten to 15% of patients with a long historyof CD develop neoplastic diseases. Lymphoma of thesmall bowel comprises half of all malignancies foundthere. The biopsies, however, which were obtained fromthe abdominal mass as well as from the small intestinedid not confirm a lymphoma, nor did they reveal anysigns of malignancy. The absence of enteropathy-associ-ated T-cell lymphoma (EATL) was further supported bythe lack of monoclonal TCR γ chain rearrangement inthe patient’s mucosal lymphocytes. However, the pa-tient’s autoantibody response and clinical course did

conform with unclassified or refractory CD, which is adiagnosis of exclusion [12]. No body of literature existson the incidence of AGA, EMA and tTG in patients withrefractory CD. Analyses of limited numbers of sera frompatients with refractory CD reveal that the results forEMA range between 50 and 60%, suggesting that refrac-tory CD may represent a different clinical disease entity[12]. Since refractory CD is a diagnosis of exclusion, allother possible causes which may lead to recurrent histo-logical or clinical characteristics compatible with CDmust be eliminated. The most common cause of treat-ment failure is unintentional ingestion of gluten [15]which cannot be absolutely ruled out in the present pa-tient although there was no serological evidence for re-peated gluten challenges. Bacterial overgrowth of the in-testine, however, is a disorder that may mimic refractoryCD [16]. The glucose-H2 breath in our patient was clear-ly consistent with small intestinal bacterial overgrowth.This finding is further supported by the rapid response toantibiotic treatment. We therefore conclude that bacterialovergrowth may have been the leading cause of diar-rhoea and malabsorption in the presented case.

The abdominal tumour in this patient had not beenfound in previous hospitalisations. The patient, in fact,was unaware of it until her general practitioner had dis-covered it on palpation when she sought his advice be-cause of ongoing diarrhoea in January 1997.

The histological examination of the transabdominalbiopsy of the tumour was non-specific due to its cell-freeappearance. Dermoid cyst fit the data obtained on themass by CT scan, histology, and plain abdominal radio-graphs. The embryonic origin of dermoid cysts, howev-er, makes this diagnosis very unlikely since this tumourmust have evolved during the fifth decade of the pa-tient’s life, earlier abdominal sonographies having failedto show it.

A rare but potentially severe condition has been de-scribed, however, which might explain the existence ofthe tumour as well as the hyposplenism and small intesti-nal mucosal atrophy. Faber et al. [6] described a patientwith a flat intestinal mucosa, splenic atrophy, and a par-ticular lesion of mesenteric lymph nodes which wastermed cavitation. Mesenteric lymph node cavitation(MLNC) is a rare complication of CD which is associat-ed with splenic atrophy. Since 1952, only 25 patientswith this rare complication have been described, primari-ly in the French medical literature (Table 3). The diagno-sis is usually made at laparotomy or autopsy in patientspresenting with chronic diarrhoea. Half of these patientshave a history of CD. Although almost all patients re-ceived a gluten-free diet as primary treatment, the prog-nosis of this disease entity was poor. There have been 13reported deaths which were mainly related to cachexia orsevere bacterial infections. Female and male patients ap-pear to be affected with similar frequency. At present,data are lacking on the serum response in MLNC, includ-

Fig. 3 Abdominal CT scan. The abdominal CT scan shows a7×8 cm mass in the left abdomen. The mass has a cyst-like ap-pearance and is isodense in comparison to internal oblique abdom-inal muscles. The capsule is hyperdense and comparable to iliaccrest absorbance suggesting a considerable degree of calcification

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Table 3 Coeliac disease (CD), hyposplenism, and lymph node cavitation (GFD gluten-free diet, CT chemotherapy, AB antibiotic treat-ment, MNLC mesenteric lymph node cavitation, m male, f female)

Patients Sex Age Clinical symptoms History Diagnosis Treatment Death/cause Year/Referenceof CD of MLNC

1 m 39 Diarrhoea (1 year) No Post mortem None Yes/cachexia 1952 [19]and weight loss

2 f 65 Diarrhoea (20 years No Post mortem GFD Yes 1960 [31]and weight loss

3 m 42 Diarrhoea (20 years) 2 years Laparotomy None Yes/not given 1969 [32]and intestinal obstruction

4 f 26 Diarrhoea (20 years) No Laparotomy GFD Yes/cachexiaand intestinal obstruction

5 m 43 Diarrhoea (20 years) 2 years Laparotomy GFD, steroids Yes/cachexia 1972 [33]and abdominal mass

6 m 58 Diarrhoea (4 months) No Laparotomy GFD, steroids No 1973 [34]and abdominal mass

7 f 38 Diarrhoea, weight loss, 5 months Post mortem GFD, steroids, Yes/cachexia 1974 [35]fever, and tetania CT, AB and pneumonia

8 f 41 Diarrhoea and weight loss 9 months Laparotomy GFD, steroids No 1983 [36]9 f 50 Chronic diarrhoea No Laparotomy GFD Yes/pneumococcal 1984 [23]

(6 years), peripheral pneumonianeuropathy, abdominal mass

10 f 63 Chronic diarrhoea No Laparotomy GFD No(28 years), growth retardation, peripheral neuropathy, abdominal mass

11 f 32 Chronic diarrhoea 1 year Laparotomy GFD, steroids Yes/infectious (7 years), intestinal pericarditisobstruction

12 f 26 Identical with patient 413 m 43 Identical with patient 514 m 21 Chronic diarrhoea 1.5 years Laparotomy GFD No

(6 years), intestinal obstruction and dermatitisherpetiformis

15 m 70 Chronic diarrhoea 6 months Ultrasound GFD, steroids Yes/intestinal 1986 [37](6 months) and weight lymphomaloss

16 m 42 Chronic diarrhoea 29 years Ultrasound GFD, steroids No 1986 [20](40 years) and abdominalmass

17 f 53 Chronic diarrhoea 28 years Ultrasound GFD,CT No 1988 [38](28 years) and abdominalmass

18 f 35 Chronic diarrhoea and 2 years Post mortem GFD Yes/localised 1990 [22]weight loss intravascular

coagulation19 m 39 Left-sided inframammary No CT GFD, steroids No 1994 [39]

pain, episodic diarrhoea,dermatitis herpetiformis

20 m 35 Weight loss, oedema 15 years Post mortem GFD Yes/cachexia 1995 [40]21 m 67 Chronic diarrhoea 1 Laparotomy None Yes/pneumonia

(2 years) and weight loss22 m 53 Anaemia and weight loss No Laparotomy GFD No23 f 44 Abdominal pain and No Laparotomy GFD, steroids No

weight loss24 m 69 Chronic diarrhoea 4 months Laparotomy GFD, steroids Yes/cachexia

(1 year), weight loss and oedema

25 f 45 Chronic diarrhoea No Laparotomy GFD, steroids No 1998 [41](1 year), abdominal pain and weight loss

26 f 42 Unexplained fever No Ultrasound GFD No 1998 [21]27 f 67 Chronic diarrhoea and No Ultrasound GFD No 1999 [42]

weight loss

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ing possible changes in levels of AGA, EMA, and anti-tTGantibody as observed in classical CD. Matuchansky et al.found in an analysis of six cases only one patient with alow titre of AGA and a weak response to gluten with-drawal, suggesting that mucosal flattening in patientswith mesenteric lymph node cavitation and hyposple-nism relates to another disease entity with some similari-ties to refractory sprue [23].

The pathogenesis of mesenteric lymph node cavita-tion is uncertain. One author hypothesised that the dam-aged intestinal mucosa elicits an extreme immune re-sponse which, in turn, results in depletion of cellularcomponents of lymph nodes and, hence, involution, orcavitation [20]. This theory is supported by an observa-tion of Bahlouli et al. in a 42 year-old patient with CDand lymph node cavitation [21]. One year after initiationof a gluten-free diet mesenteric lymphadenopathies hadfully resolved while hyposplenism persisted. However,lymph node depletion in response to gluten challengealone may not fully explain the pathogenesis of this dis-ease entity. Le Quellec et al. described a feature in a pa-tient with CD which may provide a detailed picture ofthe transition from normal to cavitated mesenteric lymphnodes [22]. This patient had died of chronic diarrhoeathat became resistant to a gluten-free diet within 2 yearsfrom diagnosis of CD. On autopsy, there was an exclu-sive mesenteric lymphadenopathy of more than tenlymph nodes that were histologically characterised byhaemorrhagic necrosis. One likely explanation for thisphenomenon is that immune complexes derived fromsmall bowel mucosal lesions induce endothelial lesionsin mesenteric lymph nodes which in turn trigger comple-ment activation, resulting in localised intravascular coag-ulation and bleeding in mesenteric lymph nodes, themonovisceral site of the immune response. It can bespeculated that mesenteric lymph node cavitation repre-

sents the sequel of haemorrhagic necrosis. Interestingly,this patient as well as ours and others expressed HLA B8and DR3 alleles [23].

Twenty-five to 75% of patients with CD have hypo-splenism [24]. In patients with sickle cell disease, thepathogenesis of hyposplenism is splenic infarction, but ingastrointestinal disorders such as CD and inflammatorybowel disease the reasons for impaired splenic functionare obscure. Two forms of hyposplenism have been de-scribed in CD, a variety that is reversible upon glutenwithdrawal and irreversible splenic atrophy [25, 26]. In-creased levels of circulating immune complexes as foundin patients with untreated CD have been claimed to func-tionally block the splenic reticulo-endothelial system [27].Functional hyposplenism is associated with a significantlyincreased risk for life-threating infection as best character-ised by overwhelming post-splenectomy infection (OPSI)[17, 18, 28]. A meta-analysis in splenectomised patientshas revealed that severe infections related to pneumococ-ci, Haemophilus influenzae, and Neisseria meningitidisare increased [29]. Recommendations for vaccinations insplenectomised or asplenic patients have been developedand the efficacy of pneumococcal vaccines to reduce se-vere infections have been clearly shown [17, 18, 30].Since at least four patients have died of infectious diseasein the course of this disease entity, it appears mandatory toprovide vaccination at least against pneumococcal infec-tions to reduce overall mortality.

We conclude that the natural course of the syndromeof mesenteric lymph node cavitation, small intestinalmucosal atrophy, and hyposplenism is associated with anextremely high mortality with significant individual vari-ation. A strong supportive problem-oriented medicaltherapy aiming at prevention of cachexia and serious in-fections is mandatory for improvement of the outcome inindividual patients.

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