Patients commonly experience diarrhea and weight loss after pancreaticoduodenectomy for a variety of reasons, including pancreatic exocrine insufficiency and changes in bile salt metabolism [1]. In many cases these symptoms are transient, and may improve with pancreatic enzyme supplementation and other conservative measures. However, rarely this constellation of symptoms heralds the unmasking of overt celiac symptoms in patients previously affected with either silent or latent celiac disease [2].

Celiac disease is characterized by damage to the proximal small bowel owing to an immunologic intolerance to gluten, a protein commonly found in wheat, barley, and rye grains. Occurring most commonly in people of Caucasian background, celiac disease requires the genetic milieu of certain HLA alleles (DQ-2, and less commonly DQ-8) to occur. However, despite the ubiquitous nature of gluten, only a minority of patients with the HLA predisposition to develop celiac disease actually does, and other yet-to-be-identified genes and/or environmental triggers may play a role [3]. The “classic” presentation of celiac disease with malabsorption and steatorrhea beginning in childhood is now uncommon, and more patients are now diagnosed in adulthood [4, 5]. Of those who present with gastrointestinal symptoms, the onset of symptoms has been correlated in some cases to a “trigger,” such as pregnancy or surgery [6, 7].

The unmasking of silent or latent celiac disease has been reported after upper gastrointestinal surgery including esophageal and gastric resection [7, 8]. Celiac disease manifesting after pancreaticoduodenectomy is uncommon, but has also been reported [2, 9–13]. In this report, we describe 6 cases of celiac disease unmasked by pancreaticoduodenectomy and a single case of silent celiac disease diagnosed histologically at pancreaticoduodenectomy that remained symptomatically silent postoperatively (patient 7). This report also summarizes the existing case reports on this association, and discusses potential mechanisms that may underlie this phenomenon.

Methods

A search of the electronic Mayo medical record was performed cross-referencing the terms “celiac disease,” “sprue,” “celiac sprue,” “non-tropical sprue,” and “gluten-sensitive enteropathy” against the terms “pancreaticoduodenectomy” and “Whipple's operation” for the years 1976–2004, and ultimately yielded the 7 cases described in this report. In each of the 7 cases, no signs or symptoms attributable to celiac disease (e.g., diarrhea, microcytic anemia, fat-soluble vitamin deficiency) preceded the pancreaticoduodenectomy. The first 3 cases were evaluated before endomysial antibodies or tissue transglutaminase antibodies were clinically available.

Results

Patient characteristics

Demographic and clinical characteristics of the 7 patients are summarized in Table 1. Five of the patients were male, and the median age was 56. All patients underwent surgery for a presumed pancreatic or ampullary malignancy, although in 2 cases of suspected pancreatic head cancer, no malignancy was demonstrated on pathologic sectioning. In 5 of the 7 patients, villous atrophy and intraepithelial lymphocytosis were present in the duodenal mucosa not involved by tumor at the time of pancreaticoduodenectomy; in 1 case only “chronic inflammation” was commented on, and in 1 case no mention was made of the duodenal mucosa. For patients 1–6, symptoms ultimately attributable to celiac disease began immediately or within weeks after pancreaticoduodenectomy, with diarrhea and weight loss being the most commonly reported symptoms. The median weight loss among these 6 patients was 10 kg, and 3 patients (1, 2, and 4) required temporary support with parenteral nutrition.

Table 1 Clinical features of 7 patients with celiac disease manifesting only after pancreaticoduodenectomy
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For patient 7, duodenal mucosal changes compatible with celiac disease were recognized at the time of pancreaticoduodenectomy. However, his recovery from pancreaticoduodenectomy was uneventful, with modest early weight loss quickly abating, and no gastrointestinal symptoms ever occurring despite a gluten-containing diet. Over 2 years of follow-up, he enjoyed good health, with no diarrhea, anemia, or evidence of malabsorption. Two years after pancreaticoduodenectomy, serologic markers for celiac disease were checked and found to be strongly positive (Table 2). Mild transaminase elevations were attributed to a radiographic fatty liver, or less likely to celiac disease, and the patient elected to continue an unrestricted diet and clinical observation.

Table 2 Laboratory and pathologic features of 7 patients with celiac disease manifesting only after pancreaticoduodenectomy
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Diagnosis of celiac disease

Patients 1–6 underwent further medical evaluation as a result of their symptoms, which led to the diagnosis of celiac disease. The laboratory and pathologic data providing the basis for the diagnosis of celiac disease in these patients is summarized in Table 2. Patients 1–6 all had repeat small bowel biopsies demonstrating villous atrophy, most with prominent intraepithelial lymphocytosis also. Serologic testing was clinically available during the time period in which patients 4–6 were evaluated (in addition to patient 7); at least 1 marker was positive in each of these patients. Symptoms completely resolved in 4 of 6 patients after initiation of a gluten-free diet, with a partial improvement seen in the remaining 2 patients. Figure 1 demonstrates intestinal histopathology in patient 4 before and after initiation of a gluten-free diet.

Fig. 1
figure 1figure 1

a Duodenal histopathology in patient 4 at the time of diagnosis of celiac disease, with villous atrophy and intraepithelial lymphocytosis (200× magnification). b Jejunal histopathology in patient 4 after eleven months on a gluten-free diet, with healthy, normal-appearing villi (400× magnification)

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It can be clearly ascertained that the histologic diagnosis of celiac disease was apparent in the pancreaticoduodenectomy specimen in 2 cases (1 and 5), yet not reported by the pathologist. This may have been the case in patients 2 and 3, although this is less certain, because the original pancreaticoduodenectomy tissue blocks were not reviewed in our institution. For patients 4 and 6, the original pancreaticoduodenectomy pathology report detailed villous atrophy and intraepithelial lymphocytosis, yet the clinical significance of these findings was not appreciated by the treating clinicians. The median delay from pancreaticoduodenectomy to diagnosis of celiac disease in patients 1–6 was 6 months.

Discussion

Diarrhea and weight loss are common after pancreaticoduodenectomy. Preoperative weight loss of 5–10 kg with pancreatic and ampullary malignancies is common, and postoperative weight loss of another 5–8 kg is typical, with the weight often stabilizing by 6 months after surgery in the absence of cancer recurrence [1, 14]. Diarrhea after pancreaticoduodenectomy is frequently encountered and may be multifactorial. Steatorrhea from exocrine insufficiency [1], accelerated colonic transit from altered bile salt metabolism [15], and the loss of inhibitory tone on intestinal motor function from sympathetic denervation are all potential diarrheal mechanisms after pancreaticoduodenectomy [16]. Empiric pancreatic enzymes and loperamide are reasonable in the initial management of these patients. However, when diarrhea and weight loss persist, clinicians should consider the emergence of previously silent or latent celiac disease.

Patients who have normal small bowel mucosa while ingesting an unrestricted diet, but later develop celiac disease had latent celiac disease. Patients who have mucosal atrophy and corroborating celiac serologies, yet no symptoms (e.g., an asymptomatic family member of a celiac patient who undergoes screening) have silent celiac disease [5]. Historically, celiac disease has been reported to emerge after various upper gastrointestinal surgeries [7, 8]. Other triggers, including pregnancy and enteric infections, may influence the emergence and activity of celiac disease [6, 17]. In these reports, the unmasking of silent celiac disease is more common than the triggering of latent celiac disease.

Celiac disease unmasked by pancreaticoduodenectomy was first reported by MacGowan et al. [2] in 2 patients, with 5 subsequent reports each describing a single case [9–13]. Including these 7 new cases from our institution, 14 reports of this phenomenon have now been described. Among all reported cases, an ampullary or duodenal adenocarcinoma was the most common indication for pancreaticoduodenectomy, occurring in 8 of 14 patients. Although pancreatic adenocarcinoma is a much more common indication for pancreaticoduodenectomy than ampullary or duodenal adenocarcinoma, patients with celiac disease are at heightened risk for these malignancies [18]. In 12 of 14 patients, the pancreaticoduodenectomy surgical pathology report was available, and thus the histology from the duodenum not involved by tumor is known. Of these 12, just 1 specimen showed normal histology [11]; thus, pancreaticoduodenectomy appears to activate silent celiac disease much more commonly than latent celiac disease. Patient 7 from our institution is the lone example of silent celiac disease that remained silent postoperatively on an unrestricted diet. Celiac disease is a premalignant condition [19], and care must be taken by pathologists and clinicians to identify and appropriately treat celiac disease when present on pancreaticoduodenectomy specimens; in our series, a delay in diagnosis was unfortunately common.

The mechanism for the unmasking of celiac disease after pancreaticoduodenectomy is not known. One potential explanation is that transient bowel hyperpermeability following upper gut surgery leads to a heightened gluten challenge. Intestinal permeability as measured by the dual sugar test (lactose and mannitol) is increased after any gut surgery [20, 21]; paracellular absorption is disproportionately increased as compared with the transcellular route. It has recently been demonstrated that zonulin (a human protein analogue of the Vibrio cholerae zonula occludens toxin) mediates intestinal tight junction function (and thus paracellular solute transit) [22], and that zonulin expression is increased in active celiac disease [23]. Thus, any disruption of the intestinal mucosal barrier and tight junction function allows enhanced paracellular delivery of gluten peptides to the lamina propria [24]. In susceptible patients with silent or latent celiac disease, the resultant challenge may stimulate the innate and adaptive immune response enough to result in clinically apparent inflammatory intestinal disease.

In summary, clinicians should consider celiac disease as a potential diagnosis in patients with failure to thrive and diarrhea after pancreaticoduodenectomy. This entity is uncommon, but may be underrecognized. The underlying mechanism may relate to an increased antigenic load secondary to postsurgical changes in intestinal physiology.