Branded For Life

By Cory A. Roberts, M.D.
 
Celiac disease (CD) affects approximately 1% of the population. There is a predilection for females of 2-3:1 that persists in both the pediatric and adult populations. It is well known that first degree relatives of patients with CD have an increased risk of also having the disease with an approximate 10% prevalence. Further, the concordance rate in monozygotic twins is 70%. Classic symptoms include diarrhea and abdominal pain/bloating. 
 
Celiac disease is a relatively easy morphologic diagnosis to suggest at the far end of the spectrum of possible histologic changes – marked villous blunting, crypt hyperplasia and increased intraepithelial lymphocytes (IEL). That histology in conjunction with appropriate serologic studies (antibodies against tissue transglutaminase) is strong evidence for celiac disease. Perhaps the true gold standard is all of the above with associated documented proof of response or improvement with a gluten-free diet. Regardless, most cases that pass over the pathologist’s microscope stage reside somewhere other than the far end of the spectrum and range from normal or near normal villous architecture to moderate blunting each with associated increased IEL.
 
Gliadin derived peptide. Immunogenic breakdown product of gliadin (gluten), playing an essential role in celiac disease. Atoms shown as spheres with conventional color coding: hydrogen (white), etc
 
CD is well known to exhibit patchy changes and thus more attention has been paid to requiring minimum numbers of pieces in a biopsy specimen to overcome potentially random sampling errors. Most agree that approximately 4 pieces of tissue are needed to account for this potential variability. Neutrophilic inflammation in the lamina propria, once thought uncommon, is a relatively common finding in CD and should not dissuade the observer. However, additional changes such as erosion and crypt abscesses should send one looking for a different cause like peptic change or nonsteroidal anti-inflammatory drugs (NSAID). Perhaps the most challenging histology is that of increased IEL with preserved, normal villous architecture, so-called Marsh 1 lesion. Such a finding occurs in approximately 1-3% of biopsies but only about 1% of the population has celiac disease. It is well known that some patients with intact villous architecture but increased IEL have previously unrecognized celiac disease. Studies place the incidence of celiac disease between 9 and 40% in such cases. Histologic clues for CD in a case of increased IEL but intact villous architecture include the IEL distribution. Greater density of IEL at the tips of villi argue for CD as compared to IEL at the sides of the villi which can be seen normally.
 
There are a number of other entities that can cause increased IEL but no alteration of the villous architecture apart from celiac disease. Among the known causes are autoimmune disorders; NSAID; immune deficiencies; inflammatory bowel disease; microscopic colitis; tropical sprue and infections such as Giardiasis, gastric Helicobacter pylori, Cryptosporidiosis and bacterial overgrowth. Studies have failed to demonstrate any reliable manner in which histologic findings alone can separate the causes of increaesd IEL. An accurate diagnosis of celiac disease requires correlation with history (including response to diet), histology and serologic data.
 
Because of the aforementioned difficulties, our diagnoses are always accompanied by a comment declaring the need to view the histomorphologic findings in conjunction with the entire clinical picture. That is true whether there is complete villous blunting or normal villous architecture with increased IEL. Moreover, we diagnose those cases with increased IEL but preserved villi descriptively (“Increased intraepithelial lymphocytes with intact villous architecture”) with a very similar comment that is used in cases which feature “classic” celiac histology. The diagnosis of CD is truly one of clinical-pathologic correlation as it requires, by definition, correlation of the histologic picture with the clinical findings including the serologic studies in particular.
 
References
1. Brown I, Mino-Kenudson M, Deshpande V, Lauwers G. Intraepithelial lymphocytosis in architecturally preserved small intestinal mucosa. An increasing diagnostic problem with a wide differential diagnosis. Arch Pathol Lab Med; 2006; 130:1020-1025.
 
2. Brown IS, Smith J and Rosty C. Gastrointestinal pathology in celiac disease. A case series of 150 consecutive newly diagnosed patients. Am J Clin Pathol 2012; 138:42-49.
 
3. Bao F, Green PHR and Bhagat G. An update on celiac disease histopathology and the road ahead. Arch Pathol Lab Med 2012; 136:735-745.
 
4. Hammer S and Greenson J. The clinical significance of duodenal lymphocytosis with normal villous architecture. Arch Pathol Lab Med; 2013; 137: 1216-1220.