Category: Trainee

Duodenal biopsy site for diagnosing coeliac disease: D1, D2, or both?

Summary

Current best practice, in line with BSG, ESPGHAN and ACG guidance, is to take biopsies from both the duodenal bulb (D1) and the distal duodenum (D2 / D3), placed in separate pots. At least one (preferably two) bulb biopsies plus four or more distal duodenal biopsies is the standard recommendation. D2 remains the principal diagnostic site, but adding D1 increases diagnostic sensitivity, particularly for ultra-short coeliac disease and paediatric cases.

Historical position: D2 only

Traditional teaching was to biopsy the second part of the duodenum and to avoid the bulb. The rationale was that the bulb is architecturally complex — Brunner glands distort villous architecture, peptic injury and gastric metaplasia are common, and orientation in the histology laboratory is often poor. These features were felt to give unreliable assessment of villous atrophy and to risk false-positive interpretations of Marsh 1–3 change.

Why D1 was added: ultra-short coeliac disease

A series of studies in the 2000s and 2010s showed that a meaningful minority of coeliac patients have disease that is confined to, or most marked in, the bulb. Bonamico and colleagues demonstrated that taking bulb biopsies in addition to distal duodenum increased the diagnostic yield in children, and identified the 9 o’clock and 12 o’clock positions as the most informative bulb sites. Evans et al. and subsequent adult series have confirmed that around 5–10% of adult coeliac patients have lesions limited to or more severe in the bulb (ultra-short coeliac disease), and that omitting D1 would miss these cases.

Practical protocol

  • At least 1–2 biopsies from the duodenal bulb (ideally from the 9 o’clock and 12 o’clock positions, per Bonamico).
  • At least 4 biopsies from the distal duodenum (D2 / D3).
  • Bulb biopsies should be submitted in a separate, clearly labelled pot so the pathologist can apply appropriate caution when interpreting villous architecture around Brunner glands.
  • Single-biopsy-per-pass technique is preferred for orientation; multiple biopsies in one bite increase tangential sectioning and false-positive villous blunting.

Caveats with bulb biopsies

Bulb mucosa is intrinsically harder to assess. Brunner gland lobules push villi apart and shorten them, gastric metaplasia is common, and peptic duodenitis can produce IEL increases unrelated to gluten. Bulb-only abnormalities should therefore be interpreted in the context of serology, HLA status, and the distal duodenal appearances before a confident coeliac diagnosis is made.

Bottom line

Biopsy both. D2 remains the principal diagnostic site, but the addition of separately-potted bulb biopsies materially improves sensitivity, particularly for ultra-short coeliac disease and in children. This is the position of the BSG, ESPGHAN and ACG guidelines.

Key references

  • Ludvigsson JF, Bai JC, Biagi F, et al. Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology. Gut 2014;63:1210–1228.
  • Husby S, Koletzko S, Korponay-Szabó I, et al. European Society Paediatric Gastroenterology, Hepatology and Nutrition Guidelines for Diagnosing Coeliac Disease 2020. J Pediatr Gastroenterol Nutr 2020;70:141–156.
  • Rubio-Tapia A, Hill ID, Kelly CP, et al. ACG Clinical Guidelines: Diagnosis and Management of Celiac Disease. Am J Gastroenterol 2013;108:656–676 (and updated 2023 ACG guideline, Am J Gastroenterol 2023;118:59–76).
  • Bonamico M, Mariani P, Thanasi E, et al. Patchy villous atrophy of the duodenum in childhood celiac disease. J Pediatr Gastroenterol Nutr 2004;38:204–207.
  • Bonamico M, Thanasi E, Mariani P, et al. Duodenal bulb biopsies in celiac disease: a multicenter study. J Pediatr Gastroenterol Nutr 2008;47:618–622.
  • Evans KE, Aziz I, Cross SS, et al. A prospective study of duodenal bulb biopsy in newly diagnosed and established adult celiac disease. Am J Gastroenterol 2011;106:1837–1842.
  • Mooney PD, Kurien M, Evans KE, et al. Clinical and immunologic features of ultra-short celiac disease. Gastroenterology 2016;150:1125–1134.
  • Lebwohl B, Kapel RC, Neugut AI, et al. Adherence to biopsy guidelines increases celiac disease diagnosis. Gastrointest Endosc 2011;74:103–109.
  • Latorre M, Lagana SM, Freedberg DE, et al. Endoscopic biopsy technique in the diagnosis of celiac disease: one bite or two? Gastrointest Endosc 2015;81:1228–1233.

Cholangiocarcinoma

https://www.aasld.org/liver-fellow-network/core-series/why-series/why-do-we-transplant-some-types-cholangiocarcinoma-and

Cholangiocarcinoma (CCA) represents a heterogeneous group of malignancies arising from the biliary epithelium. It is divided into three subtypes depending on their anatomical site of origin:

intrahepatic (iCCA),

perihilar (pCCA) and

distal (dCCA).

iCCAs arise above the second-order bile ducts, while pCCA (also called a Klatskin tumor) arise above the cystic duct with dCCA coming from below the cystic duct.

pCCA is the single largest group, accounting for approximately 50–60% of all CCAs, followed by dCCA (20–30%) and iCCA (10–20%).

In this post, we will primarily discuss pCCA and iCCA, as dCCA is treated surgically with pancreaticoduodenectomy (Whipple procedure) rather than liver transplantation.

CCA accounts for approximately 3% of all gastrointestinal cancers representing the second most common primary hepatic malignancy after hepatocellular carcinoma (HCC).

Unlike HCC, the majority of CCA cases occur in the absence of an evident chronic liver disease or other risk factor making it more difficult to catch early.

Primary risk factors are Primary Sclerosing Cholangitis (PSC), with a lifetime risk of 10%, rising to 30% in those with Inflammatory Bowel Disease (which is why we annually screen these patients with an MRI), biliary cystic disease, and less commonly hepatitis B. Outside of the United States, southeast Asian liver flukes remain a risk factor.

Intraepithelial lymphocyte cut-off for diagnosing coeliac disease: ≥20 vs ≥25 per 100 enterocytes

Summary

The IEL threshold used to flag possible coeliac disease in duodenal biopsies has fallen progressively in the literature, from 40, to 30, to 25, and more recently to 20 per 100 enterocytes. The cut-off with the strongest evidence base, and the one embedded in the major textbooks and the BSG-aligned UK practice, is ≥25/100. A cut-off of ≥20/100 is more sensitive but less specific, and is most defensible as a trigger for further workup rather than as a stand-alone diagnostic line.

The case for ≥25/100

The pivotal study is Hayat et al. (J Clin Pathol 2002), which derived an upper limit of normal of approximately 25 IELs per 100 enterocytes in well-orientated duodenal biopsies, replacing the older Marsh figure of 40. This threshold has been supported in subsequent work, including the Veress group and Mahadeva et al., and was reinforced by Walker et al. (Histopathology 2010) in the context of Marsh 1 lesions where the IEL count is the principal abnormality.

≥25/100 balances sensitivity and specificity in routine practice, is reproducible between observers when counted in well-orientated villi, and is the threshold reflected in standard texts (Shepherd & Warren; Day, Morson and Dawson’s Gastrointestinal Pathology) and in BSG guidance.

The case for ≥20/100

Subsequent work, in particular from the Finnish coeliac group (Järvinen and colleagues), has shown that counts in the 20–25 range, in patients with positive TTG, compatible HLA (DQ2/DQ8) and suggestive clinical features, are frequently associated with coeliac disease. A strict ≥25 cut-off therefore misses a clinically meaningful minority of cases, especially at the early Marsh 1 end of the spectrum.

Järvinen and colleagues also highlighted the value of counting IELs at the villous tip as an adjunctive measure (>5 IELs per 20 enterocytes at the tip), which improves sensitivity for early gluten-sensitive enteropathy independent of the global 100-enterocyte count.

Practical interpretation

  • <20/100: within normal limits.
  • 20–25/100: borderline. Correlate with serology, HLA status, drug history (NSAIDs, PPIs), H. pylori status, and clinical picture. Coeliac disease should be mentioned in the differential but not diagnosed on histology alone.
  • ≥25/100: abnormal. Raises coeliac disease and its mimics — H. pylori-associated duodenitis, NSAIDs, PPIs, SIBO, autoimmune enteropathy, common variable immunodeficiency, tropical sprue, and Giardia.

Bottom line

If a single threshold has to be picked, ≥25 IELs per 100 enterocytes is the better cut-off: it has the strongest published basis, it is the figure embedded in BSG-aligned practice and the major reference texts, and it is reasonably reproducible. ≥20 is defensible as a more sensitive trigger for further investigation, but should not be used as a stand-alone diagnostic threshold in the absence of supporting serology, HLA and clinical context.

Key references

  • Hayat M, Cairns A, Dixon MF, O’Mahony S. Quantitation of intraepithelial lymphocytes in human duodenum: what is normal? J Clin Pathol 2002;55:393–394.
  • Mahadeva S, Wyatt JI, Howdle PD. Is a raised intraepithelial lymphocyte count with normal duodenal villous architecture clinically relevant? J Clin Pathol 2002;55:424–428.
  • Walker MM, Murray JA, Ronkainen J, et al. Detection of celiac disease and lymphocytic enteropathy by parallel serology and histopathology in a population-based study. Gastroenterology 2010;139:112–119.
  • Järvinen TT, Collin P, Rasmussen M, et al. Villous tip intraepithelial lymphocytes as markers of early-stage coeliac disease. Scand J Gastroenterol 2004;39:428–433.
  • Ludvigsson JF, Bai JC, Biagi F, et al. Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology. Gut 2014;63:1210–1228.