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\begin{document}

\title{An unusual presentation of cobblestone esophagus from bisphosphonate use}



\author[1]{Tian Yu Qiu}%
\author[1]{Yi Yuan Tan}%
\author[1]{Nicholas Chin Hock Tee}%
\author[1]{Rajesh R}%
\affil[1]{Singapore General Hospital}%


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  \date{June 15, 2024}


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\textbf{Introduction}

Cobblestone esophagus is a rare finding that has been previously
described in cases of eosinophilic esophagitis (EoE), candidiasis,
barrett's esophagus or severe reflux esophagitis from distal
gastrointestinal obstruction\textsuperscript{1-4}. We describe an
unusual case of asymptomatic cobblestone esophagus secondary to
bisphosphonate use.

\textbf{Case summary}

(a) Clinical situation

A 67 years old female presented to our outpatient clinic for evaluation
of microcytic anemia that was incidentally picked up on routine chronic
disease follow-up. Her past medical history include hypertension, type 2
diabetes mellitus, hypothyroidism and osteoporosis. She was
asymptomatic; in particular she did not have any dysphagia, odynophagia
or reflux symptoms. She was started on oral alendronate 70mg once a week
a year ago when she was diagnosed with osteoporosis after a compression
fracture. Her other medications included telmisartan 80mg OM, iron
polymaltose 100mg OM, cholecalciferol capsule 2000u OM and amlodipine
7.mg OM.

(b) Course of events

She was initially only keen for non-invasive tests hence a barium meal
was performed, which showed a diffuse ``cobblestone'' appearance but no
stricture or significant gastro-esophageal reflux. She subsequently
agreed for oesophago-gastro-duodenoscopy (OGD), which showed diffused
white nodular lesions along esophagus starting from oropharynx with
cobblestone appearance, but no ulcer or mass noted. (Fig. 1) Segmental
esophageal biopsies were negative for fungal stain and did not show any
pathology. In the absence of infection, eosinophilic esophagitis and
dysplasia, her ``Cobblestone'' esophagus was attributed to bisphosphate
use, hence alendronate acid was held off.

(c) Clinical resolution

She underwent serial barium meal over the next 1 year with significant
interval improvement. (Fig. 2)

\textbf{Discussion}

Cobblestone esophagus is an uncommon finding on endoscopy that has been
associated with conditions like EoE and candidiasis but these causes
were excluded in our patient during endoscopy and biopsy. By diagnosis
of exclusion, alendronate acid use was deemed the most likely cause of
this patient's cobblestone esophagus although there is no similar case
reported before in literature.

Bisphosphonates, such as alendronate acid, are commonly associated with
drug induced esophagitis\textsuperscript{5} and can cause esophageal
irritation by breaching the protective hydrophobic mucosal
lining\textsuperscript{6-7}. The cobblestone pattern observed during
barium meal and endoscopy is a result of inflammation and edema of the
lamina propria and submucosal layers overtime\textsuperscript{8}. The
mainstay of treatment for drug induced esophagitis is cessation of the
offending medication\textsuperscript{9}. There was indeed significant
interval improvement in serial barium meal in our patient upon cessation
of alendronate acid. This underscores the importance of reviewing
medication list when encountering patients exhibiting cobblestone
esophagus, in addition to ruling out the known underlying causes
mentioned earlier.

The clinical challenge of this case lies in its atypical asymptomatic
presentation of drug induced esophagitis. Patients with drug induced
esophagitis frequently complain of symptoms such as retrosternal chest
pain which happens in about 70\% of the patients, as well as odynophagia
and dysphagia\textsuperscript{9}. In our patient, it was first picked up
incidentally on barium meal as part of anemia workup before confirming
it with endoscopy. With this in mind, it is important to counsel our
patients on the correct administration of
bisphosphonate\textsuperscript{10} so as to minimize upper
gastrointestinal adverse effect that may initially be asymptomatic and
delay timely action before long term side effects are made.

\textbf{Conclusion}

The finding of cobblestone esophagus should prompt physician to
investigate for an underlying etiology. In addition to performing
endoscopy and biopsies to exclude common etiologies, this case shows us
the importance of taking a comprehensive drug history. Patients with
drug induced esophagitis may be asymptomatic initially. It is an easily
reversible etiology that should be routinely considered for prompt
intervention against irreversible damage to the upper gastrointestinal
tract.



\textbf{References}

1. Lazowska-Przeorek I, Kakol D, Karolewska-Bochenek K, Banaszkiewicz A.
``Cobblestone'' Appearance of Esophagus: An Unusual Symptom of Pyloric
Stenosis. Journal of Pediatric Gastroenterology and Nutrition.
2017;65(5):e110.

2. Zimmer V, Emrich K. Cobblestone esophagus in eosinophilic
esophagitis. Advances in Digestive Medicine. 2023;10(1):58-9.

3. Jang KM, Lee KS, Lee SJ, Kim EA, Kim TS, Han D, Shim YM. The spectrum
of benign esophageal lesions: imaging findings. Korean J Radiol.
2002;3(3):199-210.

4. Yang GD, Lu PX, Qin J, Liu ST, Zhan NY. Radiologic diagnosis for AIDS
patients complicated with candidal esophagitis. Chin Med J (Engl).
2011;124(7):965-7.

5. De Groen PC, Lubbe DF, Hirsch LJ, Daifotis A, Stephenson W, Freedholm
D, et al. Esophagitis Associated with the Use of Alendronate. New
England Journal of Medicine. 1996;335(14):1016-21.

6. Yamamoto K, Kishino M, Nakamura S, Tokushige K. Symptoms and Upper
Gastrointestinal Mucosal Injury Associated with Bisphosphonate Therapy.
Intern Med. 2019;58(8):1049-56.

7. Abdi S, Masbough F, Nazari M, Abbasinazari M. Drug-induced
esophagitis and helpful management for healthcare providers.
Gastroenterol Hepatol Bed Bench. 2022;15(3):219-24.

8. Goldberg HI, Dodds WJ. Cobblestone esophagus due to Monilial
infection. Am J Roentgenol Radium Ther Nucl Med. 1968;104(3):608-12.

9. Kim SH, Jeong JB, Kim JW, Koh SJ, Kim BG, Lee KL, et al. Clinical and
endoscopic characteristics of drug-induced esophagitis. World J
Gastroenterol. 2014;20(31):10994-9.

10. Cryer B, Bauer DC, editors. Oral bisphosphonates and upper
gastrointestinal tract problems: what is the evidence? Mayo Clinic
Proceedings; 2002: Elsevier.\selectlanguage{english}
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