Journal of Clinical and Diagnostic Research, ISSN - 0973 - 709X

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Dr. Mamta Gupta,
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Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
On May 11,2011

Dr. Shankar P.R.

"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
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Overall, the publishing process with JCDR has been smooth, quick and relatively hassle free and I can recommend other authors to consider the journal as an outlet for their work."

Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
On April 2011

Dear team JCDR, I would like to thank you for the very professional and polite service provided by everyone at JCDR. While i have been in the field of writing and editing for sometime, this has been my first attempt in publishing a scientific paper.Thank you for hand-holding me through the process.

Dr. Anuradha
On Jan 2020

Important Notice

Original article / research
Year : 2022 | Month : June | Volume : 16 | Issue : 6 | Page : EC01 - EC05 Full Version

Clinico-pathological Evaluation of Chronic Diarrhea with Microscopic Colitis: A Cross-sectional Study

Published: June 1, 2022 | DOI:
Girija, CS Sheeladevi, HV Aradhya

1. Resident, Department of Pathology, Gadag Institute of Medical Sciences, Gadag, Karnataka, India. 2. Professor, Department of Pathology, JSS, Mysuru, Karnataka, India. 3. Associate professor, Department of Gastroenterology, JSS, Mysuru, Karnataka, India.

Correspondence Address :
Dr. CS Sheeladevi,
House No-367, Adarsha, 6th Cross, Kamakshi Hospital Road, Kuvempunagar, Mysuru, Karnataka, India.
E-mail :


Introduction: Chronic diarrhea is common in the older population accounting for 7-9 % which often markedly affects their quality of life. The causes are many and include infectious, endocrine, metabolic, neoplastic, functional, drugs. Microscopic Colitis (MC) has emerged as a distinct diagnostic entity, where the colon appears endoscopically normal, but the biopsy reveals characteristic features in the mucosa. It has two histological forms i.e, Collagenous Colitis (CC) and Lymphocytic Colitis (LC).

Aim: To study the clinico-pathological spectrum of lesions in random colonic biopsies of patients with chronic diarrhea having normal colonoscopy.

Materials and Methods: This cross-sectional study was conducted in Department of Pathology at JSS Hospital, Mysuru, Karnataka, India, from October 2017 to September 2019. Multiple random biopsies were taken from 80 patients with chronic diarrhea who had normal colonoscopy. The slides were stained with Hematoxylin and Eosin (H&E) and Masson’s Trichrome Stain (MTS). The histological features were studied under light microscopy and using computer-assisted image analysis. The Chi-square test was used to statistically analyse the data.

Results: The age of patients ranged from 11-82 years with a mean age of 43 years. Out of total 80 patients, 65 (81.25%) of the cases had non specific inflammation, 14 (17.4%) had microscopic colitis and one patient (1.25%) had probable eosinophilic colitis. The histological features were observed in computer-assisted image analysis using morphometry and interpreted by two pathologists with agreement.

Conclusion: Random biopsies are required for the diagnosis of microscopic colitis in the absence of macroscopic abnormalities on colonoscopy, which may affect the treatment strategy. A histologic examination combined with histochemical stain MTS and interpretation utilising computerized image analysis program with morphometry is more effective in cases with diagnostic uncertainty.


Biopsy, Colonoscopy, Image analysis, Intestinal mucosa

Chronic diarrhoea is the persistent alteration from the norm of stool consistency and increased frequency with ≥3 loose stools per day for greater than 4 week’s duration (1). Microscopic Colitis (MC) is one of the common causes of persistent diarrhoea and is divided into two subtypes i.e, Collagenous Colitis (CC) and Lymphocytic Colitis (LC). It is a triad of persistent watery non bloody diarrhoea, a normal/near normal endoscopy and distinctive tissue morphology (2),(3),(4).

When it was first described in 1980, it was thought to be a rare condition. Over the last two decades, the number of patients diagnosed with MC has shown an increasing trend (5).

The incidence and prevalence of MC in developed countries accounts for 4-13% of cases of chronic diarrhea. In developing countries prevalence ranges from 15 to 50% (6). However, physicians, especially those in primary care, are not as much aware of MC as a cause of chronic diarrhea. It is important to create awareness among general practitioners, surgeons, and pathologists, as MC is a frequent disease and should always be considered in patients with chronic diarrhoea (7).

Though several biomarkers exist for the diagnosis of MC, there is currently no reliable marker, and Histopathological Examination (HPE) of multiple biopsies remains the cornerstone in the diagnosis of MC (5),(6). The histological identification of each lesion will help in appropriate specific treatment (6). The histological features can be subjective. Besides the histochemical stains, the use of image analysis and morphometry may be more objective in the assessment of histological features.

Hence, objective of this study was to use a computer-assisted image analysis tool to describe the histological features in random colonic biopsies of individuals with persistent diarrhea who had a normal colonoscopy.

Material and Methods

This was a hospital-based cross-sectional study conducted in Department of Pathology at JSS, Mysuru, Karnataka, India, from October 2017 to September 2019. Institutional Ethical Committee clearance was obtained before the commencement of the study (Ethical clearance no.-JSSMC/PG/4700/2017-18).

Inclusion criteria: Biopsies of the patients who came with the history of chronic watery diarrhea of minimum three times a day lasting for more than 4 weeks but having normal colonoscopy were included in the study.

Exclusion criteria: The patients who were passing blood and mucus in stools, known case of inflammatory bowel disease, intestinal tuberculosis, bacterial overgrowth, and visible lesions on endoscopy including ulcers, growths, and inadequate biopsy were excluded from the study. The biopsies were considered inadequate when the entire thickness of mucosa was not represented in the biopsy.

Sample size calculation: Based on the number of patients who presented with chronic diarrhea to the gastroenterology clinic, the sample size of 73 was calculated using the following formula (8):

N= Z2pq/d2
Z= 1.96 (constant);
d=margin of error;
p=proportion of prevalence
N=1.96x1.96x0.05x0.95/ 0.05x0.05.


Patients who came to Gastroenterology Department with history of chronic diarrhea were evaluated clinically. The clinical details such as duration of diarrhea, other gastrointestinal symptoms such as abdominal pain, weight loss and nausea were noted. History of smoking and alcohol intake, presence of co-morbidities like hypertension, diabetes, hypothyroidism, hyperthyroidism and autoimmune diseases were documented. The laboratory data including complete blood counts, stool microscopy, thyroid, liver and renal function tests were documented if available.

Stool Microscopy: The numbers of leucocytes present were counted and expressed as the average numbers under the following categories: 0, 1-10, 11-20, 21-50 and >50 per High Power Field (HPF). The inflammation was graded arbitrarily based on the number of inflammatory cells (9) as:

• Occasional (1-4/hpf)
• Mild (5-20/hpf)
• Moderate (>20-50/hpf)
• Severe (>50/hpf)

The biopsy slides were observed for the presence of intraepithelial lymphocytes, type of inflammatory cells in lamina propria, presence of lymphoid follicles, number of eosinophils, severity of inflammation and thickness of subepithelial collagen. The severity of inflammation was categorised arbitrarily as mild when there was unequivocal increase, and severe when there was marked increase in chronic inflammatory cells (10).

Total 41 out of 80 patients underwent stool examination. Some of the patients denied, while others wanted to get it done during follow-up. Among them, some were lost for follow-up while others were free of symptoms.

All the patients were subjected to colonoscopy as a part of evaluation for chronic diarrhea after ruling out other common causes enumerated above. Random biopsies were taken from ascending colon, descending colon, sigmoid colon, rectum and ileum from those patients who had normal colonoscopic findings. The biopsy tissue was immediately placed in separate vials with 10% formalin, processed conventionally in paraffin blocks and cut into 5 micron thick sections. The slides were stained with Hematoxylin and Eosin (H&E) and Masson’s Trichrome stain (MTS).

Criteria for the Diagnosis of Microscopic Colitis are (4),(8)

Lymphocytic colitis: Mild to moderate increase in mononuclear inflammation in lamina propria, >20 Intraepithelial Lymphocytes (IEL)/100 epithelial cells, normal/slightly increased subepithelial collagen, damage to surface epithelium.

Collagenous colitis: Mild to moderate increase in mononuclear inflammation in lamina propria, subepithelial collagen >10 μ, normal/slightly increased intraepithelial lymphocytes but < than 20 IEL/100 epithelial cells, flattening and detachment of epithelial layer (4),(8).

Nonspecific inflammation: This is characterised by an increase in inflammatory cells beyond what would be expected physiologically in the corresponding anatomical sites. Predominantly chronic cellular infiltrate is seen, without architectural distortion and multiple basal lymphoid aggregates or plasma cells are present immediately above the muscularis mucosae. Lack of pathological feature of other types of inflammation of colon precludes nonspecific type of colitis (11).

Eosinophilic colitis: This is characterised by >30 eosinophils/hpf in the lamina propria. Other histological findings are eosinophil microabscesses, eosinophilic cryptitis, and eosinophils within the surface epithelial compartment (12).

Evaluation of subepithelial collagen by morphometry on both H&E and MT stains was done in all the cases. The Olympus BX41 research microscope with Jenoptix (Germany) progress Charged-Coupled Device (CCD) camera and progress capture proimaging software was used for morphometric analysis. The digital images were captured with 1X C mount CCD adapter. After transferring the microscopic images to the computer, thickness of collagen was measured by image analysis program using free style line. Histological features were analysed in light microscopy as well as in computer assisted image analysis program by two pathologists with agreement and the findings were documented. The thickness of collagen >10 μ was considered as collagenous colitis. The Subepithelial Collagen (SEC) was measured on H&E and MTS by morphometry.

Statistical Analysis

It is a descriptive study and the following descriptive statistics were employed including, mean, standard deviation, frequency and percent. Chi-square test was used to tabulate variables into categories. The statistical software namely Statistical Package for Social Sciences (SPSS) version 16.0 and Minitab (11.0) was used for the analysis of the data.


The age of patients ranged from 11 to 82 years, with a mean of 43±19.23 years There was a slight male preponderance with male:female ratio of 3:2. Along with chronic diarrhea, 45 patients presented with other symptoms like pain abdomen, loss of weight and nausea which were present either alone or in combination. Total 46 patients had co-morbidities including hypertension, type 2 diabetes mellitus, hypothyroidism and ischaemic heart disease. One patient each had chronic kidney disease, schizophrenia, bronchial asthma and post renal transplant. History of smoking and alcohol consumption was present in one case of lymphocytic colitis.

Total 65 cases revealed nonspecific inflammation of varying severity. Ileal biopsies were done in 45 cases, and majority showed mild to moderate inflammation. Out of 80, 41 patients underwent stool examination. It was mild in 14 patients (34.2%), moderate in 6 (14.6%), severe in 3 (7.3%) patients and occasional inflammatory cells in one patient.

One case of collagenous colitis showed a moderate increase in inflammatory cells. Five cases of CC showed mild increase in inflammatory cells. None of the samples revealed micro-organisms. Liver Function Tests (LFT) and Renal Function Tests (RFT) were done in 46 patients as a part of evaluation since they had co-morbidities. They were within normal limits in 43 (93%) patients. Two patients showed deranged RFT, while one patient showed deranged LFT (Table/Fig 1).

Histological features were observed and analysed in light microscopy. The mucosal lining epithelium was normal in 76 cases (93.8%). There was an increase in inflammatory cell infiltrate in the lamina propria in all the cases and was comprised of lymphocytes, eosinophils, plasma cells, and neutrophils in varying proportions. The other features observed were congestion and edema, which was seen in 5 (6.25%) cases. The crypt architecture was normal in majority (n=67) of the patients. Cryptitis/crypt abscess were observed in 13 cases. Majority of the cases (47) had mild inflammation in the lamina propria, which included seven cases of collagenous colitis, two cases of lymphocytic colitis and 38 cases of non-specific inflammation (Table/Fig 2). The average normal subepithelial collagen thickness was 5.4 μ (Table/Fig 3).

Active inflammation was noted in 13 (16.5%) cases. The number of eosinophils was counted per high power field in lamina propria. Scattered eosinophils were present in all the cases with 15 to 25 per hpf in 8 cases. An increase in intraepithelial lymphocytes was seen in four cases and was diagnosed as lymphocytic colitis (Table/Fig 4). The subepithelial collagen thickness was patchy to diffuse and was measured by morphometry on both H&E and MT stained slides. An increase in subepithelial collagen of more than 10 μ was seen in 16 cases on H&E stain. It was confirmed by MT stain in 10 cases. The SEC thickness was in the range of 10-15μ and more than 15μ in five cases each which led to a diagnosis of collagenous colitis in 10 patients (Table/Fig 5), (Table/Fig 6), (Table/Fig 7). The extravasated plasma and edema in the lamina propria were falsely interpreted on H&E stain, and MT stain was used for confirmation.

A single case showed more than 30 eosinophils per hpf and was diagnosed as probable eosinophilic colitis (Table/Fig 8). The patient was on thyroxine for hypothyroidism and had presented with skin rashes and chronic watery diarrhea. She also took Non Steroidal Anti-inflammatory Drugs (NSAID’s). Her peripheral blood and bone marrow showed eosinophilia. The antinuclear antibodies, including perinuclear- antineutrophilic cytoplasmic antibodies (pANCA) and c- ANCA (cytoplasmic) were not detected. The stool microscopy did not reveal any parasites. The other laboratory parameters including LFT and RFT were within normal limits. She was treated with steroids and her symptoms subsided. She was on follow-up since 1 year with minimal dose steroids and she was asymptomatic with normal blood counts. However, revised colonoscopy was not done.


The diseases associated with diarrhea are more common in elderly population and the causes are many including infectious, endocrine, metabolic, neoplastic, functional, drugs etc (2),(3). Read and colleagues coined the term “microscopic colitis” in 1980, for patients who had chronic watery diarrhea, with normal sigmoidoscopy and barium enema findings but with mucosal inflammation in their colonic biopsy specimens. Currently, “microscopic colitis” is a clinical term that refers to either collagenous or lymphocytic colitis (13).

In patients with normal colonoscopy, obtaining random colonic biopsies routinely to exclude microscopic colitis, is open to debate (14). The prevalence of MC is 4-13% in developed countries, while it is high in developing countries varying from 25-50%. The high prevalence of infectious gastroenteritis in the developing countries suggests an infectious etiology by isolation of organisms such as Clostridium jejuni, Y. enterocolitica, and Clostridium difficile in some patients and has been hypothesized that it precipitates MC by an autoimmune reaction (13). However, no organisms were isolated in the present study.

The mean age of patients with chronic diarrhea was 43 years, which is in concordance with various studies (6),(15). The age ranges from 19 to 98 years and even children may be affected rarely (16). Women are more commonly affected with Female-to-Male (F:M) ratio ranging from 3:1 to 9:1 in CC and 2.4:1 to 2.7:1 in LC (8),(17). The significance of association with gender may be undermined by the small sample size.

The patients with MC had symptoms of pain abdomen, weight loss and nausea, besides chronic watery, non bloody diarrhea. Temmerman F and Baert F, documented pain abdomen and weight loss in many of their patients accounting to 41% and 42% respectively (18). The seasonal variation in symptoms is also reported (19).

The association of smoking with collagenous colitis has been reported with and without statistical significance in many studies (8),(20). Vigren L et al., in their study of 116 CC patients found 37% to be smokers. It has become apparent that smoking has a negative impact in CC and it is hypothesized that smoking alters epigenetic events like methylation and histone modification of the genome (21). Only one case of LC had history of smoking which was statistically not significant.

Microscopic colitis is reported to be associated with various autoimmune diseases like rheumatoid arthritis, diabetes mellitus, psoriasis, celiac disease, autoimmune thyroiditis, antiphospholipid syndrome, with presence of antinuclear antibodies (13),(18),(21). Macaigne G et al., found autoimmune disease, particularly dysthyroidia to be a strong predictive factor for MC (22). Various studies have reported thyroid disease in 8.6 to 21% MC (22),(23). In the present study, MC was associated with co-morbidities with no statistical significance.

Because of their association with a variety of autoimmune conditions, researchers have focused their attention towards investigating HLA haplotypes and serum markers in MC (13).

Autoimmune markers may be positive, including antinuclear antibodies, pANCA (antineutrophilic cytoplasmic antibodies), rheumatoid factor, and complement C3 and C4 (17). These tests were not performed in our patients, which is a limitation. Authors found MT stain with morphometry to be very useful and objective in the interpretation of SEC thickness. The other features were moderate mononuclear inflammation in the lamina propria, flattening and detachment of epithelium. Though some authors describe the presence of IEL, others are of the opinion that it is not required for the diagnosis of CC (3),(4),(8).

The consistent expression of tenascin (an extracellular matrix protein) by IHC is an excellent aid in the diagnosis of CC (18). However, it was not done in the present study. The increased collagen is attributed to disturbances in the function of subepithelial myofibroblasts which synthesize tenascin (13). The automated image analysis of tissue sections minimizes the pathologists’ interobserver variation, as emphasized by Engel PJ et al., (4).

The biopsies are recommended from cecum and transverse colon as the thickest collagen layer is observed in these anatomical regions. There was no considerable difference in the SEC thickness at different sites of colon and rectum in the present study. The computer assisted images were analysed for IEL’s in LC and there was an agreement among two pathologists. The IHC for the identification of T-lymphocytes with CD3 may be done in cases of diagnostic uncertainty. Sonnenberg A et al observed 14% of their patients with MC to have a second lymphocytic disorder of the gastrointestinal tract, and therefore any lymphocytic disorder in the lower gastrointestinal tract should raise the suspicion for a upper gastrointestinal tract related disorder and vice-versa. In the present study, the patients were anti-Tissue Transglutaminase (TTG) negative with no gluten sensitivity and hence were not subjected for upper gastrointestinal biopsy (24). The study of rectum and sigmoid colon would provide a diagnosis in 99.5% of the patients (25).

The other histological features described in literature include, cryptitis, crypt abscesses, paneth cell metaplasia, crypt architectural distortion, surface ulceration and pseudomembranes (13). Some of the commonly used drugs like aspirin, NSAIDS, antibiotics, ranitidine, proton pump inhibitors, β-adrenergic receptor blockers and statins are known to cause MC. There was no such association in the present study (6),(13),(26).

Studies from Peru and Tunis, with high prevalence of infectious gastroenteritis, revealed MC in 40% and 29.3% of cases respectively (6). The prevalence of LC was more frequent than CC in some studies (27),(28).

The patients in the present study were treated with loperamide as a first-line therapy and with budesonide for non responders. Most of the patients responded to medications. But they were lost for follow-up and hence the data regarding management is limited. Williams JJ et al., have reported remission in 85% of LC and 91% of CC patients, when treatment is continued over 6 months (3).

A single case with marked mucosal eosinophilia was diagnosed as probable eosiniophilic colitis, which was attributed to NSAIDs. Eosinophilic Colitis (EC) is a rare entity and there is no consensus over its diagnosis and management. Bates A suggests to report the mean eosinophil counts per high-power field, if it is conspicuous, and not to use the term “eosinophilic colitis” (29). The comparison of present study with similar studies is given in (Table/Fig 9) (8),(25),(30),(31).


The CD3 T-cells, tenascin and other biomarkers were not evaluated and also the study was limited by small sample size and the lack of follow-up data in some patients.


Chronic diarrhea is one of the common symptoms for consulting a Gastroenterologist. In the context of wide range of conditions that can result in chronic diarrhoea, a pragmatic approach is necessary in the evaluation of these patients and should include colonoscopy. In the absence of macroscopic findings on colonoscopy, random biopsies from normal appearing colon is essential for the diagnosis of microscopic colitis, which may have an impact on the treatment strategy. Histologic examination still remains a valuable tool in diagnosis of patients with suspected MC. Additional histochemical stains and interpretation using computerized image analysis program with morphometry are more objective and effective in cases with diagnostic uncertainty.


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DOI and Others

DOI: 10.7860/JCDR/2022/52798.16445

Date of Submission: Oct 13, 2021
Date of Peer Review: Dec 14, 2021
Date of Acceptance: Mar 31, 2022
Date of Publishing: Jun 01, 2022

• Financial or Other Competing Interests: None
• Was Ethics Committee Approval obtained for this study? Yes
• Was informed consent obtained from the subjects involved in the study? Yes
• For any images presented appropriate consent has been obtained from the subjects. No

• Plagiarism X-checker: Oct 14, 2021
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