Pathophysiology

The causes of MC have not been clearly defined, and it is considered a multifactorial disease. Immune response, genetic susceptibility, and changes in epithelial barrier function have been implicated. These alterations promote increased mucosal permeability to antigens and bacteria. They facilitate inflammatory processes in the lamina propria, associated with the severity of symptoms, especially diarrhea, due to a decrease in sodium chloride absorption and active chloride secretion⁴.

Some studies have linked MC to bile acid malabsorption (BAM). A Spanish study found that BAM was present in 43% of patients with MC, more commonly in LC (60%) than in CC (27%). Although cholestyramine treatment was met in 86% of patients, other studies have not demonstrated the same effect¹² Furthermore, MC has been linked to the human leukocyte antigen (HLA)-DQ2, which is associated with other autoimmune diseases and alterations of the fecal microbiota (depletion of the bacterium Akkermansia muciniphila)¹⁰.

Risk Factors

In a systematic review and meta-analysis evaluating cigarette smoking as a risk factor, most studies found that smoking is a predisposing factor. Overall, patients who smoke are 3 times more likely to develop MC than non-smokers¹³.

There are hypotheses involving the change of the gut microbiota in smoking patients, which leads to a dysbiosis that alters the epithelial barrier in the mucosa, contributing to the onset of diarrhea. Other factors such as alcohol intake and dietary factors have been mentioned¹³.

Autoimmune disorders such as rheumatoid arthritis, thyroiditis, and celiac disease have been linked to the onset of MC. Furthermore, female hormonal factors and the consumption of medications such as nonsteroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), selective serotonin reuptake inhibitors, and low doses of aspirin have also been linked to MC onset¹⁴.

Patient-related risk factors were not established because this is not the objective of this study and because of incomplete records of medical histories.

Diagnosis

Many clinical guidelines focus on the treatment of diarrhea. Although, the guidance regarding the diagnostic approach is generally poor. Therefore, it can lead to the improper use of diagnostic tests, causing loss of time, unnecessary expenses, discomfort in the patient, and inaccurate results. Unfortunately, MC remains largely unknown and is overlooked by front-line physicians, including some specialists, when treating patients with chronic diarrhea.

Microscopic Colitis displays a spectrum of symptoms ranging from mild, self-limiting episodes of diarrhea to debilitating and severe abdominal pain episodes, joint pain, fatigue, and weight loss. However, in no case has it been shown to have a mortality risk, nor has it been associated with the development of colorectal cancer. It significantly affects patients’ quality of life, with an impact comparable to that of ulcerative colitis¹⁵.

Through medical history, diseases with similar symptoms such as IBD, celiac disease, and IBS-D can be ruled out. Laboratory tests, including hemograms, are usually standard, as in the case of all our patients, and similar to radiological studies, can help rule out other diseases. Non-specific changes such as elevation of C-reactive protein (CRP) and anemia can be found. Fecal calprotectin and lactoferrin have low diagnostic accuracy. Sometimes subtle mucosal changes such as edema and altered vascular pattern may be observed, but colonoscopy is usually regular, which is the case in most of our patients¹⁶. Our setting recommends colonoscopy with biopsies for all chronic diarrhea patients.

A systematic review and meta-analysis evaluating 10 studies with more than 3900 cases found a combined prevalence of IBS-D symptoms in 33.4% of people with MC. Diagnosis should be based on the patient’s clinical characteristics and confirmed by histology of step biopsies of the colon, minimum of 2 in each segment¹⁷. The number of segments and biopsies taken in our institution depends on each gastroenterologist’s criteria and the procedure’s findings. Samples of 3 segments (right, transverse, and left) are usually routinely taken.

Chronic inflammation of the lamina propria is observed in LC due to a proliferation of plasma cells, a decrease in the number of goblet cells, and the infiltration of more than 20 lymphocytes per 100 epithelial cells. In CC, the collagen layer thickens, which exceeds the standard upper limit of 7 μm. However, some authors consider thickening > 10 μm as diagnostic. In addition to these 2 histological subtypes, there is MCi, which corresponds to the presence of clinical symptoms suggestive of the disease, with histological findings that do not meet the criteria above. In these cases, the number of lymphocytes and plasma cells is < 10/100 epithelial cells, and the subepithelial collagen is < 10 μm. These findings suggest that the 2 classic forms of MC may not correspond to 2 different diseases but 2 different stages in developing the same disease^5,10. The above described corresponds to the diagnostic criteria used in the pathology department of our hospital.

So far, no specific biomarker has been found to assess disease activity. Indicators have been proposed that include the number of loose or liquid stools per day, nocturnal stools, abdominal pain, weight loss, and fecal urgency or incontinence. There is a direct correlation with MC and an indirect correlation with IBD. A study of 116 patients with CC found that patients had 3 or more stools per day, or one or more watery-looking stools, representing a negative effect on the patients’ life quality¹⁸.

Treatment

One of the fundamental pillars is eliminating all MC risk factors such as smoking, caffeine, dairy, and alcohol intake. Also, medications are recommended, especially aspirin, NSAIDs, lansoprazole, omeprazole, ranitidine, sertraline, and ticlopidine. Celiac disease and bile acid malabsorption (BAM), which may coexist with MC, should be ruled out¹⁹.

Budesonide has been recommended as the medicine of choice in the treatment of MC for more than a decade. Medications such as prednisolone, mesalazine, and bismuth subsalicylate are second-line agents. Several randomized studies agree on the efficacy of budesonide in inducing remission in CC and CL. Meta-analyses have confirmed its effectiveness in controlling active MC, showing improvement before 2 weeks, given the absence of diarrhea. Therefore, the treatment of MC ²⁰⁾ has been recommended with this drug, the one our patients take. Responsiveness and monitoring were not analyzed as this was not the study’s objective.

Twenty-eight patients were randomized in a double-blind placebo-controlled food challenge (DBPCFC) study evaluating the effectiveness of budesonide in patients with CC. Half of them received a placebo, and half received 3 capsules of 3 mg Budenofalk^® (9 mg/day) for 8 weeks. A satisfactory response (50% decrease in stool quantity at week 8) was observed in 8 of 14 patients treated with budesonide compared to 3 of 14 placebo responders (p = 0.05). Histological follow-up was performed by comparing biopsies at weeks 0 and 8, with no changes in mean collagen band thickness but a significant decrease in lamina propria infiltration (p < 0.001). It was concluded that budesonide effectively induces a short-term clinical response in CC²¹.

To compare the efficacy of budesonide and mesalazine in CC, a multicenter phase 3 study was conducted in 31 European centers, in which 92 patients were randomized into 3 groups (Budenofalk®, Salofalk®, or placebo) and a histological and clinical improvement (better stool consistency and improvement of abdominal pain) was observed in 80% of patients receiving budesonide, compared to 44% of patients receiving mesalazine (p = 0.0035)²².

Currently, budesonide is recommended by the American Gastroenterological Association (AGA) as first-line therapy. Other studies have also demonstrated effectiveness in LC and maintenance of clinical remission with budesonide at doses of 4.5 mg for 12 months^23-26.

Azathioprine, 6-mercaptopurine (6-MP), and some biologics (anti-tumor necrosis factor alpha [anti-TNF-α]) have been used in microscopic colitis, especially in patients with refractory symptoms or steroid dependence. Loperamide at 2-16 mg/day helps control symptoms¹⁹.

Corticosteroids are only recommended in patients refractory to budesonide treatment when budesonide is unavailable, and other etiologies such as celiac disease have been ruled out²⁶.

There is no consensus as to the criteria for referral. Each treatment must be individualized, determining to what point to extend it. Short-term treatment should be 6 to 8 weeks and continue for up to 12 months to avoid relapses²⁷.

Surgical treatment should be the last alternative and reserved only for patients who do not respond to medications. Small series have been reported in which subtotal colectomy, Ileoanal anastomosis, or ileal pouch-anal anastomosis (IPAA) have been performed²⁸.

As a possible bias, we should consider that it was impossible to view the total number of patients with chronic diarrhea assessed in the various consultations performed on patients at our institution. Furthermore, given that this was a retrospective study, it was impossible to evaluate the presence of associated risk factors explaining the high figures found.