Microscopic colitis

Collagenous and

lymphocytic colitis

The informed patient

6th updated and

revised edition 2020

Publisher

2020 Dr. Falk Pharma GmbH

Prof. Dr. Andreas Tromm, Hattingen (Germany)

The informed patient

Microscopic colitis

Collagenous and

lymphocytic colitis

Microscopic colitis – Collagenous and lymphocytic colitis

Address of the author

Prof. Dr. Andreas Tromm

Klinik für Innere Medizin

Augusta-Kranken-Anstalt gGmbH

Betriebsstelle EVK Hattingen

Akademisches Lehrkrankenhaus

der Universität Duisburg-Essen

Bredenscheider Str. 54

45525 Hattingen

Germany

www.klinik-gastroenterologie.de

Introduction 4

Clinical presentation 6

Causes and development of

microscopic colitis 9

Diagnosis 11

Treatment 14

Frequently asked questions

about microscopic colitis 17

Contents

Microscopic colitis – Collagenous and lymphocytic colitis

Introduction

The term microscopic colitis encompasses two different

disorders of the colon known as collagenous colitis and

lymphocytic colitis.

Both disorders are characterized by non-bloody watery

diarrhea and are sometimes referred to as watery diar-

rhea syndromes (Fig. 1).

Microscopic

colitis

Watery diarrhea

syndrome

Fig. 1: Deﬁnition of microscopic colitis.

Collagenous colitis Lymphocytic colitis

The term microscopic colitis describes a chronic in-

ﬂammatory disease of the colon (“colitis” comes from

the Latin term “colon” and the ending “-itis”, which is

used in medicine to refer to inﬂammation) that a doctor

cannot identify by colonoscopy with the naked eye

because the mucosa of the colon appears normal. In

order for the disease to be diagnosed, the doctor must

therefore remove a small tissue sample and examine

it under a microscope. This is the only way to diagnose

microscopic colitis.

For collagenous colitis, a thickened collagen layer

becomes visible when the tissue samples are stained

using special methods, whereas lymphocytic colitis

is detected as an increased number of a speciﬁc type

of white blood cells called lymphocytes (see page 12).

Our understanding of microscopic colitis has expand-

ed greatly since it was ﬁrst described in the 1970s.

Because the disease is so difﬁcult to diagnose, it is not

well known, even though it is thought to occur about

as often as the inﬂammatory bowel diseases of Crohn’s

disease and ulcerative colitis. The number of undiag-

nosed cases is likely high.

The standard of care is budesonide (taken orally as

capsules or granules), a locally-acting corticosteroid

drug that inhibits inﬂammation in the gut. Depending

on the form of microscopic colitis, budesonide can

be used to treat the symptoms of acute disease or in

case of chronic disease it can also be used to prevent

the recurrence of diarrhea.

Introduction

Microscopic colitis – Collagenous and lymphocytic colitis

Clinical presentation

Microscopic colitis primarily affects older women.

The deﬁning symptom of microscopic colitis is watery

diarrhea, which can occur suddenly and may mimic

an infection. A large study in Sweden also reported

the following symptoms:

• In almost 30% of patients: nocturnal diarrhea

• In over 40% of patients: weight loss

• In over 40% of patients: abdominal pain

• In over 20% of patients: nausea

• In over 10% of patients: ﬂatulence

Although the precise

cause of weight loss

remains unclear, it appears

likely that patients eat

fewer calories due to

well-intentioned dietary

restrictions which cause

them to lose weight.

Patients rarely have issues

with dehydration despite

the frequent diarrhea.

Fecal incontinence and fatigue are

other symptoms that occur with microscopic colitis

and greatly impair patients’ quality of life.

30–50% of patients with microscopic colitis may also

experience symptoms or conditions in other organs

outside of the gut, for example rheumatoid arthritis

of the joints, psoriasis of the skin, or even thyroid gland

dysfunction (Fig. 2). These issues require additional

treatment.

Fig. 2: Conditions that may accompany microscopic colitis.

Clinical presentation

Mucosal dryness

Thyroid dysfunction

Psoriasis

Perfusion

disorders

Celiac disease

Joint pain

Microscopic colitis – Collagenous and lymphocytic colitis

Several studies have shown that patients with micro-

scopic colitis also frequently have celiac disease

(or gluten intolerance) and vice versa.

Therefore, patients should be checked for both condi-

tions. A recent study reported that 12.9% of patients

with collagenous colitis also have celiac disease.

Microscopic colitis generally has a benign outcome,

although about 40% of patients complain of chronic

(meaning permanent or continuously recurring) watery

diarrhea. However, this diarrhea does not increase the

risk of developing colorectal cancer.

In order to diagnose the condition, doctors must rule

out the possibility of other conditions with similar symp-

toms: Typical gut disorders associated with diarrhea but

not with weight loss include irritable bowel syndrome

(diarrhea-type) and intolerance to several different types

of foods, such as the very common lactose intolerance.

Microscopic colitis can usually be clearly distinguished

from Crohn’s disease and ulcerative colitis (together

known as inﬂammatory bowel disease), since a colo-

noscopy reveals a typical pattern of intestinal mucosa

pathology with ulcers in inﬂammatory bowel disease.

When inﬂammatory bowel disease spreads to the

colon, as is often the case, diarrhea is usually bloody.

Causes and development

of microscopic colitis

Although the exact causes of microscopic colitis remain

unknown, several theories have been proposed.

Several studies have proposed that microscopic colitis

may be caused by the increased use of certain medi-

cations, typically those used to manage joint pain.

These include drugs called “non-steroidal anti-inﬂam-

matory drugs” as well as drugs used to treat high

cholesterol levels or to stop blood clotting.

Case reports have suggested that proton-pump in-

hibitors may play a role in the development of micro-

scopic colitis, but this link has not been thoroughly

investigated.

A retrospective study showed

that the percentage of

smokers is higher among

collagenous colitis patients

than among the population

as a whole. This study was

the ﬁrst

to demonstrate

a potential

effect of nico-

tine on the development of

microscopic colitis. This effect

might be based on the fact that nicotine increases

the permeability of the intestinal mucosa. Continued

nicotine consumption also reduces a patient’s response

to budesonide treatment.

It is theoretically possible that increasing the permeability

of the intestinal mucosa (the cause of which remains

unknown) may allow digested food to migrate into

the intestinal wall and disrupt the function of the gut.

A recent study reported that the microbial ﬂora of

the gut has a different composition in patients with

microscopic colitis than in healthy controls.

Causes and development of microscopic colitis

Microscopic colitis – Collagenous and lymphocytic colitis

Antibodies targeting parts of the body itself have been

detected in about half of all patients with lymphocytic

colitis. These antibodies are directed at the gut, and as

a result this disease might need to be classiﬁed as an

“autoimmune disorder”.

In contrast, antibodies are frequently found in collagen-

ous colitis patients that target bacteria – bacteria which

themselves cannot be detected in the body. This may

be a sign of a prior infection by these bacteria. Alter-

natively, it might reﬂect the increased permeability of

the intestinal wall, which could lead to the production

of antibodies against microbes located in the wall

(e.g. Yersinia species).

It is still unknown how these phenomena result in a

thickening of the collagen layer in collagenous colitis or

lead to an accumulation of immune cells (lymphocytes)

in the intestinal mucosa in lymphocytic colitis.

However, we do know that the collagen deposits found

in collagenous colitis patients do not result from the

overproduction of collagen, but rather from reduced

degradation of collagen.

Interestingly, in patients with an artiﬁcial outlet to the

gut, known as a stoma, the collagen layer in the gut

segments downstream of the stoma returns completely

normal, resulting in a cure of the disease. This suggests

that the contents of the gut are important for develop-

ing the disease.

Diagnosis

In order to conﬁrm the diagnosis of microscopic colitis,

experience has shown that patients with watery diarrhea

lasting longer than 4 weeks should be examined by co-

lonoscopy. If the results of the colonoscopy are normal,

meaning the doctor cannot detect any changes to the

mucosa with the naked eye, small tissue samples should

be collected from the intestinal mucosa (using biopsy

forceps) (Fig. 3). The diagnosis is based on an assessment

of this samples under the microscope. About 10%

of patients with watery diarrhea lasting longer than

4 weeks and normal colonoscopy results are diag-

nosed with microscopic colitis. It is important to collect

samples from different segments of the colon in all

patients, since collagenous colitis is limited only to the

ascending segment of the colon in about one-quarter

of patients, to give one example.

Diagnosis

Fig. 3: Colonoscopy with collection of

tissue samples from different segments

of the colon.

Biopsy forceps,

approx. 3 mm

Microscopic colitis – Collagenous and lymphocytic colitis

Collagen

layer

Epithelium

Surface of the intestinal mucosa

–10 µm

Crypts

Fig. 4a: Diagram (left) and microscopic image

(right) of the intestinal mucosa in a patient with

collagenous colitis. The thickened collagen

layer, which is stained pink, is clearly visible.

Fig. 4b: Microscopic image of the intestinal mucosa

in a patient with lymphocytic colitis showing

accumulation of lymphocytes (small purple dots).

When intestinal tissue samples are examined under the

microscope, both disorders are characterized by very

typical ﬁndings: Using speciﬁc staining methods, a

thickened collagen layer (pink) is visible in the intestinal

mucosa in patients with collagenous colitis (Fig. 4a).

Collagen ﬁbers are a speciﬁc protein structure in the

body that helps support tissues. While this collagen

layer is less than 5 micrometers (one-millionth of a

meter) wide in healthy people, it is at least 10 micro-

meters wide in collagenous colitis patients and is easily

visible under the microscope after staining.

For people with lymphocytic colitis, doctors ﬁnd an

increased accumulation of immune cells (lymphocytes,

a subgroup of white blood cells) in the tissue samples.

The lymphocyte count is about 4- to 5-fold higher

than in healthy people (Fig. 4b).

However, it is still not known what effect the thickened

collagen layer or the increased accumulation of inﬂam-

matory cells has on the course of the disease.

It is currently not possible to diagnose these diseases

by blood test. Levels of calprotectin, which is a marker

of inﬂammation, may be elevated. However, this ﬁnding

is not speciﬁc and does not prove somebody has micro-

copic colitis. On the other hand, it does mean that

patients with persistent diarrhea and elevated calpro-

tectin levels should always be referred to a colonoscopy

for diagnostic purposes.

Diagnosis

Microscopic colitis – Collagenous and lymphocytic colitis

Treatment

The goal of treatment is to improve or completely

eliminate the symptoms of the disease, which improves

patients’ quality of life.

Budesonide

Drug treatment using the active substance budesonide

is the standard treatment option and is the treatment

which has been tested the most in controlled studies.

Budesonide is a modern corticosteroid drug that has

very good local anti-inﬂammatory effects on the

intestinal mucosa.

The substance was originally used as a spray to treat

asthma. It has also been used to treat inﬂammatory

bowel disease since the 1990s. Budesonide, which is

given as granules or in a capsule, is not released until

it reaches the border between the small intestine and

the ascending colon thanks to a special manufacturing

process. Once it arrives in the ascending colon, it has

potent local anti-inﬂammatory effects on the mucosa

that are stronger than the effects of classical corticoster-

oids. The special beneﬁt of budesonide is the fact that

over 90% of it is directly metabolized by the liver after

being active in the gut. As a result, only a small percent-

age of the drug circulates in the bloodstream, leading

to many fewer steroid-like side effects compared with

classical corticosteroid drugs. Budesonide is thus an

optimal choice for achieving a high degree

of local effectiveness at the intestinal

mucosa while keeping the rate of

side effects low.

Budesonide is generally taken

at a dose of 9 mg per day for

8 weeks for the treatment of acute

disease. In clinical studies, this treatment

was associated with clinical improvement

and absence of diarrhea in about 80% of patients.

However, patients often experience a recurrence of

the disease 2 months after stopping the drug. If this

occurs, treatment may be resumed at a reduced dose

of 4.5–6 mg budesonide per day. The doctor and

the patient will need to discuss the precise length of

treatment. Studies have shown that this treatment

reduces the probability that symptoms will return

within 6–12 months by about 60% in patients with

collagenous colitis.

Prednisolone

The classical corticosteroid prednisolone was frequently

used in the past to treat patients with microscopic

colitis. However, in contrast to budesonide, predniso-

lone is initially absorbed into the bloodstream after

being ingested. As a result, it not only provides the

desired therapeutic effect but also frequently leads to

severe forms of the typical side effects of steroid drugs.

These include “moon face” (a rounding of the face),

abdominal obesity, high blood pressure, mental health

disorders, and weakening of the immune system.

Bismuth

This drug has antibiotic and anti-inﬂammatory proper-

ties and is included in some combination drug treat-

ment regimens when budesonide does not improve the

symptoms of disease or is not tolerated by the patient.

However, very few clinical studies have been performed

on bismuth. Furthermore, bismuth products should

not be taken for longer than 8 weeks since they may

accumulate in the body.

Other treatment options

Several open-label (i.e. non-controlled) studies and case

reports have investigated the effects of the probiotic

(bacteria that have a beneﬁcial or potentially beneﬁcial

effect on the gut) E. coli Nissle 1917 and of immuno-

suppressants (azathioprine, methotrexate, and different

antibodies targeting inﬂammatory factors). Immuno-

suppressant therapy should be taken into consideration

Treatment

Microscopic colitis – Collagenous and lymphocytic colitis

for patients who do not respond to standard treatment

with budesonide.

Loperamide, a drug that can stop acute diarrhea by

inhibiting bowel motility, is also sometimes used for

short-term symptom relief. However, it does not treat

the actual cause of diarrhea, which is inﬂammation

of the intestinal mucosa. Loperamide should be taken

as brieﬂy periods as possible and only after consulting

a doctor.

Other treatment options, such as incense extract,

cholestyramine, or mesalazine, have either not been

adequately studied at present or did not bring about

the desired treatment outcome. Therefore, these drugs

should only be taken as part of any future clinical

studies.

1985–89 1990–93 1994–97 1998–2001

Microscopic colitis

Lymphocytic colitis

Collagenous colitis

Frequently asked questions about

microscopic colitis

? How common is microscopic colitis?

According to the most recent statistics (including those

from the US), microscopic colitis is being diagnosed

with increasing frequency (Fig. 5). This increase is likely

due to both improvements in diagnosis as well as a

real increase in the number of actual cases. The ﬁgures

reveal an annual incidence (rate of new cases) of about

20 patients per 100,000 inhabitants.

Cases per 100,000 inhabitants

The annual incidence of collagenous colitis varies

greatly from one country to the next, for example

at 1–2 cases per 100,000 inhabitants in Spain versus

16 new cases per 100,000 inhabitants in Denmark.

Frequently asked questions about microscopic colitis

Fig. 5: Overview of the incidence of lymphocytic and collagenous

colitis (from a survey in the US).

Microscopic colitis – Collagenous and lymphocytic colitis

Little data is available on lymphocytic colitis. The rate

of new cases in Scandinavia is thought to be 4 per

100,000 inhabitants.

Epidemiological studies from the US and Denmark both

report an increase in the rates of new cases in both

countries (over the past several years).

? Are there any factors that increase

the chances of microscopic colitis?

All of the studies conducted to date show that women

develop microscopic colitis about 5 times as often

as men. The risk increases even more greatly among

women above the age of 65. This is true for both

collagenous and lymphocytic colitis. The reasons for

this trend are not known.

In addition, patients already suffering from certain

diseases of the immune system (called autoimmune

disorders) appear to develop microscopic colitis more

often than patients without pre-existing autoimmune

disorders. This includes patients with hypothyroidism

and celiac disease. Up to 40% of all patients with

microscopic colitis also suffer from an autoimmune

disorder.

Patients with microscopic colitis are more likely to have

celiac disease and vice versa; therefore, patients with

one of these conditions should be tested for the other

(by transglutaminase antibodies or duodenal biopsy).

About 10% of patients also report a history of cancer.

The majority of these cases involve colorectal cancer,

breast cancer, prostate cancer, or lung cancer. Cancer

patients are at a higher risk of developing microscopic

colitis than the general population, especially women

over the age of 65.

Patients with diabetes may also potentially be at a higher

risk of microscopic colitis. This appears to be the case

primarily for older men.

Overall, more research is needed to investigate a poten-

tial link between microscopic colitis and the disorders

listed here, as well as their underlying causes.

Frequently asked questions about microscopic colitis

Microscopic colitis – Collagenous and lymphocytic colitis

? What is known about the causes of

microscopic colitis?

The ultimate cause of microscopic colitis remains

unknown.

It is notable that increased use of pain medicines

(including ibuprofen and acetylsalicylic acid) has been

identiﬁed as a potential trigger in a relevant number

of patients. These medicines may increase the perme-

ability of the intestinal mucosa, which might promote

the absorption of other substances that trigger the

disease which are not yet known. However, other

drugs, such as simvastatin (used to lower cholesterol),

ticlopidine (used to reduce blood clotting), or acarbose

(used to treat diabetes), have also been reported to be

potential triggers of microscopic colitis. The potential

role of proton-pump inhibitors has not been conclusive-

ly determined.

Studies have also shown that the percentage of colla-

genous colitis patients who are smokers is signiﬁcantly

higher than in the population as a whole. Smoking

should therefore be avoided since nicotine increases the

permeability of the intestinal wall. Continued nicotine

consumption also lowers a patient’s response to bude-

sonide treatment.

Several different studies have detected antibodies to

Yersinia in about 80% of patients. Yersinia are bacteria

that can lead to an infection of the intestinal mucosa.

In contrast, Yersinia are only rarely detected in the stool

of microscopic colitis patients.

These ﬁndings can be interpreted as a reﬂection of the

increased permeability of the intestinal wall for Yersinia

leading to secondary antibody production.

There is also evidence that microscopic colitis occurs

more frequently within families. However, it remains

unclear whether this points to a genetic component.

? How does microscopic colitis differ

from irritable bowel syndrome?

The primary symptom of both microscopic colitis and

irritable bowel syndrome is chronic, non-bloody, usually

watery diarrhea.

Endoscopy ﬁndings and stool tests for microbes are

typically normal in both diseases. Collection and micro-

scopic examination of tissue samples is thus important

for the diagnosis of both. These examinations clearly

reveal the characteristic signs of microscopic colitis and

allow it to be conﬁdently differentiated from irritable

bowel syndrome.

There are also other characteristics (see Table 1) that

tend to point to one or the other condition. These

characteristics may help conﬁrm, yet cannot replace,

a microscopic diagnosis.

Primary symptoms of irritable bowel syndrome –

Microscopic colitis

Irritable bowel

syndrome

Microscopic

colitis

Initial onset of disease

often below age 50

women ≥ men

often above age 50

women >> men

Stool consistency soft – variable –

ﬁrm

watery/soft

Abdominal pain/

discomfort

obligatory variable

Nocturnal diarrhea very rare possible

Sensation of in-

complete evacuation

common no

Weight loss rare common

Fecal incontinence rare common

Bloating common rare

Autoimmune

comorbidities

no yes

Frequently asked questions about microscopic colitis

Table 1

Microscopic colitis – Collagenous and lymphocytic colitis

? What is the explanation for the thickening of

the collagen layer in the intestinal mucosa?

The increase in the size of the collagen layer in

collagenous colitis is not due to increased collagen

production but rather to decreased collagen degra-

dation. However, the precise mechanisms leading to

this reduced degradation of collagen in the intestinal

mucosa have not been studied in depth. It is also not

known whether and how thickening of the collagen

layer triggers the typical symptoms of collagenous

colitis.

? Are there any signs of microscopic colitis

outside of the gut?

Microscopic colitis may be accompanied by a number

of other different conditions that indicate a reaction

by the immune system to the tissues of the body. These

include rheumatic joint pain, psoriasis, celiac disease,

thyroid dysfunction, perfusion disorders, and mucosal

dryness (see also Fig. 2).

? Is a proctoscopy sufﬁcient for diagnosis?

Because microscopic colitis most frequently affects

the ascending segment of the colon, a proctoscopy is

not sufﬁcient for diagnosis. The entire colon should

be examined in every patient together with collection

of tissue samples from the different segments of the

colon. If this is not performed, up to 40% of patients

with microscopic colitis may be missed.

? Does microscopic colitis increase the risk

of colorectal cancer?

No. There are no indications that polyps or colorectal

cancer develop more often in patients with collagenous

or lymphocytic colitis. In general, the diagnosis of

microscopic colitis has a favorable prognosis, and the

symptoms can be managed well with the drug

budesonide.

? Are there any concerns about pregnancy?

No. There are no concerns about pregnancy with

regard to the disease itself. However, each drug taken

should be reviewed to make sure there are no restric-

tions on its use during pregnancy or while breast-

feeding. In any case, the disease tends to afﬂict older

patients who have already gone through menopause.

? Are there any dietary factors that have

a positive effect on microscopic colitis?

There are no conﬁrmed results about any potential

effects of dietary factors that might trigger these

diseases. It also remains unknown whether adding or

removing speciﬁc foods from one’s diet may have a

positive or negative effect on the course of the disease.

However, because the primary symptom

of the disease is watery diarrhea, lactose

intolerance and celiac disease should

be ruled out as potential causes

during the pre-diagnosis phase.

For both of these disorders, there is

a clear recommendation to maintain

a lactose-free or gluten-free diet.

Frequently asked questions about microscopic colitis

Microscopic colitis – Collagenous and lymphocytic colitis

Studies have shown that fasting can lead to a major

improvement in the diarrheal symptoms of collagenous

colitis. However, prolonged fasting does not represent

a long-term treatment option for microscopic colitis.

? Can surgery help microscopic colitis?

In the past, surgery has only been performed for very

severe cases of microscopic colitis, which are very rare.

However, the results from these patients have shown

that when patients have an artiﬁcial intestinal opening

(stoma) to empty their digestive tract, both the inﬂam-

mation and the thickened collagen layer heal in the

downstream segment of the gastrointestinal tract that

is now absent of stool. This fact suggests that certain

factors in the contents of the gut may be important

triggers of microscopic colitis.

? Is the disease ever improved or cured

by itself?

Studies on the long-term progression of collagenous

colitis have shown that some patients remain symptom-

free for a long time after a successful ﬁrst round of

treatment and have no need for any further medications

In one of these studies, 23% of patients still had

no watery diarrhea after 10 years. On the other hand,

symptoms returned in two-thirds of patients within

2 months of stopping treatment. If this happens, a new

round of treatment or a low-dose maintenance therapy

is recommended both for patients with collagenous

colitis and with lymphocytic colitis.

? Can binding or bulking agents have a positive

effect on diarrhea?

In cases of mild diarrhea, taking bulking agents or bile

acid sequestrants is often sufﬁcient to increase the

consistency of stool and reduce the frequency of bowel

movements. In one small study, diarrhea resolved in

over 20% of patients taking a bulking agent (such as

psyllium husk).

? How long should budesonide be taken

during the acute phase of the disease?

In the treatment studies that have been performed on

budesonide to date, the drug was given at a dose of

9 mg per day over a period of 6 or 8 weeks. The majority

of patients were nearly completely free of symptoms

within 14 days of starting this treatment plan.

Budesonide is taken as a single dose in the morning.

? Is there a maintenance therapy for

microscopic colitis?

After ﬁnishing budesonide therapy for the treatment

of acute microscopic colitis, patients frequently start to

experience diarrhea again within the ﬁrst 2 months and

thus require further treatment. Several placebo-controlled

studies have all shown that, after achieving clinical

improvement for acute disease with 9 mg budesonide,

continuing treatment with 4.5–6 mg budesonide per

day for 6–12 months can lead to a signiﬁcant reduction

in the rate of recurrence.

Frequently asked questions about microscopic colitis

Microscopic colitis – Collagenous and lymphocytic colitis

Notes

BU82E 6-8/2020 POP