Inflammatory Bowel Disease – A Review of Current Concepts

Inflammatory Bowel Disease Inflammatory Bowel Disease

Inflammatory Bowel Disease – A Review of Current Concepts

Summary

The term Inflammatory bowel disease refers to chronic illnesses mainly represented by Crohn’s disease and Ulcerative colitis. Both are characterized by relapses and flares.

Their etiology is unknown, but there have been various studies on the implication of genetics, environment, diet, and immune system.

Symptoms vary depending if we are in front of a CD or a UC, but general symptoms include fatigue, blood in stools, diarrhea, abdominal pain, anorexia, weight loss, tachycardia, and anxiety.

To reach a diagnosis, there should be a sum up of clinical examination, imaging studies, endoscopy biopsies, and laboratory tests.

The management of these diseases should be applied, thinking of the severity of the inflammatory reaction being the goal, the healing of the mucosal barrier.

Definition

References (1-6)

Inflammatory bowel diseases are chronic illnesses that include mainly two diseases Ulcerative colitis (UC) and Crohn’s disease (CD). Non-infectious inflammations of the bowel are also included in this classification.

Both UC and CD are characterized by relapsing inflammatory disorders, meaning they have periods of exacerbation and remission. Etiology is unknown, but every year more information is being discovered.

Although similar, they differ in their clinical presentation, pathophysiology, risk factors, and genetic predisposition.

  • Ulcerative colitis primarily affects the colon, with a continuous inflammation of the mucosa almost always starting from the rectum.
  • Crohn’s disease, on the contrary, causes transmural inflammation and can affect the entire gastrointestinal tract segmentally, with ulcerations and usually fistulas between segments of the bowel.

There are 3 important factors to take into account when studying the severity of these pathologies:

  • The impact on the patient (quality of life, clinical symptoms, disability);
  • The extension and severity of the inflammation;
  • The prognosis.

Malnutrition is very common in these patients; therefore, a lot of studies have spanned around dietary and pharmacological therapy as well as the link to cancer as long-term complications.

Etiology

References (5-11)

IBD is triggered in a genetically susceptible person when exposed to varied factors such as diet, infections, and tobacco since it evokes an aberrant adaptive immune response.

Tobacco Smoking

The effects of tobacco are different between UC and CD. In the first one, it may exert a protective effect, while in the second one develop more risk of developing the disease.

Nutritional Factors

The nutritional factor is very important in IBD incidence, where the high intake of saturated fats and monosaccharides and low intake of fiber increase the risk of CD. While trans fatty acids and linoleic acid have been linked to an increased risk of UC development.

Fiber consumption exerts a protective effect on IBD development, while vitamin D deficiency is a common phenomenon in patients with IBD. Alcohol consumption may have a negative effect on the risk of IBD development. (5)

Obesity and Inflammatory Bowel Disease

The effects of obesity on inflammatory bowel disease are being investigated since there is evidence that they share risk factors. Adipose tissue produces pro-inflammatory effects that affect patients with immune-mediated illnesses. These findings reaffirm the importance of diet and nutrition on IBD.

Breastfeeding and Inflammatory Bowel Disease

Breastfeeding could be a protective factor in IBD morbidity. The ways in which breastfeeding protects against IBD are unknown. (12, 13)

It has been shown that feeding in the first month of life is crucial for the development of gut microflora that stimulates innate and acquired immunity and promotes the maturity of the mucosal immune system. Some authors point out that lactoferrin (a protein only found in human milk) has a big role in this process. (14)

IBD and Psychological Stressors

An important factor of this condition is stress and psychological pathologies like depression and anxiety. Other stress situations that influence the loss of intestinal barrier integrity are trauma, burn injuries, septic shock, pancreatitis, etc., although milder stressing situations, like endurance exercise, can produce a dysfunction on the bowel barrier.

Genetical Factors of IBD

The role of microRNA in conditioning CD or UC development has also been indicated, and more than a hundred genes have been associated with inflammatory bowel disease, especially for Crohn’s disease, specifically NOD2/CARD15 mutations.

As we said before, there are various factors that influence a genetically susceptible person to IBD, and this is why it is very difficult to know the exact etiology of these diseases. Although we know the main factors are the interaction of the lumen antigens and the epithelial border.

Pathophysiology

References (15, 16)

As we know, the intestinal immune system is key in the pathogenesis of IBD. In recent years there has been a view that the disease is due to poor interaction between microflora and the immune system of the gastrointestinal tract.

There’s also evidence that suggests that an excessive immune response to a normal microflora is the key to understanding the pathogenesis of IBD.

It is set to say that the consensus of IBD pathogenesis is now thought of as a complex sum of different disorders, such as genetics, immune, mucosal, and epithelial barriers.

The main mechanism of immune response seems to be common to the different types of IBD; therefore, treatment by blocking the pro-inflammatory factors has been shown to be effective in both CD and UC.

This knowledge helps in the clinical practice to create new drugs for effective treatment against IBD, like anti-TNF-a, and antibodies targeting the inhibition of the inflammatory pathway dependent on the activation of IL23-IL23R, to name some examples.

Histopathology

Reference (16)

A microscopical evaluation shows infiltration of the lamina propria with neutrophils, macrophages, dendritic cells, and NKT cells in IBD. These findings increased the number of TNF-a, IL-1b, interferon-gamma, and cytokines of the IL-23-TH17 pathway.

In UC, we will see only the involvement of mucosa and submucosa with the formation of cryptic abscesses and mucosal ulcers, and granulomas are not seen. The lesions are usually contiguous and usually involve the rectum.

In Crohn’s disease, the entire intestinal wall is involved, and granulomas are present. Inflammation is transmural (lymphocytic infiltrate).

Microbial factors

Reference (17)

The microbial flora is now thought to play an important role in the induction of IBD, with patients affected by the disease having reduced biodiversity in the fecal microbiome compared to the control population.

The microbial flora is characterized by a lack of Firmicutes and Bacteroidetes, with an over-representation of enterobacteria, being a dysbiosis of the microflora.

In CD, there is an increase in bacteria directly on and in the colonic mucosal epithelium, mostly by E.coli. (17)

Genetics

Reference (1, 3)

Genetic investigation shows an indispensable role for autophagy in immune response in IBD, being the discovery of NOD2 (nucleotide-binding oligomerization domain containing 2) a huge step in the understanding of CD, being the first susceptible gene discovered for this disease.

  • NOD2 codes for a protein that recognizes the muramyl dipeptide (MDP), which controls autophagy involved in intracellular homeostasis and is resistant to infection and removal of intracellular microbes, which are impaired in patients with this mutation impaired in patients with mutations. It also induces a defective ability of the bowel to respond to lipopolysaccharide, which contributes to disease susceptibility.
  • CD is also linked to ATG16L1 and IRGM genes, which are involved in autophagy and have the same effect as the mutations produced by NOD2.

In recent years it has been proven that a genetic predisposition plays a larger role in CD than in UC, being more than 160 genes discovered for the first pathology, and thus leaving the first interpretation of IBD as an autoimmune disease obsolete.

Immunity factors

Reference (1)

The investigations about the implications of mucosal immunity, especially T cell response, in the pathogenesis of IBD have shown that the dysfunction of innate and adaptive immune pathways contributes to the aberrant response in patients with IBD.

Immunological studies have focused on the mucosal barrier, which has been proven to be important in the prevention of bacterial breakthroughs and intestinal inflammation. Another focus has been the epithelial barrier that, apart from being a physical barrier, secretes a number of antimicrobial peptides that have been observed as defective in patients with CD.

The behavior of innate immunity and the expression of TLRs and NOD proteins are altered in affected individuals. A British study showed that mucosal neutrophil accumulation and production of IL-1 and IL-8 in response to trauma are selectively reduced in CD patients but not in UC patients. (18)

In the behavior of adaptive immunity, CD is characterized by a Th1 immune response, while UC has been considered as a Th2-mediated disease (19).

IL-23 is a key cytokine in both immunities and has an important role in the first response against pathogens. IL23R polymorphisms have been associated with IBD.

Epidemiology

Reference (20- 22)

The incidence of IBD is affected by multifactorial interactions between environmental factors, changes in the intestinal flora, genetic predisposition, and changes in the immune system.

The influence of environmental factors has been shown in the increase of IBD in developed industrialized countries over rural populations. Crohn’s disease is more prevalent in females compared with males, but ulcerative colitis is equal in both sexes. IBD is more common in North America and Europe than in Asia and Africa and is generally a disorder of cooler climates and developed countries.

The age of appearance is between 15-30%; however, 25% of patients will develop IBD in adolescence and 15-20% after 60 years of age (20). In pediatric IBD, there is a preponderance of male patients over females in CD and equal in UC, being CD more common in children compared with adult data and also being a genetic association in 25-30% of the cases.

In patients with CD, mortality risk increased up to 50% compared to the background population, being the disease-specific cause of death, malnutrition, intestinal cancer, and postoperative complications, while in UC, we can name colorectal cancer (CRC) and postoperative complications. The risk of intestinal cancer and CRC is increased two to eightfold among IBD patients, having also more risk of extra-intestinal malignancy. (20)

Signs and symptoms

Key symptoms

Reference (20)

Crohn’s diseaseUlcerative colitis
Weight lossRectal bleeding
Abdominal painChronic diarrhea
Chronic diarrheaAbdominal pain

Crohn’s disease

Reference (16, 24)

Typical symptomsSevere casesIf small bowel involvedEnterovesical fistulae
Abdominal pain on the right side.Perianal abscess.Malabsorption.Pneumaturia.
Bloating/flatulence.Perianal CD.Weight loss.Recurrent UTI.
Chronic diarrhea (with mucus and blood).Cutaneous fistulas.Anorexia.Feculent vaginal discharge.
Fever.Abdominal pain.
Weight loss.Diarrhea.
Anemia.
Impaired growth velocity or growth failure in children.
Nausea and vomiting.

Ulcerative colitis

Reference (7, 16)

Typical symptomsSevere casesPatient with proctitisPatient with pancolitisToxic Megacolon
Bloody diarrhea (with or without mucus).Urgency.Urgency.Bloody diarrhea.Bloating.
Tenesmus.Incontinence.Tenesmus.Abdominal pain.Abdominal pain.
Abdominal pain (left hypochondrium or left side) is less of a hallmark than in CD.Fatigue.Paradoxical constipation (10% of patients) (25).Tachycardia.
Diarrhea.Malaise.
Mucus discharge.Bloody Diarrhea.
Nocturnal defecations.Hypotension.
Abdominal pain (left hypochondrium or left side) is less of a hallmark than in CD.Dizziness.
Fever.Mental confusion.
Weight loss.Shock.

Extraintestinal manifestations

Reference (2, 25-33)

Extraintestinal manifestations (EIM)

Musculoskeletal

  • Arthritis: Found in 9-53% of IBD patients and is the most common EIM (27), presenting sometimes with tendonitis, clubbing, periostitis, and granulomatous lesions of the joint and bone. To differentiate from osteoarthritis, you should ask for morning stiffness and improvement with ambulation, which is not found in inflammatory arthritis. Other EIMs are psoriatic arthritis, reactive arthritis, and idiopathic ankylosing spondylitis.
  • Peripheral arthritis: Found in 5-20% of patients with IBD involving large joints asymmetrically.
  • Spondylitis: Can occur in 1-26% of patients more frequently in males.
  • Osteoporosis: Specific risk factors are corticoid therapy, sedentarism, inflammatory-mediated bone resorption, malabsorption (specifically calcium and magnesium), Vit D deficiency, poor dietary calcium intake, decreased serum albumin levels, and ileal resorption. Patients with IBD have 40% more chances of fracture than the general population increasing with age. The risk of fracture is similar in UC and CD. (27)

Dermatological

  • Dermatological manifestation happens in 9-23% of IBD patients. (28)
  • Erythema nodosum (EN): Most common in CD than in UC. (29)
  • Pyoderma gangrenosum: The most common manifestation with EN. More frequent in UC than in CD. (30)
  • Aphthous stomatitis: Oral ulcers common in all IBD.
  • Sweet syndrome: Acute inflammatory dermatitis.
  • Other skin lesions include psoriasis, metastatic CD with ulcerating nodules with noncaseating granulomas, and eczematous lesions (sometimes as a complication of anti-TNF-alpha therapy).

Ophthalmological

  • Episcleritis: inflammation of the blood-rich episclera. Appearing with intestinal flares and resolves with treatment of the IBD. (31)
  • Scleritis: more severe as it can impair vision.
  • Uveitis.
  • Conjunctivitis.
  • Cataracts and open-angle glaucoma: Cause by steroid treatment.
  • Cyclosporine can cause optic neuropathy, ophthalmoplegia, and nystagmus.

Hephatopancearobiliar

  • PSC
  • Cholelithiasis
  • Portal vein thrombosis
  • Drug-induced hepatotoxicity
  • Pancreatitis: common side effect of 6-mercaptopurine or azathioprine therapy
  • Sclerosis cholangitis: Most frequent in UC than in CD. (30)

Renal and pulmonary

Renal: In 6-23% of patients (33)

  • Nephrolithiasis
  • Obstructive uropathy
  • Fistulization of the urinary tract: Most common in CD.

Pulmonary:

  • Chronic bronchitis;
  • Subglottic stenosis;
  • Bronchiectasis;
  • Bronchiolitis.

Thromboembolic disease

Thromboembolic disease is 3 to 4 times more common in people with IBD than in the general population and is now recognized as a common complication of CD. Patients treated with corticosteroids or that are coursing with a flare.

  • Deep vein thrombosis;
  • Stroke;
  • Pulmonary embolism.

Diagnosis

Reference (20)

The diagnosis of IBD is not straightforward, and we should collect information from the clinical examination, laboratory markers of inflammation, imaging findings, and endoscopic biopsies.

Clinical examination

Reference (15, 20)

When examining the patient, we should ask about the frequency and type of stools, if diarrhea has blood or mucus, and if there is abdominal pain, nausea or vomiting, lethargy, and weight loss, apart from the other symptoms named before.

We should remember that in children, we should focus on height and weight centiles, including BMI and tanner staging for sexual maturity. Also, we should be on the lookout for any family record of IBD and extraintestinal manifestations.

However, we should remember that no single feature establishes the diagnosis. Therefore, we should always accompany the clinical exam with complementary studies.

Laboratory markers

Reference (16, 20)

The initial blood test will contain a full blood count with erythrocyte, hematocrit and hemoglobin, erythrocyte sedimentation rate (ESR), liver and renal function including albumin, iron status, and CRP. These will help us check for microcytic anemia, thrombocytosis, leukocytosis, and hypoalbuminemia. The rise of inflammatory markers (like ESR and CRP) is common in IBD patients. However, the values may be falsely normal in mild UC (54%) or mild CD (21%). (16)

Serological markers:

Reference (15)

  • Antibodies to anti-Saccharomyces cerevisiae (ASCA). Associated with 60% of cases of CD. (20)
  • Perinuclear antineutrophil cytoplasmic antibodies (p-ANCA). Associated with 60% of cases with UC. (20)
  • Anti-E.coli outer membrane porin C antibody (anti-OmpC).
  • Antibodies to bacterial flagellin (anti-CBir1).
  • Anti-glycan antibodies.

The last three are currently under investigation.

Non-invasive stool markers

  • Fecal calprotectin. Useful parameters for non-invasive treatment monitoring.
  • Fecal lactoferrin.
  • Neutrophil protein.

Gastrointestinal infections must be excluded, like bacterial and parasitic infections. We should also discard Clostridium difficile in patients with a history of antibiotic treatment. However, it is pertinent to note that a documented enteric infection does not rule out the possibility of IBD. (20)

Another test that should be done is stool culture to rule out infectious diarrhea and Clostridium difficile, looking for their toxin, especially in patients that have received multiple antibiotics.

Imaging

References (15, 16)

The abdominal x-ray may be useful in the presence of free air to diagnose toxic megacolon (a colonic dilatation > 6 cm without any distal stenosis is diagnostic) (15) or obstruction.

Barium studies are helpful in revealing lesions in the bowel. A lead pipe appearance is indicative of UC, and sparing of the rectum or skip lesions and structure formation in the ileum are suggestive of CD.

Ultrasound (US) and magnetic resonance imaging (MRI) of the small intestine complete the initial diagnosis and, in addition to computed tomography (CT), help assess complications. MRI is helpful for evaluating rectal fistulas, stenoses, and abscesses is helpful in treatment planning, and CT is most commonly used for visualizing perforative or obstructive bowel. The US is frequently used for monitoring the course of IBD.

Endoscopy

References (15, 33)

Endoscopy is the gold standard for the diagnosis of inflammatory bowel syndromes. Endoscopy evaluations with either esophagogastroduodenoscopy or colonoscopy are essential to obtain a biopsy to confirm the diagnosis of IBD.

If CD is suspected, the terminal ileum should be studied because it is where most mucosal changes happen. We should also evaluate the upper gastrointestinal tract at the time of initial diagnosis to confirm extensive involvement, which confers a worse prognosis.

When we have a severe case of UC to make an acute diagnosis, a sigmoidoscopy is performed since maximum inflammation is almost always in the rectum.

Video capsule endoscopy (VCE) is helpful in children when ileal intubation is unsuccessful or not possible. (20)

Histological examination of the biopsies helps differentiate the two types of IBD and other bowel diseases like infections, and it also confirms diagnosis with architectural abnormalities. (20)

Differential diagnosis

Reference (16)

  • Infectious etiologies: E. coli 0157:H7 and C. difficile, parasitic like giardia, amebiasis, strongyloidiasis;
  • Microscopic, lymphocytic, and collagenous colitis;
  • Appendicitis;
  • Irritable bowel disease;
  • Celiac disease;
  • Functional abdominal pain;
  • Tuberculosis.

Treatment

Stepwise Therapy

Reference (20, 33)

It is an approach used for IBD management where medication with less toxicity is used first, and as the illness progresses from mild to moderate and severe, more aggressive therapy with higher toxicity is used. The final step is clinical trial agents that tend to be disease-specific, like thalidomide in CD and butyrate enemas or nicotine patches in UC.

The treatment of IBD aims for mucosal healing with a reduction in complications and extraintestinal manifestations.

In the following section, we will describe the specific treatments that are used in both UC and CD.

Crohn’s disease

Reference (15)

Induction of remissionIf the ileocecal region is involved: budesonide. Mesalazine (4.5 g/day) in mild to moderate symptoms
Induction of remission in relapseBudesonide and mesalazine, like before. Sulfasalazine is rarely used because of adverse effects (if the patient has joint pain)

Isolated involvement in the rectum or sigmoid colon can be treated with enema, rectal foam, or suppository containing steroid or aminosalicylate (1 mg per Kg of body weight)
Induction of remission in case of steroid relapseAnti-TNFa antibodies infliximab intravenously and adalimumab subcutaneously, and the anti-integrin antibody vedolizumab (for long-term maintenance of remission)
Maintenance of remissionOnly for patients with complicated courses.

Aminosalicylates are not effective (unlike UC).

Azathioprine or 6-mercaptopurine. If this is not tolerated, methotrexate is an alternative.

Sometimes combined treatment with thiopurine plus anti-TNFa antibodies is necessary.

In the postoperative setting: metronidazole, mesalazine, or, in complicated cases, a thiopurine drug or anti-TNFa antibodies.
Surgical treatment40% of patients with CD undergo surgery within 5 years of being diagnosed, and 70% within 10 years, with a success rate in 10 years of 90% for resection of a segment of the ileum, 40% for ileocecal resection, and 85% for colonic resection. (34)

The indication for surgical treatment is complex inflammation in the small and large bowel, with abscesses, fistulae, and terminal ileitis.

The surgical treatment for isolated small-bowel: small-bowel segment resection, stricturoplasty, ileocecal resection, and, if the duodenum is involved, gastroenterostomy.

Subtotal or total colectomy is usually performed, whereas proctocolectomy, terminal ileostomy, and discontinuous resection are less common.

Endoscopy dilatation is preferred for short stenoses inaccessible places.

Ulcerative colitis

Reference (15)

Induction of remission Initially, for mild to moderate active left colitis or pancolitis with mesalazine foam and or enema combined with oral mesalazine (at least 3 gr per day) (27)

Corticosteroids should be given systematically if remission is not achieved with the previous treatment.

In a severe relapse, intravenous steroids are used.

Induction of remission in relapse Mild to moderate active proctitis: mesalazine suppositories or mesalazine foam/enemas. Topical steroids can be applied if necessary.

Tacrolimus suppositories are a potential alternative when other treatments have failed.

Induction of remission in case of steroid failure If steroids do not induce remission in 3-4 days, the options are calcineurin inhibitors (cyclosporine and tacrolimus) and anti-TNFa antibodies (infliximab, adalimumab)

Vedolizumab has also been found to be effective for UC treatment reserved for severe cases.

Maintenance of remission Aminosalicylates should be given for at least 2 years and even for life if indicated. More frequently given by mouth (at least 1.5 g per day).

If the patient has frequent relapses or relapses despite the use of medication, combined therapy with immunosuppressants and aminosalicylates should be given.

Calcineurin inhibitors should also be switched to thiopurines. Once again, combined therapy of anti.TNFa antibodies with thiopurine are more effective than either substance alone and vedolizumab is an alternative for refractory disease.

Surgical treatment Patients with UC have 35% of chance of needing surgery at some point. (35)

The most common causes of surgical treatment are intractable disease course, dysplasia, and morbidity due to extra-intestinal manifestations. Other causes are toxic megacolon, severe hemorrhage, bowel perforation, and colon carcinoma.

Surgical treatment in active colitis is subtotal colectomy without any intestinal anastomosis, with a transient ileostoma, followed by proctectomy and pouch creation at a later time (a triple-staged procedure).

In an inflammation-free period, elective treatment is a restorative proctocolectomy with ileo-pouch-anal anastomosis (IPAA) and protective ileostoma (a double-staged procedure) (36).

Cancer and IBD

Reference (37)

Cancer secondary to chronic bowel inflammation

  • Colorectal cancer;
  • Small bowel adenocarcinoma;
  • Intestinal lymphoma;
  • Cholangiocarcinoma most common in UC (38).

Cancer secondary to immunosuppression

  • Antimetabolites drugs: Non-Hodgkin lymphoma, acute myeloid leukemia and myelodysplastic syndromes, non-melanoma skin cancers, and urinary tract cancer.
  • Anti-TNFa: Melanoma
  • Combined treatment with antimetabolites drugs and anti-TNFa: Hepatosplenic T-cell Lymphoma

See Also

Esophageal Cancer

Malabsorption Syndrome

Peptic Ulcer Disease

Acute Diarrhea in Adults

Acute Abdomen

Overview of Lung Cancer

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