Week 4/5 - E - I.B.D - (genetics, symptoms, signs, investigation, complications)- Crohn's and U.C (also primary sclerosing cholangitis)

Question 1

What are the two types of inflammatory bowel disease? Which parts of the GI tract are affected by the conditions? Extraintestinal signs are present for both and will be discussed

Answer 1

Ulcerative colitis Disorder of the colonic mucosa. It can affect * rectum (proctitis) * left sided colitits * entire colon and rectum pancolitis Crohn’s disease * Any part of the GI tract from mouth to anus * Especially the terminal ileum

Question 2

IBD is a multifactorial disease - genetic components, environmental triggers, mucosal immune system What is the best established risk factor for IBD disease development? What is the gene that has been identified that increases the susceptibility of patients to Crohn’s disease when mutated? (link with UC is uncertain)

Answer 2

The best established risk factor for development of IBD is positive family history for the disease The gene that has been identified increasing susceptibility to Crohn’s disease when mutation is NOD2 * (Nucleotide-binding oligomerization domain-containing protein 2 (NOD2), * also/used to be known as caspase recruitment domain-containing protein 15 (CARD15) or * aka inflammatory bowel disease protein 1 (IBD1))

Question 3

What is the function of NOD2? Where is the NOD2 gene located?

Answer 3

NOD2 is thought to play an important role in normal mucosal defences It encodes for a protein involved in bacterial recognition NOD2 is located on chromosome 16

Question 4

The immune system of normal intestine is geared towards tolerance to dietary antigens and commensal flora Innate immune responses are linked to the generation of corresponding adaptive immune responses Is NOD2 thought to play a role in the innate or adaptive immunity protecting the normal gut flora?

Answer 4

NOD2 is thought to contribute to the innate immunity protecting the normal intestine Encodes for a protein that is involved in bacterial recognition and therefore helps with normal mucosal defences

Question 5

Adaptive Immunity T-lymphocytes are critical to the orchestration of adaptive mucosal immunity . Normal conditions are characterised by a balance between effector and regulatory T-cell responses Maladaptive responses may arise from either * Overactive effector T-cells → Inflammation/ Disease * Absence of regulatory T-cells → Uncontrolled Inflammation/ Aggressive Disease Cd4 T cells bind to antigen presenting cells expressing MHC II What do these promote the formation of? - what type of immunity is caused by these cells

Answer 5

Cd4 cells differentiate into different T helper cells Th1 cells are involved with cellular mediated immunity Th2 cells are involved with antibody production and therefore humoral mediated immunity

Question 6

Which type of T cells are Crohn’s disease and Ulcerative colitis mediated by?

Answer 6

Crohn’s disease is associated with Th1 mediated disease (Th1 mediated disease often involved in autoimmune disorders) Ulcerative colitis is associated with Th2 mediated disease (Th2 mediated disease often involved in conditons such as atopy - stimulate antibody production (IgE)

Question 7

Environmental factors that are linked to inflammatory bowel disease What effect does smoking have? What class of drug may exacerbate the disease?

Answer 7

Smoking is thought to aggreavate Crohn’s disease however Smoking is thought to be protective against ulcerative colitis (higher incidence in non-smokers) NSAIDs are thought to exacerbate IBD

Question 8

What age group are both Crohn’s and Ulcerative colitis thought to affect? What is thought to be the cause of both conditions?

Answer 8

Both are thought to affect young patients Typically presenting at 20-40 years of age The cause of both Crohn’s and UC is poorly understood - thought to be an inappropriate autoimmune response against the gut flora in a genetically susceptible individual

Question 9

What is thought to be the risk of colon cancer from both forms of inflammatory bowel disease?

Answer 9

Crohn’s disease is though to moderately increase the risk of colon cancer Ulcerative colitis is thought to cause a high colon cancer risk

Question 10

What is a single-non invasive test that can be carried out in inflammatory bowel disease? This protein is elevated during intestinal inflammation and therefore helps to differentiate between inflammatory conditions or conditions such as IBS

Answer 10

Patient is usually given containers for stool sampling and a faecal calprotectin level is measured - high sensitivity for intestinal inflammation

Question 11

Crohn’s disease Define crohn’s disease?

Answer 11

Crohn’s disease is a chronic inflammatory and ulcerating condition of the GI tract anywhere from mouth to anus and it is most common in the terminal ileum and colon

Question 12

The presentation of Corhn’s disease is determined by the site of the disease What are the symptoms if the disease affects * Small intestine * Colon * Mouth * Anus Remember disease can affect single areas or multiple throughout its course

Answer 12

Small intestine - * Causes abdominal cramps / pain - periumbilical usually * Diarrhoea * Weight loss/failure to thrive if in children Colon * Abdominal cramps / pain - lower abdomen ususally * Diarrhoea with blood * Weight loss / failure to thrive in children Mouth - painful ulcers, angular cheilitis Anus - peri-anal pain and abscesses

Question 13

WHat is the different clinical course associated with Crohn’s disease?

Answer 13

* Chronic inflammation * Exacerbation and remissions * Unpredictable response to therapy There are a subgroup of patients who go into lasting remission within 3 years of diagnosis

Question 14

What are some of the different signs of Crohn’s disease?

Answer 14

Bowel ulceration - seen on colonoscopy Abdominal tenderness/mass Perianal abscess / fistula Anal strictures Also clubbing, skin / joint / eye problems

Question 15

What investigations are carried out in the diagnosis of Crohn’s disease?

Answer 15

Bloods - CRP raised, B12 (decreased due to malabsorption form temrinal ileum), ferritin levels, FBC Rule out the causes of GI inflammation eg gastroenteritis with microscopy and culture of stool Colonoscopy + biopsy is diagnostic investigation of choice Small bowel assessment

Question 16

Colonoscopy and small bowel assessemnt are used to stage the mucosal involvement of the disease How is the small bowel assessed?

Answer 16

Small bowel can be assessed by A Small Bowel Barium Follow Through (aka barium enema) - is an x-ray exam of your stomach and the upper section of the small intestine. To be able to see these structures on an x-ray they must be outlined with barium. Barium is a liquid that is swallowed and appears white on a x-ray picture. SMall bowel MRI is becoming increasingly common

Question 17

What is visualised on colonoscopy when investigating Crohn’s? What is seen on the biopsies taken by the colonoscopy?

Answer 17

Colonoscopy will show features suggestive of Crohn’s such as deep ulcers and patchy, segmental disease with skip lesions Histopathology will show * Transmural inflammation (inflamed from mucosal-> serosa) * Ganulmonatous inflammation (50%)

Question 18

What is the sign seen in small bowel barium follow through enema known as? - it shows strictures in the small bowel in Crohn’s diseas

Answer 18

The sign seen is known as Kantor’s string sign The gastrointestinal string sign (also known as the string sign of Kantor) refers to the string-like appearance of a contrast-filled bowel loop caused by its severe narrowing - the inflammation in Crohn’s has caused structuring of the lumen of the small bowel - usually at terminal ileum

Question 19

Chronic untreated Crohn’s disease can cause deep fissure -seen on coloscopy and on histology of the biopsy What is the appearance described as on colonoscopy? What is the appearance described as on histology?

Answer 19

The deep fissures cause what is known as cobblestoning of the mucosa to be seen on colonoscopy On histology, the deep fissures give a knife-like appearance

Question 20

What are some of the complications of Crohn’s disease?

Answer 20

Malabsorption Small bowel obstruction - due to stricturing Toxic filation of the colon Abcess formation - abdominal, pelvic or peri-anal Fistulae and anal disease Perforation Malignancy

Question 21

Malabsorption can occur in Crohn’s disease due to inflammation (usually of the small bowel) What can occur due to this?

Answer 21

There may be hypoproteinaemia, vitamin deficiency, anaemia of all types Gallstone formation - Gallstones are more common secondary to reduced bile acid reabsorption

Question 22

What are the different types of fistulae that may occur in Crohn’s disease?

Answer 22

Vesico-colic Enteroclic Gastrocolic Rectovaginal Enterocutaneous Perianal

Question 23

What are the different complications of anal disease in Crohns?

Answer 23

Anal fissures Anal sking tags Anal abscesses Perineal fistula

Question 24

ULCERATIVE COLITIS Define ulcerative colitis? Where is affected?

Answer 24

Ulcerative colitis is a chronic inflammatory and ulcerative disorder that is confined to the colon and rectum

Question 25

What is the extent of inflammation in the colon/rectum?

Answer 25

Unlike Crohn’s where there is transmural inflammation, the inflammation/ulceration in UC is mainly superficial affecting the mucosa and submucosa

Question 26

In Crohn’s disease, the inflammation/ulceration is described as segmental and patchy (skip lesions) How is the inflammation in Ulcerative colitis described? Where does it start?

Answer 26

Inflammation always starts at rectum and never spreads beyond ileocaecal valve The inflammation is described as continuous and confluent extending proximally for varying lengths

Question 27

The presentation of UC is determined by the disease extent and severity What are the two main symptoms seen in this disease? Give other symptoms?

Answer 27

Episodic or chornic diarrhoea and bleeding (also mucous) Increased bowel frequency - relates to severity Urgency and Tenesmus = proctitis Night rising Lower abdo pain - especially Left iliac fossa Also weight loss, fever, malaise

Question 28

Extra GI signs are rare in Crohns disease (clubbing, oral/skin/joint problems) However they are common in ulcerative colitis What are the extraintestinal signs that may occur due to UC? (nails, mouth, skin, joints, eyes, liver)

Answer 28

Extraintestinal signs - * clubbing, * aphthous oral ulcers, * Skin - erythema nodosm, pyoderma grangenosum * Joints - arthritis, ank spond, * Eyes - uveitis * Liver - primary sclerosing cholangitis

Question 29

How does the clinical course of UC tend to present? What is the criteria used to determine the severity of UC known as?

Answer 29

* Continuous course with exacerbation and remission * Continuous low grade activity * A single attack * Acute fulminant (severe and sudden in onset) colitis Criteria known as Truelove and Witt critera determines the severity of ulcerative colitis

Question 30

Ulcerative colitis flares can be classified as mild, moderate or severe according to the Truelove and Witt criteria Severe ulcerative colitis = 30% risk of colectomy The categories take into account the bowel movements/day and bleeding And the systemic effects they have Give a summary of mild, moderate and severe?

Answer 30

Mild UC -

• * No systemic signs

Severe UC >/=6 bloody stools /day

• * Systemic signs present (fever, tachycardia, anaemia (Hb

Moderate UC -intermediate

Patients with evidence of severe disease should be admitted to hospital.

Question 31

What investigations are carried out in the diagnosis of ulcerative colitis?

Answer 31

Bloods - CRP raised, B12 (decreased due to malabsorption form temrinal ileum), ferritin levels, FBC Rule out the causes of GI inflammation eg gastroenteritis with microscopy and culture of stool Plain AXR Colonoscopy + biopsy is diagnostic investigation of choice

Question 32

What is seen on plain AXR in ulcerative colitis?

Answer 32

Stool distribution - absent in inflamed colon Thumb print sign - same as the one seen in ischaemic colitis - due to mucosal oedema/haemorrhage Toxic dilatation of the colon (toxic megacolon)

Question 33

What is worrying about toxic megacolon? What is the colonic diameter in this condition?

Answer 33

In very severe cases, the colon becomes atonic, with marked dilatation, worsened by bacterial overgrowth. This leads to toxic megacolon, Toxic megacolon increases the risk of perforation and therefore emergency surgery is advised Transverse colon >6cm in diameter Caecum >9cm in diamter

Question 34

What is seen on endoscopy and on the biopsies taken in ulcerative colitis?

Answer 34

Endoscopy - continous, diffuse disease extending proximally from anal margin Granular mucosa Pseudopolyps may be seen Biopsy - histology Superfical ulceration and inflammation Crypt distortion and abscesses No granulomas

Question 35

What are the complications of UC?

Answer 35

Toxic megacolon - risk of perforation -. EMERGENCY High risk of colon cancer - greater if pancolitis or disease >10 years Venous thromboembolism isk Extra GI manifestations Eyes: Uveitis Liver: Primary sclerosing cholangitis Joints: Arthritis, Ank Spondylitis Skin: Pyoderma gangrenosum, erythema nodusum

Question 36

What is primary sclerosing cholangitis? What is seen on LFTs? Which type of IBD has a greater association with the disease?

Answer 36

Primary sclerosing cholangitis is a chronic inflammatory disorder of the bile ducts resulting in strictures and progressive cholestasis LFTs will show a markedly raised ALP (alkaline phosphate), raised GGT and raised bilirubin - cholestatic pattern ulcerative colitis: 4% of patients with UC have PSC, 80% of patients with PSC have UC Crohn’s (much less common association than UC)

Question 37

How does primary sclerosing cholangitis present? What is a complication of this?

Answer 37

Presents with itch and fatigue and RUQ pain Also jaundice and GI bleeding If advanced, can present with cirrhosis and hepatic failure Complication due to primary sclerosing cholangitis include Increased risk of * Cholangiocarcinoma - a malignant tumour arising from cholangiocytes in the biliary tree * Colorectal cancer

Question 38

Which antibodies are associated with UC/Primary sclerosing cholangitis?

Answer 38

p-ANCA (perinuclear anti-neutrophil cytoplasmic antibodies) aka MPO-ANCA (myloperoxidase anti-neutrophil cytoplasmic antibodies)