Lower GI Tract Flashcards
What does the lower GI tract consist of anatomically?
Specifically the large bowel
Cecum (and appendix) –> ascending colon –> transverse colon –> descending colon –> sigmoid colon –> rectum –> anus
What is the blood supply to the ileum and colon?
Ileum - supplied by branches of the superior mesenteric artery (SMA)
Colon - supplied by branches of the SMA and inferior mesenteric artery (IMA) covers left side of colon
Venous uptake from bowel is through the superior mesenteric vein (SMV) and inferior mesenteric vein (IMV) that join the portal vein which then join the inferior vena cava (IVC)
What are the 4 layers of the colon, starting from innermost to outermost?
Innermost
Mucosa - continuous with the epithelium; contains many glands to produce mucin = important in lubricating bowel = easier to pass stool
Submucosa - between the mucosa and muscularis layer; contains the submucosal plexus = enteric nerve supply (e.g. regulating GI blood flow, epithelial function etc.)
Muscularis - made up of the inner circular and outer longitudinal muscles; contains the myenteric plexus = nerve supply for controlling GI motility
Serosa - like a duvet over the other layers containing the blood vessels and nerves
Outermost
What is the sympathetic and parasympathetic nerve supply to the colon?
Parasympathetic:
Vagus = ascending colon and most of transverse colon
Pelvic nerves = more distal colon
Sympathetic:
Lower thoracic and upper lumbar spinal cord
Somatic motor fibres of pedunal nerves = external anal sphincter
What is the enteric NS composed of?
Why is the ENS important (especially in the rectum)?
Afferent sensory neurons detect pressure
Myenteric plexus in the muscularis layer
Important because:
Pressure detectors send signals to brain - important for emptying process of rectum (i.e. when to poop)
Important in Hirschsprung’s disease (no enteric intramural ganglia) - causes problems passing stool
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What are the 6 types of Lower GI disorders and what are some examples of each?
- Inflammatory
- Inflammatory Bowel Disease (IBD)
- Microscopic colitis
- Infective
- C Diff
- E Coli .. etc
- Structural
- Diverticular disease
- Haemorrhoids
- Fissures
- Functional
- Irritable bowel syndrome
- Neoplastic
- Colonic polyps & colon cancer
- Other
- Neurological, metabolic & vascular
What is inflammatory bowel disease (IBD)?
Comprised of Crohn’s disease and Ulcerative colitis
Lifelong chronic disease characterised by inflammation in the bowel, often affecting young people
What is the peidemiology of IBD?
Affects 1.5 million people in America and 2.2 million in Europe
New Zealand and Australia have particularly high rates of IBD
Several hundred thousand more worldwide
Why is IBD increasing worldwide?
Increasing number of IBD worldwide
Mixing of genetic pool, migration and movement of people
What is the health burden of IBD?
Due to chronicness of disease, patients require lifelong treatment
This is a huge health burden = Burden of therapy for patients Hospitalisation Surgery Health-related quality of life Economic productivity Social functioning
What are the 2 types of IBD?
What are their characteristics?
Ulcerative colitis (UC):
Inflammatory disorder limited to the colonic mucosa
Superficial
Continuous
Always involves the rectum
Affects males and females equally
No granulomas
Crohn’s disease (CD):
Can affect any part of the GI tract - anywhere from the mouth to the anus
Deep ulcerations and deep involvement of the mucosa
Patchy chronic transmural granulomatous inflammation (patchy = different segments of the colon)
Tendency to form fistula or strictures - strictures = fibrous, stiff tissue due to exposure to severe inflammation
Females more affected than males (1.5:1)
What are the main differences of UC vs CD?
UC vs CD
Continuous vs patchy
Superficial vs deep inflammation / penetration
Always involves rectum vs any part of digestive tract but often segments of the small and large intestine
Can type of IBD change?
Yes, patients can present with UC, then CD, and they can switch between them
What are the different types of UC?
Always involves the rectum
Proctitis = only rectum
Protosigmoiditis = rectum and sigmoid
Distal colitis = rectum, sigmoid and descending colon
Extensive colitis = rectum, sigmoid, descending and transverse colon
Pancolitis = rectum, sigmoid, descending, transverse, ascending, caecum, and appendix
What are the different types of CD?
Patchy = combination of different segments of the colon
What are the symptoms of IBD?
They depend on the side of inflammation:
Collitis = bleeding, mucus, urgency to pass stool, diarrhoea
Perianal (CD only) = anal pain, leakage, difficulty passing stool
Small bowel disease (CD only) = symptoms relate to lack of absorption of nutrients = abdominal pain, weight loss, tiredness / lethargy, diarrhoea, abdominal mass
Why does IBD present at sites outside of the colon / GI tract?
As it is an autoimmune condition - can affect other sites
What are some extra-intestinal manifestations of IBD?
Arthritis =
Axial – Ankylosing Spondylitis
Peripheral
Skin =
Erythema nodosum
Pyoderma gangrenosum
Eyes =
Anterior uveitis
Episcleritis/Iritis
Liver =
Primary Sclerosing Cholangitis (PSC)
Autoimmune hepatitis
What causes IBD?
Still unknown
A final common pathway that reflects a combination of an impaired mucosal immune response to the gut microbiota in a genetically susceptible host = in certain patients, the immune system responds inappropriately to the gut microbiota
What factors contribute the development of IBD?
Genetic susceptibility = NOD2, HLA, ATG, Il23R
Immune response = anti-saccaromyces cervisiae (ASCA) - Crohn’s; pANCA - UC
Environmental factors = diet, mycobacterium paratuberculosi, MMR?
Why does diet affect the development of IBD?
Diet affects gut microbiota
Results in dysbiosis i.e. unhealthy gut microbiota
Why factors can be protective to developing IBD?
Why do patients with appendectomy not develop UC but can develop CD?
Physically active
Those who have and appendectomies do not get UC
Oddly, smoking - patients who stop smoking can develop IBD, although smoking worsens IBD once it develops
Apprendix = holds many of the gut microbiota
What are the risk factors for developing a poor, unbalanced microbiota?
How does a poor, unbalanced gut microbiota affect IBD development?
Lack of vitamin D exposure Overly hygienic Stress Genetic susceptibility Gut microbiome Medications - e.g. antibiotics Poor diet Appendectomy - develop CD, never UC
All can contribute to development of poor and unbalanced gut microbiota, which then triggers immune response leading to autoimmunity, allergy and metabolic disorders
What are the goals of IBD management?
Induce clinical remission
Maintain clinical remission
Improve patient quality of life
Heal mucosa
Decrease hospitalisation/ surgery & overall cost
Minimise disease and therapy related complications
What are the main medications used for the management of IBD?
Steroids
5 ASA - 5 amino salicylic acids
Immune suppressants e.g. azathioprine, methotreaxate
Biologic therapies
Others – diet, FMT, antibiotics, probiotics, novel agents
Why are steroids used to treat IBD?
How do they work, how are they given to patients and how are they used?
Steroids diffuse and bind in nucleus to Glucocorticoid Responsive Elements (GRE)
GREs interact with specific DNA sequences to:
Increase anti-inflammatory gene products
Block pro-inflammatory genes
Mode of Delivery = IV, oral or rectal enemas
They are usually used:
As a bridge to other therapy/interventions
In acutely unwell patients - induce healing
Steroids stop working in the long-term, so only useful short term
Steroids also have side effects with long term use - musculoskeletal, endocrine, psychological etc.
Why are 5 ASAs used?
How do they work and how are they given to patients?
Main action = inhibition of pro-inflammatory cytokines (IL-1 and TNF-a )
Inhibition of the lipo-oxygenase pathway i.e. prostaglandin and leukotrienes
Scavenging of free radicals
Inhibition of NF-kB/ TLR via PPAR-gamma induction (perioxisome proliferator activated receptor-gamma)
Some immunosuppresive activity – inhibiting T cell proliferation, activation and differentiation
Impairs neutrophil chemotaxis and activation
Mode of Delivery = orally or rectal
What are the side effects of 5 ASA?
Intolerance Diarrhoea Renal impairment Headache Malaise Pancreatitis Pneumonitis
Why is the immunosuppressor azathioprine used?
How does it work?
Lessens immune function - suppresses the immune reaction / inflammation in IBD
6-TG is the active metabolite of Azathioprine i.e. AZA –> 6-MP –> 6TMP –>6-TG
6-TG interferes with adenine and guanine ribonucleotide production
Results in reduced number of B and T lymphocytes, immunoglobulins and interleukins
Another pathway potentially results in apoptosis of T cells
What is checked in patients before administering azathioprine and why?
AZA (azathioprine)–> 6MP
6MP can then either be converted by the TPMT enzyme to 6-MMP, or it can be converted to 6-TG by the MPRT enzyme
So the TPMT enzyme is checked in all patients - if it is low, majority of the aza is coverted to 6-TG
6-TG is the active component of immunosuppression
So before starting a patient on Azathioprine, it is important to check their TMPT funciton as if it is high, they could develop serious side effects from 6-MMP (which is hepatotoxic)
What are the side effects of Azathioprine?
Second malignancies - skin cancer, lymphoma Bone marrow suppression Pancreatitis Infection Hepato-toxicity Allergic reactions
What is checked in IBD patients being given Azathioprine?
Thiopurine Methyltransferase (TPMT) Hep B/C HIV Chicken pox Vaccinations TB Frequent bloods on starting Maintenance bloods
These diseases can be reactivated with that level of immunosuppression - often given anti-virals for hep b/c reactivation
How does methotrexate work?
Mechanism not clear
Interferes with DNA synthesis & cell reproduction
Increased adenosine levels (anti-inflammatory)
Increased apoptosis of peripheral T cells
Takes around 3 months to work
How should the drug be delivered and monitored?
What can be given to help reduce side effects?
Weekly dose - need history re liver abnormalities, need to monitor LFTs, FBC
Advised not to be taken during pregnancy
Folic acid supplements (reduces side effects)
What are the side effects of methotrexate?
Rash Nausea, mucositis Diarrohea Bone marrow suppression Hypersensitivity pneumonitis Increased liver enzymes Hepatic fibrosis/cirrhosis Known abortifacient (causing abortion) No documented increased risk of lymphoma or skin cancer
What biologic durgs ar used to treat IBD?
TNF-alpha is the main pathway involved in IBD, therefore anti-TNF-a is used – infliximab, adalimumab
Anti- α4β7 Vedolizumab
Anti-IL12/IL23 Ustekinumab
More on the way to being discovered / developed
How are infliximad and adalimunab administered to patients?
IV - infliximab
in hospital – less frequent
Induction 0,2,6 weeks
Maintenance 8 weekly
subcutaneous injection - adalimumab (humira)
160/80/ 40mg EOW
At home – more frequent
What are the side effects of biologics?
Opportunistic infections Infusion or site reactions Infusion reactions Neutropenia Infections Demyelinating disease Heart failure (HF) Cutaneous reactions, including psoriasis Malignancy Induction of autoimmunity
How is IBD managed clinically?
Combination therapy = AZA/ 6MP and aTNF act synergistically
Combination is superior in inducing and maintaining response and remission
Reduces the rate of antibody formation
Other medications =
Cilosporin
Vedolizumab (anti-integrin)
Ustekinemab (anti IL12/23)
What other considerations can be made when managing IBD?
Dietary therapy = Liquid therapy diet Increased use in children As effective as steroids Use in small bowel Crohns disease Weeks
Antibiotics =
No hard evidence
Good for sepsis
Faecal Microbiota Transplantation (FMT) =
Lots research into the role of the microbiome
Novel agents
