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Syndrome: unknown pathogenesis, cluster of symptoms

Disorder: set condition, known cause and pathogenesis

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Most common functional GI disorder

In Western populations: 1/5 report symptoms consistent with IBS

50% consult doctor

30% are referred to specialist

40% are diagnosed in gastroenterology clinics with IBS

Seeking help depends on

illness attitude scores

anxiety and depression scores

amount and severity of symptoms

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Declining/low ovarian hormone levels in women (ie during menses): contribute to occurrence/exacerbation of GI symptoms (ie. abdominal pain, discomfort, altered bowel habits, bloating) → varies across menstrual cycle phases

40% of women with IBS report influence of the menstrual cycle on their symptoms

high ovarian hormones levels → in rodents = reduce somatic and visceral pain sensitivity

hyperestrogenemia and hyperprogesteronemia a prolonged GI transit is also observed

chronic pain syndromes frequently associated with IBS, like migraine headache for example, are alleviated during the time of pregnancy

Variations in ovarian hormones modulate visceral pain perception. It also modulates susceptibility to stress, a pivotal factor in IBS occurrence and symptom severity. Hyperresponsiveness to stress promotes immune activation and impairs gut barrier function.

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Process of nutrient absorption in intestines

highly innervated and integrated

feedback system to ensure balance

1. Digestion

Nutrient absorption begins with the process of digestion, which involves breaking down complex food molecules into smaller, absorbable units. Digestion primarily occurs in the lumen of the small intestine and is facilitated by various enzymes secreted by the pancreas, liver (via bile), and intestinal mucosa.

2. Transport

From lumen into epithelium.

3. Assimilation

Once inside the epithelial cells, absorbed nutrients undergo assimilation, where they are either utilized for energy production, stored, or used for various metabolic processes.

Glucose, amino acids, and short-chain fatty acids are absorbed into the bloodstream and transported to various tissues for energy production or storage.

Some nutrients, like vitamins and minerals, are directly utilized by the epithelial cells or transported to other tissues for specific functions.

4. Transport in blood or lymph

After assimilation, nutrients are transported away from the small intestine to other tissues and organs through either the bloodstream or the lymphatic system.

Water-soluble nutrients, such as glucose and amino acids, are primarily transported via the bloodstream (systemic circulation) to the liver and then distributed to other tissues.

Lipids, including long-chain fatty acids and fat-soluble vitamins, are absorbed into the lymphatic system (lacteals) as chylomicrons, which are large lipid particles, and then transported via the lymphatic vessels to the bloodstream (thoracic duct), eventually reaching the liver and peripheral tissues.

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1. Inner mucosa

villi (finger-like surfaces) - increase surface area for absorption

enterocytes have microvilli to further increase surface area

a) Lamina propria

b) Muscularis mucosae

2. Submucosa

contains large blood and lymph vessels

nervous system is integrated

a) Submucosal plexsus

3. Muscularis externa

a) circular muscles

thicker

b) longitudinal muscles

thinner

outer layer

4. Serosa

connective tissue

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Enterocytes / simple columnar epithelium

used for absorption

Goblet cells

mucus production

Paneth cells

host defence and immunity

secrete anti-microbial peptides and other molecules to protect host against infection

Tuft cells

produce IL-25

ISC (intestinal stem cells)

regenerates every 48 hrs

Enteroendocrine cells

produce hormones

somatostatin

CCK

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Somatostatin- blocks secretion of other hormones (e.g. gastrin, bicarbonate) + inhibits CCK

CCK - promotes food delivery from stomach into small intestine

Serotonin - regulation and secretion in digestion process of GI

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Large intestine

more goblet cells

less enterocytes (most food has been absorbed)

thicker muscle layer (needs more contraction)

absorption water and electrolytes

Small intestine

absorption of nutrients and water (80%?)

production hormones

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HDL (good - transport lipids to liver for breakdown) LDL (bad - goes from liver towards bloodstream) + VLDL (bad)

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Carbohydrates

1. Starch broken down to oligo, di and mono- triglycerades, first by salivary amalyse, and then finally by pancreatic amylase

2. Absorbed through SGLT (sodium-dependent-glucose transporter)

Proteins

1. Digestion Begins: Protein digestion begins in the stomach with the action of pepsin, which breaks down proteins into smaller polypeptides and some amino acids.

2. Continued Breakdown: In the small intestine, pancreatic proteases (trypsin, chymotrypsin, and carboxypeptidase) further hydrolyze polypeptides into smaller peptides and free amino acids.

3. Final Digestion: Brush border enzymes like aminopeptidase and dipeptidase on the surface of enterocytes complete protein digestion by breaking down dipeptides and tripeptides into amino acids for absorption.

4. Absorption: Amino acids and small peptides are absorbed into enterocytes via specific transporters, then transported into the bloodstream for utilization by the body.

Fats (lipids)

DEMI

1. Emulsification by bile

2. Digestion by pancreatic lipase (hydrolysis to triglyceride and fatty acids)

3. Absorption of products of fat digestion depends on size

Water and electrolytes

1. small intestines absorb 8-9L water per day along with electrolytes

2. large intestines absorb

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Enteric nervous system: division of the autonomic nervous system that serves as the local neural control centre of the GI tract

a) Myenteric plexus - responsible for motility

b) Submucosal plexus - responsible for secretion of hormones

Motility: contraction of smooth muscles of GIT

1. move food from mouth to anus

2. mechanically mixing food to break into small particles

Types of contractions (peristalsis)

1. Circular

2. Segmental

Fasting

Phase 1: period of motor inactivity - 90 min

Phase 2: irregular contractible activity - 90 min

Phase 3: regular phasic contractions - 5-10 bursts, 90 min

During eating these phases are disrupted

After a meal = MMC pattern is disrupted → now irregular contractions (lasts 2-5 hours after meal)

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Effects of hormones during pregnancy on GIT

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Effects of hormones during pregnancy on GIT

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Dynamic changes in ovarian hormones during menstrual cycle can modulate GI contractility, transit, secretion, visceral sensitivity, and immune function

Late gastric emptying (Demi) - progesteron slows digestion

Elevated levels of hormones, such as progesterone, contribute to delayed gastric emptying. Gastric acidity is increased because of the higher production of gastrin by the placenta

Higher gastric acidity - due to higher production gastrin

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Coexisting

chronic fatigue syndrome

fibromyalgia

temporomandibular joint dysfunction

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Common factors

infectious diarrhoea precedes onset of symptoms in 7-30% of patients

stress or adverse life events often precede onset of IBS

Risk factors

female

severity and duration of diarrhoea

pre-existing adverse life events

high hypochondriacal anxiety and neurotic scores at time of initial illness

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1st: assess presence of alarm symptoms

2nd: lab tests to exclude other causes of symptoms

3rd: apply ROME-IV criteria

Rome IV 2016

In preceding 3 months, at least 1 day per week in last 3 months of recurrent abdominal pain

and 2(+):

1. related to defacation

2. onset associated with change in frequency of stool

3. onset associated with change in form (appearance) of stool

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Some common ones (these must be excluded before diagnosis of IBS is made!!):

Crohn’s disease

Celiac disease (duodenal biopsy)

Lactose intolerance (allergy testing)

Ulcerative colitis

Colon carcinoma, 50+ y.o. (colonoscopy)

Small intestine bacterial overgrowth (stool culture)

Drug effects

Parasites (stool ocp)

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Subtypes

IBS-C

mostly constipation

less than 25% loose and watery stool

IBS-D

mostly diarrhoea

IBS-M

more than 25% lumpy and more than 25% watery stool

Unsubtyped IBS

insufficient abnormalities of stool deficiencies

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Based on clinical judgement

Thorough investigation is required if patients meets criteria + one of:

rectal bleeding (hematochezia)

nocturnal pain

fever

weight loss

clinical suspicion of organic diarrhoea

raised calprotectin or lactoferrin (indicates inflammation)

family history colon cancer

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Major forms

1. Crohn's Disease (CD) - affects any part of GIT

2. Ulcerative Colitis (UC) - affects colon

Other types

3. Colitis undetermined (indeterminate colitis)

10% of cases of IBD

when definitive diagnosis is not possible due to overlap

4. Microscopic colitis

absence of macroscopic evidence of inflammaiton

a) lymphocytic type

b) collagenous type

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highest incidence in Northern Europe, UK and North America

race and ethnic origin affect incidence and prevalence

lower in Hispanic and Asian people compared to White

Jewish are more prone

increasing incidence in traditional low-prevalence areas (e.g. South-East Asia)

disease onset in youth is more extensive and aggresive

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unknown

interaction between several co-factors

genetic susceptibility (largest independent risk factor -1/5 have 1st degree relative)

environment

intestinal microbiota

host immune response

Environmental factors

Smoking

CD: exacerbates and shows increased risk of recurrence after surgery

UC: increased risk in non-/ex-smokers

UC: nicotine can be effective treatment

NSAIDS

trigger onset of IBD

can cause flares of disease in established diagnoses

Hygiene (you might die before x_x)

poor and large families living in crowded conditions have lower risk of CD

clean environment - intestinal immune system gets no exposure to pathogenic or non-pathogenic microorganisms which alters balance between effector and regulatory immune responses

Nutritional factors

many food (components) are suggested as playing a role in aetiopathogenesis (e.g. high sugar and fat intake)

breast-feeding may provide protection against development of IBD (CD) in offspring

Psychological factors

chronic stress and depression increase relapse in patients with quiescent disease

Appendicectomy (UC)

protective against development of UC - particularly if performed for appendicitis or mesenteric lymphadenitis before 20 y/o

influences the clinical course of UC

lower incidence of colectomy

reduced need for immunosuppressive therapy

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Disturbed balance of IS leading to inflammatory bowel disease (IBD)

genetic component

environmental component - can trigger onset of inflammation

Target of treatment - immune system

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Incidence

varies from country to coutnry

4-10 per 100 000 annually

Prevalence

25-100 per 100 000 annually

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Genetics

NOD1 (CARD 15) gene - expressed in epithelial cells, macrophages and endothelial cells

autophagy genes

Th17 pathway (IL-13 type 17 helper T cells)

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Macroscopic

chronic inflammatory condition

may affect any part of GIT (mouth - anus)

particular tendency to affect terminal ileum and ascending colon (ileocolonic disease)

can involve

1 small area

multiple areas with normal bowel in between (= skip lesions)

whole colon (= total colitis)

cobblestone appearance

sometimes w/o macroscopic small bowel involvement

Biopsy: transmural damage - associated with development of perianal fistulae and fissures

Microscopic

• inflammation extend through all layers (= transmural) of bowel

• increase in chronic inflammatory cell epithelioid hyperplasia

• 50-60% - granulomas - non-caveating epithelioid cell aggregates with Langhans’ giant cells

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Major symptoms

Diarrhoea

80%

usually contains blood (therefore difficult to differentiate from UC)

steatorrhoea (small bowel disease) - fatty poop

due to bile acid malabsorption - as a consequence of ileal resection of ileal disease

Abdominal pain

colicky (indicates obstruction)

Weight loss

Constitutional symptoms of malaise (in 15% of patients)

lethargy

anorexia

nausea

vomitting

low-grade fever

NO GI SYMPTOMS

Children

reduced growth velocity

delayed puberty

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Severely decreased QOL

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Physical signs

weight loss

signs of malnutrition

aphthous ulceration of mouth

occasional tenderness or right iliac fossa mass on abdominal examination

anus: oedematous anal tags, fissures or perianal abscesses

extra-intestinal features

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1. Blood test

Anaemia

common

may be normocytic, normochromic or chronic disease

deficiency of iron/folate or vitamin B12 (unusual)

serum B12 may be low

Raised ESR and CRP

and raised white cell and platelet counts

Hypoalbuminaemia

present in severe disease as part of acute phase response to inflammation associated with raised CRP

Abnormal liver chemistry

Blood cultures

required if septicaemia suspected

Serological tests

ANCA (-)

ASCA (+)

2. Stool test

C. difficile toxin assay - if diarrhoea is present

microscopy for parasites - relevant travel history

raised faecal calprotectin and lactoferrin in active intestinal disease

calprotectin is useful in monitoring IBD

3. Colonoscopy

if colonic involvement is suspected - except in patients with severe diseases (-> limited unprepared sigmoidoscope)

Endoscopic assessment of terminal ileum if CD is suspected

2 biopsies in 5 areas (including rectum and terminal ileum)

Findings

mild, patchy. superficial (apthoid) ulceration

more widespread, larger and deeper ulcers producing cobblestone appearance

4. Upper gastrointestinal endoscopy

required to exclude oesophageal and gastroduodenal disease in patients with relevant symptoms

increasingly performed in all patients to define extent of disease as guide for prognosis

5. Small bowel imaging

mandatory in patients with suspected CD

depends on availability and local expertise

a) barium swallow-through

b) CT scan with oral contrast

c) small bowel ultrasound

d) MRI enteroclysis

e) axial imaging (preferred in acute situations)

Findings

symmetrical alternation of mucosal pattern with deep ulceration

areas of narrowing or stricturing

skips lesions between normal and affected bowel sites

6. Ultrasound scanning

provides convenient radiation-free method for assessing disease activity in ileum and colon

can be performed at bedsite

7. Perianal MRI or endoanal ultrasound

evaluate perianal disease

8. Capsule endoscopy

CD patients - when radiological examination is normal

often 1st performed to exclude strictures of small bowel that would constitute a contraindication to subsequent capsule endoscopy

9. Radionuclide scans - with indium- or technetium-labelled leucocytes

used in some centres to identify small intestinal and colonic disease inflammation

to localise extra-intestinal abscesses

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1. Glucocorticosteroids

most effective

quick response

moderate-severe attacks

2. Aminosalicylates

not very effective against Crohn's

more effective in UC

3. Antibiotics

4. Exclusive enteral nutrition

5. Refractory of fulminant disease

6. Surgery

cannot always be cured because of inflammation

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Incidence

stable

6-15 per 100 000 annually

Prevalence

80-150 per 100 000 annually

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Genetics

mutations in genes associated with mucosal barrier

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therapy targeting central and end-organ pathways

investigate alarm symptoms

Lifestyle and dietary modifications

in case of mild-moderate symptoms

Low FODMAP

Consume soluble fiber

Peppermint oil

relaxes smooth muscle, targeting spasms

Pharmacological therapy

for those who fail to respond or have more severe symptoms

tricyclic anti-depressants

Gut-directed psychotherapy

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Macroscopic

can affect

rectum (= proctitis)

extend proximally from anus to involve sigmoid and descending colon (= left-sided colitis)

whole colon (= extensive colitis)

Microscopic

superficial inflammation limited to mucosa

chronic inflammatory cell infiltrate in lamina propria

crypt abscesses and goblet cell depletion

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Active disease

ulceration

Inactive

atrophy

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can be mild, moderate or severe

most patients have a course of remissions and exacerbations

General features (not as severe as CD)

diarrhoea with blood and mucus, sometimes with lower abdominal discomfort

malaise

lethargy

anorexia with weight loss

aphthous ulceration in mouth

Proctitis

limited to rectum

frequent passage

urgency

tenesmus

normally few constitutional symptoms

stool may be solid (when passed)

great inconvenience by frequency of defecation

Acute attack of left-sided or extensive UC

bloody diarrhoea

passing up to 10-20 liquid stools per day

diarrhoea at night

severely disabling urgency and incontinence

require urgent admission for intensive therapy

Toxic megacolon

serious complication associated with acute severe colitis

plain abdominal X-ray:

dilated, thin-walled colon

diameter +6 cm

gas-filled

contains mucosal islands

dangerous stage of advanced disease

impending perforation

high mortality (15-25%)

urgent surgery -> toxic dilation not resolved in 48 hrs with intensive therapy

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Infectious colitis (e.g. C. difficile and cytomegalovirus)

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1. Blood test

White cell and platelet counts

raised in moderate-severe attacks

iron deficiency anaemia is present

ESR and CRP

often raised

liver biochemistry may be abnormal with hypoalbuminaemia occurring in severe disease

pANCA

may be positive

contrary to CD (pANCA is usually negative)

2. Stool test

always performed to exclude infective causes of colitis

microscopy to exclude amoebiasis in patients with a relevant travel history

faecal calprotectin/lactoferrin elevated

3. Colonoscopy

endoscopy with mucosal biopsy (GOLD STANDARD)

allows assessment of disease activity and extent

long-term colitis -> chromoendoscopy - diagnose dysplasia

don't perform in severe attacks of disease for fear of perforation -> limited unprepared flexible sigmoidoscopy to confirm diagnosis

Chromoendoscopy

4. Imaging

Plain abdominal X-ray

patients suffering acute severe attacks to exclude colonic dilation

extent of disease is not reliably assessed

Other imaging modalities are rarely used

Ultrasound

inflammation of colonic wall

presence of free fluid within abdominal cavity

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don't use corticosteroids

1. Aminosalicylate

2. Proctitis

rectal 5-ASA suppositories: 1st line treatment

oral 5-ASA can be added to increase remission rates

3. Left-sided colitis

topical 5-ASA enemas: 1st line treatment

addition of oral 5-ASA will increase remission rates

do not respond: oral prednisolone

4. Extensive colitis

oral 5-ASA

addition of 5-ASA enema increases remission rates

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Occur in both diseases

Joint complications are most common

Type 1 (pauciarticular) - acute attack and self-limiting (less than 10 weeks)

Type 2 (polyarticular) - last longer and is independent of IBD

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Pain/gas/bloat syndrome / midgut dysmotility 

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Pain/gas/bloat syndrome / midgut dysmotility 

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Disordered motility and visceral sensation, predominantly affecting small intestines or midgut

Symptoms

pain and bloating w/o altered defecation

postprandial fullness

nausea

anorexia and weight loss

Management

not easy as it can be chronic and severe

1. Avoid narcotics

2. Combine central and end-organ-targeted treatment

3. Non-absorbed antibiotics (rifaximin)

4. FODMAP (fermentable oligo-di and monosaccharides and polyols)

alter fermentable components of diet by excluding certain food types (e.g. garlic, onion, wheat-containing products, etc.)

5. Probiotics

no clear efficacy

might help reduce pain, bloating and flatulence

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Symptoms in absence of abdominal pain

passage of several stools in rapid succession, 1st thing in the morning and no further bowel action later that day OR defecation only after meals

1st stool is formed, after that mushy, looser or watery

urgency for defecation

anxiety and uncertainty about bowel function and restriction of movement

exhaustion after defecation

Treat

loperamide combined with tricyclic antidepressants prescribed at night

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High volume (>1L) of diarrhoa

most commonly in females who surreptitiously take high-dose purgatives and are often extensively investigated for chronic diarrhoea

lower serum potassium

often occurs in association with eating disorders

patients might need psychiatric help

Diagnosis

biochemical analysis of stool

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exclude other causes of diarrhoea

always perform stool cultures

Symptoms persisting beyond 5 days - unlikely caused by infective gastroenteritis

Relevant travel history - stool microscopy for parasitic diseases (amoebiasis)

Vitamin malabsorption or malnourishment - consider CD

Children with reduced growth velocity - consider CD

Illeocolonic tuberculosis

common in developing countries (India)

make diagnosis CD difficult

microscopy and culture for TB of any available tissue

therapeutic trial anti-TB therapy may be required

Lymphomas

can occasionally involve ileum and caecum (rare)

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Infliximab - DMARD (Disease Modifying Anti-Rheumatic Drug), reduce immune system response to attacking healthy tissues (biologic agent)

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Surgery

is not curing in CD

can cure in UC - but weigh benefits