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Gastro BSc > Module 1.2: Coeliac, CRC, IBD + other intestinal > Flashcards

Module 1.2: Coeliac, CRC, IBD + other intestinal Flashcards

1
Q

Define Coeliac Disease.

A

GLUTEN SENSITIVE ENTEROPATHY.

A chronic small intestinal immune mediated enteropathy precipitated by exposure to gluten in genetically suspected individuals

  • Oslo Definitions, Ludvigsson et al, Gut, 2013
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2
Q

Name the three types of gluten

A

A gliadin - wheat
Hordein - barley
Secalin - rye

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3
Q

Frequent features of coeliac (50%)

A 
malaise
diarrhoea
steatorrhoea
weight loss
anaemia
low folate
low Fe
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4
Q

Common features of coeliac (25%)

A 
anorexia
abdo pain
oral ulcers
distension and bloating
flatulence 
low B12
low albumin
low vitD
high PTH
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5
Q

Occasional features of coeliac (<25%)

A 
Nausea
Muscle pains (due to low vitD and Ca)
Tetany
Bone pain
bruising (low vitK)
oedema
constipation
rashes
lymphoma
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6
Q

Endoscopic features of CeD

A

mosaic surface
scalloped (flattened) mucosa

Histology:
subtotal villous atrophy with crypt hyperplasia

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7
Q

Grading system in CeD

A

Marsh Grading, Gastroenterology 1992

0 - Normal mucosa
1 - increased number of intra-epithelial lymphocytes
2 - proliferation of the crypts of liberkuhn
3 - variable villous atrophy
3a - partial
3b - subtotal
3c - totla
4 -hypoplasia of the small bowel architecture

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8
Q

Serology in CeD

A

Antigliadin antibodies
- less specific than endomysial antibodies

Endomysial antibodies

  • IgA class antibodies (except in selective IgA deficiency, then IgG, 1 in 80 people)
  • detected by indirect immunofluorescence
  • high specificity (>95%) and sensitivity

Tissue transglutaminase

  • shown to be the autoantigen recognised by endomysial antibodies
  • tTG cross links glutamine residues including those in gliadin and produces neo-antigens
  • IgA antibodies measured by ELISA (easier than immunofluorescence)
  • tTG done first and endomysial antibodies done second to confirm

Deamidated-gliadin peptide antibodies
- may be as useful as TTG

Volta et al 2010 suggests that the combined search for IgA tTGA and IgG DGP-AGA provides the best diagnostic accuracy for CD

Burgin-Wolf et al, 2002:

  • All those positive for tTG will have positive EMA antibodies
  • Antibodies fall as pts started on gluten free diet”
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9
Q

Diagnosis of CeD in patients

A

ESPGAN working group recommendation, 2012

IF SYMPTOMATIC:
Based on symptoms + positive serology + histology consistent with CeD

If IgA tTG2 Ab titres > 10x upper limit of normal, CeD can be diagnosed without duodenal biopsy by applying strict protocol in further diagnostic tests

IF ASYMPTOMATIC:
based on + serology and histology
HLA-DQ2/8 useful in excluding diagnosis

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10
Q

Prevalence of CD in GP

A

1%

Prevalence of undiagnosed CeD - 10x the general population

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11
Q

Evidence for silent disease in CD

A
  • Dermititis herpetiformis - 30% have no GI symptoms
  • Population screening
  • – Catassi C, 1994 - showed a prevalance of 3.3 per 1000, silent:known cases ratio 1:5
  • – West et al, 2003 - sero-prevalence of 1.2%
  • – Sanders et al, 2003 - 1% prevalence, commoner in IBD, IDA and fatigue)
  • – Bingley et al, 2004 - 1% sero-prevalence at 7 years old, comparable to adults, suggesting you don’t develop CD in adulthood
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12
Q

Groups with prevalence of CeD between 1-5%

A

T1DM
- Cronin et al, 1997

IBS
- Sanders et al, 2007 - OR 7 for coeliacs with IBS

Osteoporosis
- Sanders et al, 2005 - overall 3x increase in CeD prevalence in those with bone problems

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13
Q

Treatment of CeD

A

GLUTEN FREE DIET - no wheat, barley, rye

Treatment of nutrient deficiencies

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14
Q

Complications in CeD

A

Dermatitis Herpetiformis
nutrient malabsorption and impaired nutritional status
Osteoporosis + osteopenia
Small bowel malignancy

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15
Q

Describe dermatitis herpetiformis

A

Vesicular rash
Intense pruritus

On skin biopsy:
- granular IgA deposits

Associated villous atrophy and gluten sensitivity

Can potentially be much worse than intestinal disease

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16
Q

Types of Small bowel malignancy in CeD

A

Lymphoma: EATL - enteropathy associated T-cell Lymphoma

Adenocarcinoma

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17
Q

Pathogenesis of CeD

A

Shan et al, 2002:

PROLAMINES (storage proteins rich in proline (P) and glutamine (Q) ) responsible for majority of immune response.

The tight junctions of enterocytes are disrupted by a2-gliadin –> large peptides can enter circulation

a2-gliadin peptide (glutamine) is DEAMIDATED by TTG to glutamate

the deamidated peptide is ENDOCYTOSED by APC and processed to 3 distinct epitopes, which are presented by either DQ2-a1 or DQ8 presenting proteins, becoming neo-antigens for HLA-restricted T-cell clones.

(95% of pts carry DQ2, 5% DQ8)

Th-Cells are activated

  • Th1 –> cytotoxic apoptosis
  • Th2 –> plasma cell maturation and anti-gliadin and anti-TTG ab production
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18
Q

What is the risk of CeD in first degree relatives?

A

10%
MacDonald et al, 1965

80% concordance in twin studie
Greco et al, 2002

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19
Q

Which chromosome is HLA coded for?

A

6

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20
Q

What are the HLA class I associations in CeD?

A

HLA-A1 and HLA-B8

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21
Q

What are the HLA class II associations in CeD?

A

HLA-DR3 and HLA-DQ2

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22
Q

Describe HLA-DQ2

A

heterodimeric cell surface receptor molecule on lymphocytes, in linkage disequilibrium with all the ones mentioned above.

Most Coeliacs have DQ2 but around 5% are DR4-DQ8 but these individuals have no phenotypic difference in CeD pathology

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23
Q

Describe the evidence for non-HLA genes in CeD

A

HLA-DQ2.5 found in 90% of northern European CeD pts but also in 20% of non-celiac controls.

Concordance in HLA-matched siblings is 30%

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24
Q

Three strategies to map non-HLA genes in CeD

A

GWLS - genome wide linkage studies
Candidate gene analysis
GWAS

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25
Q

non-HLA genes implicated in CeD in GWLS

A

• There were 13 studies with variable, often non-confirmed

o CELIAC 1
HLA implicated in most studies

o CELIAC 2
5q31-33 (cytokine cluster)

o CELIAC 3
2q33 (CD28-CTLA-ICOS region)

o CELIAC 4
19p13.1 (myosin 9B)

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26
Q

Describe the role of 2q33 in CeD

A

3 genes involved in immune processing: CD28, CTLA4, ICOS

CTLA4/CD8 binding regulates T-cell activation
- If there is CTLA4 with no CD8 on a T-cell, there is T-cell anergy

Hunt et al 2008

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27
Q

Describe the role of non-HLA loci within the MHC in CeD

A

strong LD found in the region of extended haplotypes mostly due to DQ2

MICA5.1 allele has shown to have an OR 8.6 in coeliacs
–> INVOLVED IN NK/CD8+ cell binding

Lopez-Vasquez et al, 2002

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28
Q

Describe the role of 19p13.1 in CeD

A

Monsuur 2005
homozygous individuals have a 2.3x higher risk of developing CeD

Von Heel et al 2007
Myosin 9B may have role in actin remodelling

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29
Q

Summarise the findings of candidate gene analysis in CeD

A

HLA class II (DQ2.5)
2q33
MICA
19p13.1

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30
Q

Findings of the CeD GWAS

A

o HLA-DQ2.5cis shown in 89.9% coeliacs patients
o CD28-CTLA4-ICOS region implicated again
o But no association with 19p13.1 (Myo9B)

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31
Q

HLA DQ2 Serotypes

A
  • HLA-DQ (a10501, b102) is a heterodimeric cell surface receptor molecule on lymphocytes
  • It can be encoded in DNA in a:
     - Cis form – polypeptide subunits encoded on the same chromosome
     - -> HLA-DR3 (65-95% of N European patients)

 - Trans form – polypeptide subunits encoded on different chromosomes
       - ->HLA-DR5/DR7 (Mediterranean patients)
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32
Q

Function of Chromosome 4q27 in CeD

A

o Demonstrated further risk variants in region harbouring IL2 and IL21

o Rs13119723 = best marker
o Rs6822844 = strongest association overall in combined cohorts, coeliacs have the major allele in recent meta-analysis

o IL21

  • Enhances B, T, NK cell proliferation + IFNy production
  • Implicated in intestinal inflammation
  • Greatly increased expression in untreated coeliac

o IL2

  • Key cytokine for T cell activation and proliferation
  • Modest reduction in untreated coeliac
  • Synthetic region in mouse (Idd3) determines susceptibility to autoimmune diseases in the NOD mouse by influencing IL2 mRNA/protein level and CD4+ and CD25+ regulatory T cell activity

o KIAA1109

  • Modest reduction in untreated coeliac
  • Unknown function

o TENR/ADAD1
- Expressed in testes

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33
Q

Summary of initial coeliac genetic studies

A
  • HLA-DQ
  • IL2 – IL21
  • 7 more risk variants and regions identified by GWAS
  • Genes from 8 regions involved in immune response
  • 4 of 9 regions overlap with T1DM
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34
Q

Further GWAS in CeD, Trynka et al 2009

A

• Further GWAS follow up found 2 novel coeliac regions:
o 6q23.3 (OKIG3-TNFAIP3)
o 2p16.1 (REL)

both involved in the NFkB pathway

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35
Q

Other environmental factors affecting development of coeliac

A

•Gluten

•Weaning and tolerance
o	DAISY study revealed age of exposure to wheat, barley or rye was important:
o	1-3m = 23 hazard ratio
o	4-6m = 1 (all good)
o	Over 7m = 4 hazard ratio

•Influences at time of exposure
o Rotavirus infection increases risk of coeliacs in children
- DAISY study revealed multiple infections with rotavirus in children increased risk ratio of coeliacs

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36
Q

Summarise the inherited predispositions to CRC

A
  1. Mendelian Dominant
    - FAP
    - Lynch snydrome
  2. Mendelian Recessive
    - MYH associated polyposis
  3. Rare low penetrance variants
    - APC T3920A
  4. Common low penetrance variants
    - identified by GWAS
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37
Q

What % of CRC risk is genetic?

A

15% - Nordic twin studies, Mucci et al 2016

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38
Q

Summarise the features of FAP

A

Autosomal dominant
>100 polyps/adenomas
Will progress to CRC by 40-45y
10% has no FHx –> High mutation rate

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39
Q

Extracolonic features of FAP

A

GARDNER’S –> Osteomas and epidermoid cysts

TURCOT’S –> medulloblastomas

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40
Q

Summarise the features of APC mutations

A

APC is a tumour suppressor gene on Ch5
1st hit = genetic
2nd hit = inactivates the normal allele

Controls proliferation of colonic epithelial cells via the Wnt pathway which affects Myc expression

Occurs early in tumorigenesis

APC is frequently mutated in sporadic CRC

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41
Q

Types of mutation in APC

A

TRUNCATING MUTATIONS –> polyposis (avg age 40)

POINT MUTATIONS (e.g. T3920A) –> fewer polyps

3’ and 5’ mutations –> attenuated polyposis (avg age 50-60)

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42
Q

Management of FAP

A

referral to genetic/polyposis registry of the family

full colectomy if polyposis arises

There may be a role for aspirin in FAP

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43
Q

Summarise the features of Lynch Syndrome

A

Autosomal dominant

early age of onset

Lifetime risk of CRC is 35% and endometrial cancer of 34% - Bonadona et al 2011

NICE: all those diagnoses with CRC tested for this

2-3% of CRCs - Hampel et al 2005

Right sided - 2/3 occur in proximal colon

Caused by defective DNA mismatch repair, which leads to diploid tumours with MICROSATELLITE INSTABILITY

proportion of BRCA1 and BRCA2 mutations in those with Lynch syndrome - Yurgelin et al 2015

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44
Q

Genes involved in Lynch Syndrome

A

MLH1 + PMS2 - lost together
MSH2 + MSH6 - lost together
EPCAM

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45
Q

Lynch Classification

A

Lynch I - Familial colon cancer

Lynch II - other cancers of the GI, extra colonic sites: endometrial, ovarian, small bowel, ureter, renal pelvis

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46
Q

Diagnosis of Lynch syndrome

A

Genetic testing - MSI profiling - BAT25 used to identify MSI

Immunohistochemistry for mismatch repair gene expression

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47
Q

Management of Lynch syndrome

A

GENETIC TESTING of family members!!!

Colonoscopy every 2 years

Surveillance for associated cancers

Risk reducing surgery - esp oophorectomy and hysterectomy for women who have had families

Chemoprevention studies:

  • CAPP2, Burn et al 2009/2011
  • – Aspirin usage can reduce risk by up to 50% in 6y
  • – No difference at 2y
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48
Q

Name 4 hmartomatous polyposis syndromes and their causative genes

A

Peutz-Jeghers - LKB1 pathway

Juvenile Polyposis - SMAD4 pathway 20% and BMPR1A in 20%

Cowden’s - PTEN

Hereditary mixed polyposis - GREM1

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49
Q

Summarise the features of MYH associated polyposis

A

only autosomal recessive inherited CRC

mutation: DNA base excision repair gene which repairs oxidative damage
- Due to transversion

Multiple adenomas

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50
Q

What is transversion and transition

A

Transversion: purine to pyrimidine or vice versa

Transition: purine to purine or prymidine to prymidine

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51
Q

Summarise the genetic pathways in CRC tumorigenesis

A

CHROMOSOMAL INSTABILITY (85%)

  • APC gene mutation
  • Aneuploid tumours
  • Growth control genes e.g APC, GREM1

MICROTELLATE INSTABILITY

  • methylation MLH1 gene promoter
  • diploid tumours
  • DNA repair:
    • mismatch repair
    • base excision repair
    • polymerase proofing
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52
Q

Roles of POLE and POLD1 in CRC

A

POLD1 - encodes DNA polymerase delta catalytic subunit enzyme

POLE - encodes DNA polymerase epsilon enzyme

Both involved in DNA replication and repair

Mutations in them occur in the PROOFREADING domains leading to a DEFECT IN CORRECTION OF MISPAIRED BASES

These tumours are MICROSATTELITE STABLE

MSI is the phenotypic evidence that DNA mismatch repair is not functioning

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53
Q

Summarise PPAP

A

Polymerase proofreading associated polyposis

multiple adenomas
early onset CRC
duodenal adenomas and carcinomas
POLD1 endometrial cancers
accellerated tumourigenesis
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54
Q

Two types of CRC according to Cancer Genome Atlas 2012

A

NON-HYPERMUTABLE - 84%

  • chromosomal instability
  • <1 mutation/10^6 bases

HYPERMUTABLE - 16%

  • MSI/diploid
  • – 75% hypermethylation of MLH1 mismatch repair gene
  • – 25% mutation o POLE (MS stable)
  • > 100 mutations/10^6 bases
  • fare better with chemo
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55
Q

Explain the role of immunotherapy and personalised medicine in CRC

A

hypermutable cancers have many somatic mutations that lead to multiple new non-self antigens

these tumours are characterised by lymphocyte infiltration

these can be targeted by immunotherapy

PROGRAMME DEATH 1 PATHWAY is an immune checkpoint that prevents autoimmunity. This is upregulated in MSI tumours to prevent cytotoxic cells from killing tumour cells

PEMBROLIZUMAB - PD1 checkpoint inhibitor -> 80% response rate and increases survival to 40%

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56
Q

Definition of phenotype

A

the physical characteristics of something living resulting from the interaction between its environment and genetic make-up

57
Q

Phenotypes of Crohn’s

A 
Sometimes spares rectum
Mouth-to-anus
transmural (full thickness)
patchy (skip lesions)
F>M 3:2
granulomas in 60%
fistulae and strictures common
58
Q

Phenotypes of UC

A 
always involves rectum
confined to colon
superficial
continuous
M=F
no granulomas
fistulae and strictures rare
59
Q

Advantages of phenotyping

A

provide an insight into pathogenesis with respect to genetic predisposition

defining responses to treatment and so enabling clincians to offer the right treatment

help define prognostics, improving the Tx plan

60
Q

Disadvantages of phenotyping

A

concept defined by humans so may not represent all biologically important categories

may change over time so only true for a particular instance

61
Q

Vienna and Montreal Classification for Crohn’s

A 
VIENNA 
- Age
A1 below 40
A2 above 40
- Location
L1 ileal
L2 colonic
L3 ileocolonic
L4 upper
- Behaviour
B1 non-stricturing
B2 stricturing
B3 penetrating
MONTREAL
- Age
A1 below 16
A2 16-40
A3 40+
- Location
L1 ileal
L2 colonic
L3 ileocolonic
L4 isolated upper disease (modifier that can be added to L1-L3)
- Behaviour
B1 non-stricturing
B2 stricturing
B3 penetrating
p Perianal disease modifier (can be added to B1-B3)
62
Q

Montreal Classification of UC

A

EXTENT and SEVERITY

E1 - ulcerative procritis
E2 - left sided (distal) UC
E3 - extensive UC - pancolitis

S0 - clinical remission - asymptomatic
S1 - mild UC - passage of 4 or less stools/day with out without blood, no systemic illness and normal ESR
S2 - moderate UC - +4 passage/day, minimal systemic toxicity
S3 - severe UC - at least 6 bloody stools/day, pulse +90 bpm, temp >37.5, Hb <10.5, ESR >30

63
Q

Antibodies implicated in UC and Crohns:

A 
UC = pANCA
crohns = ASCA
64
Q

examples to the genes implicated in IBD

A

NOD2, HLA, ATG

65
Q

What are the methods available to investigate the aetiology of IBD

A
  • genetic studies
  • studies of bacterial flora - difficult as only 40% can be colonised
  • surrogate markers
  • mechanistic studies
66
Q

Summarise the extraintestinal manifestations of IBD (KEY KNOWLEDGE)

A

Arthritis - axial (ankylosing spondylitis) or peripheral

Skin - erythema nodosum, pyoderma gangrenosum
– erythema nodosum: up to 10% of patients, raised nodules on shins, associated with HLA-B62

Eyes - anterior uveitis, episcleritis, iritis
— associated with HLA-B27, HLA-B58, HLA-DR103

Liver - PSC, autoimmune hepatitis

67
Q

Summarise the two types of peripheral arthopathies in UC and Crohn

A

TYPE 1 - UC - pauciarticular

  • less than 5 joints
  • self-limiting episodes
  • associated with HLA-B27 and HLA-DR103

TYPE 2 - Crohns - polyarticular

  • more than 5 joints
  • persistent symptoms independent of IBD
  • associated with HLA-B44
68
Q

Define Linkage disequilibrium and its significance in IBD.

A

the likelihood of two genes being inherited together

The genes that determine the individual EIMs might be in LD

TNFa its between HLA-DR and HLA-B, close to MICA

  • TNFa is proinflammatory cytokine. Treatment with infliximab is effective in Crohns, RA and AS
  • – explains overlapping clinical syndromes in practice
69
Q

Describe the role of IBD1/NOD2 in IBD

A

Ogura and Hugot 2001:

NOD2 is the specific gene whose frameshift mutation incurs suceptibility to Crohns

    • LRRs interact with bacteria LPS
  • – once the LPS is bound to LRRS on NOD2, this oligomerises and binds to CARD ROCK.
  • – Rick then oligomerises to transmit the signal to IKK complex, activating NFkB pathway –> cytokine secretion

Revised studies suggest that these have a truncated NOD2 which downregulates NFkB activity and the immun sytstem???

poorly understood

70
Q

Give examples to the enviornmental factors influencing IBD

A

smoking
appendicectomy
vit D

Microbiota

71
Q

Epidemiology of UC and CD

A

West > East
North > South
UC > CD
-Rising incidence in the east –> westernisation Ng Sc, 2013

72
Q

How does population movement affect the prevalence of IBD?

A

Li X et al 2011

first generation immigrants from low incidence countries show low incidence compared to native population

Benchimol et al 2015

younger age at time of arrival to western country increased risk to that of native country

children born to immigrants in western country had the same incidence as native children

73
Q

Effect of smoking on IBD and why?

A

Mahid SS et al 2007

Makes you suceptible to CD (OR 1.76) and less suceptible to UC (OR 0.58)

Smoking increases NO in endothelial cells –> increansed guy permeability –> access to immune cells granted to microbiota –> inflammation

Also alters microbiota

74
Q

Effect of appendicectomies on IBD and why?

A

protective in UC

Andersson et al 2001

increased risk of CD with appendicectomies that drops over time

Kaplan et al 2008

May be due to alteration to microbiota and hense to immune response following appendicectomy –> Roblin 2012

75
Q

Effect of vitamin D on IBD and why?

A

higher levels of Vit D –> reduced risk of CD

76
Q

Effect of microbiota on IBD and why?

A

altered composition of gut flora in IBD

  • reduction in diversity - Frank et al 2007
  • reduction in beneifical species - Sartor 2008
  • Increase in pathogenic species - Feller 2007
77
Q

Describe how the microbiota directs immune response in IBD

A

affected by the number of IL-17/Th17 cells in the mucosa

T0 cells, if primed by IL-23, cause a Th17 response. If primed by IL-2, cause a Th1 response. Both are pro-inflammatory.

Th17 cells are potent effectors of inflammation

Differentiation from naive T-cells require TGFb, IL-6, IL-21, and IL-23

they produce pro-inflammatory IL-17 and IL-22 –> role in patholgenesis of Crohns

Th17 cells do not develop in the absence of microbiota

78
Q

Autophagy in IBD

A

ATG16L1 codes for mechanisms of autophagy

essential process for maintenance of cellular homeostasis

engulf waste and deliver to lysosome for degradation

Phases: initiation–> nucleation –> elongation –> maturbation

ATG16L1 is important in elongation and cargo selection

If one has defective autopahgy –> defective homeostasis in the intestines

  • – increased bacterial permeability
  • – decreased bacterial defense
  • – decreased bacterial clearance
  • – decreased peripheral T-cell numbers
  • – decreased Ab production
  • – Expansion of microbiota
79
Q

Describe the familial aggregation of IBD

A

5-22% have an IBD-affected relative

1st degree relatives have 10-15x increased risk (more CD than UC)

TWIN CONCORDANCE - BMJ 1996
Monozygotic twins:
- CD 35%, UC 11%

Dizygotic twins:
- CD 7%, UC 3%

80
Q

Examples to genes of interest in CD

A

CARD15 (NOD2)
ATG26L1
IL23R
TLLs

81
Q

Examples to genes of interest in UC

A

HLA II

IL23R

82
Q

Role of CARD15/NOD2 in CD

A

CARD15 encodes NOD2 on ch16

There are three main variants of this gene

x1 NOD2 variation increases CD risk x2-4
x2 NOD2 variation increased CD risk x20-40

These variants aren’t present in Asian CD pts –> there are other genes

83
Q

Describe the function of CARD15/NOD2

A

codes for a protein present in monocytes, macrophages, Dendritic cells, epithelial and paneth cells

Involved in recognising bacterial MDP through its LRRs –> NFkB secretion to protect host from invasion

The variants cause a loss of function of this pathway –> decreased clearance of bacteria

84
Q

Role of ATG16L1 in CD

A

found on ch2

protein forms part of autophagy complex

variant has reduced capacity to capture bacteria

85
Q

Role of IL23R in IBD

A

variant present in 14% of healthy europeans

associated with DECREASED risk of IBD –> PROTECTIVE

IL23 is a pro-inflammatory cytokine

86
Q

Role of Toll Like Receptors in CD

A

TLR4 recognises LPS in G-ve bacterial cell walls

Polymorphysm increases CD risk

TKR5 recognises flagellin on motile gut bacteria

Polymorphysim protective in CD

87
Q

Role of HLA Region IBD3 in IBD

A

Chr6

IBD associated with HLA II

Chrohns with:

  • DRB*0701
  • DRB1*0103
  • DRB1*04

UC with:

  • DRB1*0103
  • DRB1*1502

It is likely that HLA genes play a disease-modifying role rather than affecting suceptibility

88
Q

summarise the anatomy of the small intestine

A

villous hight about 3x crypt depth

muscularis mucosa

Another layer of muscles found in human: transverse and longitudinal muscles involved in pushing contents along

mucosal surface amplified by folds of Kerkring (x3), villi (x10) and microvilli (x20) so total surface area >200m2

89
Q

Mechanisms of absorption in the small intestine

A

Disgestive enzymes: gastric, intestinal and pancreatic + biliary secretions

transport of products through the intestinal mucosa

Villous tip

  • ACTIVE TRANSPORT
  • abundant brush border hydroxylases, high nutrient transporter and involved in water and ion absorption

Crypt

  • high secretion of net water and ions
  • highly permeable
  • passive permeability
90
Q

Where are stem cells found in the small intestine

A

3-4 cells up from the crypt

91
Q

What types of cells can small intestinal stem cells make?

A

Enteroendocrine cells - involved in making gastrin, GIP, GLP1/2, PYY, secretin

Goblet cells - produce mucus

Absorptive enterocytes

Paneth cells

M-cells - involved in immune system (antigen sampling) - Peyer’s patch in ileum

92
Q

What are other cell types that originate elsewhere in the body in the small intestine?

A 
intraepithelial lymphocytes
lamina propria lymphocytes
DCs
monocytes
myofibroblasts
vascular and lymphatic cells
neuronal cells - two plexi that allow movement of contents: myoenteric and submucosal plexi
93
Q

Describe the process of cell turnover in the small intestine

A

cell death occurs at the top of villi

Stem cells divide and move up from crypt to the tip of villi to replace those lost

Turnover time: 48-72h

No of cells lost = no of cels formed

Cells are linked up in a linear fashion

94
Q

Describe the locations of absorption of different nutrients in the small intestine

A

glucose: mainly in duodenum and jejunun with little in ileum
protein: mostly in jejunum and ileum, 20% not absorbed
fat: most in jejunum, some in ileum, 5% not absorbed

95
Q

Describe the digestive process in the stomach

A

food enters digestive system

VAGUS leads to production of ACh –> HISTAMINE production –> GASTRIN production (in antrum)

Parietal cells make H+ –> low pH

pepsinogen I and I made to be activated later

Fundic cells make gastric lipase –> Some lipolysis in stomach (20-30%)

Triglycerides + phospholipids –> diglycerides + FAs

Most lipolysis in JEJUNUM

96
Q

Describe the process of JEJUNAL lipolysis

A

COLIPASE: TG –> FA + MG

PHOSPHOLIPASE A2: PL –> FA + lysolecithin

CHOLESTEROL ESTERASE: cholesterol ester –> FA + cholesterol

These are then put into mycelles which carry lipids to BRUSH BORDER by FACILITATED DIFFUSION and bind to specific transporters allowing to move into enterocytes

Inside enterocytes, lipids are RE-ESTERIFIED –> TG + PL + CE reformed into a lipid vesicle

(enterocytes only form chylomicrons and VLDL)

LIPID VESICLES come together with APOLIPOPROTEINS (formed in ER)

Travel to golgi –> form secretory vesicle containing chylomicrons and VLDL

fuse with cell membrane and release chylomicrons and VLDL

go into LACTEAL and into LYMPHATIC SYSTEM –> released to blood

97
Q

Describe the structure of mycelles

A

hydrophilic -OH outside, lipophilic parts inside lipid bilayers with lipids carried in the centre

98
Q

Describe the different classes of amino acids

A

All proteins have an -NH2 an a -COOH side chain

ACIDIC: glutamine, glutamate, aspartate

BASIC: Lysine, hystadine

NEUTRAL:

  • aliphatic: leucine, valine
  • aromatic: tyrosine, tryptophan
  • Imino: glycine, proline
  • Sulfur: cyteine, methionine
99
Q

How many AAs are there?

How many essential AAs are there?

A

21

8

100
Q

Describe the process of proteolysis

A

ENTEROPEPTIDASE activates trypsinogen –> trypsin

Trypsin activates all other pro-proteases to their active forms:
Chymotrypsinogen –> chymotrypsin
Proelastase –> elastase
Procarboxypeptidase A/B –> carboxypeptidase A/B

NOTE: carboxypeptidases are EXOPEPTIDASES - they work on the end of the chain

Proteins are split up into peptides and aa’s

These are further broken down to oligopeptides

AA diffuse via specific transporters into villus capillaries at the basolateral membrane

Once these diffuse into the blood, the liver breaks them down further

AA transporters can be proton-coupled OR sodium coupled

The transport across the membrane is:

  • active transport
  • facilitated diffusion
  • passive transport
  • vectorial flow
101
Q

Describe the different pumps and their uses in the GI system

A

these pumps are ATPases

Na/K ATPase –> uses 30% of ATP production in the body. K into cell, Na out

Ca2+ ATPase –> 1000fold difference between inside and outside

H+/K+ ATPase –> works in the stomach to produce low pH

Pumps for counter-transport:

  • Na+/H+
  • Cl-/HCO3-
  • – these use existing gradients to exchange molecules

Co-transport:

  • Na+/glucose cotransporter (SGLT1)
  • Na+/AA cotransport
  • H+/AA cotransport

Passive transport:

  • Ca channels
  • K channels
102
Q

Describe the role of the Na/K/2Cl cotransporter in the small intestine

A

important in JEJUNUM

Cl- exits enterocytes at the apical membrane via passive transport through a channel.

K+ exits through a channel on the apical membrane whilst Na is pumped out using Na+/K+ ATPase

In CF, there are problems regulating this Cl channel

103
Q

Summarise the absorption of nutrients in the intestines

A

sugars:

broken down to glucose, galactose and fructose by enzymes at the brush border. these come into the cell via channels or co-transported with Na

Proteins:

broken down by proteases on the brush border and enter the cell via Na+ or H+ coupled absorption. Peptidases break these down in enterocytes to AA which are taken out of cell to blood via channels

Fats:

broken down on the brush border into FA + MG and transported into enterocyte via transporters (FATptr). Then attached to a FABP to allow them to be present in cytoplasm. The apolipoptoteins are transported to golgi via MTTP. Both APOs and FAs join in Golgi to make TGs

104
Q

Describe the means of abnormal digestion in the intestines

A

reduced gastric tissue/secretion
loss of pancreatic tissue
impaired bile secretion
reduction in intestinal brush-border enzymes

105
Q

Describe the means of abnormal absorption in the intestines

A

loss of functional enterocytes
pre and post mucosal effects
single gene disorders

106
Q

Describe the tests for malabsorption

A

Tubeless tests

  • Xylose absorption
  • pancreolauryl test
  • schilling test

Fecal Pancreatic Elastasr 2

  • stable during passage through GI.
  • small sample of stool collected
  • high sensitivity and specificity to diagnose pancreatic insufficiency
  • values below 200ug elastase/g stool indicate exocrine insufficiency
107
Q

Explain how B12 insufficiency can be assessed

A

MACROCYTOSIS or NEURO SYMPTOMS –> measure B12

If B12 LOW:
- Intrinsic factor +ve –> pernicious anaemia

  • Pt pregnant –> discuss with haematologist
  • IF -ve –> consider other causes
  • – gastric/ileal/pancreatic disease
  • – drug induced (PPI, H2 receptor antagonists, chronic alcoholism)
  • – dietary (strict vegan)
  • – biological competition (bacterial overgrowth, fish tapeworm infestation)
108
Q

Causes of malabsorption

A

Coeliac (most common)

Small bowel bacteria overgrowth - caused by fistulae e.g. crohns, strictures, impaired peristalsis

Pancreatic insufficiency

LESS COMMON:
chronic infections, lymphoma, radiation enteritis, intestinal lymphangiectasia, drugs, allergic, immunodeficiency

109
Q

Describe abetalipoproteinaemia

A

recessive

presents in early childhood

malabsorption of fat and fat-soluble vitamins

Abnormal MTTP –> failure to form chylomicrons and subsequent fat droplets in enterocytes

due to mutations in Apo-B gene (C -> T)

110
Q

Explain the prinicples of the sugar breath test in lactose intolerance

A

H2 produced by bacterial action on sugars

Fasting breath H2 <20 ppm

Sugar taken by mouth

Breath samples every 30m for 2-3h

increase of 20 ppm significant

Lactose is ingested orally. When it reaches the caecum, if it has not been absorbed, then lactobacilli will use this to make H2

Low lactase activity in the small intestinal brush-border membrane results in failure to digest lactose

111
Q

Describe the mechanisms of lactase persistance

A

Neonates have high lactase

Lactase non-persistance is the usual adult human phenotype worldwide

Lactase persistance occurs in most Northern Europeans

Majority of those affected with lactose intolerance originate from Asian/African countries

The tolerance of lactose has allowed for the domestication of dairy animals which have provided milk–> transition from hunter-gatherer to agriculture

Genetic basis of lactase persistance
Protein active in childhood but not in adults
polymorphysms in laftase gene

Heterozygote studies showed cid acting elements
Transcription factors regulating expression of lactase

DEVELOPMENTAL SWITCHES

Enattah 2002 - polymorphysm associated with persistance/non-persistnce in Finnish population

112
Q

Describe the findings of Glucose-Hydrogen breath test for small intestinal bacterial overgrowth

A

Breath H2 high

small intestinal bacterial count is high

Some glucose is metabolised to H2

113
Q

Causes of small intestinal bacterial overgrowth

A 
gastric surgery
jejunal diverticula
intestinal blind loops after surgery
intestinal strictures
fistulae 
impaired peristalsis
114
Q

Describe the principles of the lactulose hydrogen breath test

A

lactulose not digested or absorbed by small intestine

Broken down by bacteria to give H2

Rise in breath H2 measures

115
Q

Examples to functional GI disorders

A

psychogenic vomiting
functional dyspepsia
chronic abdo pain
IBS

116
Q

Describe the classification

A

ROMA IV

A. Oesophageal

B. Gastroduodenal

C. Bowel
— IBS

D. Centrally Mediated Disorders of GI pain

E. Gallbladder and sphincter of oddi

F. Anorectal

G. Neonate/Toddler

H: Child/Adolescent

117
Q

Summarise the epidemiology of IBS

A

WW prevalence 11.2%

Incidence 1.35-1.5%

F>M

Younger people more likely to be affeced

118
Q

Summarise the types of IBS

A

Abdominal pain AND bloating

  • gas production - MAJOR factor
  • bacterial fermentation
  • rapid small bowel transit
  • Visceral hypersensitivity

Can be classed as

  • CONSTIPATION PREDOMINANT
  • DIARRHOEA PREDOMINANT
  • MIXED
119
Q

What are the functional bowel disorders as classified by Rome IV?

A

C1 - IBS
C2 - functional constipation
C3 - functional diarrhoea
C4 - functional abdominal bloating/distension
C5 - unspecified functional bowel disorders
C6 - opiod induced constipation

120
Q

What are the diagnostic criteria for IBS?

A

recrurrent abdominal pain on average 1/week in the last 3 months

AND at least 2 of:

  • related to defecation
  • change in frequency of stool
  • change in appearance of stool

Diagnosis of a functional bowel disorder –> presumes absence of a structural or biochemical explanation

121
Q

Summarise the Bristol Stool Chart

A 
Type 1 - like nuts
Type 2 - sausage shape, lumpy
Type 3 - sausage with cracks
Type 4 - sausage, smooth and soft
Type 5 - soft blobs, clear edges
Type 6 - fluffy pieces with ragged edges, mushy
Type 7 - watery, no solid pieces
122
Q

Symptoms associated with IBS-related psychiatric disorders

A 
panic disorder
palpitations
early insomnia
ruminative thinking
diaphoresis
constant worries
agoraphobia
depression
change in appetite
late insomnia
loss of interest
loss of libido
fatigue
123
Q

Investigations and Tx in diarrhoea predominant IBS

A

Nat Rev Gastroenterol Hepatol 2014

Exclude carcinoma!!! - faecal calprotectin, colonoscopy etc

Exclude coeliac & other malabsorption - TTG Abs etc

Consider spurious diarrhoea - colonic transit x-ray

Consider bile acid diarrhoea - SeHCAT

Anti-diarrhoeals - loperimide, codeine

Psychological support

consider dietary review and modifications

124
Q

Describe the dietary factors in IBS

A

Constipation predominant: water, fibre

Diarrhoea predominant: lactose, fat/bile malabsorption

Abdo pain and bloating: meal size, gas consumption, gas production

125
Q

Summarise the Tx of constipation predominant IBS

A

exclude obstruction, hypothyroid, drugs
increase fibre and fluid

BULKING AGENTS: ispaghula, cellulose

Osmotic laxatives: Mg2+ salts, lactulose, movicol

evacuation assessment, biofeedback/training

psychological support

126
Q

Summarise the Tx of abdominal pain/bloating in IBS

A

exclude obstruction, ulcers, gallstones, ischaemia, chronic pancreatitis

dietetic advice - meal size, gas consumption

Treat constipation/urgency/diarrhoea

Anti-spasmodics - MEBEVERINE

Anticholinergics/SSRIs

CBT to deal with pain

127
Q

What are FODMAPs?

A 
Fermentable oligosaccharides (fructose, galactose)
Disaccharides (lactose)
Monosaccharides (fluctose)
and
Polyols (sorbitol)
128
Q

How can FODMAPs contribute to the symptoms of IBS

A
  • being osmotically active –> increased water delivery –> luminal distension
  • by being rapidly fermented –> increased gas production –> luminal distension

luminal distension can cause motility changes, bloating, pain and wind

Found by Staudacher 2012 that fermentable carb restriction improved bloating, urgency and overall symptoms

129
Q

What are the Rome criteria on the diagnosis and Tx of functional constipation?

A

straining 25% of the time
lumpy hard stool 25% of the time
sensation of incomplete emptying 25% of the time
Anorectal obstruction sensation in 25% of the time
manual manouvers to facilitate 25% of the time
fever than 3 defecations/week

any 2 of the above + insufficient criteria for IBS

Tx:
exclude obstruction
diet: fibre + fluids
bulking agents: ispaghula, cellulose
omotic laxatives
psychological support
130
Q

Diagnostic Rome criteria for functional bloating

A

BOTH of

  • recurrent bloating OR distension >1d/week
  • insufficient criteria for a diagnosis of IBS, functional constipation/diarrhoea or postprandial distress syndrome
131
Q

Diagnostic Rome criteria for functional diarrhoea

A

loose mushy or watery stools WITHOUT PAIN in > 25% of defecations

132
Q

Describe the normal bile acid homeostasis

A

bile acids synthesised in liver from cholesterol

conjugates with glycine or taurine

secreted via biliary tree into small intestine

there they solubilise lipids in micelles

REABSORPTION

  • passively in jejunum if unconjugated
  • actively in ileum if conjugated

Then reuptake by hepatocytes from blood and resecreted

133
Q

How is bile acid diarrhoea classified?

A

Fromm & Malavolti 1986

TYPE 1: SECONDARY
- ileal resection, ileal disease (Crohns), bypass

TYPE 2: PRIMARY

  • idiopathic BA malabsorption
  • primary BA diarrhoea

TYPE 3: MISC
- radiation enteropathy, post-cholecystectomy, ulcer surgery, chronic pancreatitis, coeliac disease, SIBO

134
Q

Describe the mechanism of bile acid diarrhoea

A

Waters 2014

Excess bile acids in colon
o Unabsorbed by the small intestine?
o Increased production?

Bacterial transformation of bile acids
o Deconjugation + dehydroxylation

Stimulation of colonic secretion if bile acid accumulates in the colon
o Anion secretion
o Watery stool

135
Q

Diagnosis of bile acid malabsorption

A

Walters et al 2010

Fecal bile acids

  • 24h stool collection
  • unpopular as it’s not easy for pt or staff

SeHCAT

  • synthetic 75Se radiolabelled bile acid analogue
  • detected by g-camera
  • limited radiation exposure
  • measure bile acid retention
  • – 7 day retention normal >15% hense <10% is diagnostic

7a-hydroxy-4-cholesten-3-one (C4) = CYP7A1 product
o Measure of bile acid synthesis
o Measured by HPLC
o Inversely correlates with SeHCAT

136
Q

Possible mehcanisms of bile acid diarrhoea

A

Secondary (Type 1)
- Surgical removal of functioning ileal tissue/inflammatory changes leading to impaired ileal gene expression/

Primary (Type 2)
- Normal structure and function but abnormal transporter function perhaps due to mutant proteins or reduced expression

137
Q

Summarise the absorption of bile acids in the ileum

A

SLC10A2 gene (apical sodium-dependent transporter – ASBT + ileal bile acid transporter – IBAT)

FABP6 gene (ileal lipid binding protein – ILBP + ileal bile acid binding protein – IBABP)

OST-alpha/OST-beta heterodimer

Idiopathic bile acid malabsorption may be caused by

  • Defective BA transport (rare cases of ABST mutations)
  • However there is evidence of normal BA uptake in biopsies hence it may be to do with:
  • – Rapid small intestinal transit time in vivo
  • – Deconjugation
  • – Changes in BA pool size
  • Decreased FGF19, which regulates BA synthesis

Normally BA binds FXR which upregulates FGF19 expression/secretion

  • In the liver FGF19 binds FGFR4 which activates, this increases SHP which represses BA synthesis
  • In decreased FGF19 there would be increased bile acid synthesis leading to more entering the colon → secretory diarrhoea
138
Q

Summarise the treatment of bile acid diarrhoea

A

BILE ACID SEQUESTERANTS - Hofmann 1969

Questeran & Cholestid = powders
Choestagel = tablet

poor long-term compliance
bloating may worsen
can bind other drugs
optimal dosing uncertain

Gastro BSc (13 decks)

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