GI Flashcards
what disease causes gene defect of UDP enzyme deficiency
crigler najjar - severe form from birth
gilbert syndrome - mild hyperbilirubinaemia
UGT1AT gene defect, causes UDP deficiency
so less bilirubin metabolism causing high UNconjugated bilirubin
what gene defect causes Dublin-johnson syndrome
MRP2 gene defect
what does INR measure
extrinsic coagulation
3+7 -> 10 -> 2 (thrombin) -> 1 (fibrin)
bilirubin/INR measure prognosis
what are time scales for acute, subacute, chronic liver diseases
acute <6wk, subacute 6-25wk, chronic 25+wk
what are the stages of progressive liver disease
normal -> steatohepatitis -> fibrosis ->
(IRREVERSIBLE) cirrhosis -> hepatocellular carcinoma
fibrosis is reversible, cirrhosis is not
cirrhosis is when liver architecture replaced by fibrotic nodules
how does cirrhosis appear on liver US
heterogenous irregular liver
splenomegaly, ascites
how is hepatic fibrosis assessed invasively + non
non:
ALT/AST levels
fibroscan for liver stiffness
FIB-4 scan
ELF test
invasive: biopsy (gold standard)
what are features of decompensated liver disease
jaundice
ascites
vatical bleed/haemorrhage
hepatic encephalopathy
coagulopathy INR >2
what is acute liver failure
jaundice -> encephalopathy within 4wk
no pre-existing liver disease
if pre-existing disease, acute on chronic liver failure instead
what is Budd chiari syndrome
portal vein thrombosis = main vessel to liver
triad - ascites, abdo pain, hepatomegaly
what is screened for in:
hepatitis serology
autoimmune hepatitis
ASH/NASH
PBC
alpha-1 antitrypsin deficiency
wilson disease
hereditary haemochromoatosis
hepatitis: hepA IgM, hepB sAg, hepC Ab, hepE IgM
autoimmune: ANA, anti-smooth muscle, LKM antibodies
ASH/NASH depends on ALT/AST ratio, if ALT high = fatty, if AST high = alcohol
PBC: anti-M2 (mitochondrial)
alpha-1: serum alpha-1 AT, phenotype
wilson: low serum Cu, low serum caeruloplasmin
HH: high serum ferritin
what is autoimmune hepatitis (what is it associated with) and how is it treated
usually affects women
associated with HLA DRB1/3
ANA, anti-smooth muscle, LMK Ab
treat with immunosuppression
what is PBC and how is it treated
usually affects women 40-50yr
causes granulomatous hepatitis affecting interlobular bile ducts
anti-M2
causes jaundice, pruritus/itch
treat with ursodeoxycholic acid (2nd line obtecholic acid)
what is PSC and how is it treated
associated with UC
triggered by bacteria and PAMP entering portal circulation via inflamed intestine
affects intra + extra hepatic bile ducts
biopsy shows concentric fibrosis of intra+extra-hepatic ducts
no effective treatment
increased risk of cholangiocarcinoma
what are congenital cholestatic syndromes
PFIC/PBIC
PFIC1 - ATP8 18q gene = reduced cholesterol secretion into bile
PFC2 - ATP11 2q gene = reduced bile acid secretion into bile, so hepatic BA accumulation and slowed hepatic BA flow
PFC3 - ACB4 7 q gene = less PL secretion, so bile more toxic
how do acute + chronic hepatitis differ
acute 1-3months = more florid
chronic 6month+ = abnormal LFT, positive serology
how many stages of hepatic fibrosis
6
s1-s3 = fibrosis of more portal areas
s4 = fibrosis bridging portal areas
s5 = probable cirrhosis
s6 = confirmed cirrhosis
summarise the different hepatitis viruses
A = acute infection, RNA picornavirus transmitted via faecal/oral route
investigate by checking HepA IgM
B (VACCINE) = acute->chronic, DNA virus transmitted via blood
most common cause globally
investigate with serology
if HepB sAg +ve, then treat (1st line: peginterferon a2, 2nd live: tenofovir/ectovir)
C = chronic, RNA virus transmitted via blood (body fluids - needles, sex OR vertical transmission)
usually IVDU
if HCV RNA +ve, then treat (sofosbuvir)
D = chronic, RNA virus that only infects if HepB also present, so spread via blood
treat with pegylated interferon-a (low success rate)
E = acute, ssRNA spread via faecal-oral route
if pregnant, risk of fulminant hepatitis
how does HBV replicate
DNA virus
via reverse transcription of RNA intermediate
how does immune system down regulate HBV viral replication and protein synthesis
TLR3 recognises HBV’s PAMP with RIG-I signalling
IFN NF-kB activates interferon stimulating genes
these form IFN a/B that reduce viral replication + protein synthesis
also promote adaptive immunity via MHC-class1 expression on APC
causing cell death via perforins
what antibody provides lifelong immunity against HBV
HepB sAb - neutralising Ab against HBsAg that prevents uptake by uninfected hepatocytes
early priming of CD4+ and CD8+ intrehepatically
how does HBV persist to cause chronic infection
HBX protein protects cccDNA, preventing antigen presentation/processing
T-reg express more FoxP3, suppressing CD4/CD8
CD28 upregulated causes apoptosis of HBV specific T cell
IFN-a/y inhibited
what does HBV DNA correlate to
risk of fibrosis + HCC
why does HDV rely on HBV
HDV is an incomplete RNA virus, enclosed in shell of HBsAg
HDV is a satellite virus, so can not make its own viral proteins or replicate independently
how is chronic HBV + HCV treated
HBV - pegylated interferon-a2, tenofovir, ectovir (if HBsAg +ve)
HBV vaccine available
HCV - sofosbuvir (if HCV RNA +ve)
no vaccine for HepC
how does HCV cause chronic infection
RNA virus with rapid replication rate, so high viral load
many mutants (quasi-species that escape immune system) form as high error rate of RNA-polymerase
HCV non-structural viral proteins disrupt RIG-I signalling, inhibiting innate immunity
neutralising Ab develop too slowly and don’t last long
why does HCV re-infection occur
neutralising AB develop too slowly and don’t last long enough
where does HCV replication occur
in cytoplasm only
what are the symptoms of inflammatory diarrhoea
constant diarrhoea
worse when eating
how does inflammation cause diarrhoea
inflammation -> ulcer -> necrosis
disrupts mucosal immunity
so mucous, serum and blood are lost into stool
what are effects of thickened mucosa from inflammation, on absorption
SB - malabsorption of nutrients
LB - poor water reabsorption
what causes inflammatory diarrhoea
bacteria - campylobacter, shigella, salmonella, c.doff, e.coli
parasite - giardiasis
ischaemia - vasculitis
how do Crohn + UC differ
crohn - anywhere in GIT (mouth to anus - perianal disease)
skip lesions with transmural inflammation
crypt hyperplasia
goblet cell hyperplasia
granulomas, lymphoid hyperplasia
strictures, fistulas
UC - only LI, starts distally in rectum then spreads proximally
continuous mucosa/submucosa inflammation
crypt abscess/distortion
goblet cell depletion
on colonoscopy, how do UC + crohn look
UC - pseudopolyp
crohn - cobblestone appearance
what is impact of smoking on IBD
worsens crohn
protective for UC
what is osmotic diarrhoea
osmotic solutes (lactose, bile salts) not absorbed into lumen
so salt/water reabsorption inhibited
MOA for osmotic laxatives - macragol, lactulose, Mg
how to stop osmotic diarrhoea
not eat
what disease causes osmotic diarrhoea
coeliac disease
malabsorption of bile salts prevents salt/water reabsorption
what is coeliac disease
intolerance to dietary gluten
associated with HLA-DQ2/8
damages SI - mainly proximal in jejunum, then extends distally to ileum
how is coeliac disease diagnosed + what is seen on biopsy
initial investigation - TTG IgA Ab, anti-endomysial, anti-gliadin
definitive - endoscopy + jejunal biopsy
shows: crypt hyperplasia, villous atrophy, intra-epithelial lymphocytes, lamina propria inflammation
what is secretory diarrhoea
increased gut secretions - toxin, hormone, stimulant laxative, rectal cancer
does fasting help with secretory diarrhoea
NO
when is an erect CXR + AXR done
erect CXR = free gas, airspace disease (lower lobe pneumonia)
AXR = obstruction, perforation, IBD, calcification
how do SBO + LBO differ on AXR
SBO = centrally dilated loops >3cm, valvulae conniventes - extend full width
LBO = peripherally dilated loops >6cm, haustra
(+associated SBO)
what is triad for gallstone ileus
rigler triad - SBO, pneumobilia (air in bile duct), ectopic gallstone
what is sigmoid volvulus
coffee bean sign
summation line - large bowel gas upstream
what is toxic megacolon
medical emergency - complication of UC
dilated transverse colon
mural oedema, creating thumb-printing
what contrast studies are done for
UGI
LGI
small bowel
UGI - OGD
LGI - colonoscopy, CT colonography, flexi-sigmoidoscopy if volvulus
small bowel - MR enterography
why is a barium swallow done
post-OGD
test for functional disease - benign (achalasia) or malignant
what are the different types of colorectal cancer
colon cancer = laparoscopic surgery, if node -ve then chemotherapy as well
rectal cancer = MRI staging, neo-adjuvant chemo/RT, anterior resection
oligo-metastatic disease = MRI/PET, metastatectomy
widespread metastatic disease = palliative chemo + support
what is histology of colorectal cancer
adenocarcinoma
what is progression of colorectal cancer
progression from normal mucosa -> polyps -> cancer
normal mucosa
APC gene forms initial adenoma
k-RAS gene forms intermediate adenoma
DCC gene causes loss of long-arm of chr18 causes late adenoma
TP53 gene causes loss of short-arm of chr17 causes cancer
what genes are involved in colorectal cancer
APC gene forms initial adenoma (from normal mucosa)
k-RAS gene forms intermediate adenoma
DCC gene causes loss of long-arm of chr18 causes late adenoma
TP53 gene causes loss of short-arm of chr17 causes cancer
what are 6 hallmarks of cancer
1 - sustain proliferative signalling
2 - evade growth suppressors
3 - activate invasion + metastasis
4 - enable replicative immortality
5 - induce angiogenesis
6 - resist apoptosis
what are emerging hallmarks + enabling characteristics of cancer
emerging hallmark: dysregulate cellular energetics, avoid immune destruction
enabling characteristic: tumour-promoting inflammation, genetic instability/mutation
what causes point mutations
accidental silencing (epigenetic loss) of mismatch repair genes
causing point mutations
which 2 hereditary syndromes linked to colorectal cancer
all with AD inheritance
FAP - inherited loss of APC so multiple polyps form during teens, driving further mutation to cause cancer
virtually guaranteed colorectal Ca in 20s so need prophylactic pan-proctocolectomy
Lynch/HNPCC - inherited mutation of MLH1/MSH2 in mismatch repair genes, causes multiple point mutations increasing risk of cancer
colorectal, endometrial, small bowel, pancreatic
(also juvenile polyposis, peutz-jegher syndrome - STK11 mutation)
what cancers affected in Lynch/HNPCC
colorectal, endometrial, small bowel, pancreatic
what are management options for FAP/Lynch
direct referral for genetic testing
(1st degree relative 2-4x risk)
FAP - consider prophylactic pan-colectomy at 40yr
HNPCC - regular screening colonoscopy, preventative treatment with 600mg aspirin daily
where does colorectal cancer metastasise
liver - via portal circulation
lung - via venous circulation
resection/ablation of lung/liver may be curative
what cellular dysfunction occurs in colorectal cancer
activating mutations in k-RAS
esp in polyp -> cancer progression + left-sided or rectal cancers
if right-sided MMR tumour, usually BRAF mutation
how is colorectal cancer classified
with Duke + TNM staging
from Duke C or TNM stage 3, adjuvant chemo needed as lymph node involvement
Duke
A - not beyond muscularis
B - beyond msucularis
C - regional lymph nodes involved
D - distant metastasis
what is colorectal cancer screening
FIT every 2yr for anyone aged 60-74yr
if +ve referred for colonoscopy
if histology +ve, CT TAP to stage
if rectal cancer = MRI/endorectal US to identify local invading disease
what is urgent 2WW for colorectal cancer
> 40yr with weight loss + abdo pain
> 50yr with unexplained rectal bleeding
> 60yr with Fe-deficient anaemia OR changed bowel habit
red-flag: rectal bleeding +
abdo pain, changed bowel habit, weight loss OR Fe-deficient anaemia
how are colon + rectal cancers managed
if stage 1-3 = surgical resection
if stage 3 = surgery + post-op chemotherapy (as lymph nodes involved)
same for rectal cancer
if tumour >8cm from anal canal or in proximal 2/3 of rectum = anterior resection
if tumour <8cm from anal canal or in distal 1/3 rectum = abdomino-perineal resection
