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Y2S1- Neuro, GI, Liver > Gastrointestinal > Flashcards

Flashcards in Gastrointestinal Deck (293)
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general anatomy of liver

• Large, lobated exocrine and blood-processing gland, with vessels and ducts entering and leaving at the porta.
• Enclosed by a thin collagen tissue capsule, mostly covered by mesothelium.
• Collagen tissue of the branching vascular system provides gross support.
• Parenchymal cells are supported by fine reticular fibres


blood supply of liver

The portal vein brings 75% of blood (filled with nutrients) to the liver while the hepatic artery (oxygenated blood) brings 25%.


nerve supply of liver

sympathetic & parasympathetic supply of perivascular structures but very little at sinusoidal level


hepatic lobule structure

consists of hexagonal plates of hepatocytes stacked on top of each other. Within each plate, the hepatocytes radiate outwards from a central vein
Hepatic sinusoids travel between the strips of hepatocytes, draining into the central vein


hepatic lobule structure

There are hepatic lobules in each segment of the liver. They are formed from hexagonal shapes and in each corner there is a hepatic artery, portal vein and a bile duct. In the middle there is a central vein for drainage.
Hepatic sinusoids travel between the strips of hepatocytes, draining into the central vein


types of liver blood vessels

a) Central vein / terminal hepatic venule - very thin wall; lies in the centre of a lobule, with sinusoids converging towards and opening into it.
(b) Sublobular/intercalated vein - thicker wall; lies alone at the periphery of the lobule.
(c) Branch of portal vein - again at the periphery of the lobule, but accompanied by one or more small hepatic arteries/arterioles, one or more bile ducts/ductules lined by cuboidal epithelium, and lymphatics.


Hepatic lobular blood flow is:

(a) from branches of the portal vein and hepatic artery; from the periphery towards the centre (mixed so blood is oxygenated and rich in nutrients)
(b) in the sinusoids, between the cell plates.
(c) Blood collected in central veins goes to sublobular veins, then to collecting veins, and then hepatic veins leaving the liver.


Rappaport's liver acinus=

functional unit comprising parts of three or so lobules.
tries to explain differences in exposure to the blood supply among various parts of lobules.
Such differences are reflected in varied functional activities and degrees of susceptibility to toxic agents - a metabolic zonation.


Acinus territories

• 1 periportal
• 2 intermediate
• 3 perivenous (close to the central vein) zones, with the initial periportal zone being roughly spheroid, and isolated from periportal zones of adjacent acini.
Acinus with different areas of metabolic function of hepatocytes


where are undifferentiated stem cells in the liver?

In the periportal area, there are more undifferentiated stem cells that are ready to differentiate if there is evidence of liver damage.


Sinusoids =

low pressure vascular channels that receive blood from terminal branches of the hepatic artery and portal vein at the periphery of lobules and deliver it into central veins


what are liver sinusoids lined by?

fenestrated endothelial cells, loosely attached and rest on microvilli of underlying hepatic cells, without a basal lamina intervening


what do sinusoids hold?

hold phagocytic Kupffer cells (larger, stellate, with a pale oval nucleus)


Space of Disse

• Plasma can pass through the sieve plate, formed by the lining cells, out into the perisinusoidal space of Disse to interact with the hepatocytes. Some of this fluid may pass to the periphery of the lobule to be collected as lymph.
• Disse's 'space' contains ECM materials, but not a visible basal lamina.


hepatic sinusoid detoxification process

• Sinusoids are lined by highly specialised fenestrated liver sinusoidal endothelial cells (LSECs) which maintain blood cells in the sinusoid but allow passage of substances (<200 nm) and exosomes into the space of Disse
• Process ensures exposure of these particles to hepatocytes and stellate cells within the space of Disse, allowing hepatocytes to perform their crucial role within the liver of maintaining metabolic homeostasis, storing nutrients, secreting bile and detoxifying drugs


hepatocytes structure and arrangement

The cells are polygonal in shape and their sides can be in contact either with sinusoids (sinusoidal face) or neighbouring hepatocytes (lateral faces).
- A portion of the lateral faces of hepatocytes is modified to form bile canaliculi. Microvilli are present abundantly on the sinusoidal face and project sparsely into bile canaliculi.
- Hepatocyte nuclei are distinctly round, with one or two prominent nucleoli, majority of cells have a single nucleus, but binucleate cells are common


liver cirrhosis pathophysiology

many inflammatory cells circulate the sinusoids, the Kupffer cells get activate and stellate cells get activated and produce collagen
Fenestrations start closing up because of collagen deposition  sinusoidal pressure builds up  many hepatocytes die, other hepatocytes are surrounded by fibrous tissue (all gates close)


liver lymphatic system

- Lymph is formed by filtration of plasma into the spaces of Disse as blood flows through the sinusoids.
- Then lymph percolates between the space of Disse and portal tracts then lymphatics are formed that run along portal vessels and biliary ducts.


bile pathway

Bile caniculi join together to form bile ductules → bile ducts in portal tracts in periphery of lobule → intrahepatic bile ducts that join to form hepatic ducts leaving each lobe


bile duct epithelium

- Bile ducts' epithelium changes to columnar mucous cells and, extrahepatically, the ducts acquire smooth muscle as well as collagen tissue.


when does the cystic duct allow bile reflux into the gallbladder?

- Cystic duct allows reflux into the gallbladder, when sphincter of Oddi at the duodenal outlet of the common bile duct is closed.


microbial food poisoning

acute gastroenteritis due to eating (or drinking) food containing microorganisms or their toxic products


characteristics of campylobacter species

microaerophilic, gram negative curved rods, grow well at 42°C


C. jejuni and C. coli food poisoning

- Associated with poultry (frozen), wild birds and other animals- milk and water
- Sporadic
- Incubation: 24-72h, duration: 1 week
- Symptoms: diarrhoea, sever stomach cramps
Rare but significant cause of Guillain-Barre Syndrome (peripheral neuropathy)


Non-typhi Salmonella spp food poisoning

- Associated with poultry/eggs
- Sporadic and outbreaks
- Incubation: 6-48h, duration: 1-7 days
- Often serious: fever, diarrhoea, vomiting


Clostridium Perfringens food poisoning

- Associated with bulk cooking of meat
- Often large outbreaks.
- Incubation: 8-22h; duration: 1-2 days
- Severe abdominal cramps with diarrhoea
- Warm food - contamination by spores which germinate


pathophysiology of Clostridium Perfringens

• A culture of vegetative bacteria is ingested
• Bacteria sporulate in small intestine and produce an enterotoxin
• Destruction of villus tips with resultant pain and diarrhoea


toxins of common food poisoning agents

• Botulism= neurotoxins
• Staphylococcal enterotoxins= classic superantigens
• Bacillus cereus enterotoxins
• Mycotoxins
• Paralytic shellfish intoxications


Clostridium Botulinum food poisoning

- Anaerobic, spore-forming, types A-G
- Widely distributed in nature
- Produces the most powerful natural toxin (1mg lethal for 200000 mice or one human)
- Causes classical food-borne intoxication (Botulism), rare wound botulism, infant botulism and equine grass sickness


Staphylococcus Aureus food poisoning

- Common skin organism
- Contaminates salted foods and dairy produce
- Incubation: 2-6 h; Duration: 1-24 h
• Very acute vomiting response often followed by diarrhoea
• Staph enterotoxins are bacterial superantigens


Bacillus Cereus food poisoning and pathophysiology

- Often associated with cooked rice
- Acute vomit response followed by diarrhoea
- Incubation: 1-5 h; Duration: 12-24 h
• Spore germinate in warm cooked rice
• Toxin produced
• Heat stable, survives re-cooking
• Separate toxins for vomiting and diarrhoea responses


Norovirus food poisoning- small round-structured viruses

- Sporadic
- Usually spread directly, but some outbreaks associated with shellfish (filter feeders/sewage contamination)
- Vomiting, diarrhoea, low grade fever
- Incubation: 48h; Duration: 1-2 days


Escherichia Coli forms of GI pathogen

• ETEC Enterotoxigenic E. coli (similar to V. cholerae CT=EcLT)
• EPEC Enteropathogenic E. coli (most common)
• EIEC Enteroinvasive E. coli
• EHEC Enterohaemorrhagic E. coli
• VTEC Verotoxin-producing E. coli


Routes of transmission of EHECs:

- Food-borne (faecal contamination)
- Faecal-oral
- Environmental contamination by domestic animals
EHECs are highly infectious agents
- Infectious dose= ~10 bacteria


pathophysiology of escherichia coli

Attachment and effacing lesion and TTSS
- Typical of EPECs
- Requires product of eae gene: intimin which allows organism to bind to cells
- Destruction of microvilli of enterocytes
- Pedestal formation due to accumulation of polymerized actin.
- Type III secretion system
- Diarrhoea


Enterocyte attaching and effacing lesions of Escherichia Coli

The organism located on the border of microvilli in the villus and attach and efface the microvilli to form a pedestal where the organism sits on a pedestal of actin and fibrin.


virus general pathogenesis

- Are not able to replicate by themselves but require host cells and its cellular biochemiacal machinery to generate progeny
- Attach to host cell using receptor-binding proteins targeting host cell surface molecules that also serves as virus specific receptors


clinical symptoms of hepatitis

- Yellowing of skin and eyes (jaundice)- there can be other causes of jaundice
- Dark urine
- Clay-coloured stool
- Nausea and vomiting
- Loss of appetite
- Fever abdominal pain
- Weakness


transmission of Hep A & E

- transmitted faecal-oral (via stool into water and then consumed), have to be more persistent so don’t have envelopes


HEP B, C & D transmission

- transmitted parenteral, can cause chronic infections, stays in body after primary infection, can be treated (typically B & C), enveloped (more sensitive)


who can Hep D infect?

Hep D can only infect people who are Hep B+= coinfection or superinfection


Hepatitis A

- Non-enveloped ss+ve RNA picornavirus
- At least 6 major genotypes, I-VI ( type I is prevalent worldwide)
- Incubation time= 10-50 days
- Primarily children and young adults
- No seasonality
- Fecal-oral transmission, liver enzymes increase dramatically
- Abrupt onset, commonly with pyrexia
- Resolves spontaneously (without chronicity i.e no carrier state) followed by lifelong immunity
- Fatality rate <0.5% in icteric (permanent liver failure) cases- increase in age increases mortality


Markers in Hep A Course of Infection

• IgM antibody to HAV in blood indicates recent HAV infection and persists for up to 4-6 months post infection
• HAV RNA in blood is present at the onset of symptoms/signs
• Anti-HAV IgG in blood indicates HAV infection (or vaccine response), detectable by onset of symptoms/signs and persists for life


where is HAV mainly prevalent?

HAV is mainly prevalent in Sub-Saharan African and South Asia (India).


Hepatitis B

- Enveloped partially dsDNA hepadnavirus
- At least 8 main genotypes (type A is most prevalent in Europe)
- Incubation time= 40-180 days
- Primarily babies and young adults
- No seasonality
- Parenteral, vertical (mum to the foetus), sexual transmission (close contact)
- Insidious onset, sometimes apyrexial
- Virus remains in hepatocytes for life and may re-activate under immunosuppression (anti-HBcAb IgM may become detectable again)
- Chronic infection (carrier state) develops in 5-10% of adults (95% of neonates) and is associated with hepatocellular cancer
- Up to 2% fatality rate in icteric cases


treatment for chronic infection of Hep B

Treatment (for chronic infection): interferon alpha or antivirals (eg. tenofovir, entecavir), HBsAg seroconversion will occur in a small proportion of cases treated with interferon alpha but is even less likely to occur with antivirals (are very effective in suppressing virus replication)


Recombinant HBV surface antigen vaccine

- glycoprotein on the envelope (and immunoglobulin) available, neutralising antibodies are able to prevent infection, 95-98% efficient
There are non-responders who do not develop protective surface antibodies


Hepatitis B surface antigen (HBsAg)

- Found in HBV envelope and indicates active HBV infection found in serum during acute and chronic (carrier) state infection
- Anti-HBsAg (antibody) Indicates past HBV infection or immune response to HBV vaccine or passive antibody transferred following administration of HBV Ig


Hepatitis B core antigen

- Part of the HBV nucleocapsid
- Anti-HBcAg IgM (IgM antibody to core) Indicates a recent HBV infection and persists for four- six months post infection
- Anti-HBcAg IgG Indicates recent or past infection with HBV and is detectable by onset of acute symptoms and persists for life


Hepatitis B E Antigen (HBeAg)

- Associated with HBV nucleocapsid and indicates active HBV infection
- The antibody indicates HBV seroconversion


Hepatitis C Virus

- Enveloped in ss+ve RNA flavivirus
- At least six main genotypes (type 1 & 2 are prevalent in Europe)
- incubation time is 15 to 160 days
- primarily adults
- no seasonality
- parenteral transmission (sexual route)
- acute phase often very completely asymptomatic
- chronic infection established in 70 to 90% of cases, chronic infection (carrier state) is associated with hepatocellular cancer
- up to 1% fatality rate in icteric cases


treatment of Hep C

- treatment: interferon alpha together with ribavirin or direct acting antivirals (DAAs) such as protease inhibitors (eg. boceprevir, telaprevir) and/or polymerase inhibitors (sofosbuvir)
- increasingly, with advent of DAAs, HCV is fast becoming largely curable (>90% [genotype independent]) infection


markers over course of Hep C infection

- Anti HCV antibodies which indicate recent and or past HCV infection and take up to three months to develop
- HCV antigen reflects viraemia (active infection)
- HCV PCR determines viraemia and thus whether the infection is an active one (which requires treatment): success depends on genotype
- IL28B genotype (single nucleotide polymorphism)- helped to determine susceptibility to antiviral therapy but is of reduced/limited use now


Hepatitis D Virus

- Enveloped circular ss-ve RNA
- At least three major genotypes type one is most prevalent worldwide
- similar to HBV envelope contains HBsAg
- defective virus that needs HBV for replication
- Co infection with HBV: severe acute disease, low risk of chronicity
- superinfection on chronic HBV infection- chronic HDV infection and high risk of severe chronic liver disease


Hepatitis E Virus

- Non-enveloped ss+ve RNA hepevirus
- 7 genotypes (1-4 in humans, type 1&2 cause outbreaks in humans and type 3&4 are also found in animals (swine, deer), type 3 found worldwide)
- Faecal oral transmission
- incubation time 15 to 60 days
- overall fatality rate is 1 to 3% but 15 to 25% in pregnant women in outbreaks: HEV genotype 1
- No chronicity identified except in the immunocompromised
- probably endemic in Europe but underdiagnosed


what provides protection against HDV?

HBV vaccination provides indirect protection against HDV


treatment of HEV

- no vaccine (HEV genotype 1 vaccine available in China)
- treatment= supportive, ribavirin can be used to treat chronic infection


HAV treatment and vaccine

- Inactivated virus vaccine (and immunoglobulin) available
- Treatment= supportive


Other viral Causes that can also cause Hepatitis:

- Non-A/E hepatitis
- Epstein-Barr virus (EBV)
- Cytomegalovirus
- Herpes simplex virus type ½
- Rubella virus
- Enteroviruses
- Yellow fever viruses


functions of the liver

detoxification, protein synthesis, energy storage


Failure to clear bilirubin-> Failure to clear gut derived toxins (NH3) ->

Failure to clear bilirubin  jaundice
Failure to clear gut derived toxins (NH3)  encephalopathy


Failure to produce clotting factors ->
Failure to produce clotting inhibitors ->
Failure to produce albumin ->

Failure to produce clotting factors  coagulopathy on blood tests
Failure to produce clotting inhibitors  lack of balance in clotting
Failure to produce albumin  oedema, impaired binding of drugs


Failure to store or release glucose ->
Failure to utilise carbohydrate ->

Failure to store or release glucose  hypoglycaemia
Failure to utilise carbohydrate  muscle breakdown


time scale of acute vs chronic liver failure

- Time scale: <2-3 months vs >2-3 months


acute liver failure=

- Rapid onset with no underlying chronic liver disease


uncommon and rare presentation of acute liver failure

- Severe acute liver injury +jaundice = high ALT UNCOMMON
- Acute liver failure + jaundice/coagulopathy
+ encephalopathy = high ALT RARE


common presentation of acute liver failure

- Acute liver injury= high alanine aminotransferase (ALT)


causes of ALF

common case of ALF is paracetamol. Less common causes include:
- Other drugs
Antibiotics esp. anti-TB meds
- Ecstasy
- Acute viral infections -hepatitis B (and A, E)
- Autoimmune hepatitis
- Seronegative (non-A to E) hepatitis


Correction of Coagulopathy in ALF

1. Vitamin K (for Koagulation
- Substrate required for certain clotting factor synthesis (II, VII, IX, X dependant on Vit K)
- If dietary deficiency, clotting will look worse than liver function really is, so give them Vit K
- Replacement will not ‘mask’ liver dysfunction as it won’t be able to use the Vit K

2. FFP (fresh frozen plasma)
- Blood product containing clotting factors
- Replacement will prevent use of clotting times as a marker of liver function so try to avoid giving it


Prognosis in Paracetamol ALF

The patient is unlikely to recover spontaneously if:
- PT> 100 AND
- Anuric/ creatine >300 AND
- Grade 3-4 encephalopathy (stupor/coma)


Prognosis in Non-paracetamol ALF

- Age (<10 or >40 worse)
- Aetiology (drug/seronegative worse than viral)
- PT>50 or INR>3.5
- Bilirubin >300
- Time from jaundice to encephalopathy <7d
3/5= unlikely to recover spontaneously


Paracetamol vs Non-Paracetamol ALF

Paracetamol causes hyper acute liver failure
- Rapid progression of coagulopathy over hours rather than days
- Usually encephalopathy in less than 1 week
Other causes usually have a more gradual onset, progression over several weeks.


ALF Management

- Identify and treat the underlying cause
• N-acetyl cysteine for paracetamol
• Antivirals for hepatitis B
• Steroids for autoimmune hepatitis
- Supportive care
- Close monitoring (esp paracetamol)
- Liver transplantation if appropriate


chronic liver failure

Impaired hepatocyte function: jaundice, coagulopathy, low albumin


liver failure causes hepatic encephalopathy: features and triggers

- Failure of hepatocyte function (NH3 clearance)
- Portosystemic shunting
- Constipation
- Drugs- opiates, sedatives
- Dehydration- diuretics
- Infections
- GI bleeding


ascites causes

low albumin, portal hypertension or renal hypoperfusion


Causes of CLF are

generally any cause of cirrhosis:
- Alcohol
- Non-alcoholic fatty liver disease
- Hepatitis B or C
- Haemochromatosis
- Wilson’s Disease
- Primary biliary cholangitis
- Primary sclerosing cholangitis
- Autoimmune hepatitis


CLF management

- Identify and treat underlying cause
• Abstinence for alcohol
• Antivirals for hepatitis B/C
• Steroids for autoimmune hepatitis
- No treatment for jaundice
- Low salt diet and diuretics for ascites
- Laxatives and antibiotics for encephalopathy
- Liver transplantation if appropriate


glucose metabolism in fasting

• ↓ insulin and ↑ glucagon from pancreas → normoglycaemia
- Glycogen breakdown in periportal hepatocytes
• Major glucose store in body
• Gluconeogenesis from: lactate, pyruvate, amino acids and glycereol


glucose metabolism in feeding

• ↑ insulin and ↓ glucagon → hepatic glucose uptake
- Glycogen deposition in hepatocytes


Phase 1 Metabolism of drugs in liver

oxidation, reduction and hydrolysis reactions
Inactivating the drug and making it water soluble for excretion
hepatic synthesis of cytochrome P450 is increased by some classes of drug- enzyme induction, can increase the rate of phase 1 reactions


Phase 2 Metabolism of drugs in liver

Phase 2 conjugation reactions: These reactions include glucuronidation, sulphation, acetylation and methylation amongst others. Conjugates are almost always pharmacologically inactive, more water soluble and easily exerted in urine/bile.
conjugation with glutathione - major pathway for drug detoxification


stellate cells function

storage and transport of retinoids (vitamin A compounds)


cytochrome P450 system in Phase 1

employs P450 to NAPQI (toxic byproduct of paracetamol) in overdose


overdose reversal of paracetomol

Glutathione-S-transferase is capable of detoxifying NAPQI to mercapturic acid if GSH is available
•N-acetylcysteine is a source of glutathione substrate


phase 3 metabolism of drugs

secretion into the bile, exertion is mediated by ATP


proteins synthesised by the liver

• Albumin
• Transport proteins
• Caeruoplasmin and Transferrin- transport of copper and iron
• Ferritin- iron storage
• Protease inhibitors
• ɑ1 antitrypsin- lead to liver disease
• CRP- marker of inflammation, in liver dysfunction it may not make enough so not perfect marker
• AFP- rise in AFP may alter to presence of hepatocellular carcinoma
• Complement
• Coagulation factors- Fibrinogen, II, V, VII, IX and X


bile is made up of

600ml of bile per day is made up of:
• Bile acids primary (made in liver) and secondary (absorbed): allow digestion of dietary fats through emulsification
• Phospholipids
• Cholesterol
• Conjugated drugs
• Electrolytes: Na+, Cl-, HCO3- and copper
• Bilirubin


bilirubin production

Haem is a breakdown product of RBCs and it gets converted to unconjugated bilirubin. In the liver it is conjugated with glucuronic acid. Conjugated bilirubin is converted to urobilinogen and some of it is converted to stercobilin (gives stool the brown colour), some is reabsorbed and some is absorbed into blood and kidneys convert urobilinogen to urobilin and excrete it in the urine.


bile duct obstruction stool

In bile duct obstruction you can have floaty stool and pale stool as bilirubin is needed for the brown colour.


absorption of bilirubin

Conjugated bilirubin is not absorbed but bile is deconjugated in small bowel and colon. These are more hydrophobic.


storage of vitamins in liver

• Vitamin A, D and B12 are stored in large amounts
• Small amounts of Vitamin K and folate are rapidly depleted with decreased dietary intake
• Metabolises cholecalciferol vitamin D3 → activated 25-(OH) vitamin D


minerals stored in liver

• Iron stored in ferritin and haemosiderin
• Copper


immunological function of liver

• “firewall” filtering all blood from gut- first line of defense against pathogens absorbed from the gut
• Kupffer cells phagocytose pathogens from gut
• Supply of important chemokines:
o Interleukins
o Tumour necrosis factor
• Priming T cell responses


liver cirrhosis definition

• Development of regenerative nodules surrounded by fibrous bands in response to chronic liver injury
→ portal hypertension and end stage liver disease


cause sof liver cirrhosis

- Viral infection
o Hepatitis B and C
- Alcohol
- Non Alcoholic Steato-Hepatitis
- Autoimmune disorders
o AIH (autoimmune hepatitis)
- Cholestatic liver disease
o PBC (primary biliary cholangitis) and PSC (primary sclerosing cholangitis)
- Metabolic causes


reversal of fibrosis

Fibrosis is reversible through removal of underlying cause or antifibrotic drug/ cell therapy.


cirrhosis formation from fibrosis and risk

if insult continues you can have disrupted architecture, loss of function and aberrant hepatocyte regeneration which leads to cirrhosis. Current treatment= liver transplant as cirrhosis is not reversible, with cirrhosis you have higher risk of hepatocellular carcinoma


hepatocyte injury

Whatever the cause of injury, it leads to apoptosis of hepatocytes and this leads to recruitment of activated macrophages and activation of hepatic stellate cells.


fibrosis pathology

Inflammatory recruitment of dying hepatocytes leads to the secretion of pro-inflammatory and fibrotic mediators which encourage differentiation of stellate cells to activated myofibroblasts and fibroblasts to myofibroblasts too. These lead to matrix synthesis with a-SMA and collagen 1 leading to matric deposition, the whole process results in a reduction in matrix degradation. By removing cause of injury, there can be decreased activity of pro-inflammatory cytokines which increases MMPs and results in matrix degradation and loss of myofibroblasts.


stellate cells in liver fibrosis and cirrhosis

Very potent in generation of fibrosis and cirrhosis. Activation of quiescent stellate cell and portal/perivascular fibroblast to make myofibroblast which leads to increased collagen production and decreased MMPs  collagen accumulation


sequence of collagen deposition

1. myofibroblasts increased 10x increasing type 1 & 3 fibrillar collagen
2. decreased metabolite and oxygen exchange across space of Disse > hepatocyte dysfunction
3. increased angiogenesis, sinusoidal remodelling
4. increased sinusoidal resistance and portal hypertension


portal hypertension leads to:

- Formation of portosystemic collaterals- blood can pass from portal circulation to systemic without being filtered by liver
- Varices- extra BVs around oesophagus and stomach which can lead to bleeding
- Portal venous blood inflow- worsens portal hypertension
- Splanchnic vasodilation
- Increased risk of HCC


diagnosis of fibrosis/cirrhosis (pros and cons)

- Liver biopsy
✓ Gold standard, quantative
✕ Sampling error, morbidity
- Serum markers
✓ Widely available, non-invasive
✕ Nonspecific, grey zone for intermediate fibrosis
- Elastography
✓ Non-invasive, fast and user friendly, validated in chronic hepatitis
✕ Cost, confounding factors (body habitus)
Fibroscan (elastography)- liver should be like jelly but as fibrosis increases then the liver becomes more solid, the probe can measure this


serum markers of liver cirrhosis

• Albumin
• Decreases in end-stage liver disease due to decreased synthesis
• T1/2: 20 days therefore useful in cirrhosis
• Prothrombin time
• Decreased synthesis of clotting factors (I, II, V, VII, X) →↑ PT
• In cirrhosis associated with more advanced disease
• Bilirubin
• Increased in end stage cirrhosis due to decreased clearance
• Platelets
• Decreased in cirrhosis
• Splenomegally →↑ consumption
• Decreased Thrombopoietin production by cirrhotic liver


child-pugh scores

Child-Pugh scores can be used to assess risk and mortality by categorising patients into class A, B or C.


excretion of bilirubin in the bile

The water-soluble conjugated bilirubin is excreted in the bile which travels through the small intestine to the bowel.


pre-hepatic jaundice

In pre-hepatic jaundice, the level of unconjugated bilirubin increases and it exceeds the ability of the liver to conjugate. As it is water insoluble, it does not enter the urine. Eg. Haemolysis, Glucoronyl transferase deficiency (Gilbert’s), 10% of the population


hepatic jaundice

In hepatic jaundice, there is damage in the hepatocytes meaning that the liver cannot take up bilirubin nor can it conjugate it.


causes of hepatic jaundice

Caused by:
o Viruses – hepatitis, CMV, EBV
o Drugs: paracetamol, anti-TB,
o Alcohol
o Cirrhosis, autoimmune diseases
o Sepsis
o Right heart failure


post hepatic jaundice

In post hepatic jaundice, conjugated bilirubin spills out into the bloodstream and is excreted by the kidney. Symptoms of this is pale stool, dark urine and itch (bile salts that can’t get through so end up in skin). This can be caused by obstructive jaundice.


classification of causes of post hepatic jaundice

Classification of causes: within the lumen (gallstones), within the wall (cholangiocarcinoma), external compression


Whipple operations

Whipples are operations where the gallbladder, distal bile duct, duodenum, part of the stomach are removed and pulling up the jejunal end to join everything back together.
Option for people with pancreas cancers and distal bile duct cancers.


examination for jaundice

• Peripheral stigmata of liver disease:
 finger clubbing, palmar erythema, Dupuytren’s, sclera for jaundice, Virchow’s nodes, spider naevi, gynaecomastia
• Hepatomegaly
• Splenomegaly (portal hypertension)
• Ascites
• Palpable Gallbladder


treatment of jaundice underlying causes

Treat underlying causes:
o Pre-hepatic: stop haemolytic process
o Hepatic: anti-virals, prevent deterioration of cirrhosis, eg alcohol, drugs
o Obstructive causes: ERCP/stenting, surgery, palliation


treatment of jaundice symptoms

Treat symptoms:
o Analgesia
o Antibiotics if septic
o Vitamin K & chlorphenamine


clinical presentation of gallstones

• RUQ or epigastric pain
• Colicky or constant
• Dyspepsia, nausea, vomiting
• Biliary colic
• Obstructive jaundice
• Acute cholecystitis (inflammation of gall bladder)
• Acute pancreatitis


management of gallstones

• Analgesia
• ? Antibiotics
• Percutaneous drainage
• Surgery


ERCP- endoscopic retrograde cholangiopancreatography

ERCP is camera that can image the ampulla and bile duct, samples can be taken.
Stents can be placed to go through the cancer and create a pathway for bile to drain to get rid of the jaundice symptoms.


what can produce ATP?

glycolysis, fatty acid oxidation, amino acid breakdown, TCA cycle and ET chain


why do babies have greatest energy requirements?



2 forms of glucose metabolism

- Aerobic to CO2
- Anaerobic to lactate


where does ketone body production occur

only in the liver


why can't fatty acids be metabolised by brain

Fatty acids cant be metabolised by the brain as they don’t cross the BBB but the liver, exclusively, can covert fatty acids to ketone bodies which can circulate in plasma and be used by the brain & other tissues.


normal process of deglutition in the oesophagus

— Deglutition (process of swallowing) – carried out by striated muscle
o UOS (upper oesophageal sphincter) relaxes
o Food enters oesophagus
o Primary peristaltic wave triggered all the way down
o LOS (lower oesophageal sphincter) relaxes as soon as swallow initiated
o Food into stomach


common symptoms of oesophageal disease

- Dysphagia
- Odynophagia
- Heartburn
- Acid regurgitation
- Waterbrash- increased salivation due to discomfort


oropharyngeal dysphagia causes

§ Neuromuscular
§ Skeletal Muscular Disorders
§ Mechanical obstruction
§ Miscellaneous:
-Decreased saliva (medications, radiation, Sjogren syndrome [reduced salivation so bolus can’t move down])
-Alzheimer Disease


Oesophageal- gets stuck in oesophagus- dysphagia causes

§ Mechanical obstruction
§ Motility Disorders
§ Miscellaneous:
-Gastroesophageal reflux


Clinical Signs of Oesophageal Disease

- Dental erosion in GORD
—- Weight loss- oesophageal cancer, severe motility disorders
- Anaemia
— - Lymphadenopathy


GORD-Reflux with transient lower oesophageal relaxations

- More common
- Daytime reflux
- Small or no hiatus hernia (part of the stomach slides through diaphragm into the chest)
- Often no oesophagitis


GORD- Reflux with low lower oesophageal sphincter pressure

- Less common (20%)
- Nocturnal reflux
- Often large hiatus hernia
- More severe oesophagitis
- Barrett’s


typical symptoms of GORD

— - Heartburn
— - Acid regurgitation
— - Waterbrash



— - Burning discomfort behind the breast bone spreading upwards (“pyrosis”)
— Very Common and on many occasions accompanied by Acid regurgitation (effortless)
— Often meal related, postural



— - hypersalivation secondary to gastro-oesophageal reflux


Investigations in Oesophageal Disease

— Endoscopy and biopsy
— Barium swallow- less invasive, monitor motility, cannot diagnose early disease
— Oesophageal function tests (Manometry, pH and impedance monitoring- detect material refluxing into the oesophagus) look at motility and measure exposure of acid


oesophageal cancer investigations

- Urgent upper GI endoscopy
- CT
- Endoscopic ultrasound


Reflux oesophagitis

- Often result of the gastroesophageal reflux
- If acid is in oesophagus long enough, patient gets linear erosions


Barrett’s Oesophagus

- Specialised intestinal metaplasia in the lower esophagus (stratified squamous to simple columnar)
- Commonest in obese men >50
- Often asymptomatic
- Premalignant –
low grade dysplasia-> high grade dysplasia-> adenocarcinoma
- Approx 0.3% p.a (ie 1/300pt years)
- Surveillance vs. Ablation (prevent malignancy)
- Long term Tx with proton pump inhibitors


GORD Complications

• Oesophagitis
• Peptic stricture
• Barrett’s oesophagus
• Adenocarcinoma


treatment of GORD

— Lifestyle measures (smoking, alcohol, diet, weight reduction)
— Mechanical (posture, clothing, elevate bed-head)
— Antacids
— Acid suppression (PPIs-omeprazole , H2RA-ranitidine)
— Surgical- fundoplication


Motility Disorder: Achalasia

- Failure of the lower oesophagus relaxation
- Absence of peristalsis
- Incidence 1/100,000, typically present in young people
- Degenerative lesion of oesophageal innervation
- Presents with dysphagia to liquids and solids, weight loss, chest pain
- Endoscopic appearances usually normal
- Can progress to oesophageal dilatation and respiratory complications


Treatments of Achalasia

BoTox (paralyse LOS, not long lasting), Endoscopic Dilatation (and disruption of LOS, very effective in young patients, risk of perforation), Surgical myotomy (cut LOS opening lower end), POEM (endoscopic myotomy)


Eosinophilic Oesophagitis

— Common presentation with food bolus obstruction, dysphagia
— Younger age, M>F, prevalence 50/100,000
— History of atopy (asthma, hay fever)
— Endoscopy - furrows, rings, exudates, strictures
— Biopsy for diagnosis ( >15 eosinophils /pof)


Treatment of Eosinophilic Oesophagitis

— Diet – elimination (egg, wheat, milk, nuts, soya, fish)
— Drugs – PPI, topical sterois ( budesonide fluticazone)
— Dilatation – for strictures
— Natural history/course uncertain
first described 1993, 15X rise in prevalence since


benign causes of oesophageal stricture

- Barrett’s
- Extrinsic compression
- Post radiotherapy
- Anastomotic (following surgery/ oesophagectomy)
- Rings and webs
- Corrosive ( accidental or suicidal ingestion)


treatment of benign oesophageal stricture

proton pump inhibitors (eg. omeprazole), dilatation, push dilators (balloon,
Celestin gradual dilators up to 18mm
Savary-Gillard polyvinyl dilators)


oesophageal adenocarcinoma

- Lower third oesophagus
- Younger
- Reflux (Barrett’s)
- Obesity
- More common and increasing


Oesophageal Squamous Cell Carcinoma

- Mid/upper oesophagus
- Older
- Smoking
- Alcohol
- Less common and declining


diagnosis of dysphagia in elderly and young

— In the elderly think of neurological causes particularly if intermittent / long standing or sinister causes (oesophageal Ca) if new, progressive with regurgitation and weight loss.
— In the younger think of dysmotility (achalasia, or 2ndary to acid reflux,).
— In dysmotility syndromes dysphagia for liquids is as bad as for solids.
— Young patients with food bolus obstruction: think of eosinophilic oesophagitis.


how does oesophageal cancer present?

presents with progressive dysphagia for solids first then liquids.


—If there is regurgitation of food on previous days think of

pharyngeal pouch- herniation between the thyropharyngeus and cricopharyngeus muscles


H.pylori resides in and causes

It resides in the gastric pits and causes recruitment of inflammatory cells. It interferes with acid secretion and can increase acid secretion in the duodenum, alters the balance between hyperacidity and mucosal defence in the stomach -> end result is ulceration.


how can H.pylori reside in the stomach

The pH is neutral in the area of mucosal lining of the stomach allowing the organism to reside there.
H.pylori can also utilise urea and split into ammonia and bicarbonate -> bicarbonate further neutralises pH


non invasive diagnosis of H.pylori

• Breath test
• Antibody measurement (Serology)
• Stool antigen test


Invasive diagnosis of H.pylori

• Culture
• Histology
• CLO test-> biopsy is taken and presence is found if H.pylori splits urea to ammonia


H.pylori Eradication Therapy- Lothian Guidelines

First Line (90% efficacy)
Lansoprazole 30mg twice daily (or omeprazole 20 mg BD)
Clarithromycin 500mg twice daily
Metronidazole 400mg twice daily
all three for 1 week only


• Maldigestion:
• Malabsorption:
• Malassimilation:

• Maldigestion: impaired breakdown of nutrients, lumenal phase (eg pancreatic insufficiency)
• Malabsorption: defective mucosal uptake and transport of adequately digested nutrients. Selective or global.
• Malassimilation: encompasses both.


Luminal Phase of absorption consists of

- nutrient hydrolysis
- fat solubilisation
- luminal availability


the following problems in nutrient hydrolysis may be due to:
o Enzyme deficiency:
o Enzyme inactivation:
o Inadequacy of mixing:

o Enzyme deficiency: pancreatic insufficiency
o Enzyme inactivation: ZE syndrome
o Inadequacy of mixing: rapid transit, surgical resection


the following problems in fat solubilisation may be due to:
o Decreased bile salts:
o Bile salt deconjugation:
o Bile salt loss:

o Decreased bile salts: cholestasis, cirrhosis
o Bile salt deconjugation: bacterial overgrowth
o Bile salt loss: ileal disease or resection


the following problems in luminal availability may be due to:
o Bacterial consumption of nutrients (bacterial overgrowth):
o Decreased intrinsic factor (pernicious anemia):

o Bacterial consumption of nutrients (bacterial overgrowth): B12 deficiency
o Decreased intrinsic factor (pernicious anemia): B12 deficiency


mucosal phase of absorption consists of

• Brush border hydrolysis: lactase deficiency (post gastroenteritis, alcohol, radiation)
• Epithelial transport


the following problems in epithelial transport in absorption may be due to:
o Reduced absorptive surface
o Damaged absorptive surface
o Infections –
o Infiltration –

o Reduced absorptive surface - resection
o Damaged absorptive surface – coeliac disease, tropical sprue, Crohn’s disease, ischaemia
o Infections – Giardia, SIBO
o Infiltration – lymphoma, amyloid


Post-Mucosal Phase of Absorption and what can this be affected by

Post-absorptive processing – lymphatic obstruction (lymphangectasia, neoplastic, TB)


Clinical Features of Malabsorption:

• Diarrhoea and weight loss despite adequate intake
• Bloating, distention, cramps, borborygmi
• Lethargy, malaise


Malabsorption syndrome

(steatorrhea, distention, weight loss, oedema), RARE presentation


skin clues of malabsorption

o angular cheilitis, glossitis
o dermatitis herpetiformis
o oedema


Neurologic (B12) clues of malabsorption

o Peripheral neuropathy
o Ataxia (posterior column)
o Psychosis, dementia


Clues in Laboratory Tests of malabsorption

• Microcytosis: iron deficiency (common in coeliac, otherwise suspect GI blood loss)
• Macrocytosis: B12, folate deficiency, but also common in coeliac, alcohol
• Elevated ALP +/- low Ca
• Hypoalbuminaemia
• Evidence of multiple nutritional deficiencies


common causes of malabsorption

Coeliac disease, Pancreatic Insufficiency, Small bowel overgrowth (SIBO)


coeliac disease definition

Small bowel disorder characterised by:
- Mucosal inflammation
- Villous atrophy
- Crypt hyperplasia
Which will occur upon exposure to dietary gluten and which demonstrates improvement after withdrawal of gluten from the diet.


factors that contribute to coeliac enteropathy

- genetic predisposition- HLA DQ2, DQ8
- exposure to gluten (gliaden) in wheat, barley, rye
- gliaden-reactive T lymphocytes
- tissue transglutaminase antibodies (can be tested for diagnosis)


Main microscopic feature of coeliacs

absence/atrophy of villi on intestinal wall leading to reduce surface area for absorption


Clinical Presentation of Coeliacs

o Diarrhea
o Anaemia
o Dyspepsia
o Abd pain, bloating
o Weight loss
o Mouth ulcers
o Fatigue
o Neuropsychiatric symptoms


Diseases associated with Coeliac’s:

• Osteoporosis
• Infertility
• Dermatitis herpetiformis
• Lymphocytic colitis
• Ulcerative jejunitis
• Lymphoma


serological markers for Coeliac's

o Anti-tissue transglutaminase antibody (IgA) (TTG) Sensitivity and specificity >95%
 Anti-endomysial antibody (IgA)
 Anti-gliadin antibody (IgA, IgG)


coeliac disease small intestinal mucosa

- scalloping
- loss of Kerking's folds
- mosaic pattern


treatment of Coeliacs

• Gluten free diet (life-long)
• Dietician
• Nutritional supplements
• Screen for complications – bone disease
• Very rarely, need for immunosuppressant medication for refractory cases


Pancreatic Exocrine Insufficiency (PEI

- Pancreas produces 1.5L/day of bicarbonate and enzyme rich fluid
- Enzymes for digestion of fat, protein, carbohydrate
- Lipolytic activity declines first so fat absorption mainly affected
- Overt clinical consequences unlikely unless 90% of function lost
- Steatorrhea, weight loss, vitamin deficiency (A,D,E,K), also more minor symptoms


causes of PEI

• Chronic pancreatitis
• Pancreatic cancer
• Cystic fibrosis
• Haemochromatosis
• Pancreatic resection
• Gastric resection


chronic pancreatitis causes

• Alcohol – 80% present with pain
• Duct obstruction – tumours, stones
• Cystic fibrosis, other genetic causes
• Systemic disease eg SLE
• Autoimmune (IgG4) pancreatitis


Cystic Fibrosis

- Autosomal recessive, CFTR gene
- Impairment in bicarbonate and chloride secretion – thick sticky mucus
- Pancreatic involvement most common GI problem, esp in more severe genotypes
- 85% affected, starts v early.
- Commonly leads to PEI in childhood


• Tests of exocrine pancreatic function

o Direct – eg Secretin stimulation tests (sensitive but cumbersome)
o Indirect – eg Faecal elastase, Pancreolauryl (only reliably detect moderate to severe PEI)


PEI Treatment

- Pancreatic enzyme replacement
- Taken with meals and snacks
- Gastric acid suppression
- Vitamin supplements


Small Intestinal Bacterial Overgrowth (SIBO)

- Normally 105 to 109 bacteria/ml present in distal small bowel
- Colon has up to 1012 bacteria/ml
- Mostly Gram- aerobic bacteria in ileum, Gram+ anaerobic bacteria in colon
- In bacterial overgrowth this balance is lost


in what diseases is SIBO a feature?

liver disease, IBS, obesity, CF, coeliac disease


Causes of bacterial overgrowth:

• Stasis
o Strictures
 Crohn’s disease
 Tuberculosis
o Hypomotility
 Old age
 Opiate analgesics
 Diabetes
 Systemic sclerosis
• Blind loops, Diverticulae
• Immunodeficiency
• ?Obesity


blind loops as a cause of SIBO

Gastric bypass surgery would often result in a blind loop which is out of continuity with the normal flow through the gut- bacteria are less likely to be flushed through.


Consequences of bacterial overgrowth:

• Vitamin B12 malabsorption
• Bile acid deconjugation
• Intraluminal protein utilization
• Brush border damage
• Ulceration of mucosa
• Bowel dysmotility


Diagnosis of SIBO:

- Quantitative culture of jejunal fluid is the gold standard (> 105/mL is abnormal)
- Glucose/Hydrogen breath test more practical
- Small bowel radiology to look for anatomical abnormalities


SIBO Treatment:

- Treatment within 2 weeks of antibiotics eg. tetracycline, ciprofloxacin, rifaximin
- Often needs repeat treatment


Bile Acid Malabsorption (BAM)

- Bile acids specifically absorbed in the ileum
- Cause secretory diarrhoea in colon
- Affected by ileal disease or resection
- Also impaired in post cholecystectomy, rapid transit and other malabsorptive states
- Primary BAM may reflect over-production rather than malabsorption


causes of different types of BAM

Type 1: ileal disease or resection
Type 2: idiopathic
Type 3: associated with cholecystectomy, rapid transit, coeliac, SIBO, chronic pancreatitis


Giardia Lamblia

• Non-invasive pathogen
• Malabsorption due to multiple factors
• Treatment of choice is metronidazole


Malabsorption due to multiple factors of giardia lamblia

Brush border damage
o Reduction in absorptive surface
o Bile acid utilization
o Induction of hypermotility
o Enterotoxin


other parasites causing malabsorption

• Protozoa- mainly problem in immunosuppressed
• Tapeworms- cause damge to gut and blood loss- iron deficiency rather than global
• Nematodes


whipple's disease

• Uncommon bacterial infection in older men
• Caused by Tropheryma whippleii
• Presents with diarrhoea, arthritis, fever, cough, headache, muscle weakness
• Intestinal mucosa is infiltrated by foamy macrophages containing PAS-positive material
• Antibiotic therapy for months to years.



test to detect hidden or 'occult' blood in stool samples. qFIT test uses antibodies that specifically recognise human haemoglobin and are consequently more sensitive and specific test than the guaiac based FOB test.


Colonic Polyps:

• Not all colonic polyps progress to adenocarcinoma
• Adenomas have the highest progression potential to adenocarcinoma
• Hyperplastic ( metaplastic) polyps don’t have malignant potential
• A special type of hyperplastic polyp called serrated polyp has some malignant potential.


APC protein (tumour suppressor)

encoded by the APC gene a negative regulator that controls beta-catenin concentrations and interacts with E-cadherin, which are involved in cell adhesion. Deletion of the APC gene predisposes to cancer.


Colorectal Cancer Alarm Features:

• Weight loss
• Rectal bleeding
• Anaemia, thrombocytosis (high platelet count)
• Persistent diarrhoea (lack of day-day variability) common in R side colon cancers ( ascending colon and caecal tumours)
• Frequent nocturnal symptoms
• New onset over 50 yrs
• FHx bowel cancer/


Risk Factors for Colorectal Cancer:

• A diet high in red meats and processed meats raises colorectal cancer risk.
• Cooking meats at very high temperatures (frying, broiling, or grilling) creates chemicals that might raise cancer risk.
• Diet low in fibre
• Obesity.
• Physical inactivity.
• Smoking/alcohol excess.
• A family history of colorectal polyps or colorectal cancer.
• History of inflammatory bowel disease.
• Older age


Colorectal Cancer Screening

• The prevention of death from colorectal cancer by identifying and treating pre-invasive disease (adenoma) and early invasive adenocarcinoma.
• Population over the age of 50 routinely and regularly checked for occult blood (qFIT)
• If positive they get a colonoscopy
• Removal of adenomas is curative.
• Detection of adenocarcinoma before it has spread to lymph nodes, liver or elsewhere increases the chances of surgical cure.
• Patient survival is strongly linked to the extent of spread of adenocarcinoma (stage)


most prevalent location of colorectal cancers

Most prevalent in the rectosigmoid area


why is the mucosa susceptible to ischamic injury?

blood supply comes from vessels penetrating through the muscularis propria from outside which combined with high metabolic activity of epithelial cells makes mucosa susceptible to ischaemic injury


GI tract secretions that can cause mucosal injury

o Acid and pepsin in stomach
o Biliary and pancreatic secretions


types and causes of acute gastritis

- Acute erosive/ haemorrhagic gastritis
o Ingestion of irritant chemicals
- Acute H.pylori infection
o Usually no or minor symptoms so seldom seen in biopsies


types and causes of chronic gastritis

- Non atrophic gastritis
o Chronic H.pylori infection
- Atrophic gastritis
o Autoimmune gastritis
o Chronic H.pylori infection


Atrophy of the gastric body mucosa leads to

loss of the acid secreting parietal cells and pepsin secreting cells in the mucosa.


autoimmune gastritis and megaloblastic anemia

In autoimmune type gastritis, antibodies are generated against parietal cells and these are detectable in blood, there is also a loss of intrinsic factor secretion- needed for Vit B12 absorption > megaloblastic anemia


Chronic Gastritis “special forms”

- Chemical gastritis eg. bile reflux, NSAIDs
- Radiation gastritis
- Lymphocytic gastritis
- Non-infectious granulomatous gastritis eg. Crohn’s disease, sarcoidosis
- Eosinophilic gastritis eg. food sensitivities
- Infectious gastridities (non H.pylori)


Hallmark of intestinal metaplasia:

goblet cells- large pale staining cells containing mucin vacuoles, increased risk of neoplasia development


Histological Features of coeliacs

• Variable villous atrophy
• Chronic inflammation
• Increased CD8+ T lymphocytes in epithelium
• Epithelial damage
• Crypt hyperplasia


what does coeliac disease lead to increased risk of?

- Leads to increased risk of small bowel adenocarcinoma and enteropathy associated T cell lymphoma


ulcerative colitis

- Chronic relapsing and remitting condition typically presenting with recurrent episodes of rectal bleeding
- Highest incident 12-25 yrs with smaller peak at 60-70yrs, no gender difference
- Inflammation confined to mucosa unless severe
- Typically involves rectum and/or left colon
- Involvement of whole colon (pancolitis) is in a continuous distribution


pseudo polyps in UC

islands of residual mucosa that appear to be polypoid because they are surrounded by areas of extensive ulceration
They extend into submucosa but generally not deeper


Crohn’s Disease

- Chronic, multifocal relapsing condition that can affect any part of the GI tract
- Peak incidence 20-30 yrs with smaller peach 60-70yr, no gender difference
- Variety of presentations depending on what part of GI tract is involved eg. abdominal pain, diarrhoea, weight loss, strictures and obstruction, fistulae
- Transmural inflammation is often patchy and discontinuous (skip lesions)


Granulomas in CD

- Present in 70% of cases
- More common in left colon than right
- Common in children
- Tend to be larger in adults
- Fewer after 2 years of illness
- Particularly helpful in the diagnosis of CD when present deeper within the wall of the GI tract or within draining lymph nodes


Neoplasia in iBD

- Risk increased in both UC and CD (highest in UC)
- Risk increases with times since diagnosis (mean duration 17-21 years)
- Most commonly colorectal carcinomas but also increased risk of small bowel carcinomas and other malignancies eg. bile duct carcinomas, leukemias


Causes of colonic strictures

- CD
- Ischaemic colitis
- Diverticular disease
- Diaphragm disease -NSAIDs
- Neoplasia


Microscopic Colitis

- Usually presents as chronic watery diarrhoea
- Normal appearance of colonic and rectal mucosa at endoscopy
- Increase in chronic inflammatory cells in lamina propria
- 2 patterns: collagenous and lymphocytic colitis
- Cause often not identifies
- Lymphocytic colitis can be associated with coeliac disease
- Drugs implicated in some cases esp lansoprazole and NSAIDs
- Can be treated with steroids (budesonide)


anemia and iron deficiency definitions

Anemia- where serum haemoglobin levels are 2 standard deviations below the normal
Iron deficiency- when the total body iron is low as a result of absorption not matching demand


causes of anemia and iron deficiency

- Poor intake of dietary iron
- Reduced absorption (malabsorption) e.g coeliac, post-surgical
- Increased iron (blood) loss e.g. menstruation, cancer
- Increased demand e.g. pregnancy, adolescence


signs and symptoms of anemia and iron deficiency

• Common symptoms: tiredness, dyspnoea, headache
• Common signs: pallor, atrophic glossitis (inflammation of the tongue)
• Rarer signs: koilonychia (thin concave nails), leukonychia (white discolouration on nails), tachycardia, angular cheilosis (inflammation of corners of mouth)


iron absorption

Ferrous iron found in red meat and seafood, readily absorbed
Ferric iron  needs to be converted to ferric iron
Iron is absorbed in the duodenum and high jejunum.



too much iron is absorbed on enterocyte surface, no mechanism for iron excretion



The body stores iron within cells as ferritin. Ferritin is a marker of total body iron stores not serum iron- how iron is moved around body.


iron absorption enhancers

ascorbic acid, fructose, sorbitol, alcohol


why is ferritin elevated in inflammation

acute phase reactant


ways that chronic disease causes anemia

• Increases hepatic synthesis of hepcidin- inhibits release of iron from endothelial system.
• Reduces erythropoietin release- less erythropoiesis going on, less iron available to make blood, more iron won’t help it
• Inhibits erythroid proliferation-
• Augments hemophagocytosis


when is iron deficiency defined as low haemoglobin?

o Low ferritin (best diagnostic marker)
o Low serum iron in the presence of transferrin >3.0


causes of iron deficiency anaemia

o Loss of iron (menstrual blood loss, GI blood loss, renal tract blood loss)
o Malabsorption (previous gastric surgery, Coeliac disease)
o Poor dietary iron intake (poor diet, lifestyle choices or cultural beliefs)
o May be contributing factors:
 Menstrual blood loss is the commonest cause overall
 Testing for Coeliac disease (anti tTG antibodies) is worthwhile


treatment of anemia

• Optimise diet
• Oral iron supplementation for 3 months after iron deficiency corrected
• Main side effects- constipation, GI upset and dark stools
• If unable to tolerate then some evidence to suggest once daily dosing/alternate day dosing is effective
• If unable to tolerate that then IV iron now safe and quick.


2 main categories of borderline tumours

- Tumours that show extensive local invasion but almost never metastasise- these are prone to local recurrence if incompletely excised
- Tumours that appear entirely benign at the time of diagnosis but which can develop distant metastases often presenting many years after the initial diagnosis


Symptoms of GI Neoplasia:

• Tiredness (anaemia)
• Bleeding
• Anorexia and vomiting
• Weight loss
• Pain caused by obstruction
• Dysphagia
• Alteration in bowel habit


oesophageal carcinomas and risk factors

- 90% of oesophageal cancers worldwide
- Aetiology uncertain

Risk Factors:
- Tobacco and alcohol
- Diet
- Infection- fungal oesophagitis?
- Genetic factors


oesophageal adenocarcinoma

- Commonest type in UK
- Most associated with acid reflux and Barrett’s oesophagus
- Tobacco and alcohol less important


gastric adenocarcinoma

- Highest rates in Japan and eat Asia, eastern Europe and parts of America
- Incidence increases with age
- Males >females
- Often presents late
- Familial link in about 10%, small percentage have germline mutations eg. TP53, CDH1 genes
- Aetiology multifactorial: diet, H.pylori, bile reflux


2 main gastric adenocarcinoma histological patterns

- Intestinal
o Majority of cases in high incidence areas
o Increase risk in patients with FAP (familial adenomatous polyposis)
- Diffuse
o Relatively more common in low incidence areas
o Often younger patients
o female over male
o mutation or inactivation of CDH1 gene a common feature


neuroendocrine tumours in the small intestine

o Epithelial tumours associated with the synthesis of hormone or neurotransmitter like substances
o Range from well-differentiated benign tumours through to aggressive and poorly differentiated malignancies such as small cell carcinoma
o Can be difficult to predict behaviour, risk depends on size, site and grade (based on mitotic activity)- yellow colouration common



(GI stromal tumours)
o Soft tissue tumour that can arise anywhere in the GI trcat
 Related to Pacemaker cells in the muscularis propria
 malignant tumours are a type of sarcoma
 75-80% of GISTs have activating mutations in the KIT receptor tyrosine kinase gene
o Stomach is commonest site
o Difficult to predict behaviour, risk depends on size, site and proliferative activity


types of colorectal polyps

- Inflammatory- IBD, lymphoid
- Hamartomatous eg.
o Juvenile polyps and polypois
o Peutz-Jegher syndrome
- Hyperplastic
- Lesions in the submucosa eg. lipoma
- Neoplastic
o Adenomas
 Tubular
 Tubulovillous
 Villous
o Adenocarcinomas


types of colorectal adenomas

- Tubular- short crypts with rounded crypt profiles
- Villous- long finger like projections
- Tubulovillous- combo of 2
More villous= high risk of progression to malignancy


APC/beta catenin pathway role in colorectal cancer

- Inactivation of PAC tumour suppressor gene seen in about 80% of colorectal carcinomas
- Genetic basis of the inherited condition FAP
- Early event in the abnormal carcinoma sequence
- Subsequent accumulation of multiple mutations and chromosomal instability


Microsatellite Instability Pathway role in colorectal cancer

- 10-15% of sporadic colorectal carcinomas (R>L)
o Inactivation of DNA mismatch repair genes
o Others include MSH6, PMS1, PMS2
- Inherited mutation in one of these genes is the basis of hereditary non-polyposis colorectal carcinoma (HNPCC) syndrome (Lynch Syndrome)
- Loss of one of these genes increases mutation rate by up to 1000 fold
- Not associated with normal adenoma-carcinoma sequence


‘Serrated Neoplasia’ Pathway role in colorectal cancer

- More recently identified
- Associated with distinctive precursor lesions showing similarities to hyperplastic polyps
- More common in the right colon
- Thought to have more rapid progression to malignancy
- Typically have a mutation in either BRAF or KRAS proto-oncogenes
- Can also show microsatellite instability often due to methylation of mismatch repair gene promoter regions rather than actual mutation


prevention of colorectal cancer

faecal occult blood test (FOBt) or faecal immunochemical test (qFIT) with referral for colonoscopy if positive result


prognosis of colorectal cancers

- STAGE higher= reduced survival
- GRADE poorly differentiated tumors more aggressive
- Presentation with obstruction or perforation (usually indicates advanced disease)


Protective Factors of the Body and Pathogenic mechanisms of opportunistic pathogens can circumvent these factors

- pH (antacid drug)
- Redox potential/ oxygen tension
- Flow rate (ileus- appendicitis)
- Mucus
- Prescence of bile and digestive enzymes, intestinal microbiota (antibiotic)
- Barrier function (sepsis)


Opportunistic pathogens can become obligate pathogens through pathogenic mechanisms:

- Adherence mechanisms- stick to gut wall to prevent being flushed by flow rate
- Toxin production- protein/enzymes to harm the body
- Motility- burrow through the mucus layer
- Site of pathogenicity- features that are specific to the site eg. pH, penetration
- Avoidance of immune mechanisms eg. secretory antibody (IgA)- capsules and lipopolysaccharides


clinical manifestations of food poisoning

- >3x a day
- Liquid: more than 80% of water
- >300g/ 24h

- Reflex, mechanism of protection
- Humoral or neuronal stimuli


h.pylori bacteria features

• Curved/spiral, Gram negative, microaerophile
• Motile
• Produces urease (area  ammonia)


h.pylori clinical features

Clinical Features:
- Gastritis
- Gastric and duodenal ulcers
- Gastric carcinoma


features of vibrio cholerae bacteria

• Causes cholera
• Transmission= contaminated water or food (seafood)
• Gram negative, comma shaped bacterium- motile with polar flagellum
• Vv sensitive to drying out, sunlight & acid (-> high bacterial load needed)
• Virulence factors: pili (adherence to mucosae), toxin


Cholera toxin

 A bipartite, ADP-ribosylating toxin
 5x B subunits bind to GM1 (enterocytes)
 1x A subunits is active part


clinical features, diagnosis and treatment of cholera

Clinical Features:
- Watery diarrhoea- SECRETORY
- Rice water stools
- Severe dehydration

- Clinical aspects
- Stool culture

- Rehydrate (oral rehydration salt), IV
- Antibiotics


shigella bacteria features

• Enterobacteriaceae
• Non-motile, facultatively anaerobic, gram negative rods
• Transmission= contaminated water or food, very low infectious load
• Four species- S. dysenteriae common
• Invasive pathogen -> inflammation of gut epithelium
• S. dysenteriae produces shiga-toxin


Physiopathology of shigella

1. Bacteria enter the mucosal cells via the M-cells: injested by macrophages
2. Macrophages killed by apoptosis  release of cytokines  inflammation  tissue destruction


clinical features and complications of shigella

- Bacterial dysentery= bloody diarrhoae (+pus/mucus) + abdominal cramps + fever
- Local: toxic megacolon
- Systemic: autoimmune> toxin


c.diff bacteria features

• Gram positive, anaerobic
• Motile, spore former (vv resistant)
• Environmental pathogen, spores can be in healthcare facilites
• Produces toxins
• Promoted by antibiotic use
• A combination of direct cellular damage and immunopathology


pathophysiology of c.diff infection

Colonisation resistance compromised by antibiotics
Gut becomes susceptibility to colonisation by C.difficile
C. difficile evades immune response and multiplies, producing toxins A & B


clinical features of c.diff

- Asymptomatic carriage
- Diarrhoea/ simple colitis
- Pseudomembranous colitis
- Fulminant colitis


diagnosis and treatment of c.diff

- Clinical features with:
- Stool analysis of antigen- toxin, bacteria (enzyme)
- Culture

- Antibiotics
• Metronidazole or vancomycin?
• Fidaxomicin
- Faecal transplants
- Immunotherapy


Prevention/Control of c.diff

Infection control: removal of spores of C. difficile from the hospital environment- cleaning
Antibiotic stewardship: restriction of antibiotics know to precipitate CDI- 3rd gen cephalosporin, clindamycin, fluoroquinolones


The UK ‘hyper-virulent’ Strain of c.diff

- They also have the same tcdC gene deletion
- Hyper-toxin producers
- Resistant to quinolone antibiotics
- tcdR alternative sigma factor- positive regulator of toxin production
- tcdE encodes a holin-like protein
- Toxins transcribed on entry to stationary phase


most common cause of nosocomial diarrhoea

c.diff infection, frequent among elderly patients and it can cause sudden bowel incontinence



weight that is 60-80% of that expected for their age, normally total energy intake is sufficient but there is an inadequacy of protein in the diet
characteristic swollen bellies- enlarged liver, oedema due to albumin deficiency, muscle wasting, diarrhoea



weight that is less than 60% of expected, protein and calorie deficiency


degradation of extracellular proteins

If circulatory proteins are damaged in any way, they are recognised as ready for degradation and they are taken up by various cells by endocytosis. After the cell binds to a receptor: an endosome (closed compartment within the cell) which has a membrane that originated as plasma membrane
Endosomes fuse with lysosomes (degradative organelles with low pH) which degrade the protein and amino acids are liberated into the cell.
Endocytosed membrane and receptors return to the surface.


degradation of intracellular proteins

Proteins in cells are recognised for degradation and tagged by the attachment at the C-terminus of ubiquitin (small). It acts as a label for degradation. Degradation carried out by proteasome in a ATP dependant process, the protein enters a cavity within the proteosome and is degraded releasing amino acids. Ubiquitin is spared and reused.


parietal cell structure

apical side (digestive tract) = proton concentration is very high, gastric ATPase (proton pump)- pump prtoons into the gastric lumen in exchange for potassium ions
basolateral side= more neutral, anion transporter, CO2 is hydrated to carbonic acid which ionises to protons which are pumped into gastric lumen and to bicarbonate (exported to plasma in exchange for chloride ions)
both sides have different protein compositions
As gastric lumen is acidified, lumen is alkalified.


Omeprazole and Vonoprazan

inhibitors of gastric ATPase and used to treat gastric ulcers.


Acidification of stomach lumen leads to

inhibits bacterial growth and denatures dietary proteins- more easily unfolded and hydrolysed by proteolytic enzymes that are secreted into digestive tract


principle enzyme degrading protein=

pepsin secreted by chief cells


amino acid uptake in intestine

Amino acids are taken up into intestinal cells with sodium ions by series of co-transporters which recognise different amino acids
Leftover peptides are further degraded by peptidases that are bound to the intestinal cells or taken up intact and degraded within cells
Overall results of protein degradation is appearance of free amino acids in the blood.


transamination in peripheral tissues

Transamination can occur in peripheral tissues but alanine is transported rather than glutamate.
Glutamate formed by transamination can be transaminated with pyruvate to from alanine. Alanine enters plasma and taken up into liver and converted to glutamate.


ketogenic and gluconeogenic amino acids

If amino acid broken down into Acetyl-CoA= ketogenic
If broken down into TCA cycle intermediate= gluconeogenic


pernicious anemia

Pernicious anaemia- autoimmune destruction of parietal cells in digestive tract, these cells then cannot secrete intrinsic factor into the stomach meaning that VitB12 is not absorbed > failure of pathway


antifolate drugs

inhibitors for dihydrofolate reductase. Cycloguanil is an inhibitor and a component of the antimalarial drug- malarone, trimethoprim, sulfonamides, methotrexate.


uptake of glucose in the intestine

1. Creation of sodium ion gradient by ATPase
2. Use of gradient by symporter that catalyses the uptake of glucose into intestinal cells with 2 Na ions (sodium down gradient & glucose up gradient)
3. Glucose pumps down conc gradient to lower conc in plasma through uniporter called GLUT-2


oral rehydration therapy

glucose and salt mixture= combatting loss of water by increasing concentration of sodium ions in the body (through the symport process), glucose promotes sodium ions uptake which expands the plasma and retrieves water


Glucose Homeostasis

Glucose travels to the plasma and then the liver.
Glucose concentration increases which is noticed by endocrine pancreas which secretes insulin. Insulin promotes uptake of glucose into fat and muscle, also affect glucose utilisation in the liver. Insulin has short half-life in plasma so its conc falls which leads to normal glucose.
Increase in insulin lowers conc of non-esterified fatty acids in the plasma because insulin inhibits lipolysis.


aminotransferases LFT

- Aminotransferases (ALT & AST)- hepatocyte damage
o AST/ALT- cytoplasmic (released in hepatocellular damage
o ALT is more liver specific than AST (found in muscle also)



- Gamma glutamyl transferase (GGT)- drug/ethanol (induction not damage)
o Induced by alcohol, certain drugs, cholestasis
- membrane bound


Alkaline phosphatase LFT

- + alkaline phosphatase (alk phos)- cholestasis (impaired bile flow)
o GGT & Alk Phos- membrane bound (induced synthesis in cholestasis)
o Alkaline phosphatase is not induced by drugs/alcohol but can be of bone origin


Prothrombin time ratio

clotting factor synthesis


Protein synthesis of liver:

- Albumin (changes only occur in chronic liver disease or dehydration)
- Clotting factors (eg. thrombin)
- Transport proteins
o Thyroxine-binding (TBG)
o Transferrin


bilirubin presence in plasma and urine

Plasma= unconjugated bilirubin (small amounts)
Urine= bilirubin absent (albumin bound- too large to be filtered by kidney



- Premature babies may not be able to conjugate bilirubin until UDP glucoronyl transferases are expressed
- Can get severe unconjugated hyperbilirubinaemia
- Toxic to brain
- Phototherapy


Gilbert’s Syndrome

- Autosomal dominant
- Reduced activity of UDP glucuronyl transferase
- Asymptomatic normally
- Increased periods of haemolysis presents with mild jaundice



Surgical emergency wherein the bowel twists around itself to form a close ended loop causing obstruction and high risk of perforation


staging of colorectal cancers

T1 tumours grow to the mucosa and submucosa
T2 tumours grow to the muscularis propria
T3 tumours grow to the serosa (/adventitia)
T4 tumours grow to the surrounding organs


AST:ALT ratio values and causes

scores >2 : alcoholic liver disease
<1 more :NAFLD/NASH.