Wk13 - GI & Liver Flashcards
Normal liver structure
Vasculature - Incoming portal vein and hepatic artery - Outgoing hepatic vein Parenchymal liver cells Biliary system Connective tissue matrix
All arranged as portal tracts and parenchyma
Broad causes of injury to the liver
Drugs or toxins incl. alcohol Abnormal nutrition/metabolism Infection Obstruction to bile or blood flow Autoimmune liver disease Genetic/deposition disease Neoplasia Others
Injury and inflammation to liver
Inflammation = body’s response to injury
Acute inflammation = agent causes injury but is then removed
Days to weeks
N.B. “Fulminant” = severe acute, rapidly progressing towards liver failure
Chronic inflammation = agent causes injury and then persists
Months to years
“Acute-on-chronic”
Chronic liver disease often presents with acute exacerbation plus evidence of underlying chronicity e.g. fibrosis
Inflammation to liver - target and type
Injurious agent causes cell damage and sometimes death, often with inflammatory cell infiltrate
Liver injury often mainly to parenchyma (hepatocytes); but bile ducts or rarely blood vessels can be the main target
Parenchyma, bile ducts, blood vessels and connective tissue are inter-dependent, so damage to one damages the others
Chronic inflammation common in liver and may increase connective tissue (fibrosis)
Cirrhosis =
= End-stage liver disease
Definition is three-fold:
Diffuse process with
Fibrosis &
Nodule formation
Liver disease is the fifth most common cause of death in the UK
Trying to avoid progression to cirrhosis is main aim of diagnosing and treating chronic hepatitis
Clinical approach to possible liver damage
History, symptoms and signs by examination
Investigations:
Blood tests: LFTs, haematol, viral and autoimmune serology, metabolic tests
Radiology: usu. at least ultrasound
Usually yields firm diagnosis without biopsy but at least should tell us either 1) Diffuse Liver Disease or 2) Space Occupying Lesion
Histological patterns of diffuse liver disease
Acute hepatitis
Acute cholestasis or cholestatic hepatitis
Fatty liver disease (steatosis and steatohepatitis)
Chronic hepatitis
Chronic biliary/cholestatic disease
Genetic/deposition disease
Hepatic vascular disease
Acute hepatitis
Diffuse hepatocyte injury is seen as swelling. A few cells have died, seen as ‘spotty necrosis’. There is inflammatory cell infiltrate in all areas: portal tracts, interface and parenchyma.
Shows dying hepatocytes - celled acidophil body
Acute cholestasis or cholestatic hepatitis causes and features on histology
Causes:
Extrahepatic biliary obstruction
Drug injury e.g. antibiotics,
Histology: brown bile (bilirubin) pigment +/- acute hepatitis
What stain is used to look at liver during histology?
Masson stain
Features of hepatitis B seen on histology
ground glass cytoplasm in hepatocytes = accumulation of “surface antigen”, one of three main HB viral antigens
Chronic billiary/cholestatic disease causes and histological features
Causes:
Primary biliary cirrhosis (PBC)
Primary sclerosing cholangitis (PSC)
Histology: Focal, portal-predominant inflammation and fibrosis with bile duct injury; granulomas (arrow) in PBC
Mainly inflammation affecting the portal tracts and bile ducts
Genetic deposition to liver disease
Haemochromatosis (iron)
Wilson’s disease (copper)
Alpha-1-antitrypsin deficiency
Specific causes of diffuse liver disease
Hepatitis viruses esp A & E Hepatitis viruses esp B & C (& D) Drug injury Autoimmune liver disease Extrahepatic biliary obstruction Alcohol Metabolic syndrome e.g. obesity Chronic biliary disease e.g. PBC Vascular disease e.g. venous obstruction Genetic/deposition e.g. haemochromatosis
Morphology and causes of diffuse liver disease
-
Features of drug induced liver disease
Drugs can cause almost any pattern of liver disease
Therefore usually will be in differential diagnosis for cause, esp. acute hepatitis and acute cholestasis/cholestatic hepatitis
Most drug hepatotoxicity idiosyncratic (rare but usually single clinical pattern) thus difficult to investigate e.g. Augmentin (co-amoxiclav: may cause acute cholestatic hepatitis)
Occasional predictable liver damage e.g. paracetamol, methotrexate
Don’t forget non-prescribed drugs e.g. over internet or herbal
Focal liver lesions =
= Space occupying lesions (SOL)
Can be non-neoplastic (developmental/degenrative e.g. cysts or inflammatory e.g. abscess) or neoplastic - (benign or malignant)
Liver cysts
Usually developmental or degenerative in origin
Commonest = Von Meyenberg complex (= simple biliary hamartoma)
Important because can resemble metastases by naked eye at operation; often submitted for pathology including urgent intra-operative frozen section
No treatment required
Liver neoplasms
Hepatocellular adenoma & Hepatocellular carcnioma
Haemangioma and hepatic adenoma
Importance because of differential diagnosis with metastases
Haemangioma
Benign blood vessel tumour
Biopsy avoided because of risk of bleeding
Hepatic adenoma
Rare
Mainly young women, often associated with hormonal therapy
Risk of bleeding and rupture so excision if large
Hepatocellular carcinoma
Most common primary liver tumour
Usually arises in cirrhosis and associated with elevated serum AFP (alpha feto-protein)
Screening available
Discussed in case learning this week and previously
What are the standard liver function tests
Bilirubin; Aspartate Aminotransferase (AST); Alanine Aminotransferase (ALT); Gamma Glutamylytransferase (GGT); Alkaline Phosphatase (ALP); Albumin
Function of liver is indicated by
Albumin, bilirubin, prothrombin time
Investigation of abnormal liver blood tests suggesting chronic liver disease
Ultrasound Look for: Chronic viral hepatitis HBV, HCV Autoimmune liver disease ANA / SMA / LKM (AIH); AMA (PBC); Immunoglogulins (elevated IgG indictaes autoimmune hepatitis; elevated IGM indicates primary biliary cholangitis) Metabolic liver disease Ferritin (haemochromatosis); Caeruloplasmin (Wilson’s Disease); 1 anti-trypsin deficiency
Investigation of abnormal liver blood tests suggesting acute liver injury
Ultrasound Acute viral hepatitis HAV, HBV, (HCV), HEV, CMV Autoimmune liver disease ANA / SMA / LKM (AIH); Immunoglogulins ( Can get immunoglobulin back within couple of hours - IgG indicates automimmune hepatitis) Paracetamol levels
The most common causes of abnormal liver blood tests
FATTY LIVER - Alcoholic Liver Disease or Non-alcoholic Fatty Liver Disease (NAFLD)
CHRONIC VIRAL HEPATITIS - Chronic Hepatitis C
AUTOIMMUNE LIVER DISEASE - Primary Biliary Cholangitis; Autoimmune Hepatitis
HAEMOCHROMATOSIS
Stages of fatty liver disease
A: macrovesicular steatosis with lipid vacuole filling the hepatocyte cytoplasm.
D: steatohepatitis: neutrophils and lymphocytes surrounding hepatocytes with Mallory hyaline.
E: pericellular fibrosis as well as bands of fibrous tracts between portal tracts.
ALD -
NAFLD -
NAFDL
In Western populations, NAFLD prevalence between 20 and 30%, rising up to 90% in morbidly obese individuals.
Main associations are Obesity, Type 2 Diabetes and Hyperlipidaemia
Management of NAFLd
Lifestyle measures - weight loss
Differentiation of NAFLD vs ALD
-
Clinical spectrum of ALD
Malaise Nausea Hepatomegaly Fever Jaundice Sepsis Encephalopathy Ascites Renal Failure Death
The newly jaundiced ALD patient: Alcoholic hepatitis
‘Clinically relevant’ Alcoholic Hepatitis
Essential Features
- excess alcohol within 2 months
- Bilirubin > 80mol/l for less than 2 months
- Exclusion of other liver disease
- Treatment of Sepsis/ GI bleeding
- AST < 500 (AST: ALT ratio >1.5)
Characteristic Features
hepatomegaly fever +/- leucocytosis +/- hepatic bruit
SHORT-TERM MORTALITY AS HIGH AS 60%
Features of Hepatitis C
RNA flavivirus
170 million people affected world-wide; 20 - 30% likely to develop significant morbidity
Rate of progression related to:
male sex
age >40 at time of acquisition
alcohol >50g/week
Is treatable - Direct Acting antiviral drugs (95-95% chance of celarance)
Risk factors of HCV
IVDU (80% of users); blood transfusion (1 in 103000)
Sexual transmission:
- Increased prevalence with multiple partners
- No special precautions for stable monogamous couples, save testing partner.
Vertical transmission:
approx. 3% rate
Needle-stick transmission
approx. 5 - 10% rate
What non-invasive test can test liver fibrosis
Fibroscan - measures liver stiffness - can differentiate stages of fibrosis
Blood based assessment of liver fibrosis
APRI, FIB-4 and NAFLD fibrosis score
Commercially Available Blood Tests:
- Enhanced Liver Fibrosis Test (ELF)
- FibroTest
Signs of chronic liver disease
stigmata: spiders, fœtor, encephalpathy.
‘synthetic dysfunction’:
prolonged prothrombin time, hypoalbuminaemia.
Signs of portal hypertension
caput medusa
hypersplenism:
Thrombocytopenia
(pancytopenia)
Assessment of severity of chronic liver disease
Childs-Turcotte-Pugh Score
MELD
Assessment of ascites
Cell count:
>500 WBC/ cm3 and/ or >250 neutrophils/cm3 suggest spontaneous bacterial peritonitis (SBP)
Inflammatory conditions can also increase WBC count
Lymphocytosis suggests TB or peritoneal carcinomatosis
Albumin:
Serum ascites albumin gradient (SAAG) =
serum albumin MINUS ascitic albumin g/l
SAAG >11g/l = portal hypertension
Management of ascites
Low salt diet
Diuretics
Spironolactone:
- Start 100mg/day. Max effect 3days. Max dose 400mg/day (divided doses)
- Side-effects e.g gynaecomastia, hyperkalaemia, hyponatraemia, impotence
Frusemide (Furosemide)
- Max 160mg/day (divided doses)
- Side-effects e.g.hyponatraemia
Paracentesis
Transjugular intrahepatic portosystemic shunt (TIPSS)
Liver transplant
Aim for weight loss of 0.5-1 kg/day.
Monitor renal function and electrolytes
Aldosterone antagonists - Spironolactone, Furosemide
Common precipitating factors of hepatic encephalopathy
Gastrointestinal bleeding Infections Constipation Electrolyte imbalance Excess dietary (esp. animal) protein
All leads to:
Red hpeatic or cerebral function
Stimu;ation of an inflammatory response
Increasing ammonia levels
Grading of hepatic encephalopathy
Conn Score
Treatment of hepatic encephalopathy
Non-absorbable Disaccharides (ie lactulose)
aim for 2-3 soft stool/day
Non (minimally)-absorbable antibiotics
Gut ‘decontamination’ reduces urease and protease activity
Non specific symptoms of hepatitis
Malaise, fever, headaches, anorexia, n&v, dark urine,l jaundice
DEfine acute hepatits, chronic hepatitis
Acute = usually symptomatic
Chroinc - hepatitis virus present for more than 6 months. usually asymptomatic at this stage
Routes transmission - faecal oral (A,E), blood borne - contact with body fluids (B,C,D)
Causes of acute hepatitis
-
Lab diagnosis of viral hepatitis
DEtection of specific immune response (IgM, or IgM)
Viral nucleic acid detection (RNA or DNA), or Antigen detection (HBV and HCV)
Hepatitis A
RNA virus
Transmission - faeco-oral, human resorvoir
Virus can survive for months in contaminated water
Virus shed via billiary tree into gut
No chronic carriage
Good immunity afetr infection ro vaccination
Incubation period ~30days
Age is mainly determinant of severity:
- Mostly asymptomatic in children <5
No specific treatments - people just get better
Maintain hydration, avoid alcohol
Usually self-limiting illness
No role for vaccine or IgG
Hepatitis A vaccination
Inactivated virus
2nd dose gives life protection
Hepatitis A immune globulin - collect antibodies from donors - used in outbreaks
Features of Hepatitis E
RNA virus
More common than hep A in UK
Transmission - faeco-roral, prok products, minimal person-to-person trasmission
Incubation period 40 days
4 genotypes
Similar clinical features to hep A but may be neurological deficit (Guillaine barre syndrome, encephalitis, ataxia, myopathy)
Treatment is supportive
No vaccine
Chronic Hep E seen in very immunosuppressed patients. Treatment with ribavirin
Hepatitis B features
DNA virus
2 million deaths per year
HBV vaccination included in immunisation schedule in most countries
Transmission - transfusion (blood), fluids (blood, semen), organs and tissue transplantation, mother to baby at time of birth (vertical transmission - most common), contaminated needles and syringes, child to child (horizontal transmission - blood mucus in close contact)
Incubation - 2-6months
Age determines severity of acute illness, risk of chronic HBV infection (CHB)
Infection at brith/young chil is usually asymptomatic but leads to chronic infection
Infection as an adult is usually symptomatic but is cleared
Weight loss, abdo pain, fever, cachexia, mass in abdomen, bloody ascites. HBsAg +ve = Hepatocellular carinoma - biggest risk with HBV
Also with chronic HBV = cirrhosis, decompensation, HCC, death
Hepatitis B lab tests
sAg - surface antigen - marker of infection
sAb - surface antibody - marker of immunity
cAb - Core antibody
eAg - e antigen - suggests high infectivity
eAb - suggests high infectivit
eAb - e antibody - suggests low infectivity
HBV DNA - can be used to measure treatment response
Treatments for Hepatitis B
Acute HBV - no treatment
Chronic HBV - most do not require treatment, only treat those with liver inflammation…
Prevention of HBV
Education - safe sex, injecting etc…..
Features of hepatitis D
ss RNA virus Requires HBV to replicate Transmission same as Hep B Vertical Tm rare Acquired by - con-infection with HBV, super infection of chornic HBV carriers
Increases risk of chronic liver disease
Treatment with Peg IFN only
Hepatitic C features
RNA virus Transmission - injecitgn drugs (most common), transfusion and transplant, sexual/vertical rare No vaccine, no post exposure prophylaxis No reliable immunity after infection Multiple genotypes of HCV Incubation period of 6-7 weeks Can get cirrhosis or HCC.. Mostly asymptomatic Most diagnosed by screenign of high risk groups - drug users, immigrants to UK from high prevalent countries
Diagnosis - Anti HCV IgG positive = chronic infection or cleared infection; PCR or antigen positive = current infection/viraemia
Treatments for HCV
DAAs inhibit different stages of the replication cycle
DAAs often dispensed from community pharmacies with methadone on daily observed basis
- Very treatable
Bile
Bile is 97% water and 500mls is secreted by liver daily
Cholesterol secreted in bile is not water soluble and is kept in solution by micelles containing bile acids and phospholipid
Colour of bile is caused by the bile pigment, bilirubin which is a breakdown product of haemoglobin
Lithogenic (stone forming bile)
Bile becomes lithogenic for cholesterol if there is excessive secretion of cholesterol or decreased secretion of bile salts.
Excessive secretion of bilirubin (eg haemolytic anaemia) can cause its precipitation in concentrated bile in the gallbladder.
Acute Cholecystitis
The first indication of the presence of gallstones in a third of patients
Severe right upper quadrant pain, tenderness and fever
Leucocytosis and normal serum amylase
Usually resolves spontaneously but can progress to empyema, gangrene and rupture
Initiated by stone obstruction of cystic duct causing supersaturation of bile and chemical irritation
Chronic Cholecystitis may be a sequel to …
May be a sequel to repeated attacks of acute cholecystitis
Gallstones virtually always present
Inflammation secondary to chemical damage (supersaturated bile) rather than bacterial infection
Causes of acute pancreatitis
30% secondary to gallstones
50% secondary to alcohol abuse
20% other causes including post ERCP, hypercalcaemia, drugs (eg azothioprine), mumps
Presents with severe upper abdominal pain, fever, leucocytosis and raised serum amylase
Pancreatic abscess
Potential complication of acute pancreatitis
Infected pancreatic necrosis
Avascular haemorrhagic pancreas good culture medium
Drainage or necrosectomy plus antibiotics
Chronic pancreatitis - causes and features
85% of cases occur in those who abuse alcohol
Commoner in wine drinking countries
Stones and concretions in ducts
Can be hereditary
Usually painful
May present with exocrine or endocrine failure
Pseudocyst
Potential complication of acute pancreatitis
No epithelial lining Commonly in lesser sac High concentration of pancreatic enzymes May resolve spontaneously May be drained into stomach
Differential of pancreatic cysts
Intraductal papillary mucinous neoplasm – in continuity with main pancreatic duct or side branch duct, dysplastic papillary lining secreting mucin
Mucinous cystic neoplasm – mucinous lining, “ovarian-type” stroma
Serous cystadenoma – no mucin production; (almost always) benign
Carcinoma of pancreas
5% of cancer deaths 66% in head of pancreas Ductal adenocarcinoma most common subtype Perineural invasion Pre-malignant PanIN asymptomatic
Risk factors for pancreatic cancer
Germline mutations (e.g. BRCA) account for small proportion of patients, but smoking is by far the biggest risk factor
Signs and symptoms of pancreatic cancer
Painless obstructive jaundice
New onset diabetes
Abdominal pain due to pancreatic insufficiency or nerve invasion.
Tumours in head may obstruct pancreatic duct and bile duct – “double duct sign” on radiology
Whipples resection
Only for tumours of head of pancreas
??
Treatment for pancreatic cancer
Whipples resectin
Neoadjuvant therapy - Folfirinox chemotherapy
Pancreatic neuroendocrine tumours
Rare
May secret hormones (functional)
Commonest functional tumour is insulinoma which presents with hypoglycaemia
90% of insulinomas are benign
Malignant endocrine tumours have much better prognosis than pancreatic carcinoma.
Carcinoma of ampulla of vater
Presents when smaller (earlier presnetation) than carcinoma of pancreas
May arise from pre-existing adenoma
25% 5 year survival following Whipples’ resection
Cholangiocarcinoma
Classified as intrahepatic / extrahepatic depending on origin
Intrahepatic cholangiocarcinoma needs to be distinguished from
metastatic adenocarcinoma (which may have similar histology)
and hepatocellular carcinoma
Extrahepatic cholangiocarcinoma has similar morpholopgy and
prognosis to pancreatic carcinoma.
Treatment is currently Whipple’s operation to remove common
bile duct and involved pancreas/duodenum. Trials likely to start
looking at value of neoadjuvant therapy.
Carcinoma of the gallbladder
Rare
Gallstones present in 80% of cases
Adenocarcinoma
Dismal prognosis unless found incidentally in a gallbladder removed for chronic cholecystitis
Local infiltration may make gallbladder seem abnormally stuck down at theatre
Pancreatic function
Exocrine - manufacture and secretion of enzymes to digest food
Endocrine - glucose control
Diagnosis of acute pancreatitis
2 out of 3:
Pain in keeping with pancreatitis (abdo pain and vomitting)
Amylase 3 times upper limit of normal (>= 300)
Characterisitc CT appearance
Different severities of acute pancreatitis
Mild - Absence of organ failure/ local/ systemic complications - fluid and analgesia
Moderately severe - Presence of transient organ failure or presence of local/ systemic complications in absence of organ failure
Severe - Persistent organ failure
The pain is the same wether its mild or severe.
Causes of acute pancreatitis
Gallstones (most common cause) Alcohol Trauma/ ERCP Other drugs/ high lipids/ autoimmune/ viral
Initial treatment of acute pancreatitis
ABC’s Fluids Oxygen Organ support Antibiotics ?? (e.g. meropenem)
Investigations fo acute pancreatitis
US to assess for gallstones
MRCP to assess for CBD stones
CT if diagnostic doubt or concern about complications
Phases of acute pancreatitis
Early phase - Systemic disturbance from host response to local pancreatic injury (usually over by one week). SIRS may progress to MODS.
Late phase - local and septic complications
Sequelae of pancreatitis
Complete resolution with/without organ dysfunction Necrosis with/without infection Fluid collection: - Peripancreatic fluid collection - Pseudocyst - Pancreatic fistula
After pancreatitis:
May be diabetic
May require creon pancreatic enzyme supplements
May require restorative surgery
Significant impact on quality of life
If gallstones - needs gallbladder removed
Pancreatic necrosis
Non-enhancing pancreas on venous phase CT.
Predicts complicated disease but initial management not altered.
Serial CT for resolution, or repeat if deterioration in organ function/increase in organ support.
Infected pancreatic necrosis
Ongoing sepsis and progression to MODS Requires intervention: - Open necrosectomy - Percutaneous necrosectomy - Radiological drainage
Complications of pancreatic necrosis
Bleeding - interventional radiology
Erosion to surrounding structures - surgery
Interventional radiology for bleeding (as a consequence of pancreatic necrosis)
Access via groin.
Selective cannulation of coeliac trunk.
Commonly splenic artery aneurysm, may be gastroduodenal artery
Pancreatic pseudocyst
May settle without intervention (almost always by 12 weeks)
If symptomatic may require drainage
Can drain to stomach laparoscopically or endoscopically
May drain transpapillary
Pancreatic fistula
May require period of parenteral nutrition
Would attempt endoscopic treatment in first instance
May require salvage distal pancreatectomy
Risk factors for cancer in GI tract
Smoking and alcohol
HPV (mainly tonsil, oropharynx)
Layers of oesophagus
4 layers Mucosa (non-keratinising stratified squamous) Muscularis mucosae Submucosa Muscularis propria Advenitia
Common oesophageal pathology
Infections: Candida albicans (fungus), Herpes simplex virus
Inflammation – chemicals:
Peptic oesophagitis / GORD: reflux of acid, bile
Caustics: lye (NaOH, caustic soda)
Pills: iron, bisphosphonates, tetracyclines, etc
Diverticula, achalasia, schatzki ring, systemic sclerosis, hiatus hernia…
What stain shows candida albicans in oesophagus?
PAS stain confirms spores and hyphae of candida albicans
Features of barretts oesophagus
Barrett’s oesophagus; a metaplastic response to mucosal injury e.g. from long term GORD.
Squamous epithelium becomes glandular, usually intestinal with goblet cells. (Squamous to columnar change)
Associated with the development of benign strictures but also with adenocarcinoma.
Goblet cells seen in mucosa
Red velvet tongues of mucosa seen on endoscopy
Risks of Barretts oesophagus
Dysplasia represents a spectrum of morphological changes
‘Indefinite for dysplasia‘
low grade dysplasia
high grade dysplasia
Dysplastic epithelium is architecturally and cytologically abnormal
Low grade- Cells polarised, Nuclei stratified.
High grade - Polarity lost, Nuclei rounder, vesicular
prominent nucleoli, abnormal mitoses, necrosis
But beware inflammation/reactive changes! These can mimic dysplasia
Barretts oesophagus to carcinoma - risk
Dysplasia can progress to carcinoma over years
Males > Females. Increasing.
Definite LGD or HGD: increased risk but progression to cancer still slow, but pathologists do not always agree. LGD agreed by 3 pathologists nearly same cancer risk as HGD
Role of surveillance / screening controversial - Four biopsies (aka Seattle Protocol) every 2cm effective at finding dysplasia, but laborious, Targeted biopsy may eventually replace it with improvements in endoscopy
Endoscopic treatments may avoid need for radical surgery
Radiofrequency ablation - reduced cancer risk
Oesophageal cancer
Squamous carcinoma associated with smoking and drinking
Adenocarcinoma associated with gastro-oesophageal reflux (GORD), Barrett’s oesophagus and obesity
Acute vs chronic gastritis
Acute - Alcohol, Medication e.g. NSAIDs, severe trauma, burns [Curling’s ulcers], surgery
Chronic
A: Autoimmune
B: Bacterial (H pylori)
C: Chemical
Autoimmune gastritis
Autoimmune destruction of parietal cells due to auto-antibodies against intrinsic factor and parietal cell antibodies in blood
Leads to
complete loss of parietal cells with pyloric and intestinal metaplasia.
Achlorhydria -> bacterial overgrowth.
Hypergastrinaemia -> endocrine cell hyperplasia /carcinoids.
Persistent inflammation which can lead to epithelial dysplasia and may lead to cancer.
Helicobacter pylori, gastritis and peptic ulceration
H. pylori colonises gastric mucosa causing active chronic inflammation; IL-8 from epithelial cells attracts neutrophils
After exposure to H pylori the resulting gastritis can occur in 2 patterns - Antral-predominant gastritis -> hypergastrinaemia and duodenal ulceration; Pangastritis -> hypochlorhydria, multifocal atrophic gastritis, intestinal metaplasia, cancer
Microbe-host interface is thought to be the reason 2 patterns emerge; patients with higher IL-8 production tend to get pangastritis, lower IL-8 levels are associated with antral gastritis
Peptic ulceration isn’t solely due to ‘too much’ acid, again host/microbe interface is important - Impaired mucosal defense (due to NSAID interfering with mucosal prostaglandin synthesis; bile reflux); Microbe factors (CagA + variants associated with more severe inflammation)
Consequences of peptic ulceration
Haemorrhage, perforation, fibrosis (leading to stenosis)
Chemical gastritis
Few inflammatory cells. Surface congestion oedema, elongation of gastric pits, tortuosity, reactive hyperplasia / atypia, ulceration
Seen in antrum more than corpus
Causes include bile reflux, NSAIDs, ethanol, oral iron
Features of gastric cancer
Strongly associated with chronic gastritis: H pylori or autoimmune.
Background atrophic mucosa, chronic inflammation, intestinal metaplasia, dysplasia.
Morphologically classified via the Lauren classification into ‘intestinal’ or ‘ diffuse’ types.
Diffuse - young patients, has worse prognosis
Intestinal - frequently exophytic and ulcerated tumours and occurs in the proximal and distal stomach more than diffuse type does
Diffuse gastric cancer
Individual malignant cells with mucin vacuoles (‘signet ring’ cells)
May invade extensively without being endoscopically obvious, so called linitis plastica (‘leather bottle stomach’)
Weaker link with gastritis.
Metastasis to ovaries (‘Krukenberg tumour’)
Supraclavicular lymph node (‘Virchow’s node’)
‘Sister Joseph’s nodule’ (umbilical metastasis)
Upper GI bledding presents with
haematemesis,
“coffee ground” vomiting or melaena
Due to a bleeding source from oesophagus, stomach or duodenum
Causes of upper GI bleeding
Peptic ulcer (due to acid, h.pylori, NSAIDs), oesophagitis, gastritis, duodenitis, varices, malignany, mallory-weiss tear ((tear of gastro-oesophageal junction), other
Upper GI bleeding management
Resuscitate if required - pulse & BP; IV access for fluids/blood (check bloods, esp Hb & urea); lie flat & give oxygen
Risk assessment & timing of endoscopy:
High risk: emergency endoscopy Moderate risk: admit & next day endoscopy
Low risk: out-patient management?
Risk scors for upper GI bleeding - useful for all other patients
Endoscopic Rockall Clinical “admission” Rockall Glasgow Blatchford (predicts need for intervention or death - GBS≤1 identifies those at very low risk of poor outcome: can be discharged for out-patient endoscopy) AIMS 65
Timing of endoscopy after upper GI bleed
Most patients: endoscope within 24 hrs (even at weekend)
Very low risk (GBS≤1): can be discharged for out-patient endoscopy
Very high risk (haemodynamic instability or severe ongoing bleeding): emergency endoscopy
Cautery of a duodenal ulcer through endoscope
Endoscopic therapy for upper GI bleeding
AdrenaIine injection Heater probe Endoscopic clips Hemostatic powders (thrombin, laser)
Other option for ulcer bleeding (not by endoscopy)
Radiological embolisation of bleeding vessel uncontrolled by endoscopy
Medication for upper GI bleeding
IV PPIs - not beneficial prior to endoscopy; Reduces rebleeding & mortality if given post-endoscopy to the high risk patients who required endoscopic therapy
If on antiplatelts (e.g. aspirin, NSAIDs) - continue low dose aspirin after upper GI blled once haemostasis achieved (add PPI). Stop NSAIDs
If on anticoagulants (e.g. clopidogrel, warfarin & DOACs) - Once haemostasis achieved, assess risks vs. benefits, but generally aim to restart these medications as mortality high from cardiovascular disease
Transfuse blood only once Hb <7-8g/dL
[Transfuse platelets if actively bleeding & platelet count <50x109/L
FFP if INR>1.5
Prothrombin complex concentrate (PCC) if on warfarin & active bleeding]
Treatment of varices
Endoscopic banding, TIPS or B-blocker durgs
Management of acute variceal bleeding
Resuscitation - restore circulating volume; transfuse once Hb<7 g/dL; consider airway protection
Diagnosis - endoscopy
Therapy - antibiotics early (prophylactic); vasopressors (Terlipressin) early; endoscopic band ligation; rescue TIPS
Uncontrolled variceal bleeding - Sengstaken tube
Guidelines:
- Primary Prophylaxis: Beta-blockers or Band ligation
- Acute bleeding:
Antibiotics & Terlipressin (in A&E)
Banding first line for oesophageal variceal bleeding
TIPS for uncontrolled variceal bleeding
Balloon tamponade (as temporary salvage)
- Prevention of re-bleeding - Beta-blocker + repeated Band ligation
Causes of inflammation of the intestines
Coeliac Disease (small intestine) Idiopathic Chronic Inflammatory Bowel Disease - Crohns Disease, Ulcerative Colitis (large intestine) Infection Ischaemia Radiation colitis Diversion colitis Microscopic colitis
Features seen on histology in coeliac disease
Crypt hyperplasia
Villous atrophy
Intraepithelial lymphocytes
Coeliac disease - features
Immunological response to gliadin
It has a strong hereditary component; the prevalence of the condition in first degree relatives is approximately 10%
Strong association exists between celiac disease and HLA haplotypes DQ2 and DQ8
Gluten derived peptide gliadin presented by HLA molecules to helper T cells => lymphocytic response => epithelial damage => flattening of villi => less surface area for absorption of nutrients => malabsorption
Serum TTG elevated in classical coeliac sprue
Manage by removal of gluten-containing foods from diet
Features of chronic IBD
Chronic changes mainly due to regeneration following ulceration Crypt distortion Loss of crypts Submucosal fibrosis Paneth cell metaplasia Neuronal Hyperplasia
Acute changes seen during active disease - cryptitis, loss of goblet cells, crypt abscess formation, ulceration
Symptoms of ulcerating colitis - & complications
UC - Diffuse mucosal inflammation limited to the colon.
Proctitis = distal colitis limited to rectum or rectuma dn sigmoid (proctosigmoiditis)]Left sided colitis to splenic flexure
Extensive colitis to hepatic flexure
Pancolitis
Symptoms: relapsing, bloody mucoid diarrhoea (stringy mucus) with pain/cramps relieved by defecation; lasts days/months, then remission for months/years; initial attack may cause medical emergency for fluid and electrolyte imbalance
60% have mild disease; 97% have one relapse per 10 year period
Extraintestinal manifestations: migratory polyarthritis, sacroiliitis, ankylosing spondylitis, erythema nodosum, clubbing of fingertips, primary sclerosing cholangitis, pericholangitis, cholangiocarcinoma (rare), uveitis
Complications: perforation, toxic megacolon (Colon stops contracting - no peristaltic movements - due to inc. pressure within lumen –> makes it harder for blood to flow –> tissue starts to become weaker) ,iliac vein thrombosis, carcinoma, lymphoma
Treatment of ulcerative colitis
Treatment: local or systemic steroids
30% require colectomy during first 3 years due to uncontrollable diseasse
Regular colonoscopy with biopsy recommended in patients with long-standing extensive colitis to detect precancerous dysplastic changes.
Features of Crohn’s disease
Transmural granulomatous disease affecting oesophagus to anus but discontinuous, usually involves small intestine and colon with rectal sparing, less severe in distal vs. proximal colon (i.e. preferential right-sided involvement)
Presence of granulomas
Skip lesions
Symptoms of Crohn’s disease
Episodic mild diarrhoea
Fever
Pain
May be precipitated by stress; if colon affected, may have anaemia
20% have abrupt onset, resembling acute appendicitis or bowel perforation
Complications of Crohn’s disease
Fibrosing strictures (common in terminal ileum) Fistula Malabsorption Toxic megacolon Carcinoma ( but lower risk than in U.C.)
Histology features of Crohns disease
Skip lesions Fistulas/sinus tracts Malabsorption (if ileum involved) Granulomas Deep ulcerations Marked lymphocytic infiltration Serositis
Long term risks of IBD
Crohn’s disease and Ulcerative colitis both associated with higher risk of colonic carcinoma than general population.
Colonic/rectal adenocarcinoma is the most common intestinal malignancy
Definition of adenoma of the colon
defined by dysplastic, and the majority are polyps
Differential of adenomas in colon
Hyperplastic (metaplastic) polyps
Hamartomatous polyps
Inflammatory polyps
Submucosal lesions (e.g. lipoma, leiomyoma)
CRC risk factors
Adenoma - size, number
IBD – Ulcerative colitis, Crohn’s to lesser extent
Family History
Other Carcinomas
Polyposis syndromes:
– FAP (associated with APC gene)
– Lynch syndrome (associated with mismatch repair defects)
What staging criteria is used for CRC
Duke’s staging - 4 stages (A-D) - A&B have far better prognosis (don’t need chemotherapy
TNM staging
Epidemiology of IBD
Disease of young people
Peak incidence between 10-40 years
Pathogenesis of IBD
Aetiology unknown
‘Abnormal host response to environmental triggers in genetically susceptible individuals’ - e.g. IBD5, NOD2
Numerous genetic factors implicated.
Smoking - Increases risk of crohns Reduces risk of UC
History and examination of IBD
History: Stool frequency, consistency, urgency, blood Abdo pain, malaise, fever Weight loss Extraintestinal symptoms (joint, eyes, skin) Travel Family Hx Smoking
Examination: Weight Pulse Temperature Anaemia Abdominal tenderness Perineal examination
Investigations of IBD
FBC, ESR U&Es, LFTs CRP Stool cultures + C.difficile toxin Faecal calprotectin AXR
Rigid sigmoidoscopy (limited use)
Colonoscopy preferable to felxible sigmoidoscopy
Avoid endoscopic examination in sever disease (as high risk of perforation)
Small bowel radiology
Labelled WCC scanning
IBD treatment
Tx common to Uc and Crohns - Corticosteorids (Glucocorticoids - IV hydrocortisone, methylprednisolone, oral prednisolone (40mg daily/1 week, reduce by 5mg/week). Newer products - Budesonide, Beclometasone), Thiopurines, Biologics
For UC alone - 5ASAs
For Crohns alone - Methotrexate, Immune modulating diets
Steroids - rapid induction of remission; poor evidence for maintaining remission
SE - immunosuppression, impaired glucose tolerance, osteoporosis, weight gain, cushingoid appearances
Aminosalicylate - anti-inflammatory: Mesalazine most widely used Mainrole - induction of remission in mild-moderate UC & maintenance of remission in UC Renal impairment (interstitial nephritis, nephrotic syndrome) is rare and idiosynchratic
Thiopurines - Azathioprine (1.5-2.5mg/kg/day) and mercaptopurine (1-1.5mg/kg/day) are unlicensed for IBD but are widely used.
Effective as maintenance therpay for UC and Crohns
Steroid sparing agent.
Essentially prevents T cell clonal expansion in response to antigenic stimuli
TPMT (Thiopurine methyl transferase), meMP and 6TG are important in metabolism
SE - leucopenia, N&v, arthralgia, pancreatitis, hepatitis, squamous skin cancers, haematological malignancy
Mehotrexate - anti-metabolite
Folate scavenger - need folate supllements
15-25mg weekly
Effective in Crohns
SE - GI upset, hepatotoxicity, immunosuppression, sepsis, pulmonary fibrosis
Biologics - e.g. Infliximab - Mruine anti-TNF alpha monoclonal antibody.
2 monthly IV infusion. Expensive.
Adalumimab - humanised anti-TNF alpha. Fortnightly SC injections. Marginally cheaper.
Golimumab - humanised anti-TNF. 2 weekly sc injections. Licensed for moderate to sever UC (not Crohns) than Crohns
SE of biologics - infeciton risk (TB, hep B), neurological (MS, multifocal leucocephalopathy), Malignancy (possibly inc. lymphioma risk)
Investigation of acute severe colitis
Daily FBC, ESR, U+Es, CRP
Stool cultures (including C.Difficile)
Daily AXR
?Sigmoidoscopy
Tx of acute severe colitis
Prophylatic LMW heparin
IV hydrocortisone 100mg QDS or Methylprednisolone 30mg BD
Treat for 72 hours
Improving then oral prednisolone 40mg
No improvement – rescue therapy
Rescue therapy: Ciclosporin 2mg/kg/day IV Infliximab 5mg/kg single dose Surgery If medical therapy doesn’t work then surgery indicated
Surgery in IBD
UC:
Surgery ‘curative’
Ileo-anal pouch or ileostomy
Crohns:
Indicated fir stricturing, perforation, fistulizing disease
Sparing as will come back
Histological changes seen in coeliac disease
What blood test with high sensitivity and specificity for diagnosing untreated coeliac disease could you request?
Crypt hyperplasia
Villous atrophy
Intraepithelial lymphocytes
Neutrophil polymorphs are seen in between epithelial cells of the crypts
Blood test: IgA endomysial antibody (IgA EMA) IgA tissue transglutaminase antibody (IgA tTG) IgA deamidated gliadin peptide (IgA DGP) IgG deamidated gliadin peptide (IgG DGP)
Causes of inflammation in the intestines
Coeliac disease (small intestine) Idiopathic Chronic Inflammatory Bowel Disease (Crohns, Ulcerative Colitis) Infection Ischaemia Radiation colitis Diversion colitis Microscopic colitis
Features of Coeliac disease
Pathogenesis of coeliac disease
Immunological response to gliadin.
It has strongly hereditary componenent; the prevalence of the condition in first degree relatives is approx 10%.
Strong association exists between coeliac disease and HLA haplotyps DQ2 and DQ8
Gluten derived peptide gliadin presented by HLA molecules to helper T cells –> lymphocytic response –> epithelial damage –> flattening of villi –> less SA for absorption of nutrients –> malabsorption.
Serum TTG elevated in classical coeliac sprue
Manage by removal of gluten-containing foods from diet
Pathogenesis:
Coeliac disease is an inflammatory disorder of the small bowel caused by immune sensitivity to gluten.
• Loss of immune tolerance to gliadin peptide antigens derived from wheat, rye, barley and related grains, in genetically susceptible individuals (HLA-DQ2 or DQ8).
• Malabsorption occurs because of loss of absorptive area and the presence of a population of immature surface epithelial cells.
(The mechanism of innate immune activation is not fully known. Thought to involve T cells (hallmark is a T cell mediated chronic inflammatory reaction) and tissue transglutaminase enzyme, which
modifies gliadin.)
Acute changes seen during active disease of IBD
Cryptitis Loss of goblet cells Crypt abscess formation with pain/cramps relieved by defacation; lasts days/months, then remission for months/years; initial attack may cause medical emergency for fluid and electrolyte imbalance. Ulceration Fibrin also seen
Symptoms of Ulcerative Colitis
Relapsing, bloody, mucoid diarrhoea (stringy mucus)
Extra-intestinal manifestations of UC
Migratory polyarthritis, sacroilitis, ankylosing spondylitis, erthema nodosum, clubbing of fingertips, primary sclerosing cholangitis, pericholangitis, cholangiocarcinoma (rare), uveitis
Complications of ulcerative colitis
Perforation, toxic megacolon, iliac vein thrombosis, carcinoma, lymphoma
Symptoms of Crohns disease
Episodic mild diarrhoea
Fever
Pain
May be precipitated by stress; if colon affected, may have anaemia
Complications of Crohns disease
Fibrosing strictures (common in terminal ileum) Fistula Malabsorption Toxic megacolon Carcinoma (but lower risk than in UC)
Histology of IBD - specific to Crohns
Skip lesions Fistulas/sinus tracts Malabsorption (if ileum involved) Granulomas Deep ulcerations Marker lymphocytic infiltration Serositis
Long terms risks of IBD
Crohn’s and ulcerative colitis both associated with higher risk of colonic carcinoma than general population
Colonic/rectal adenocarcinoma is the most common intestinal malignancy
36 year old staff nurse at GRI. Type 1 diabetes mellitus since aged 14 years old. Admits she has ‘always been thin’ but over the past 6 months has lost 1 stone in weight unintentionally. She is concerned about her weight loss and complains of associated lethargy. She also complains of ‘diarrhoea’ for the past 6 months. She currently passes loose, watery stools up to 6 times daily (including occasionally at night). She denies any blood PR and the stools flush away easily. Prior to her bowel habit was normal once daily. She denies any foreign travel and no close contacts have been unwell. She complains of intermittent upper abdominal pain and ‘bloating’. Previously she suffered from heartburn but this has settled. She has had no vomiting, dysphagia, haematemesis or melaena. Her bowels are ‘black’ but she has restarted iron supplements. Her Hb 2 weeks ago was 93g/l. She has previously had iron deficiency anaemia, put down to ‘heavy periods’ but she has not had a period for almost 6 months.
DDx for her presentation
- This short history should allow students to focus on potential causes of weight loss. The history of T1DM raises the possibilty of poor diabetic control or another endocrine cause (e.g. thyrotoxicosis, addison’s disease). However diarrhoea and anaemia should focus on a potential GI cause and raise the possibility of malabsorption. The differential diagnosis of diarrhoea should include small bowel (e.g. coeliac, small bowel crohn’s)- typically causing watery diarrhoea, or large bowel (e.g. ulcerative colitis)- typically including blood and mucous. May differentiate into osmotic or secretory causes and should discuss relevance of steatorrhoea (fat malabsorption may point to pancreatic insufficiency). Infective gastroenteritis should be considered and possible pathogens discussed (e.g. salmonella, campylobacter or shigella). The importance of travel, ill contacts or recent antibiotics (Clostridium Difficile) should be highlighted. Should discuss the importance of upper and lower GI alarm symptoms which would prompt further investigation. Could also discuss potential causes of iron deficiency anaemia e.g. blood loss, malabsorption, dietary.
Faecal calprotectin =
protein produced in the gut as a result of any inflammatory process. It has been shown to have a high negative predictive value. In patients presenting with lower abdominal symptoms, it can be used to differentiate between functional and organic GI disorders. It is sensitive but non-specific and can be elevated due to any cause of underlying inflammation (e.g. coeliac, NSAIDs, IBD or infection)
Faecal elastase
elastase is a pancreatic enzyme, which helps to break down connective tissue. It is present in the serum, urine and faces. Pancreatic elastase does not undergo any significant degradation during intestinal transit and, therefore, acts as a useful marker of pancreatic activity. A low faecal elastase (<500) points to pancreatic exocrine insufficiency.
Main investigation for suspection/want to rule out IBD
OGD and duodenal biopsy - should take 4 biopsies from distal duodenum for maximal yield as changes may be patchy (must be on gluten-rich diet at time)
Investigations for coeliac disease
FBC
Immunoglobulin A-tissue transglutaminase (IgA-tTG)
Skin biopsy - if suggesting dermatitis herpetiformis
OGD - Small-bowel histology is essential and the gold-standard test to confirm the diagnosis.
Two biopsies of the bulb and at least four biopsies of the distal duodenum should be submitted for histological analysis.
Tx/Mx of coeliac disease
Gluten-free diet
Calcium and vitamin D supplementation +/- iron
Corticosteroid e.g. budesonide, prednisolone
