Gastroenterology

Ammad Mahmood GUMSA Revision Lectures

Contents
Peptic ulcer disease Coeliac disease Alcoholic liver disease Obstructive jaundice Hepatitis

Peptic Ulcer Disease

Gastric Acid Production

Parietal cells produce hydrocholoric acid which:
Destroys microorganisms Activates enzymes eg pepsinogen Helps in digestion by breaking down and coagulating proteins and by combining with calcium and iron to produce salts

H+ ions are produced by dissociation of H2O and pumped into the stomach by H+/K+ exchangers
The OH- ions combine with H2CO3 to produce H2O and HCO3- which is pumped into the blood by HCO3-/Clexchangers The Cl- ions are pumped into the stomach with the K+ brought in by the H+/K+ exchanger or move by diffusion

Control of Acid Secretion

At rest the H+/K+ exchangers are held in intracellular vesicles stimulus to produce acid causes them to be fused with the membrane which throws the membrane into folds called secretory canaliculi increasing the surface area for secretion
Stimuli to produce acid include:
Acetylcholine increases acid production Histamine increases acid production Gastrin increases acid production Prostaglandin E2 decreases acid production Somatostatin decreases gastrin release

All of these function by having an effect on protein kinases, through Ca2+ levels or G-proteins, which control the activity of the H+/K+ exchangers

Helicobacter Pylori
Gram ve rod bacteria, spread person to person, very common (90% in developing world, %=age in developed world) Produces urease, an enzyme which produces ammonia from urea allowing it to survive in very acidic environments Using flagella it moves to the alkaline mucus layer in the stomach, irritating the gastric epithelium and causing an inflammatory reaction in this area (gastritis)

Peptic ulcers
A break in the epithelium of the stomach or duodenum caused by an imbalance between gastric acid production and mucosal resistance
Around 80% located in duodenum, 20% in stomach Causes
H Pylori infection NSAIDs Zollinger Ellison syndrome Post surgery Smoking

Ulcers are large (2-10cm), round, with perpindicular walls and a smooth base which can extend through to the muscularis externa or further

They contain fibrin deposition and layers of granulation and scar tissue

Peptic ulcers
Duodenal ulcers
Ammonia released by H Pylori in the stomach causes increased gastrin production which causes excessive acid production Excess acid causes damage to the duodenal mucosa and can lead to ulceration or gastric metaplasia Acid also precipitates the bile salts in the duodenum which would normally have stopped infection The islands of gastric mucosa can be infected by H Pylori further worsening the problem

Gastric ulcers
Epithelial damage and destruction of the protective alkaline mucus barrier leads to ulceration

Clinical features
Epigastric pain worse at night and before meals
Nausea, vomiting, dyspepsia

Anorexia, weight loss

Can be asymptomatic before complications Complications
Perforation causes peritonitis Penetration ulcer enters adjacent organ Haemorrhage ulcer erodes into a blood vessel and bleeds causes haemetemesis and melaena

Investigations
Diagnosis of H Pylori infection
urea breath test 14C is ingested and if H Pylori is present it will break urea down to ammonia and CO2. If 14C is detected in a breath test it is positive Serology for antibodies Stool test using immunoassays Rapid urease/CLO test Gastric biopsy added to solution containing urea and pH indicator, if ammonia is produced pH will increase Biopsy culture and histology
14C

Endoscopy
Carried out for over 55s or those with alarm symptoms (dysphagia, weight loss, anorexia) Gastric ulcers are always biopsied

Treatment
H Pylori infection is treated with eradication triple therapy
Proton pump inhibitor omeprazole Antibiotics clarithromycin + amoxicillin or metronidazole

Drugs for treatment of dyspepsia Management of complications

Surgery for perforation or massive bleeds may require partial gastrectomy Bleeding ulcers can be injected with adrenaline endoscopically

Management of Dyspepsia
Dyspepsia refers to any disorder related to gastric acid Drugs used include:
Proton pump inhibitors eg omeprazole inhibit H+/K+ pumps, effective as it works regardless of the stimulus for acid secretion Antacids eg calcium carbonate buffer acid and increase pH H2 receptor antagonists eg ranitidine antagonise histamine to reduce acid production Anticholinergics eg atropine reduce acid production but have too many side effects Synthetic prostaglandins eg misoprostol reduce acid production and increase mucus and bicarbonate production

Coeliac Disease

Coeliac disease
Abnormal reaction to gluten in the diet leading to malabsorption 1 in 2000 prevalence in the UK, higher in Western Ireland Aetiology not fully understood but a component of gluten called gliadin is believed to stimulate enterocytes to mount an inflammatory reaction

Other factors include:

Genetics related to the HLA B8 antigen which is also involved in the condition dermatitis herpetiformis Environmental a factor such as a viral infection may explain the variable age of onset

Pathology
Primarily affects the proximal SI around the jejunum Epithelial cell loss accelerates to the point where cell proliferation in the crypts is unable to maintain a normal amount of functioning cells This leads to the classical histological findings of subtotal villous atrophy and crypt hyperplasia

The immature cells which populate the brush border cannot absorb as efficiently and hormone secretion is also impaired

Clinical Features
Can present at any age but most common is women in their 40s Symptoms are variable and non-specific:
Malnutrition and weight loss Anaemia Fatigue and malaise GI symptoms steatorrhoea, diarrhoea, bloating, discomfort/pain

Investigations
Jejunal biopsy
Gold standard, obtained by endoscopy

Antibodies
IgA endomysial antibodies (IgA EMA) Tissue transglutaminase antibodies

Blood tests
Macrocytic anaemia due to folate deficiency Iron deficiency

Management
Gluten free diet
Substitute wheat, rye and barley for rice, maize, soya, some oats

Vitamin and mineral supplementation

Compliance to gluten free diet can be assessed by testing antibodies at 4-6 weeks following start of diet

Obstructive Jaundice

Jaundice
Caused by hyperbilirubinaemia Symptoms
Yellow discolouration of the skin and sclera due to cutaneous deposition of bilirubin Pruritus Pale stools (absence of stercobilin) and dark urine (excretion of conjugated bilirubin) in obstructive jaundice

Causes divided into:

Pre-hepatic unconjugated hyperbilirubinaemia usually due to haemolysis Hepatic mixed hyperbilirubinaemia, variety of causes, due to hepatocellular damage Post-hepatic conjugated hyperbilirubinaemia due to blockage of the biliary tree gallstones or pancreatic tumours

Gallstones (Cholelithiasis)
Types of stones:
Cholestrol large yellow stones 20% Bile Pigment small black irregular 5% Mixed 75%

Typical patient fair, fat, fertile Depending on anatomical site gallstones have different effects:
Silent Impaction in Hartmanns pouch/cystic duct biliary colic, acute cholecystitis Impaction in CBD choledocholithiasis, ascending cholangitis Gallstone ileus Pancreatitis

Gallstones
Biliary colic
Impaction at Hartmanns pouch which the gallbladder tries to contract against Causes RUQ colicky pain for 2-3 hours after eating which can radiate to right shoulder, patient characteristically lies still Not systemically unwell, not jaundiced

Acute cholecystitis
Prolonged impaction at Hartmanns pouch/cystic duct causing the gallbladder to be irritated as it fills with concentrated bile. Becomes infected and fills with pus Persisting RUQ pain + fever Chronically can lead to a fibrosed gallbladder and chronic cholecystitis

Gallstones
Choledocholithiasis
Impaction in the CBD Causes RUQ pain + jaundice If obstruction is not relieved the pressure can cause liver damage

Ascending cholangitis
Infection behind an impacted CBD stone Causes RUQ pain + jaundice + fever (Charcots triad) High morbidity and mortality

Investigations
Ultrasound
Gallstones Thickened gallbladder surrounded by fluid CBD dilation

AXR
10% of gallstones are radio-opaque

MRCP
Specialised MRI scanner to image biliary tree and pancreas

ERCP
Endoscopic retrograde cholangiopancreatography An endoscope with a side view camera to visualise sphincter of Oddi Diagnostic and therapeutic eg sphincterotomy, stone retrieval

Bloods LFTs, coagulation screen for procedures

Management
Depends on which pathology is present Measures include
Analgesia eg morphine Antibiotics (eg amoxicillin, gentamicin, metronidazole) and rest Removal of stone by ERCP or rarely using lithotripsy Cholecystectomy either within 72h or after 6 weeks after the inflammation has settled

Alcoholic Liver Disease

Alcohol Metabolism

ADH alcohol dehydrogenase ALDH aldehyde dehydrogenase CYP2E1 an enzyme which is part of the microsomal ethanol oxidising system (MEOS) High levels of acetaldehyde and its derivatives in the genetically susceptible are hepatotoxic

Alcoholic Liver Disease

Fatty liver
Excess fat deposition in the liver, reversible Occurs in 50% of heavy drinkers Causes derangement of LFTs but normal coagulation Few symptoms, no encephalopathy Also occurs without alcohol non-alcohol steatohepatitis, occurs in metabolic syndrome

Acute hepatitis
Occurs in 40% of heavy drinkers More deranged LFTs, prolonged clotting time Moderate symptoms, encephalopathy possible

Cirrhosis
Severe alcohol abuse Features of chronic liver disease eg encephalopathy, portal hypertension

Clinical Features
Some clinical features are common to chronic liver disease due to any cause and some are specific to alcohol excess Chronic alcohol abuse leads to:
Neural damage due to the thiamine deficiency and alcohol neurotoxicity. This leads to cortical and cerebellar atrophy resulting in reduced cognition and cerebellar ataxia Thiamine deficiency leads to Wernicke Korsakoff syndrome which involves Wernickes encephalopathy in the early stages and eventually causes Korsakoff psychosis
Classically presents with confusion, gait ataxia and mild nystagmus Immediate memory recall retained but have anterograde and retrograde amnesia, display confabulation

Peripheral neuropathy Psychiatric problems

Chronic Liver Disease

Ascites - Excess fluid in the peritoneal cavity due to:
Reduced albumin and oncotic pressure Portal hypertension leading to transudation of fluid into peritoneal cavity Peripheral vasodilation leading to water retention by kidneys

Portal hypertension
The normally low pressure in the portal system is elevated due to back pressure caused by liver cirrhosis Blood finds alternative pathways to the systemic circulation which bypass the liver leading to portosystemic shunting and distension of these vessels eg oesophageal varices Thus the protective first pass metabolism of the liver is lost Oesophageal varices have a tendency to rupture and with concurrent coagulopathy this can be fatal

Chronic Liver Disease

Hepatic encephalopathy
Portosystemic shunting leads to blood which has not been detoxified reaching the brain Neurotoxins such as ammonia, FFA, excess GABA cause neural damage Patients are irritable, confused and disorientated, can lead to coma Signs include fetor herpeticus and asterixis

Other features:
Jaundice Coagulopathy Proximal muscle weakness Hepatorenal syndrome

Management
Investigations
Bloods FBC, U+E, LFTs, coagulation Imaging liver ultrasound, CT scan

Detox thiamine and benzodiazepines

Alcohol abstinence psychiatric input, antabuse drugs eg disulfiram

Liver cirrhosis is incurable and requires transplant

Viral Hepatitis

Hepatitis
Hepatitis is inflammation of the liver and has many causes Viral causes include:
Hepatitis A to E EBV CMV Yellow fever Herpes Simplex

Hepatitis A
Most common but least serious type ssRNA hepatovirus Spreads by faecal oral route, infects liver via gut, shed in faeces for 2 weeks before and 1 week after onset of symptoms 90% of children in developing countries infected by 5 years Clinical features
Non specific symptoms eg nausea, malaise Some may develop jaundice Severe disease leading to liver failure rare

Investigations
LFTs marked increase in transaminases IgM indicates acute infection (IgG indicates previous infection)

No specific treatment, most recover by 3-6 weeks Vaccine recommended for travellers etc, inactivated virus which gives immunity for 1 year or 10 years with a booster. IgG treatment provides protection quickly for 3-4 months

Hepatitis B
dsDNA virus with three important antigens:
HBsAg surface antigen surrounding virus core HBcAg core antigen surrounding DNA HBe secreted by core, appears on hepatocyte surface, targetted by immune system

Spread by blood (eg blood products, needles, tattoos), sexual intercourse and vertical transmission from mother to child Infected 2bn people worldwide with 300m carriers low prevalence in the Western world

The majority of cases involve a mild or subclinical transient infection hence which requires no treatment

Death
99% 1%

Recovery

Acute hepatitis

Subclinical Infection

25%

65%

Acute HBV Infection

1-10% 10-30% 70-90%

Chronic HBV infection

Chronic Hepatitis Carrier

Cirrhosis

Hepatocellular Carcinoma

Reaction to HBV infection

The immune response is made by cytotoxic T cells the type of response depends on the type of T cell Th1 responses (IL-2, gamma interferon) lead to clearance of the virus Th2 reponses (IL-4,5,6,10,13) lead to chronic infection A poor cell mediated response eg in children is more likely to lead to carrier status but adults are more likely to suffer liver damage Chronic infection goes through two stages:
Replicative stage virus is replicated, patient is highly infectious Integrative phase viral DNA is integrated into host DNA and transcribed with it, inflammation decreases but cirrhosis and cancer more likely

Investigations
A number of viral antigens and host antibodies can be detected to monitor the state and course of HBV infection:
HBsAg surface antigen is present in acute infection but rapidly cleared, persistence beyond 6 months indicates chronic infection Anti-HBs appears a few weeks after clearance of HBsAg, indicates immunity Anti-HBc appears in symptomatic infection, persists following any infection Anti-HBc IgM appears in symptomatic acute or highly infective chronic infection, disappears over 6-9 months HBeAg appears in acute infection but generally cleared, persists in highly infective carriers Anti-HBe only detected in low infectivity carriers

LFTs would show hepatitis Imaging eg US or CT and biopsy in chronic infection

Treatment
Interferon
Bind to host ribosomes and prevent translation of viral mRNA Pegylated interferon 2a (pegylated means it is conjugated and stays in circulation longer) Clear HBeAg in 40% of patients Severe side effects eg fever, headache, malaise, depression, diarrhoea, hair loss, infection

Antivirals
Nucleoside or nucleotide analogues which inhibit enzymes involved in viral replication eg reverse transcriptase or DNA polymerase Lamivudine used reverse transcriptase inhibitor

Vaccination
Active immunisation using the HBsAg antigen In the UK it is administered to high risk groups Passive immunisation can be given using HBV antibodies Post exposure prophylaxis with both active and passive immunisation should be given to people exposed to HBV eg needle stick injuries

Hepatitis C
ssRNA flavivirus spread through blood, blood products, needles, tattooing etc Sexual or vertical transmission is less likely than HBV

Identified in 1989, has infected around 240m people worldwide

The course of illness also depends the immune response mounted but progression to chronic illness is much more likely than HBV

20-30%

Acute HCV Infection

Acute hepatitis
70-80%

Recovery

Chronic HCV infection

70%

Chronic Hepatitis
1-4% per year 20%

Hepatocellular Carcinoma

Cirrhosis
4-5% per year

Decompensated Liver Failure

Management
Investigations
Anti-HCV antibodies, HCV DNA and viral load LFTs Imaging and biopsy in chronic infection

Treatment (similar to HBV)

Pegylated interferon 2b Ribavirin viral DNA polymerase inhibitor No vaccine

Questions?