Histopathology Part 2- (p149-166- GI, Pancreatic + Liver) Flashcards
What is the epithelial cytology of the oesophagus?
Squamous epithelium for proximal 2/3
Columnar epithelium for distal 1/3
Joined by Z line/squamo-columnar junction
What is the commonest cause of oesophagitis?
GORD
What are the complications of GORD?
Ulceration, haemorrhage->haematemesis or melaena, Barret’s oesophagus, stricture, perforation
How is GORD treated?
Lifestyle- stop smoking, weight loss
PPI/H2 receptor antagonists
What is Barrett’s oesophagus?
Intestinal metaplasia of squamous mucosa -> columnar epithelium -> upwards migration of z line
Can lead to adenocarcinoma
Risk factors for squamous cell oesophageal carcinoma?
ETOH Smoking Achalasia of cardia Plummer-Vinson syndrome Nutritional deficiencies Nitrosamines HPV 6x more common in Afro-carribeans
How does squamous cell oesophageal carcinoma present?
Progressive dysphagia (solids -> fluids) Odynophagia (pain) Anorexia Severe weight loss Rapid growth and early spread to LN, liver and to proximal strictures
What are varices?
Engorged dilated veins usually due to portal HTN
Pt vomits units of blood
How do you treat varices?
Emergency endoscopy -> sclerotherapy/banding
How do gastric ulcers present clinically?
Epigastric pain +/- weight loss
Worse with food, relieved by antacids
RFs for gastric ulcer?
H. pylori, smoking, NSAIDs, stress, delayed gastric emptying, elderly
Histology of gastric ulcer?
Breach through muscularis mucosa into submucosa
What causes gastric lymphoma?
H. pylori- chronic antigen stimulation
How do you treat gastric lymphoma?
Remove H.pylori using triple therapy- PPI, clarithromycin + amoxicillin or metro
How does duodenal ulcer present clinically?
4x more common than GU
Epigastric pain worse at night
Relieved by food and milk
Younger adults
RFs for duodenal ulcers?
H. pylori Drugs Aspirin NSAIDs Steroids Smoking Drugs Acid secretion
What is the pathophysiology of coeliac disease?
T cell mediated autoimmune disease (DQ2 or DQ8), gluten intolerance results in villous atrophy and malabsorption
How does coeliac disease present?
Young children and Irish women- EMQ Steatorrhoea Abdo pain Bloating N+V Weight loss Fatigue IDA Failure to thrive Rash
Serological tests for coeliac disease?
Anti-endomysial ab, anti-tissue transglutaminase, anti-gliadin
Gold standard Ix for coeliac disease?
Upper GI endoscopy and duodenal biopsy
Treatment of coeliac?
Gluten free diet
What is Hirschsprung’s disease and how does it present clinically?
Absence of ganglion cells in the myenteric plexus (Genetics- RET proto-oncogene Cr10+)
Presents with symptoms and signs of obstruction in young babies, mainly males
How is Hirschsprung’s treated?
Resection of affected segment
Causes of bowel obstruction?
Constipation
Diverticular disease
Adhesions
Herniation
External mass e.g. fetus, aneurysm, foreign body
Volvulus- complete twisting of bowel loop at mesenteric base around vascular pedicle, small bowel
Intussusception
Epidemiology of Crohn’s?
Western population
Peak onset 20s, F>M
White 2-5x>non-white
Smoking worsens symptoms
Epidemiology of UC?
Slightly more common
White>non-whites
Peak age 20-25
Aetiology of Crohns?
Unknown
MZ twin concordance 50%
Hygiene hypothesis
Aetiology of UC?
Unknown
MZ twin concordance 15%
Pathophysiology of crohn’s?
Whole GI tract (mouth to anus)- most common terminal ileum and caecum
Patchy distribution -> ‘skip lesions’
Healthy mucosa lies above diseased mucosa -> cobblestone appearance
Aphthous ulcers (rosethorn)
Non caseating granulomas seen
Transmural inflammation
Fistulas and fissures common
Pathophysiology of UC?
Extends proximally from rectum
Continuous involvement of mucosa
Small bowel not affected normally
Extensive superficial broad ulcers
Inflammation confined to mucosa
No granulomas/fissures/fistulae/strictures
Islands of regenerating mucosa bulge into lumen -> pseudopolyps
Clinical features of crohn’s?
Intermittent diarrhoea
Pain
Fever
Clinical features of UC?
Associated more with bloody diarrhoea, mucus
Crampy abdo pain relieved by defecation
Extra GI manifestations of IBD?
A PIE SAC Aphthous ulcers Pyoderma gangrenosum Iritis Erythema nodosum Sclerosing cholangitis Arthritis Clubbing of fingertips
Complications of Crohn’s?
Strictures (requiring bowel resection)
Fistulae
Abscess formation
Perforation
Complications of UC?
Severe haemorrhage
Toxic megacolon -> perforation
30% require colectomy within 3y
Adenocarcinoma (20-30x risk)
Ix for Crohn’s?
Systemic markers of inflammation e.g. ESR, CRP, Barium contrast, endoscopy
Ix for UC?
Rectal biopsy
Flexi sig/colonoscopy
AXR
Stool culture
Management of Crohn’s?
Mild- Prednisolone
Severe- IV hydrocortisone, metronidazole
Additional- azathioprine, methotrexate, infliximab
Management of UC?
Mild- pred + mesalazine
Mod- Pred + Mes + steroid enema bd
Severe- Admit, nbm, IV fluids and IV hydrocortisone, rectal steroids
Remission- Mes + azathioprine (2nd line)
What is the pathophysiology of c difficile infection?
Use of abx e.g. cipro or ceph’s kill off commensals allowing c.diff to flourish. It’s exotoxins cause pseudomembranous colitis
How do you investigate c diff infection?
Stool culture
How do you treat c difficile infection?
Metronidazole (covers anaerobic) or vancomycin (2’ line)
What is probably responsible for the high incidence of diverticular disease in the west?
A low fibre diet
What is the pathophysiology of diverticular disease?
High intraluminal pressure results in outpouchings at weak points in the bowel wall (can be seen on barium enema CT or endoscopy)- 90% occur in left colon- often asymptomatic but sometimes PR bleed
Complications of diverticular disease?
Diverticulitis- fever and peritonism, gross perforation, fistula, obstruction (due to fibrosis)
What is carcinoid syndrome?
Diverse group of tumours of enterochromaffin cell origin which produce 5-HT (serotonin)
Commonly found in bowel and usually slow growing
Presents with bronchoconstriction, flushing and diarrhoea
Can lead to carcinoid crisis
How do you investigate carcinoid syndrome?
24h urine 5-HIAA (main metabolite of serotonin)
How do you treat carcinoid syndrome?
Octreotide- somatostatin analogue
What is an adenoma?
Benign dysplastic lesions that are the precursor to most adenocarcinomas
Found in 50% >50y in western world
Most important risk factor for malignancy in adenomas?
Large size, in addition to dysplasia and increased villous component
What types of non-neoplastic polyps are there?
Hamartomatous polyp
Hyperplastic polyp
Inflammatory- pseudopolyp
What is the second most common cause of cancer death in UK?
Colorectal
What percentage of colorectal cancers are adenocarcinoma?
98%
Aetiology of colorectal cancer?
Diet (low fibre, high fat), lack of exercise, obesity, familial syndromes, chronic IBD
Investigations in colorectal cancer?
Protoscopy Sigmoidoscopy Colonoscopy Barium enema Bloods e.g. FBC CT/MRI Carcinoembryonic antigen (CEA)- monitor disease
With which system and how is colorectal cancer staged?
Duke's staging- helps decide treatment A- confined to mucosa B1- extending into muscularis propria B2- transmural invasion, no LN involved C1- Extending into muscularis propria, with LN metastases C2- transmural invasion with LN mets D- distant mets
How is colorectal cancer managed?
Surgery
Radiotherapy- post-op to decrease local recurrence
Chemo in palliation- 5-FU
What mutations are responsible for familial adenomatous polyposis (FAP)?
70% AD mutation in APC gene (C5q1)
30% AR mutation in DNA mismatch repair genes
How does FAP present?
Around 10-15y, >100 adenomatous polyps- ALL will progress to adenocarcinoma if not treated by 30 so prophylactic colectomy
What mutations are responsible for hereditary non-polyposis colorectal cancer (HNPCC)?
AD mutations in DNA mismatch
What is the role of the pancreas?
Produces 2L a day of enzymic HCO3- rich fluid, stimulated by secretin and CCK
Where is secretin produced and what does it do?
Produced by s-cells of duodenum, controls gastric acid secretion and buffering with HCO3-
Where is cholecystokinin (CCK) produced and what does it do?
Made by I-cells in duodenum.
Responsible for stimulating digestion of fat and protein by causing release of digestive enzymes
What are the exocrine functions of the pancreas?
Secretes digestive enzymes into ducts- proteases, lipases and amylase
What are the endocrine functions of the pancreas?
Secretes products e.g. hormones into blood stream
Alpha cells- glucagon
Beta cells- insulin
Delta- Somatostatin regulates above cells
D1- Vasoactive peptide, stimulates secretion of H2O into pancreatic system
How do you diagnose DM?
Fasting plasma glucose>7
or random plasma glucose >11.1
What is the pathophysiology of T1DM?
Autoimmune destruction of beta cells by CD4+ and CD8+ T lymphocytes, may present with DKA
Pathophysiology of T2DM?
Linked to obesity and insulin resistance
Complications of diabetes?
Macrovascular- cardiac, renal, cerebral
Microvascular- retinopathy, PVS
Other- polydipsia, polyuria and recurrent infections
What score is used to assess acute pancreatitis?
GLASGOW- 3 or more leads to ITU referral
Causes of acute pancreatitis?
I GET SMASHED Idiopathic Gallstones Ethanol Trauma Steroids Mumps Autoimmune Scorpion venom Hyperlipidaemia ERCP Drugs e.g. thiazides
Presentation of acute pancreatitis?
Severe epigastric pain radiating to back, relieved by sitting forward
Vomiting prominent
Amylase only transiently increased, serum lipase is more sensitive
Can lead to pseudocyst formation
Histology of acute pancreatitis?
Coagulative necrosis
Causes of chronic pancreatitis?
Alcoholism Cystic fibrosis Hereditary Pancreatic duct obstruction e.g. stones/tumour Autoimmune- IgG4 sclerosin
Presentation of chronic pancreatitis?
Epigastric pain radiating to back, malabsorption due to lack of enzymes to digest food
Histology of chronic pancreatitis?
V similar to Ca pancreas- fibrosis and loss of exocrine tissue, duct dilatation with thick secretions, calcification
Presentation of acinar cell carcinoma?
Non-specific sx, abdo pain, wt loss, nausea and diarrhoea
Histopathology of acinar cell carcinoma?
Neoplastic epithelial cells with eosinophilic granular cytoplasm. Positive immunoreactivity for lipase, trypsin and chymotrypsin
Prognosis of acinar cell carcinoma?
Median survival 18m from diagnosis. 5y survival <10%
Most common pancreatic malignancy?
Ductal adenocarcinoma of pancreas (85% of all pancreatic malignancies)
M>F
RF for pancreatic carcinoma?
Smoking
Diet
Genetic e.g. FAP, HNPCC
Clinical features of pancreatic carcinoma?
Weight loss and anorexia Upper abdo and back pain Jaundice (PAINLESS), pruritis, steatorrhoea DM Trousseau's syndrome (25%)- recurrent superficial thrombophlebitis Ascites Abdo mass Virchow's node Courvoisier's sign
Ix in pancreatic carcinoma?
Bloods- low Hb, raised Bili + Ca2+
CT/MRI/ERCP
Ca19-9 >70IU/mL
Management of pancreatic carcinoma?
Chemotherapy is palliative (5-FU)
Surgery- Whipple’s procedure
Prognosis v poor- <5% 5y survival
What are the different types of multiple endocrine neoplasia (MEN)?
MEN1- PPP- Parathyroid hyplasia, pancreatic endocrine tumour (often phaeo), pituitary adenoma
MEN2A- Parathyroid, thyroid, phaeo
MEN2B- Medullary thyroid, phaeo, neuroma, marfanoid phenotype
What are the 5 main functions of the liver?
Metabolism- glycolysis, glycogen storage, glucose, amino acid and fatty acid synthesis, hormone, lipoprotein and drug metabolism
Protein synthesis- makes all circulating proteins except gamma globulins
Storage- glycogen, vit A, D, B12, K, folate, iron + copper
Bile synthesis- 600-1000ml daily
Immune function- antigens from gut reach liver via portal circulation. Phagocytosed by Kupffer cells
What benign liver tumours are there?
Hepatic adenoma
Haemangioma
What malignant liver tumours are there?
Hepatocellular carcinoma Angiosarcoma Hepatoblastoma Cholangiocarcinoma Metastases from other primary tumours
What drug is hepatic adenoma associated with?
OCP
Causes of hepatocellular carcinoma?
Hep B+C, alcoholic cirrhosis, haemochromatosis, NAFLD, aflatoxin, androgenic steroids
Investigations for hepatocellular carcinoma?
Alpha-fetoprotein
USS
Causes of cholangiocarcinoma?
PSC Parasitic liver disease Chronic liver disease Congenital liver abnormalities Lynch syndrome type II
Most common malignant liver lesion?
Mets from other primary tumours- GI tract, breast or bronchus
Define cirrhosis?
Diffuse abnormality of liver architecture that interferes with blood flow and liver function- hepatocyte necrosis, fibrosis, nodules, portal HTN
7 major causes of cirrhosis?
Alcoholic liver disease Non-alcoholic fatty liver disease Chronic viral hepatitis Autoimmune hepatitis Biliary- PBC + PSC Genetic- haemochromatosis, Wilson's, alpha-1 antitrypsin deficiency etc Drugs- e.g. methotrexate
How is cirrhosis classified?
According to nodule size:
Micronodular <3mm- uniform liver involvement- caused by alcoholic hepatitis or biliary tract disease
Macronodular >3mm- variable nodule size- caused by viral hep, Wilson’s or alpha-1 antitrypsin def
What is used to indicate prognosis in liver cirrhosis?
Modified Child’s Pugh Score
What is the pathophysiology of portal HTN?
Increased portal pressure secondary to increased vascular resistance in liver, hyperdynamic circulation, sodium retention and plasma volume expansion
Leads to venous system dilating and collateral vessels forming
Causes of portal HTN?
Prehepatic- portal vein thrombosis (e.g. Factor V Leiden)
Hepatic- pre-sinusoidal- schistosomiasis, PBC, sarcoid, sinusoidal- cirrhosis, post-sinusoidal- veno-occlusive
Post-hepatic- Budd-Chiari syndrome (occlusion of hepatic vein)
What are the macroscopic characteristics of hepatic steatosis (fatty liver)?
Large, pale, yellow and greasy liver
What are the microscopic characteristics of hepatic steatosis (fatty liver)?
Steatosis- accumulation of fat droplets in hepatocytes
Chronic exposure -> fibrosis
How can hepatic steatosis be reversed?
Fully reversible if alcohol avoided
What are the macroscopic characteristics of alcoholic hepatitis?
Large fibrotic liver
What are the microscopic characteristics of alcoholic hepatitis?
Hepatocyte ballooning and necrosis due to accumulation of fat, water and proteins
Mallory bodies
Fibrosis
What are the macroscopic characteristics of alcoholic cirrhosis?
Yellow-tan, fatty, enlarged
Transforms into shrunken non-fatty brown organ
What are the microscopic characteristics of alcoholic cirrhosis?
Micronodular cirrhosis- small nodules + bands of fibrous tissue
What is most common cause of chronic liver disease in west?
Non-alcoholic fatty liver disease
Who does Non-alcoholic fatty liver disease commonly occur in?
Mainly in obese individuals with hyperlipidaemia/metabolic syndrome
Diabetes also a RF
When does autoimmune hepatitis commonly occur?
Common with other autoimmune diseases e.g. coeliac, SLE, RA, thyroiditis, sjogrens, UC
What are the 2 different types of autoimmune hepatitis?
Type 1- ANA (antinuclear Ig), anti-SMA, anti-actin Ig, anti-soluble liver antigen Ig
Type 2- Anti-LKM Ig
How do you treat autoimmune hepatitis?
Immune suppression until transplant, but disease returns in upto 40%
What is the pathology of Primary Biliary Cirrhosis (PBC)?
Autoimmune inflammatory destruction of medium sized intrahepatic bile ducts -> cholestasis -> SLOW development of cirrhosis
What is the F:M ratio of PBC?
10:1
PSC is M>F
What would blood tests show in PBC?
Increased serum ALP, cholesterol, IgM, AMA in 90% and hyperbilirubinaemia
What would a US scan show in PBC?
No bile duct dilatation
What would histology of PBC show?
Bile duct loss with granulomas
How does PBC present?
Fatigue, pruritus, abdo discomfort, skin pigmentation, xanthelasma, steatorrhoea, vit D malabsorption, inflammatory arthropathy
How do you treat PBC?
Ursodeoxycholic acid in early phase
What is the pathology of primary sclerosing cholangitis (PSC)?
Inflammation and obliterative fibrosis of extrahepatic and intrahepatic bile ducts -> multi-focal stricture formation with dilation of preserved segments
What condition is PSC associated with and which condition does it increase your risk of?
IBD (especially UC)
Risk- Cholangiocarcinoma
What would blood tests show for PSC?
Increased serum ALP, several auto-Ig especially p-ANCA
What would a US scan show for PSC?
Bile duct dilatation
What would an ERCP show for PSC?
Beading of bile ducts due to multifocal strictures
What are the 3 genetic causes of cirrhosis?
Haemochromatosis
Wilson’s disease
Alpha1 antitrypsin deficiency
Inheritance pattern of haemochromatosis?
Autosomal recessive
What is the pathology of haemochromatosis?
Mutated HFE gene at 6p21.3 -> increased Fe gut absorption which deposits in liver, heart, pancreas, adrenals, pituitary, joints, skin -> fibrosis
What is the histology of haemochromatosis (and what stain would be used)?
Fe deposits in liver- stains with Prussian blue stain
Signs and symptoms of haemochromatosis?
Skin bronzing (melanin deposition) Diabetes Hepatomegaly with micronodular cirrhosis Cardiomyopathy Hypogonadism Pseudogout
What investigation findings would you see in haemochromatosis?
Increased iron and ferritin
Transferrin saturation >45%
Decreased TIBC
How do you treat haemochromatosis?
Venesection
Desferrioxamine
What age does Wilson’s disease present?
11-14yo
Inheritance pattern of Wilson’s disease?
Autosomal recessive
Pathology of Wilson’s disease?
Mutated gene ATP7B- encodes copper transporting ATPase expressed on canalicular membrane -> decreased biliary Cu excretion and deposition in liver, CNS, iris
What does copper stain with?
Rhodanine
Signs and symptoms of Wilson’s?
Liver disease- acute hepatitis, fulminant liver failure or cirrhosis
Neuro disease- parkinsonism, psychosis, dementia
Kayser Fleischer rings- copper deposits in Desemet’s membrane in cornea
Investigation findings in Wilson’s disease?
Decreased caeruloplasmin and serum copper
Increased urinary copper
Treatment for Wilson’s disease?
Lifelong penicillamine
What is the inheritance pattern for Alpha1 antitrypsin deficiency?
Autosomal dominant
What is the pathology of A1AT deficiency?
A1AT accumulates in hepatocytes -> intracytoplasmic inclusions -> hepatitis
Lack of A1AT in lungs -> emphysema
Histology of A1AT deficiency?
Intracytoplasmic inclusions of A1AT which stain with Periodic acid Schiff
Signs and symptoms of A1AT deficiency?
Neonatal jaundice in kids
Emphysema and chronic liver disease in adults
Investigation findings in A1AT deficiency?
Decreased A1AT
Absent alpha-globulin band on electrophoresis
