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Student Submitted Resources

Gastroenterology

Anonymous

Last Update: January 2017 | File ID: GASTR2017.01.00

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Table of Contents • Helicobacter Pylori

o Helicobacter pylori Infection o Helicobacter pylori and ulcers o Helicobacter pylori and gastric

adenocarcinoma o Helicobacter pylori and MALT lymphoma o Helicobacter pylori and cancer

• Oesophagus o Oesophageal hernia o Eosinophilic oesophagitis o Candida oesophagitis o Viral oesophagitis o Barret Oesophagus o Neoplasia in oesophagus o Oesophageal varices o Oesophageal atresia and fistula o Oesophageal diverticular (including

Zenker) o Achalsia (functional disorder) o Ulcerative oesophagitis

• Small Bowel and appendix o Duodenitis/ulcer o Coeliac disease o Meckel diverticulum o Infection - Giardia lamblia o Infection - Cryptosporidium parvum o Infection - Strongyloides stercoarlis o Crohn’s disease o Small intestine – neoplastic o Acute appendicitis o Infection — enterobius vermicularis o Appendix – neoplastic

• Large bowel and anal malignancies o Diverticular disease o Angiodysplasia o Acute infectious colitis o CMV colitis o Entamoeba Histolytica o Pseudomembranous colitis o (Chronic) idiopathic inflammatory bowel

disease (IBD o (Chronic) microscopic colitis o Ischaemic colitis o Iatrogenic colitis o Polyp o Neoplasia of the large bowel o Familial adenomatous polyposis (FAP)

syndrome

o Hereditary non-polyposis colorectal carcinoma (HNPCC)

• Stomach o Gastritis o Chronic gastritis o Gastric peptic ulcer o Autoimmune gastritis o Intestinal metaplasia o Stomach tumours o Dysplasia o Early adenocarcinoma o Linitis plastic o Gastrointestinal stromal tumour (GIST) o Gastric MALT lymphoma o Gastric diffuse large B cell lymphoma o Neuroendocrine tumour o Hereditary diffuse gastric carcinoma

• Nausea and Vomiting • Liver

o Jaundice o Three main histological patterns o Hepatitis o Hepatitis A o Hepatitis B o Hepatitis C o Hepatitis D o Hepatitis E o Steatosis o Pre-hepatic steatosis o Intrahepatic steatosis o Post-hepatic steatosis o Cholestasis o Liver abscess o Parasitic liver infections o Biliary diseases o Primary biliary cirrhosis (PBC) o Primary sclerosing cholangitis o Metabolic diseases o Hereditary haemochromatosis o Alpha-1 anti-trypsin deficiency o Wilson’s disease o Cirrhosis o Alcoholic liver disease o Acute liver failure

• Gallbladder o Cholelithiasis (gallstones) o Cholecystitis

• Pancreas o Pancreatitis o Pancreas divisum o Acute pancreatitis o Chronic pancreatitis (CP) o Hereditary pancreatitis o Autoimmune pancreatitis

• Hepatobiliary and pancreatic neoplasms o Hepatobiliary and pancreatic neoplasms o Liver cell adenoma o Hepatocellular carcinoma o Cholangiocarcinoma o Metastatic liver tumours o Pancreatic tumours o Serous cystadenoma o Mucinous cystic neoplasm (MCN) o Intraductal papillary mucinous neoplasm

(IPMN) o Pancreatic cancer o Pancreatic duct carcinoma o Pancreatic neuroendocrine neoplasms

(Pan-NET)


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Gastrointestinal Tract/Hepatobiliary/Nutrition

Helicobacter pylori infection

Disease Pathology, aetiology and epidemiology Signs and symptoms

Diagnosis, management and prognosis

Helicobacter pylori infection

Very common spiral organism 50% of world’s population infected M>F, and more common in >50/60yo developing nations more common reduced prevalence due to sanitation and economic progress organism requires urea to survive in environment to raise surrounding pH Transmission probably oro-oral or faec-oral re-infection (recrudescence) rate low (<2%) children <5yo more easily re-infected Virulence factors - VacA gene which is a passive urea transporter - CagA not cytotoxic but antigenic Higher frequency of pre-malignant gastric lesions - 85-100% of duodenal ulcers have CagA (+) strains - CagA/VacA stimulate IL8, a major mediator of inflammatory response, leading to ulceration There are many other factors (iceA, babA2, oipA) Urease enzyme, produces ammonia, buffers acid, protective cloud, passes into mucus where it can replicate. Inflammation destroys D cells which increases acid in stomach. Disease associations for helicobacter pylori: Duodenal ulcer (most common) gastric ulcer gastric cancer gastric lymphoma asymptomatic carrier has a 1% per annum incidence of developing peptic ulcer disease

Clinical presentation: chicken skin appearance on endoscopy

Diagnosis Complexity and costs increase Serology, faeces antigen, urease breath test, culture main lab, histology (H&E stain and silver stain) but serology has good sensitivity and specificity already Gold standard diagnosis is serology, urease test, endoscopic biopsy, histology, culture HP eradication: Triple therapy serology not accurate for proof of cure testing 1. PPI

Esomeprazole (Nexium HP7) Iansoprazole (Klacid HP7)

2. Amoxicillin 3. Clarithromycin; use metronidazole if penicillin/clarithromycin allergic; however not as successful: 7-14 day course has a 90-95% success Other antibiotics • Metronidazole only if penicillin/clarithromycin allergic • Tetracycline • Quinolones - floxacins • Bismuth Antibiotics which can be reused (helicobacter pylori resistance is rare) amoxicillin (first line) bismuth and tetracycline Other drugs easily confer HP resistance (almost always due to enzyme mutation/inactivation) Clarithromycin Metronidazole – can’t reuse



Quinolones (Levofloxacin etc) Rifamycins (e.g. rifabutin) Post-infection eradication serology unreliable urease breath test — gold standard 4 weeks following completion of triple therapy and PPI cessation if still positive, consider treatment compliance, bacterial resistance need for culture and sensitivity 2nd line - quinolone

Helicobacter pylori and ulcers

Ulcer pathogenesis increased gastric acid secretion gastric metaplasia of duodenum mucosal response to acid stimulates immune response, especially IL8 but also IL1, IL2 and TNF alpha impairs mucosal defence, down regulate EGF and TGFalpha H pylori blocks D cell and G cell communication; G cells then continuously stimulates parietal cells (gastrin) to produce gastric acid

Helicobacter pylori and gastric adenocarcinoma

distal gastric cancer: strong association (gastric adenocarcinoma often in antrum in HP positive) proximal gastric cancer not due to HP (fundus) vast majority of HP infected do not develop cancer other host factors e.g. IL1beta polymorphism CagA strains more implicated 40-50% of gastric cancer solely due to helicobacter pylori

Helicobacter pylori and MALT lymphoma

B cell lymphoma CagA strains more implicated some gastric MALT lymphoma can be treated by HP eradication (50-80%) APC activates CD4+ T cell which binds to aberrant B cell (uncontrolled proliferation)

Helicobacter pylori and cancer

The link between colon cancer and helicobacter pylori is controversial; gastrin receptors identified in a variety of colon cancers, remembering that HP infection results in hypergastrinaemia (excess of gastrin in the blood).



The link between pancreatic cancer and helicobacter pylori is controversial — mainly CagA strains

Oesophagus



Hernia Hiatus hernia When stomach goes through oesophageal hiatus into thoracic cavity Sliding hernia – most common, part of stomach is pulled up above the diaphragm forming a bell shaped dilated segment Due to congenitally short oesophagus or due to secondary defect like scarring of the oesophagus following chronic injury Rolling/Paraesophageal hernia —> portion of cardiac end of the stomach pushes through the diaphragm and rolls up alongside the esophagus – less common (<10%) Both disrupt lower esophageal sphincter —> results in reflux

Gastro-intestinal reflux

Causes – lower oesophageal sphincter (LES) defects, hiatus hernia, increased volume or food, inefficient gastro-

Endoscopic findings Erythema – very common



(GORD) esophageal clearance Lifestyle (smoking, spicy foods) Damage to mucosa —> can result in secondary infections

Normal mucosa Non-confluent erosions (also common) Confluent and circumferential erosions Ulcer, Barrett’s structure Microscopically Hyperplasia of squamous epithelium thicker epithelium, basal cells more predominant thickening of basal cell layer Swollen cells/spongiosis inflammatory cells (neutrophils, lymphocytes, eosinophils) erosions ulceration Complications – asthma, aspiration pneumonia, peptic stricture, Barrett oesophagus, adenocarcinoma, polyps or stenosis of the larynx

Eosinophilic oesophagitis

Allergen initiated – most patients have personal or FHx of allergies. Seasonal variation of symptoms

Clinical presentation - abdominal pains - vomiting - dysphagia (painful swallowing) - food bolus - impaction - reflux

Endoscopic appearance – mucosal rings/webs, vertical lines or furrows, narrowed oesophagus, stricture Microscopic appearance – highly eosinophilic (15-20 eosinophils per HPF) - microabscess - subepithelial fibrosis/scarring - patchy so multiple biopsies may be needed - can overlap with reflux (need more than just GOJ biopsy — also need one from mid oesophagus)

Candida oesophagitis

Cause is by candida species like albicans, tropicalis, etc Risk factors – immunosuppression, chemotherapy, steroids, major abdominal surgery

Clinical: Dysphagia (difficult and painful swallowing)

Treatment: Antifungal Tx White plaques endoscopically Micro – fungal spores and branching pseudohyphae

Viral oesophagitis

Herpes simplex or herpes zoster Risk factors – immunosuppression but may also occur in otherwise healthy individuals CMV Immunocompromised, rarely in immunocompetent

Clinical: Chest pain, dysphagia, odynophagia, upper GI bleeding CMV - same presentation as

Endoscopically – shallow ulcers present throughout Micro – H&E viral inclusions compressing normal chromatin, multinucleated cells CMV Longer, linear ulcers than herpes



herpes oesophagitis

Barrett Oesophagus

Metaplasia – change from specialized squamous epithelium of the tubular oesophagus to specialized intestinal glandular type epithelium with goblet cells (intestinal metaplasia) —> in response to damage Causes – GORD, smoking, obesity, EtOH use (more common in white races/males)

Clinical: heartburn, cough, reflux symptoms, some asymptomatic

Endoscope – large red tongues of metaplasia pushing into squamous epithelium Pre-malignant lesion —> can lead to dysplasia and neoplasia

Neoplasia in oesophagus

Two main primary cancer types in oesophagus • Adenocarcinoma – malignant epithelial tumour with

glandular differentiation • Squamous cell carcinoma - malignant epithelial tumour

with squamous cell differentiation Adenocarcinoma Risk factors: male gender, GORD, obesity, smoking, EtOH 80% male, average age 65 years Squamous cell carcinoma – most common Risk factors - Tobacco, EtOH, nutrition, vitamin deficiencies, thermal injury, HPV, Plummer-Vinson syndrome (ring/web and iron deficiency anaemia), Achalasia – failure of smooth to relax/motility disorder, tylosis – thickened skin on hands and feet, coeliac disease (due to anaemia), PHx of corrosive ingestion Other tumours Papilloma, leiomyoma, lipoma, granular cell tumour, gastrointestinal stromal tumours (GIST), melanoma, carcinoid, sarcoma and metastasis

Adenocarcinoma Presentation - Dysphagia, Retrosternal pain, Epigastric pain Squamous cell carcinoma – most common Presentation – difficulty swallowing

Adenocarcinoma Treatment – endoscopic treatment for early lesions (laser Tx, photodynamic Tx and mucosal resection), chemoradiation and surgery for high stage tumours Micro – complex and irregular glands, invade into stroma, marked cellular atypia Squamous cell carcinoma – most common Treatment - Combination RTx, CTx, and surgery Many SCC develop in middle third

Oesophageal varices

Alcoholics, end stage liver disease – portal hypertension

Oesophageal atresia and fistula

Oesophageal atresia refers to a congenitally interrupted oesophagus. One or more fistulae (abnormal passage) may be present between the malformed oesophagus and the trachea. The lack of oesophageal patency prevents swallowing. In addition to preventing normal feeding, this problem may cause infants to aspirate and literally drown in their own



saliva, which quickly overflows the upper pouch of the obstructed oesophagus.

Oesophageal diverticular (including Zenker)

An oesophageal diverticulum is a pouch, or pocket, of stretched tissue that develops anywhere along the oesophagus, pushing outward through its muscular wall. They are rare, and can be congenital or acquired. Typically a single pouch forms, most often near the top of the oesophagus; this is called Zenker's diverticulum.

Achalsia (functional disorder)

Achalasia is a failure of smooth muscle fibres to relax, which can cause the lower oesophageal sphincter (LES) to remain closed and fail to open when needed.

Ulcerative oesophagitis

From gastro-oesophageal reflux disease (GORD) the most common reason why people take antacids acid eating away at mucosa

‘cobble-stone appearance’

tilt person up by 10-15 degrees etc and neutralise acid



Small bowel and appendix



Duodenitis/ulcer peptic duodenitis is inflammation and damage to the proximal duodenum secondary to chronic exposure to gastric acid peptic duodenitis associated with:

• NSAID use (the longer you’re on NSAIDs, the higher our risk for ulcer/complication)

• Helicobacter pylori infection of stomach Risk factors for serious GI events with use of non-selective NSAIDs Risk factors for duodenitis: Advanced age, history of ulcer or GI complications, high dose or multiple NSAIDs, concomitant corticosteroid use, major illness, concomitant anticoagulant use, disability Social risk factors: smoking / alcohol intake Can progress to duodenal ulceration which may perforate requiring surgery

The M2A capsule (endoscope) can provide images of bowel for diagnosis lesions/ ulcerations of small bowel mucosa. Superficial ulcers can lead to chronic peptic ulcers - In duodenitis, loss of normal villous architecture - ulceration; blood, inflammatory cells mixed in with fibre - regenerative areas and scarred - normal cells of duodenum can start looking like gastric epithelium— aplastic areas - can lead to narrowing of lumen which can lead to obstruction

Coeliac disease Malabsorption due to chronic immune-mediated reaction to dietary gluten (wheat, rye, barley) T cell mediated Interplay between genetic predisposing factors (MHC HLA-DQ2/DQ8), host immune response and environmental factors

Diarrhoea, malabsorption, steatorrhoea (the excretion of abnormal quantities of fat with the faeces owing to reduced absorption of fat by the intestine), abdominal pain, weight loss, iron deficiency anaemia, failure to thrive

Laboratory tests - tissue transglutaminase (tTG) about 90% specific and sensitive - anti-endomysial antibody (AKEMA) similar but more difficult to perform Complication - T Cell lymphoma but can be adenocarcinoma of small bowel, breast or squamous carcinoma of oesophagus -long term risk of malignant disease is 2x normal In celiac disease — normal villous structure is markedly abnormal; damaged. villous blunting and broadeningscalloping of mucosal folds on endoscopy Other complications: - ulcerative jejunoileitis



Meckel diverticulum

Most common congenital malformation of GI tract Ileal outpouching due to the persistence of the congenital vitelline duct .

Most asymptomatic but can present with pain in the right lower quadrant secondary to obstruction (40%), diverticulitis (20%), GI bleeding, perforation or abscess

Rule of 2’s 2 inches in length (average) Located within 2 feet of ileocaecal valve Usually symptomatic before age 2 See in 2% (1-4%) of the population

Infection - Giardia lamblia

Leading protozoal infection in USA Occurs in temperate and tropical regions

Present with diarrhoea (often watery, foul smelling and explosive), abdominal pain, fever, nausea and vomiting Symptoms may be chronic leading to severe weight loss, anaemia and malabsorption

Endoscopy generally unremarkable; biopsy or stool sample Treat with metronidazole providing excellent outcome Pear-shaped organisms (teardrop etc?) in between villi

Infection - Cryptosporidium parvum

Protozoan that is an obligate intracellular parasite causing intestinal infection Worldwide distribution

Present with diarrhoea (watery, mucoid, non-bloody) that is often protracted, dehydration, malaise, vomiting, fever and variable nausea

Endoscopy often normal No effective antimicrobial therapy — can lead to dehydration, and can infect animals Some antimicrobial agents have variable success Usually self-limited in immunocompetent patient organisms bulge through apex of epithelial cells along lumen sometimes down deep in crypts

Infection - Strongyloides stercoarlis

Nematode with worldwide distribution Endemic in southeast USA Usually infects immunocompromised adults Steroids are predisposing factor

Diarrhoea, abdominal pain, nausea, vomiting, weight loss + occ. non-GI symptoms

May involve stomach, small bowel, large bowel Endoscopically see hypertrophic mucosal folds, ulcers and massively thickened folds

Crohn’s disease Inflammatory bowel disease Relapsing, discontinuous transmural granulomatous inflammation from oral cavity to anus Usually involves small intestine and colon, but small bowel only (particularly terminal ileum) in 40%, colon only in 30%

Variable presentation include episodic mild diarrhoea, fever and pain; can also get some blood. Can present like acute appendicitis

Complications: - Fibrosing structures (common in terminal ileum), fistulas to loops of bowel, bladder, vagina, perianal skin - Also protein losing enteropathy, generalised malabsorption, vitamin B 12 deficiency, bile salt malabsorption with steatorrhoea, perforation, abscesses 5x risk for GI carcinoma, usually adenocarcinoma of ileum — can look quite different to sporadic carcinomas Cobblestoned mucosa with fat wrapping; ulcerative



regions etc Fat around it to isolate inflammation and stop spread Stenosed lumen (wall thickening) — can lead to obstruction? Histologically — fissuring ulceration, transmural inflammation, patchy mucosal ulceration, muscle hypertrophy In adjacent mucosal; crypt abscess — cystically dilated glands Possible presence of granuloma (a few granulomas — more likely to be Crohn’s disease)

Small intestine - neoplastic

1. Metastasis (most common, especially melanoma) 2. Adenocarcinoma 3. Neuroendocrine tumours (carcinoid) Adenocarcinoma Invasive adenocarcinoma arising in small intestine is much less common than in colon Risk factors • Crohn’s disease • Coeliac disease • Polyposis syndromes (familial adenomatous

polyposis, Lynch syndrome, neurofibromatosis) Carcinoid tumour (neuroendocrine tumours) More common Neoplasm composed primarily of cells with neuroendocrine differentiation; the bigger it is the more aggressive it is 50% of small bowel tumours Most common in ileum also jejunum and distal duodenum Associated with celiac disease, bowel duplication, Von Recklinghausen’s disease (Neurofibromatosis 1)

Adenocarcinoma Present with abdominal pain, obstruction, anaemia, GI bleeding and/or weight loss Carcinoid tumour (neuroendocrine tumours) n/a

Adenocarcinoma Elevated edges with central ulceration — infiltrating into wall of small bowel histologically - tumour mass extends through submucosa into muscular propria - irregular glands infiltrating subumucosa Usually advanced stage at diagnosis with deep wall penetration, nodal metastases Carcinoid tumour (neuroendocrine tumours) Small bowel carcinoids have worse prognosis than those in stomach or rectum Slow growing but can metastasise to regions - lymph nodes, liver, bone, skin, thyroid nested trabecular pattern carcinoid islands present histologically — typical endocrine appearance with small round cells having round nuclei and pink to pale blue cytoplasm

Acute appendicitis

Most common abdominal surgical emergency Peak incidence during 2nd and 3rd decade Pathogenesis unknown Luminal obstruction with secondary infection low-fibre diets primary infection

Present with abdominal pain, initially periumbilical of gradual onset that with increasing severity localises to RLQ

Purulent exudate on surface of appendix, serosal hyperaemia (congested vessels) Mucosal ulceration and neutrophilic inflammation extending through the wall of the appendix

Infection — Enterobius vermicularis (pinworm) - worms reside in Most infections Histology — transverse section - ova, spine etc worms



enterobius vermicularis

cecum — 1.3cm long; cause itchiness of anus at night Most common helminthic infection in children , rarely cause tissue damage. May be associated with appendicitis.

asymptomatic intestinal tract and such Not ulcerated, not much inflammation in mucosa

Appendix - neoplastic

1. Mucinous cystic neoplasm 2. Neuroendocrine tumours (carcinoid) 3. Adenocarcinoma

Mucinous cystic neoplasm Proliferation of low-grade or high-grade dysplastic mucin producing epithelium that may distend appendix and fill it with mucin 20% perforate appendix Variable cystic luminal dilation usually filled with viscid mucus Neuroendocrine tumours (carcinoid) Neoplastic proliferation of neuroendocrine cells 75-85% of all appendices tumours Found in up to 1.5% of appendiceal tumours Found in up to 1.5% of appendicectomy Adenocarcinoma Accounts for 0.2% of appendectomy specimens — rare Usually ages 40-69 years (similar to colonic adenocarcinoma) Ulcerative colitis and familial adenomatous polyposis appear to confer increased susceptibility

Mucinous cystic neoplasm n/a Neuroendocrine tumours (carcinoid) Most often incidental/asymptomatic Adenocarcinoma 75% are symptomatic, with symptoms of acute appendicitis, abdominal mass or intestinal obstruction

Mucinous cystic neoplasm If spreads beyond appendix, survival rates were 100%, 86% and 45% at 3K and 10K years mucus extruded at ruptured tip of appendix, mucocoele present histologically - dilated lumen with thin wall filled with mucin; extravasated mucin present also Neuroendocrine tumours (carcinoid) 5 year survival 85% Survival >95% if confined to appendix Larger tumours showing angiolymphatic spread have poorer prognosis grey yellow carcinoid tumour; associated inflammation Adenocarcinoma n/a



Large bowel and anal malignancies



Diverticular disease Acquired pseudodiverticula outputting of mucosa and submucosa prevalence increases with age, 60% over age 70 years sigmoid colon affected in 95% cases; can extend to more proximal in some cases western nations > Asia, Africa, developing countries Aetiology and pathogenesis diet common in western nations low fibre diet; small volume stools; hyper contractility and hyper-segmentation; increased intraluminal pressure; mucosal herniation primary abnormality in the muscular layer of the bowel; increased elastic layer of the muscularis propria resulting in a muscular layer that is less pliable leading to shortening of colon, and concertina effect, leading to redundant mucosa and prolapse leading to diverticula Low fibre diet —> uptake of a protein —> deposition in elastic layer?

Clinical features: most patients are asymptomatic symptoms: alternating constipation, and diarrhoea, mimic IBS intermittent cramping, continuous lower abdominal discomfort, diarrhoea, tenses fever chronic or intermittent blood loss massive haemorrhage

Macroscopic diverticula tend to form in two rows between anti-mesenteric taenia and mesenteric taenia (three separate longitudinal ribbons of smooth muscle on the outside of the ATDS colon) form at points of weakness - vessels and nerves penetrate the muscular wall chronic idiopathic inflammatory bowel disease microscopic colitis Microscopy herniation of submucosa through wall of large bowel

Angiodysplasia Acquired condition characterised by clusters of malformed submucosal and mucosal blood vessels associated with aging, most common after 6th decade most often in caecum/right colon (tension is high due to larger diameter) prevalence <1% but is 2nd most common cause of lower GI bleeding in the elderly Pathogenesis intermittent occlusion of veins penetrating muscular propria due to normal distension and contraction, leading to focal dilation and tortuosity of overlying submucosal and mucosal vessels overtime degenerative changes in the composition and structure of the extracellular matrix of the bowel wall with age — contributes to loss of structural integrity

GI bleeding in elderly recurrent/chronic massive haemorrhage

Microscopically - collection if dilated torsion’ed vessels



Acute infectious colitis

Inflammation of the colon secondary to an infectious organism GI infections important cause of morbidity and mortality worldwide More than 2000deaths/day among children in developing countries and >10% of all deaths <5 years old worldwide many infections transmitted through contaminated food and water Aetiology Bacteria — campylobacter, salmonella, shigella, E.coli, clostridia, Yersinia, aeromonas Pathogenesis Host defence — gastric acidity, intestinal motility, mucus, intestinal microflora, systemic and local immune mechanisms Bacterial virulence — adherence, enterotoxin production, cytotoxin production, mucosal invasion, others (evasion of phagocytosis, altering intestinal motility, mucolytic enzymes which disrupt mucus layer etc) Other causes: Parasites: entamoeba histolytica (amoebiasis) Viruses - CMV Fungal

Clinical features: Abdominal pain, nausea, vomiting, tenesmus (needing to pass stools), urgency, diarrhoea, fevers/chills, malaise, arthralgia/myalgia

Microscopic: Mucosal and intraepithelial neutrophil infiltrates, particularly within the superficial mucosa +/-cryptitis/crypt abscesses normal architecture Outcome/complications: Self-limiting (vast majority), supportive treatment, specific antimicrobial therapy Dehydration, sepsis and shock, toxic megacolon, death, extra intestinal infections (haemolytic-uremic syndrome, Gullian-Barre syndrome)

CMV colitis

macroscopically - congested haemorrhage mucosa with ulceration microscopically - viral inclusions in stromal and endothelial cells

Entamoeba Histolytica

macroscopically - patchy erosion and ulceration microscopically - amoebic organisms in ulcer slough (resemble macrophages)



Pseudomembranous colitis

Inflammatory condition of the colon characterised by pseudomembranes generally caused by clostridium difficile Associated with use of antibiotics — disrupt normal colonic microbiota allowing C. difficile overgrowth; disease caused by exotoxin production which can be detected in stool

Presents with diarrhoea (may be blood), abdominal pain and fever

May be complicated by fulminating colitis with toxic megacolon or perforation Macroscopically: yellow-white pseudomembranes that bleed when scraped off Microscopically - volcano lesion with intercrypt necrosis and ballooned crypts - pseudomembrane composed of fibrin, mucin and neutrophils

(Chronic) idiopathic inflammatory bowel disease (IBD)

1. Ulcerative colitis 2. Crohn’s disease

Chronic illness; punctuated by exacerbations/remissions typically teens or early adulthood UC peak 3rd to 4th decade CD peak 2nd to 3rd decade (smaller peak 6th to 7th decade) males and females affected, CD slightly more common in females geographic and ethnic variation (more common amongst industrialised countries; N America, N. Europe, Australia; less common in Asia, Africa; Ashkenazi Jews 3-5x risk) Aetiology and pathogenesis Precise cause is unknown (environment, abnormal immune response, genetics) immunologic attack is cause of tissue injury Crohn’s disease: predominantly TH1 and TH17 mediated process; macrophage/neurophil Ulcerative colitis: atypical TH2 disorder

Crohn’s disease Abdominal pain, diarrhoea, constitutional symptoms (anorexia, weight loss, fever, lassitude), rectal bleeding and mucus, growth retardation (children), perianal fistula/abscess, malabsorption and deficiency (e.g. vitamin B12). Fibrosis, from mucosa out to lining of gut to lymph nodes and manifestations outside of gut. Ulcerative colitis Diarrhoea, rectal bleeding and mucus, urgency, tenesmus, abdominal pain, constitutional symptoms (fever, weight loss, anorexia) superficial ulcers

Morphology distinction of UC from CD distribution morphologic expression of disease Crohn’s disease sharp demarcation, skip lesions apthous ulcers, linear ulcers, deep fissuring ulceration -fistula formation mucosal “cobblestone” appearance transmural oedema, inflammation, fibrosis and muscle hypertrophy leading to intestinal wall thickening/stricture mucosal inflammation, ulceration, architectural distorsion, paneth cell metaplasia non-caseating granulomas transmural inflammation, ulceration - classically “rose thorn” submucosal fibrosis, muscularis hypertrophy Ulcerative colitis left sided disease but extends proximally continuous - no skip lesions hyperaemia, granularity, friability broad based ulceration (not linear) with pseudopolyps/islands of regenerating mucosa; muscular and serosa are normal. No transmural inflammation architectural distorsion with gland disarray/atrophy, Paneth cell metaplasia -persists between attacks Lymphoplasmacytic inflammation (granulomas); acute inflammation - crepitates, crypt abcess



Extraintestinal manifestations skin — erythema nodosum, pyoderma grangrenosum eyes — episcleritis, uveitis, iritis, conjunctivitis mouth - oral aphthous ulcers joints - seronegative arthropathy (pauciarticular; polyarticular); axial arthropathy (ankylosing spondylitis, sacroileitis) hepatobiliary - primary sclerosing cholangitis Outcome and clinical course chronic illness; exacerbations and remission smoking is a risk factor for CD, protective in UC stress may precipitate flares in UC treatment: supportive therapy, immunosuppressive therapy, surgery, surveillance for malignancy surgery curative for UC, disease often recurs at anastomotic or other sites in CD Crohn’s disease Perforation, abscess, strictures, fistula, malabsorption, nutritional deficiency (B12, iron deficiency), neoplasia (intraepithelial neoplasia, and carcinoma) Ulcerative colitis Toxic megacolon, perforation, neoplasia: intraepithelial neoplasia and carcinoma

(Chronic) microscopic colitis

Encompasses two entities collagenous colitis; thickened sub-epithelial collagen band lymphocytic colitis; intraepithelial lymphocytes (>20/100 epithelial cells) and epithelial injury, chronic inflammation, normal architecture. No thickened sub-epithelial collagen band middle age to older; F>M radiologically and colonoscopy are normal associated with autoimmune diseases (e.g., Grave disease, RA, autoimmune or lymphocytic gastritis), drugs (e.g., NSAID), coeliac disease

Chronic non-bloody diarrhoea

Microscopically Intraepithelial lymphocytes and epithelial injury, thickened sub epithelial collagen band, chronic inflammation, normal architecture Outcome and prognosis course of microscopic colitis is benign and prognosis is excellent. Most patients respond to cessation of potential risk factors (e.g. NSAID) and symptomatic measures. Anti-inflammatory measures if needed (e.g. mesalamine, budesonide, corticosteroids) >70% of patients experience long-term cessation of diarrhoea, others experience relapse and require repeated therapy following period of remission



Ischaemic colitis Inflammatory disease of colon due to reduced blood flow, leading to ischaemic injury and secondary inflammation Aetiology occlusive

• arterial (thromboemboli; cholesterol emboli) • venous (strangulated hernia, volvulus,

obstruction, venous thrombosis, external compression)

non-occlusive • hypotension, hemorrhagic shock, heart failure,

sepsis, medications

Clinical features acute severe abdominal pain and tenderness nausea and vomiting, bloody diarrhoea loss of bowel sounds, abdominal rigidity, shock/vascular collapse chronic/ subacute nonspecific symptoms, episodes of bloody diarrhoea, blood loss, sepsis

Macroscopic — mucosal, mural, transmural infarction Complications: perforations, massive haemorrhage, sepsis, stricture (fibrosis which closes off the lumen)

Iatrogenic colitis Diversion colitis, drug-induced colitis, radiation, GVHD (post bone marrow transplantation)

Polyp Mass that protrudes to the lumen of the gut: • sessile • tubular (more common, more benign)/villous • pedunculated • abnormal mucosal proliferation • abnormal connective tissue proliferation • adenomas, hyperplastic polyps, hamartomatous

polyps, non-epithelial polyps

Neoplasia of the large bowel

Adenoma • tubular • villous • tubulo-villous • serrated ALL adenomas are dysplastic with NO INVASION (low or high grade) Adenoma carcinoma sequence high prevalence of adenoma and carcinoma in similar population and similar distribution in colorectum early invasive carcinoma show residual adenoma risk of carcinoma related to number of adenomas surveillance programs that detect and remove adenomas result in reduction of the incidence of carcinoma

Polyp • asymptomatic • screening (national

bowel cancer screening program)

• incidental • FOBT +ve (faecal

occult blood test) Adenoma carcinoma • fatigue, anaemia,

weakness • anaemia PR, altered

bowel habits • screening • metastatic disease

Colorectal adenocarcinoma Diagnosis clinical, endoscopic and radiological features confirmation of malignancy: pathological features of endoscopic biopsies (pre-treatment) Pathological assessment in CRC Pre-treatment diagnosis prognostication: staging, other features Therapy mutational analysis K-Ras, N-Ras response to treatment genetic and familial syndromes



Epidemiology peak incidence; 60-70 (except familial cases) environment, dietary (high calorie, low fibre, refined carbs, red meat, reduced protective micronutrients) NSAIDs -?protective Facts rectosigmoid - 55% caecum/ascending colon - 22% transverse - 11% descending colon - 6% most - single Morphology proximal - polypoid, exophytic (proliferating externally) distal - ulcer, annular stricture — proximal dilatation invasion of submucosa —> muscle —> series Colorectal adenocarcinoma dysplastic glands + invasion to the submucosa and beyond Colorectal carcinogenesis most sporadic only 1-3% are familial and associated with predisposing conditions e.g. IBD stepwise accumulation of multiple mutations APC-beta catenin pathway; loss of APC gene Microsatellite instability pathway; genetic lesions in the DNA mismatch repair genes (MSH2, MSH6, MLH1, PMS1, PMS2) Serrated pathway Invasion/spread direct invasion to adjacent structures blood vessels - liver lymphatics - lymph nodes When the polyp breaches the muscularis mucosa.



Dysplasia are pre-cancerous lesions Disordered growth, differentiation and maturation of cellular components of tissue CONFINED to the epithelium; no invasion morphologic expression of disturbance of growth regulation individual dysplastic cells show features similar to malignant cells Benign non epithelial neoplasms (rare): • leiomyoma • neuroma, schawnnoma • haemangioma • lipoma Neuroendocrine tumours (carcinoid) neuroendocrine cell lineage at least low grade, a few are high grade neuroendocrine carcinoma Appendix - most common site, SI (ileum), rectum, stomach, colon Gastrointestinal stromal tumours (GIST) spindle cell neoplasm interstitial cells of Cajal (ICC) or precursors - special cells of the GUT wall coordinating peristalsis 80% CD117 (C-kit) and 10% PDGFRA (platelet derived growth factor receptor Alpha) high and low risk malignant potential Lymphomas 1-4% of GIT malignancies Types of lymphomas B cell lymphomas: marginal zone lymphoma (MALT), Diffuse large B cell lymphoma (DLBCL), Burkitt lymphoma, mantle cell lymphoma, other - T cell lymphoma; associated with malabsorption syndromes i.e. coeliac



Familial adenomatous polyposis (FAP) syndrome

Familial adenomatous polyposis (FAP) is an inherited condition in which numerous adenomatous polyps form mainly in the epithelium of the large intestine. While these polyps start out benign, malignant transformation into colon cancer occurs when they are left untreated.

Hereditary non-polyposis colorectal carcinoma (HNPCC)

Lynch syndrome is an autosomal dominant genetic condition that has a high risk of colon cancer as well as other cancers. The increased risk for these cancers is due to inherited mutations that impair DNA mismatch repair.



Stomach



Gastritis Classifications of gastritis and gastropathies: acute, common, uncommon, chronic etc infecitous gastritis, crohn disease, eosinophilic gastritis etc

Chronic gastritis A more common biopsy active chronic gastritis; mix of acute and chronic most common cause of chronic gastritis in Australia is Helicobacter Helicobacter associated gastritis helicobacter normally in antrum; if loss of acid producing cells more proximally — they may move up to those areas

Acute gastritis: pain, nausea vomiting

Can produce acute gastritis usually presents as chronic dyspepsia endemic in most communities antral predominant gastritis initially then loss of acid producing cells migration proximally Diagnosis Visualise, biospy urease test, breath urease test, serology

Gastric peptic ulcer

biopsy of ulcers generally taken to exclude malignancy acute inflammatory fibrin exudated from ulcer — detect ulceration Complications of gastric ulcerations if ulceration leads to blood vessel — can lead to haemorrhage and massive blood loss leading to chronic iron deficiency anaemia deeper erosion can lead to perforation of gastric wall

Treatment cease cause if possible (medications) helicobacter eradication if present antisecretory therapy (PPI) surgery now very rare

Autoimmune gastritis

Presentation: pernicious (megaloblastic) anaemia (vitamin B12 deficiency) —> IF production for VB12 —> no IF = no absorption of VB12 iron deficiency (microcytic) anaemia (hypochlorhydia) —> no acid production in stomach — > no absorption of iron may be associated with other autoimmune Pathogenesis: immune response against parietal cells (acid and IF producing)

Histology Chronic inflammation, atrophy need to know where in the stomach the image is taken from different characteristics in different areas etc?

Intestinal metaplasia

In normal, apical mucosa large globules ; small bowel mucosa — intestinal



metaplasia occurs in response to chronic injury; increased risk factor for subsequent formation of carcinoma/dysplasia

Stomach tumours

Stomach tumours: • epithelial • dysplasia/carcinoma (tubular/poorly cohesive) • mesenchymal: • gastrointestinal stromal tumour (GIST) • lymphoid: MALT lymphoma • neuroendocrine • carcinoid (NET)

Signs and symptoms • mass arising in the wall of a hollow tube (stomach) • often asymptomatic until late • obstruction - dysphagia, constipation • pain due to disordered contraction • bleeding from ulceration • anaemia • haematemesis / malaena - shock • perforation • peritonitis • tumour seeding

Dysplasia Dysplastic - more crowded on histology, closer to each other and cells in gland are darker intestinal metaplasia - goblet cells with mucous vacuoles Dysplasias are graded — high grade or low grade

Early adenocarcinoma

tubular type — glands are architecturally abnormal; fuse into one another - lack of nuclei etc, glands infiltrated through smooth muscle capillary type solid type poorly cohesive(?) — sheet like formation, signet ring cell. can be quite bland in appearance; missing a lot of features of atypia, nuclei aren't particular large, lack of gland architecture

Linitis plastica mucosa intact, gastric wall thickened in all areas— rigid wall no distinctive mass forming lesion; may be missed as usually looking for lesions Deep vs shallow tumours medications resection (endoscopically) — shallow tumours deeper probably need to have open laproscopy?

Gastrointestinal stromal tumour (GIST)

Tumour of soft tissue — can occur anywhere in GI tract, oesophagus to rectum more common in stomach

Overlining mucosa is intact; tumour arising within gut wall and pushing mucosa up mucosa wall begins to thin, and thus can lead to ulceration tumour is generally solid, some haemorrhagic areas



fairly well circumscribed - epithelioid tumour? — appearance that people used to differentiate GIST from other forms of mesenchymal tumours desmin stain — stain against a component of smooth muscle; tumour is negative for design DOG1 stain - tumour is quite strongly positive (DOG = discovered on GIST) - good way to diagnose KIT (rTK) marker used in diagnostic algorithm for GIST transmembrane protein; dimerises in presence of co-factors phosphorylates leading to cascade and proliferation of cells mutations lead to permanent dimerisation = permanent proliferation of cells tyrosine kinase inhibitors can block it GIST risk stratification mitotic index, size, area of tumour and then determine risk of progression larger tumour + higher mitotic index = higher risk of progression

Gastric MALT lymphoma

Mucosa associated lymphoid tissue (MALT) – of saliva, etc. thickening/ulceration

infiltrate muscularis propria, which gastric tissue shouldn't do deep inflammation is abnormal cells are small in size lymphoepithelial lesions; invasion and formation of nests in gastric mucosa Normal reactive B cell population — produce mixture of kappa light chains and lambda light chain immunoglobulins ratio usually 3:1 (kappa:lambda) aplastic only produces: single type light chains (kappa or lambda, flow cytomety used to pick it up) MALT lymphoma - strongly associated with underlying gastritis, in particular with helicobacter pylori (?)



Gastric diffuse large B cell lymphoma

Neoplastic process large, morphologically atypically difficult to differentiate between cohesive carcinoma

Neuroendocrine tumour

Specialised form of epithelial cell AKA carcinoid tumour trabeculae formed, no gland formation/nest formation nuclei in low grade are bland; fairly same size IHC K chromogranin; stain highlights infiltrative nature of tumour neuroendocrine tumour can arise spontaneously but are strongly associated with autoimmune gastritis; acid producing (parietal) cells are being largely destroyed by autoimmune process — stimulus by gastrin to chronically produce acid... hyperplasia of endocrine cells leading to neoplasm

Hereditary diffuse gastric carcinoma

Syndrome; strong history of gastric carcinoma usually before age of 40 mutation in gene — intensive surveillance (endoscopy) or have prophylactic gastrectomy High power — foci of invasive carcinoma; diffuse type signet ring cell gene of interest is e-cadherin; adhesion molecule!



Nausea and vomiting

Disease Pathology, aetiology and epidemiology Signs and symptoms Diagnosis, management and

prognosis Nausea and vomiting

Causes of nausea and vomiting multiple and heterogenous Gastrointestinal; outflow obstruction, stasis, mucosal inflammation, infections Chemical irritation; drugs (opioids, antibiotics, chemotherapy), radiotherapy, biochemical (urea, liver failure, calcium), toxins Vestibular; motion sickness, cerebellar tumour, Meniere’s disease CNS; raised ICP , anxiety pregnancy — multitude of receptors and pathways involved in nausea and vomiting Pathophysiology vomiting centre in the brain multiple distributed nuclei in the brainstem located within the lateral medullary reticular formation coordinates complex act of vomiting four main sources of afferent input chemoreceptor trigger one (CTZ) vestibular system vagal and spinal afferent nerves from GI tract Other areas in CNS Chemoreceptor trigger zone (CTZ) caudal end of fourth ventricle within the area postrema, outside the BBB emetogenic stimuli from blood or CSF (drugs/toxins) Dopamine (D2), opioid, serotonin (5HT3) and neurokinin (NK1) receptors Vestibular system motion sickness via CNVIII muscarinic (M1) and histamine (H1) receptors

Clinical approach to nausea and vomiting • imperative to determine cause • obtain accurate history • onset/associations, duration,

content of vomitus (undigested food — obstruction, partially - bile etc)

• sick contacts (infectious), recent travel, EtOH intake, THC use (marijuana use), sexual history

• PMHx, recent treatments • Accompanying signs and

symptoms • abdominal pain, distension,

peritonism (bowel ischaemia or appendicitis?)

• diarrhoea (gastroenteritis) • fever, neck stiffness (meningits) • vertigo (labrynthine issue or CN8) focal neurology (space occupying lesion)

Non-pharmacological: • Environment

o avoiding strong odours o open area with air movement

• Diet o small amount of food o avoid spicy, rich, fatty and very

sweet foods o ginger (mixed evidence)

• Complementary and alternative medicine o acupuncture o hypnosis

• Psychological (with more respect to anxiety causing vomiting)

o providing explanations and reassurance

o behavioural therapy for anticipatory N/V associated with chemotherapy

Pharmacological: • Metoclopramide • Prochlorperazine • Domperidone • 5HT3 antagonists (-setrons)

o Ondansetron o Granisetron o Palonosetron

• Aprepitant • Fosaprepitant • Hycoscine • Cyclizine • Lorazepam



Vagal and spinal afferent nerves from GI tract rich in serotonin receptors irritation to the mucosa —> release of mucosal serotonin by enterochromaffin (EC) cells distension, infections, radio/chemotherapy afferents to vomiting centre as well as CTZ CNZ raised ICP anxiety/stress (i.e. anticipatory vomiting prior to chemotherapy) Nausea itself is different to vomiting conscious recognition of the excitation of an area closely related to vomiting centre often prodrome of nausea (not always) Vomiting caused by motor impulses that originate in the vomiting centre CN V, VII, IX, X, and XII to upper GI tract vagal and sympathetic nerves to lower GI tract spinal nerve to diaphragm and abdominal muscles



Liver

Disease Pathology, aetiology and epidemiology Signs and symptoms Diagnosis, management and prognosis Jaundice Yellowish tint to body tissue due to high levels of

bilirubin (high levels of bilirubin is toxic) caused by 1) excessive red cell destruction (haemolytic jaundice) assay blood? excess unconjugated BR 2) obstruction (gallstones, hepatitis, cancer) of bile ducts or damage to hepatocytes (obstructive jaundice)— produces bilirubin but can’t get rid of it because of obstruction assay blood? excess conjugated bilirubin

Yellow Jaundice of the neonate newborn infants have poorly developed bilirubin conjugation enzymes and jaundice is common premature infants more affected unconjugated bilirubin in the brain causes permanent damage kernicterus — often lethal, can result in low IQ etc how to prevent brain damage in neonates? phototherapy — phototherapy converts bilirubin to a form that is water soluble (excreted by kidneys) —K more destruction of RBC, not enough enzymes running to process destruction = premature infants more susceptible

Three main histological patterns

• hepatitis — inflammation of liver • steatosis — fatty liver • cholestasis — retention of bile

Hepatitis Hepatitis is inflammation of the liver can be caused by infection (viruses), toxins (alcohol, carbon tetrachloride), medication adverse effect (paracetamol) A necro-inflammatory process comprising inflammation, hepatocyte necrosis and repair, involving the portal and lobular regions (periportal, central) Viral hepatitis notifications in Australia Hepatitis C dominates (7600), hepatitis B (4600), hepatitis A (263) can only get hepatitis D if you have hepatitis B Autoimmune hepatitis - florid lobular and portal inflammation, interface hepatitis, hepatocyte “rosettes”, plasma cells, autoimmune antibodies

Acute less than 6 months symptoms often include (not always present); insidious onset with fatigue, anorexia, fever, nausea and vomiting, RUQ tenderness and jaundice Chronic greater than 6 months symptoms not often present but can include; weakness, tiredness and maltase Scarring Obstructed blood vessel

Acute typically lasts 2-4 weeks and resolves minority progress to acute liver failure (may need transplantation or can be fatal) Chronic often identified on blood test screening aetiology dictates progression rates of damage and development of cirrhosis and carcinoma Diagnosis • Clinical picture • Biochemistry: bilirubin may not be raised; hepatic

(mostly ALT rise) vs. cholestatic picture (mostly ALP , GGT rises)

- can have both pictures (e.g. viral infections starts with hepatic picture (high ALT), and inflammation of liver, can restrict bile flow movement and thus cholestatic picture can be present; ALP/GGT rises [EBV/glandular fever has mixed picture])



Prescription drugs - celebrex; hepatitis with eosinophils — allergic type reaction Alcoholic liver disease - fat; neutrophils destroying hepatocytes (in acute phase), mallory body (condensed structural filaments) Histological features • portal tract inflammation • lymphocytes, macrophages, neutrophils, plasma

cells, eosinophils, granulomas • limiting plate - interface hepatitis (piecemeal

necrosis) • lobular inflammation and hepatocyte necrosis -

apoptosis or coagulative necrosis • repair - macrophages, hepatocyte regeneration +/-

fibrosis which may progress to cirrhosis • many aetiologies, similar mechanisms and histology • often non-specific histologic features with clinical

history, serology and/or radiology needed After inflammation and damage, repair (regeneration and fibrosis) occurs

Acute causes: viral - hepatitis A, B, C, D, E immunosuppressed/transplant - CMV, EBV, HSV other infections - toxoplasma, Q fever, leptospirosis, brucellosis Alcohol drugs - paracetamol Toxins - mushrooms, carbon tetrachloride Ischaemia pregnancy autoimmune conditions metabolic - Wilson’s disease Chronic causes: viral; hepatitis B and C alcohol drugs - methotrexate, amiodrone, isoniazid autoimmune hepatitis (AIH) biliary

Hepatitis - biopsy diagnosis assess whether hepatitic, steatotic, cholestatic, fibrotic, overlap or another rarely make a diagnosis in isolation combination of serological, clinical and/or radiological not infrequently a non-specific pattern however, some aetiologies can produce characteristic patterns that may be highly suggestive of a particular cause



Primary biliary cirrhosis (PBC) primary sclerosing cholangitis (PSC) metabolic alpha-1-antitrypsin deficiency Hereditary haemochromotosis Wilson’s disease NAFLD (non-alcohol fatty liver disease)

Hepatitis A RNA virus belonging to hepatovirus related to picornavirus (e.g. polio) infection gives life-long immunity spread by faecal-oral route oysters, water contaminated by sewage, berries excretion for 1-2 weeks before illness to 1 week after onset found world-wide; hyper endemic in developing countries

Incubation period about a month; can be asymptomatic or mild illness in young children

Diagnosis detection of IgM for acute disease (lasts 6-9 months) PCR of blood and stool Vaccine is inactivated whole virus 1 dose protects at least 1 year, 2 doses at least 10 years Used for post-exposure prophylaxis NHIG (normal human immunoglobulin) useful due to prevalence of HAV IgG in blood donor population, gives immediate protection Can be used for contact and outbreak management, give within 2 weeks of exposure but vaccine preferred

Hepatitis B Aetiology DNA virus; lipid coated virus (from host cell), and surface proteins (HBs) Virus binds to host cell and moves into cell, translocates to nucleus and forms dsDNA episome, transcribed into hep B proteins and nuclear component of virus ccDNA; transcribed to form mRNA for proteins and also converted back into DNA copy for virus Facts infectious blood borne virus Geographic distribution of HBV; problem in Subsaharan Africa, Asia (2/3 of Hep B carriers in Asia) 300m people in world with Hep B stable infection so when infected, lifelong infection Acute hepatitis B in adult 95% of neonates get chronic infection, 5% of adults symptoms appear — antibodies are made antibodies appear, and virus come undetectable and antibodies persist for life core antibody detected; past infection

Consequences in HBV carriers • no fibrosis with

minimal risk of complications

• moderate fibrosis of liver but normal function; can still develop hepatocellular carcinoma

• develop chronic liver disease (cirrhosis) - more common if high HBV viral load, HBeAg +ve, raised ALT, older, other liver toxins (e.g. alcohol)

• develop hepatocellular carcinoma - more common if cirrhotic, family Hx, ethnicity, male

Treatment of HBV Treat if has or at risk of developing fibrosis (prevent bad outcomes of liver disease; difficult to eradicate ccDNA from cell so aim of treatment is to suppress infection) active inflammation (raised ALT) Commonest outcome of treatment is suppression of the HBV to improve prognosis Markers of successful treatment: HBeAg seroconversion to antiHBeAb, suppression of HBV DNA, settling of raised ALT loss of HBsAg Kve with treatment uncommon (<10%) — most people remain HBsAg positive but suppress infection Interferon cytokine induced by viral infection, does not act directly on viruses but makes cells resistant to infection blocks viral mRNA synthesis and protein synthesis used to treat hepatitis B and C



Natural history of Hep B carriers carriers; 6 month rule can detect virus for longer than 6 months; defined as a carrier or chronic infection compared to acute infection immune tolerant phase (immature immune system); virus replicates at high level and E antigen is detectable; ALT normal cause no immune response to virus Teens or 20’s— immune system begins to react against virus; results in ALT going up (immune response to hepB causes the hepatitis) and viral load comes down convert from HBeAg + to HBeAg - (E antigen positive to negative). Seroconversion occurs; viral load low, liver settles down to low ALT levels Reactivation phase - escape mutants (virus escapes immune system)

Active hepatitis; active virus/inflammation; inflammatory cell pattern with eosinophils, nonspecific feature of hepatitis (ground glass hepatocytes— opaque appearance from hep B surface antigen)

now conjugated to PEG for longer plasma half-life Nucleoside/nucleotide analogues nucleosides; Lamivudine, entecavir (more potent, less resistance) nucleotides; Tenoforvir (more potent, less resistance) — hepatitis surface antigen stays high as the drugs work at DNA polymerase stage (blocking reverse transcriptase) HBV vaccine universal for infants since 2000, very effective subunit vaccine (HBsAg only). Immunity indicated by HBsAB level >10mlU/mL Can use with hepatitis B immunoglobulin for post exposures.

Hepatitis C Lipid coated virus with envelope proteins on surface RNA virus implications when it comes to treatment HepC — RNA virus which is error prone in replicating genome; very unstable genome generates quasispecies within weeks of infection — Escapes immune system if quasispecies diverse enough, chronic infection can occur Hepatitis C has genotypes; geographically spread around the world within genotypes are subtypes and within subtypes are quasispecies Hepatitis C exists all around the world; In australia, genotypes 1 and 3 are commoner Transmission risks • parenteral (blood exposure) • developed countries; IVDU, tattoos, transfusions • developing countries; medical practices, traditional

practices • vertical; 3-5% risk overall for HCV RNA positive

mothers • sexual

Non-specific symptoms • tiredness 43% • RUQ discomfort 18% Until complications • cirrhosis,

hepatocellular carcinoma

• extrahepatic manifestations

• essential mixed cryoglobulinaemia

• porphyria cutanea tarda

• lichen planus • membranoproliferative

G • stigma of diagnosis Clinical features among 51 patients with acute HCV infection: • jaundice: 68%, • Flu-like symptoms:

Diagnosis HCV antibody indicates infected with HCV at some time false negative results can occur in: immunosuppressed (e.g. HIV infected), window period (7-8 weeks to convert) PCR defines active infection becomes +ve before antibody test in acute infection (1-2 weeks) Aim of HCV treatment is to cure produce a sustained virological response HCV PCR negative 3-6 months after completion of therapy ALT normalises and liver inflammation settles halts liver fibrosis and may even improve Sustained virological treatment response (SVR?) genotype 1 responds less well to treatment compared to C PEGKR interferon has best success rate (but only half with genotype 1 cured) New directly acting antiviral agents (DAA)



• very low risk, possibly increased with genital ulceration; higher risk with anal intercourse

Highest groups of Hep C in Australia; 20-29 years of age, then 15-19 years of age (those that use drugs) — 1% of Australia’s population has Hep C Natural history 10% develop acute hepatitis, 90% asymptomatic 75% of acute hepatitis develop chronic infection cirrhosis will develop in those that have chronic infection Slow indolent infection; things happen over years to decades Low grade hepatitis, lymphoid aggregates, steatosis, apoptotic cells

55%, • Dark urine & white

stool 39% • Nausea 34% • Abdomen pain 25% Many don’t get symptoms

protease inhibitors telepravir, bocepravir, now simeprivir improved SVR for genotype 1 from 38-46% to 67-75% current standard of care; triple therapy of IFN, ribavirin and protease inhibitor IFN free oral combination therapy is on the horizon combination of polymerase inhibitors, protease inhibitors, other antivirals

Hepatitis D deltavirus - defective satellite RNA virus found globally uses HBsAg coat so only in hepatitis B infected people

those with HBV and HDV have more cirrhosis

• diagnose by serology (IgM and IgG) • no vaccine treat with interferon therapy to control HBsAg

Hepatitis E RNA virus related to rubella found worldwide, especially SEA, India, Middle East, Africa, Mexico enteric transmission and illness like HAV

• 5% develop jaundice • mortality up to 20% in

pregnancy chronic hepatitis in immunosuppressed

• diagnose by serology • no vaccine therapy usually not required, can use Interferon or Ribavirin in chronic hepatitis E infections in immunosuppressed

Steatosis Fatty liver macrovesicular one vacuole is filling the cytoplasm, variable in size but often large alcohol acute hepatitis - hepatocyte necrosis with a neutrophil infiltrate, Mallory’s hyaline chronic changes - portal tract chronic inflammation and fibrosis, central vein sclerosis, often a mild increase in iron NASH (non-alcohol steatohepatitis) associated with obesity, diabetes, GI surgery, TPN, metabolic syndrome features - fat, mallory’s hyaline, inflammation, fibrosis Drugs - methotrexate, amiodarone hepatitis C virus



microvesicular multiple small vacuoles filling the cytoplasm of a hepatocyte uncommon • Reye’s syndrome (childhood, URTI, aspirin) • Acute fatty liver of pregnancy • Drugs - tetracycline, valproic acid • Congenital metabolic disorders, urea cycle

disorders, Jamaican vomiting sickness Histology macrovesicular vesicles of fat filling hepatocyte cytoplasm; nucleus displaced to side microvesicular numerous small lipid droplets are present in hepatocyte cytoplasm; not necessarily displacing nucleus to side Fatty liver disease NAFLD from obesity/over nutrition and sedentary lifestyle 25% western population has NAFLD Second hit (genetic predisposition) — fibrosis and inflammation occurs (5-10% western population) develop cirrhosis + liver cancer Spectrum of NAFLD K Healthy liver —> fatty liver —> NASH (non-alcoholic steatohepatitis)—> Cirrhosis (irreversible) — steatohepatitis (inflammation/fibrosis) - Fat, ballooned hepatocytes, inflammation and sinusoidal fibrosis

Pre-hepatic steatosis

Excess production of bilirubin (RBC breakdown)

Intrahepatic steatosis

• Inborn errors • Drugs - flucloxicillin (destroy the bile ducts) • PBC (primary biliary cirrhosis) - 4 stages • duct lesion - duct damage, portal inflammation,

granulomata • ductular proliferation - expanded portal tracts,



interface hepatitis • scarring - fibrosis, loss of bile ducts • cirrhosis • PSC (primary sclerosing cholangitis) - large duct vs.

small duct • inflammation and concentric fibrosis around ducts

resulting in epithelial necrosis and duct loss

Post-hepatic steatosis

Extrahepatic biliary obstruction (gall stones, tumours in the head of pancreas) - bile plugs in ducts ; may rupture to form bile lakes +/- ascending cholangitis (neutrophils in bile ducts), abscesses

Cholestasis - incomplete excretion of bile - general histological features

- feathery degeneration of hepatocytes - bile plugs - cell death with inflammation - bile ductule proliferation at edge of portal tracts - fibrosis - cirrhosis

Liver abscess three major forms bacterial (80%) relatively rare by high mortality rate; 5K30% with treatment, uniformly fatal if not treated source due to location or portoKsystemic blood flow (biliary sepsis 60%, other GIT sources 24% (more in right lobe than left lobe due to flow), haematogenous 15%) bowel flora most common amoebic (10%) fungal (candida) (10%) (usually someone treated for lymphoma etc)

Presents with fever Malaise RUQ pain

Ix: neutrophilia, raised ALP , blood cultures positive in 50% abscess aspirate definitive for aetiology CT scan 95+% sensitive, U/S 80-90% sensitive Rx: antimicrobials dependent on aetiology bacterial: antibiotics for 4-6 weeks, drainage amoebic: 7 days metronidazole fungal: amphotericin, gluconazole, drainage percutaneous drainage not required for amoebic abscesses; amoeba lives on rim of abscess so don’t need drainage surgical drain if >5cm, ruptured, failed catheter drainage

Parasitic liver infections

Hydatid cysts due to echinococcus tapeworm (predator-prey life cycle between dogs/wolves and sheep/deer/pigs/camel) Schistosomiasis

Disease due to pressure, secondary infection or rupture; cysts can get very large and patient can still be asymptomatic

Hydatid cysts Dx: serology, imaging Rx: PAIR (puncture, aspirate, injecte, reaspirate) procedure or surgery to excise cyst albendazole



found in Africa, Middle East and Asia; sits in water, burrow into skin and then get into veins and then through circulation to lungs and up through bronchi and then you swallow it chronic inflammatory reaction to eggs causes periportal fibrosis Fasciola (liver fluke) World wide, esp Asia where sheep and cattle; snails etc Consumption of aquatic plants Biliary obstruction, inflammation from adults

Schistosomiasis Dx: serology, eggs in stools Rx: praziquantel Fasciola (liver fluke) Dx: eggs in stool, serology Rx: triclabendazole

Biliary diseases • primary biliary cirrhosis • primary sclerosing cholangitis • extra-hepatic biliary obstruction • histopathology • inflammation/damage centred on bile ducts • cholestasis • bile ductule proliferation • hepatocyte damage • fibrosis

Primary biliary cirrhosis (PBC)

Duct damage, portal inflammation, granulomas fibrosis, bile ductule proliferation granulomatous duct damage, fibrosis, bile ductule proliferation, bile builds up (a toxin in large quantities) and large area of damage with fibrosis Alpha-1 antitrypsin deficiency excess = toxic; cells die — inflammation and fibrosis, eventually fibrous bands with residual nodules of hepatocytes

Primary sclerosing cholangitis

Bile duct with inflammation and fibrosis concentric fibrosis around ducts and inflammation

Metabolic diseases • inborn errors (congenital) • hereditary haemochromatosis • alpha-1 anti-trypsin deficiency • Wilson’s disease • cystic fibrosis (liver can be involved too)

Investigations LFTs enzymes (hepatocellular — AST/ALT cholangiocellular — GGT/Alk Ph) bilirubin synthetic function - albumin and prothrombin Infective agents - antibodies or PCR to HAV, HBV antibodies to virus or PCR for viral DNA/RNA serology - autoimmune Ab, iron studies



Antinuclear Antibodies (ANA) Antineutrophil cytoplasmic antibodies (ANCA) Antismooth muscle antibodies (SMA) Antiliver/antikidney microsomal antibodies (anti-LKM) Soluble liver antigen (anti- SLA) or Liver pancreas (LP) antibodies Tumour markers – alpha-feto protein (tumours) Imaging +/K FNA for mass lesions Xray U/S CT MRI ERCP Cholangiogram, MRI Cholangiogram, PTC Liver biospy Diagnosis, grading an staging of disease Iron and copper studies

Hereditary haemochromatosis

Hereditary haemochromatosis (iron overload); autosomal recessive disorder (takes a long time accumulate enough for symptoms) iron granules present in liver cells; dark granules in liver hepatocytes/sinusoids and portal tracts iron also deposits in GIT elsewhere and pancreas and heart

Alpha-1 anti-trypsin deficiency

Globules in cytoplasm of hepatocytes; increased fibrosis and cirrhosis, increased risk of hepatocellular carcinoma

Wilson’s disease Copper storage disease. Autosomal recessive disorder.

Cirrhosis Definition: diffuse alteration of normal architecture by fibrosis septa separating nodules of regenerating hepatocytes The end point of many disease processes The histology may or may not show specific features to indicate the aetiology Macronodular vs micronodular (<3mm) Micronodule whole liver involved; nodules similar size generating hepatocytes between fibrous bands Macronodule more varying sizes

Clinical symptoms and signs of cirrhosis no symptoms, abnormal LFTs non-specific symptoms and signs malaise, abdo pain, tenderness in RUQ, hepatomegaly (smooth or irregular — cirrhosis) signs/symptoms of liver failure multi-organ failure/death

Treatment of cirrhosis remove/treat aetiology antiviral medication stop drinking alcohol/medications immunosuppression remove iron (venesection) and copper support and await repair/regeneration transplant



Fibrous sepate Diffuse alteration of the architecture nodules of regenerating hepatocytes Aetiologies of cirrhosis any cause of chronic liver disease can end up with cirrhosis Alcohol/drug, viral hepatitis (A, B, C, D, E, F, G, EBV, CMV etc) Autoimmune hepatitis Metabolic diseases (genetic haemachromatosis [iron overload], alpha-1-antitrypsin deficiency, Wilson’s disease [copper overload]) Biliary tract disease (PBC, PSC) Idiopathic

Alcoholic liver disease

Fatty, Mallory’s hyaline, neutrophils, cirrhotic HCV low grade hepatitis, lymphoid aggregates, steatosis, apoptotic cells Auto-immune hepatitis florid piecemeal necrosis, hepatocyte rossettes, plasma bodies

Acute liver failure Acute liver failure (can destroy so much liver that can become fatal) loss of liver function that occurs rapidly - in days or weeks - usually in a person who has no pre-existing liver disease hyperacute is within 1 week, acute is 1-4 weeks and subacute is 4-12 weeks AKA fulminant hepatic failure complications include: hepatic encephalopathy; impaired protein synthesis (measured by levels of serum albumin and prothrombin time in blood) Acute liver failure usually due to fulminant viral hepatitis (loss of cells; sinusoid skeleton left over) or a drug toxicity/reaction macroscopic liver is usually swollen, soft and yellow microscopic usually massive necrosis of cells without specific features

Panadol overdose - pericentral necrosis nutmeg liver with spots of hepatocyte necrosis, usually around central veins liver gets saturated with paracetamol; excess goes down toxic breakdown pathway which kills liver



Gallbladder



Cholelithiasis (gallstones)

Causes of gall stones: • too much absorption of water from bile • too much absorption of bile acids from bile • too much cholesterol in bile • inflammation of epithelium • blockage; problem with bile modification and

gallstones can precipitate, precipitation = gall stones Gall stones can also cause inflammation of epithelium (cycle of gallstones?) GS present in 10-20% adult population 20% will develop biliary colic or other complication essentially consists of: • cholesterol • bilirubin • calcium salts Classification based on amount of cholesterol in stones cholesterol (>50% crystalline cholesterol monohydrate) pigment (black or brown) — bilirubin calcium salts

Clinical presentation estimated 80% patients remain asymptomatic biliary pain/colic Complications Cholecystitis Empyema Perforation Fistula Cholangitis Obstructive cholestasis, Pancreatitis Gallstone ileus Increased risk of carcinoma



Pathogenesis of cholesterol stones bile salts and phospholipids -> cholesterol soluble in bile when bile cholesterol concentration exceeds solubilising capacity of bile = SUPERSATURATION cholesterol nucleates into solid cholesterol monohydrate crystals four conditions result in cholesterol GS Formation supersaturation hypo-motility of GB cholesterol nucleation hyper-secretion of mucous traps nucleated crystals leading to aggregation (biliary sludge; mucus traps cholesterol crystals — smaller stones trapped in mucus) Pigment stones blackstones — disorders that lead to elevated levels of unconjugated bilirubin in bile e.g. haemolytic syndromes, severe ilea dysfunction predispose to pigment stone formation (unconjugated bilirubin combines with Ca2+ to form Ca2+ bilirubinate) brownstones - tend to form in bile ducts, contain bacterial degradation products of biliary lipids, Ca2+ salts of FA, unconjugated bilirubin and precipitated cholesterol



Cholecystitis acute, chronic (acute or chronic/subacute) calculous (in association with GS)/ acalculous (can’t find GS or biliary sludge) Acute cholecystitis — ulceration, change of lumen, congestion and acute inflammation — background of chronic changes (wall thickened, metaplastic changes etc) Chronic cholecystitis • calculous (90%) and acalculous • may be identified after repeated bouts of acute

cholecystitis or develop in the apparent absence of antecedent attacks

• most common symptom is episodic abdominal pain in epigastrium or RUQ, ca be precipitated by food

• mild to moderate tenderness can be elicited on palpation of the GB Mechanisms: similar to acute cholecystitis; supersaturation of bile leading to chronic inflammation and stone formation

Macroscopic findings: serosa may be dulled, fibrous adhesions, shrunken and fibrotic, wall thin or thick, attenuated and trabeculated mucosa • predominantly mononuclear inflammatory infiltrate in

the LP with or without extension into the muscular and periholecystic tissues; patchy chronic inflammation

• fibrosis of tissue (thick wall) • metaplastic changes • RokitanskyKAschoff sinuses • Dystrophic calcification (porcelain GB) K Hydrops

(clear fluid)/ mucocele of GB Acute calculous CS acute inflammation of GB precipitated in vast majority of cases by GS obstruction of neck or cystic duct obstruction chemical/mechanical irritation ischaemia in gall bladder superimposed infection

Clinical presentation • acute abdomen • mild presentation,

resolve without medical intervention

• Acute biliary pain + fever (constant or acute pain) - RUQ tenderness; can radiate to back

• Guarding • N & V • Persistence of

symptoms beyond 24 hours - leukocytosis

• Hyperbilirubinemia — obstruction of CBD

Investigations • Bloods (liver functions) • CXR • US — GB wall thickening, pericholecystic fluid, GS • TcKHIDA nuclear medicine scan K radioactive tracer

excreted into bile; delay/reduction/absence of radioactive tracer after a defined period of time = abnormality

• CT scan Treatment • observe vital signs, nil by mouth and pain relief • surgery, either acutely or more often after the acute

attack has settled down • surgery should be performed within 2K3 days of

onset of symptoms. After this period, development of adhesions an transmural inflammation increases risk of complications

• can be an open or laparoscopic operation



Acute acalculous CS 2-15% of patients that undergo cholecystectomy associated conditions — trauma, non-biliary surgery, sepsis, burns, parenteral nutrition, mechanical ventilation, multiple blood transfusions, prior use of narcotics or AB mechanisms: bile stasis and increase viscosity resulting in obstruction, mucosal ischaemia, infection, external obstruction of biliary tree clinical symptoms similar but may be insidious and masked by precipitating/associated conditions incidence of gangrene and perforation higher specific histological differences between acute calculous and acalculous cholecystitis are lacking Macroscopically • enlarged and tense • red blotchy appearance • green black discolouration • fibrin over serosa • suppurative exudate in severe cases • obstructing stone • lumen may contain turbid fluid or pus (empyema) K

thick and oedematous wall • Necrosis (gangrenous) • Emphysematous Histology mucosal damage — ulceration inflammation — acute/chronic mucosal regeneration with hyperplasia fibrosis (repair) Chronic changes on histology: muscle hypertrophy diverticula (RokitanskyKAschoff sinuses)



Pancreas



Pancreatitis • pancreas has close proximity to duodenum Pancreas • develops as an outpouching of duodenum, formed by

fusion of ventral and dorsal bud; fusion of ventral and distal portion of the dorsal duct forms the MPD (main pancreatic duct), the proximal portion of the dorsal duct can persist to form the accessory duct of Santorini

• Pancreas has several parts to it: head, uncinate, neck, body and tail -

• Two histological components - o endocrine (islets of Langerhan - beta, alpha,

delta, PP, D1 and enterochromaffin) and, o exocrine (80-85%) pancreas - digestive

enzymes (acinar cells, and ductal system: trypsinogen, chymotrypsinogen, proelastase, prophospholipase)

• Lots of fat in pancreatic parenchyma (Clear on histology) - Islet are paler staining (pink)

Pancreas divisum

Most common congenital anomaly — incidence of 3-10% Caused by failure of fusion of foetal duct systems of dorsal and ventral pancreatic primordial Bulk of pancreas drains through dorsal pancreatic duct and small caliber minor papillae Only small portion of head drains through larger caliber major papillae of Vater Predisposes to development of chronic pancreatitis if minor sphincter had a blockage and only small portion drains through major papilla, chronic pancreatitis is more easily developed?



Acute pancreatitis

Reversible pancreatic injury associated with inflammation 10-20 cases per 100k Aetiological factors • Genetic: mutations in cationic trypsinogen (PPSS1)

and trypsin inhibitors (SPINK1) genes • Metabolic: ETOH, hyperlipoproteinaemia,

hypercalcaemia, drugs • Mechanical: GS, pancreatic tumours, trauma,

iatrogenic, ?pancreatic dividum, parasites • Vascular: shock, atheroembolism, vasculitis • Infectious: mumps Mechanism of injury Pancreatic duct obstruction Primary acinar cell injury Defective intracellular transport of proenzymes within acinar cells End result is autodigestion of pancreas by inappropriately released and activated pancreatic enzymes (trypsin key enzyme, as it can activate other proenzymes, the kinin system, clotting and complement systems) Fat necrosis, interstitial inflammation, vascular damage and haemorrhage, parenchymal necrosis Fat necrosis K release of FA which bind calcium and magnesium ions to form insoluble soaps (fat saponification) Acute pancreatitis - swollen and hemorrhagic with fat necrosis (yellow areas) - calcified fat Histological sections Areas of fat necrosis (ghost outlines of fat cells) Saponificaiton; a little bluer Neutrophilic infiltration associated with it Acute inflammation Thrombosis and vascular damage; acinar and tissue is necrotic Ghost outline of acinar cells

80% cases mild and 20% severe Severe cases Shock with multiorgan failure due to release of toxic enzymes, cytokines and other inflammatory mediators into circulation

Atlanta classification of acute pancreatitis; Requires 2 of 3 following features • Abdominal pain consistent with AP (acute onset,

persistent, severe, epigastric pain often radiating to back)

• Serum lipase/amylase at least 3 times greater than upper limit of normal

• Characteristic findings on US, CT or less commonly MRI

Investigation Biochemical (lipase/amylase) US CT - diagnostic uncertainty after US, severe cases, failure to improve or deterioration, complications (pseudocysts) ERCP - gallstone aetiology result’g in cholangitis/ jaundice Management Nil by mouth, supportive, +/KAB (antibiotics, especially with complications), relieve obstruction, manage complications Complications Local Peripancreatic fluid collection Pseudocyst; develops as complication of pancreatitis; cavitation?

no epithelium lining (not a real cyst), lined by inflammatory cells etc (amylase rich fluid)

Necrotic collection Gastric outlet dysfunction Splenic and portal vein thrombosis Systemic Exacerbation of pre-existing co-morbiditiy Organ failure



Chronic pancreatitis (CP)

Fibroinflammatory disorder in which acinar compartment is replaced by fibrosis leading to exocrine insufficiency and in the late stages destruction of endocrine parenchyma; non-reversible Most patients don’t develop exocrine insufficiency till late in the disease Prevalence is between 0.04-5% Significant overlap between etiological factors involved in AP and CP CFTR (CF transmembrane conductance regulator) gene — decrease bicarbonate secretion by pancreatic ductal cells – protein plugging and CP , occur in 25-30% patients with idiopathic pancreatitis Pathogenesis Ductal obstruction — ETOH increases protein concentration in pancreatic fluid and these proteins plug the pancreatic ducts Toxic metabolic theory K ETOH has a direct toxic effect on acinar cells (pancreas is involved in the metabolism of ETOH) Necrosis-fibrosis theory K CP is a consequence of repeated episodes of AP. Pancreatic stellate cells activated by cytokines or direct effects of ETOH and metabolites K fibrosis Chronic pancreatitis Shrunken, hard, pale due to fibrosis, note the calcification Histological Inflammation, loss of acinar tissue, fibrosis loss of exocrine glands; retaining islets of Langerhans (become prominent and crowd because you lose the other tissue) MPD - stricture, dilatation, obstruction Smaller ducts may also be dilated and filled with protienacous material with or without calcification Retention cysts, pseudocysts Fibrosis with glandular atrophy Mild inflammatory component - lymphocytic

• Acute or recurrent episodes of AP

• Constant pain (epigastric pain radiates to back and can be partially relieved by sitting up and leaning forward)

• Symptoms related to local complications e.g. pseudocyst, carcinoma

• Endocrine or exocrine insufficiency



Islets may appear particularly prominent after atrophy and fibrosis, in very late stage of disease, a disease is also seen in the endocrine component PanIn (pancreatic intraepithelial neoplasia?) and carcinoma

Hereditary pancreatitis

Up to 20% with AP have no known associated processes Characteristically • Recurrent bouts of pancreatitis beginning in childhood • Germline mutations either result in enhanced

activation of trypsin or inhibit/impede its inactivation • Cumulative risk of pancreatic carcinoma at 50yrs is

11% and at 75yrs is 49-55%

Autoimmune pancreatitis

MASS forming inflammatory lesion of the pancreas (may mimic cancer) Two clinicopathological subtypes: • AIP type 1 K IgG4 related disease • AIP type 2 K not IgG4 related Aetiology Multifactorial (genetic factors, bacterial infection, autoimmunity)

Treatment is with steroids (can reduce mass)



Hepatobiliary and pancreatic neoplasms



Hepatobiliary and pancreatic neoplasms

Bile duct; extra and intra-hepatic Liver - hepatobiliary primary

• hepatocellular carcinoma (don’t use hepatoma) • cholangiocarinoma (bile duct) • hepatoblastoma — most common liver tumour

in the young benign haemangioma - most common (originates from vasculature?) hepatocellular (liver cell) adenoma (hepatocytes are specialised epithelial cells; form bile) malignant metastatic — GI tract

Liver cell adenoma more common in young women, associated with oral contraceptives D/D — HCC (hepatocellular carcinoma) complications rupture — sub capsular rare progression to HCC (certain subtypes can progress to HCC) Morphology Adenoma pale, yellow/tan bile stained well demarcated usually microscopically — sheets of hepatocytes (looks normal) but absent portal tracts in adenoma & prominent arterial vessels and draining veins



Hepatocellular carcinoma

Highest incidence in Asia Less in North America, Western Europe High incidence in countries with high HBV, HCV infections, +/- Cirrhosis

20-40 years West: most with cirrhosis, rarely before 60 years Aetiology HBV/ HCV Chronic alcoholism Food contamination by aflatoxins Haemachromatosis Other Morphology Liver enlarged Single, multiple or diffusely infiltrative 9 usually paler than surrounding liver Strong predilection to invasion of vascular channels -intra-hepatic metastases — satellite nodules — liver is a very vascular organ so easy to invade Under the microscope Hepatocytes look malignant; large nuclei, nucleoli, mitoses, thick liver cell plates - well differentiated Acinar/pseudoglandular formations, or just solid Poor to undifferentiated (anaplastic) (carcinoma can be graded from poor to undiff [completely diff looking]) Fibrolamellar variant - young - rarer variants

Pre-operative pathological diagnosis • Needle (core) biopsy • Cytology Treatment • Resection • Transplantation; often seen in setting of chronic

liver disease • Chemo-radiation • Other

Cholangiocarcinoma Malignancy of the biliary epithelium (intrahepatic, extrahepatic) Associated with PSC, congenital diseases e.g. Carols disease, exposure to thorotrast (not used now) Orients: chronic infection of the biliary tree by liver flukes Morphology Mass or often thickening and narrowing of bile ducts - may track along the portal tracts Markedly desmoplastic (fibrotic) stroma



Adenocarcinoma Mixed: cholangio-hepatocellular carcinomas Vascular invasion Haematogenous spread - lungs, bone, brain

Metastatic liver tumours

Most common hepatic malignancy Tends to be multiple (if comes from elsewhere; portal vein feeds into liver) — if it is multiple, more likely to be metastatic GIT most common Breast, lung and other tumours

Pancreatic tumours Exocrine Benign tumour: serous cyst adneoma Cystic neoplasms (any cystic neoplasm may have component of carcinoma): • Mucinous cystic neoplasm (MCN) • Intraductal papillary mucinous neoplasm (IPMN) -

low and high grade +/- carcinoma Malignant Pancreatic adenocarcinoma (most dangerous) Acinar cell carcinoma (5%) Endocrine Pancreatic neuroendocrine neoplasms (PEN) - low and high grade

Serous cystadenoma

Not common Almost always benign Glycogen rich cells line multiple cysts filled with thin straw coloured fluid - F:M - 2:1

Mucinous cystic neoplasm (MCN)

Mostly in women, rare reports in men - more common in body/tail Filled with thick mucin Lined by mutinous epithelium and the wall contains ‘ovarian type stroma’ - can be associated with invasive carcinoma NO communication to PD (pancreatic duct) system Both MCN and IPMN aren’t carcinomas but can potentially become cancerous.

MCN/IPMN prognosis Gastropancreato-duodenectomy (Whipple procedure), or distal pancreatomy Depends on the site in the pancreas (head/body, tail) With no invasion: excellent prognosis With invasion: better than de novo PDC (pancreatic duct carcinoma)

Intraductal papillary mucinous

Originate in PD system Main or branch ducts Mixed main + branch ducts

MCN/IPMN prognosis Gastropancreato-duodenectomy (Whipple procedure), or distal pancreatomy



neoplasm (IPMN) Filled with thick mucin Lined by mutinous epithelium (granular) with dysplasia (always dysplastic but not malignant)+ papillary formation Solid areas / mural nodules? can the nodules be a spot of invasion? can become a carcinoma Communicates with the PD system Both MCN and IPMN aren’t carcinomas but can potentially become cancerous.

Depends on the site in the pancreas (head/body, tail) With no invasion: excellent prognosis With invasion: better than de novo PDC (pancreatic duct carcinoma)

Pancreatic cancer 4th leading cancer deaths 85% present with advanced/unresectable lesions Australia: the 6th highest cause of cancer related deaths with a dismal 5 year survival of 6% 2013 WA cancer registry data Aetiology and precursor lesions

Pancreatic duct carcinoma

Age, more common >65 years Smoking — cigarette smokers are 2K3 times more likely to develop pancreatic cancer More common in people with new onset diabetes Precursor lesions; IPMN and MCN Family history Chronic pancreatitis with damaged ducts Duct epithelium: adenocarcinoma Well, moderate, poor or undifferentiated Variants, e.g. colloid carcinoma (adenocarcinoma with abundant extracellular mucin production) Can’t remove pancreas by itself that’s around head; need to remove a great amount of stomach, duodenum... called Whipple resection — tumour in tail of pancreas is easier to just resect

Spread direct infiltration: T stage Spread along peri-neural spaces Early lymph node involvement: N stage Blood stream, fairly early —> liver..: M stage Prognosis is poor Precursor lesions • Pancreatic intraepithelial neoplasia (PanIN) —

dysplasia of pancreatic ducts • PanIN 1-3 grade (low to high grade) • Cystic neoplasms Molecular carcinogenesis • KKras, Gnas • P53 • SMAD4 • HER2 • Other

Pancreatic neuroendocrine neoplasms (Pan-NET)

Pan-NET; pancreatic neuroendocrine neoplasms (tumours) Low grade: look very much like neuroendocrine tumours D/D: islet cells

Prognosis is very different from other pancreatic cancers... Cystic PAN-NETs Other cystic neoplasms Ki67 index (another aspect of grading), cytology...



High grade: obvious malignant D/D: PANKNET vs. other neoplasms (need to differentiate from other tumours); lost most of differential features; obviously malignant

Preoperative diagnosis: EUS diagnosis Endoscopic ultrasound guided (EUS) FNA/Brush (get a little bit of tumour before resection) Team; radiological/clinical, endoscopy and cytology Rapid on site evaluation (ROSE) Cytological assessment


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