Digestive Pathology


 Anaemia: deficiency of RBC
- male threshold is 0.13g/ml
- female threshold (non pregnant) is 0.11g/ml
 Mechanism of anaemia:
- decrease production of RBC due to lack of raw material such as iron, depression of bone marrow and infiltration of bone marrow (cancers)
- excessive destruction of RBC
- blood loss (hemorrhage)
- nutritional deficiency with folate, iron, vitamin B12 the commonest
- increased demand of iron by pregnancy, lactation, infants and adolescent
 Gastrectomy: surgical procedure where the stomach is cut from the proximal duodenum and is reattached to a more distal position. This causes iron deficiency as the food bypass the proximal small intestine where the iron absorption occurs.
 Iron loss: ulceration, bleeding disorders and menstruation (very common) and infections with H pylori and hookworms.
 Laboratory test for anaemia:
- serum ferritin: storage of iron is usually depleted first so level of serum ferritin drops
- total iron binding capacity: amount of iron binding to transferring decrease hence leading to more potential iron binding spaces, i.e. extent that can be saturated
- RBC production: decrease production and result RBC are microcytic and hypochromic
- Oral iron: taken to check for cause
 Vitamin B12:
- decreased intake and absorption due to intrinsic factor deficiency. Occurs with pernicious anaemia and gastrectomy
- defective uptake caused by terminal ileal disease or resection or drug related
- increase demand
 Folate:
- decreased intake due to unbalanced diet etc (alcoholic)
- increased demand from pregnancy and infancy
- malabsorption such as sprue, a celiac disease
 Method of examination:
- upper GI endoscopy: biopsy of tissue. May discover ulceration but 10-20% of cases are dual pathology hence require further investigation
- lower GI endoscopy: increase validity of finding. May find colon cancer as the main cause of ulceration and bleeding
- Capsular endoscopy

Ulcers, Reflex, H.Pylori and Pathology

 Abnormal gastric motor function
- Rapid emptying: occur usually after gastric surgery with dumping symptoms. Bypass of proximal duodenum causes poor mixing of food with pancreatic and biliary secretion and nutrient malabsorption
- Delayed emptying: with vagotomy or diabetic gastroparesis. Loss of vagus nerve to LES by neuropathy of diabetes or truncal vagotomy (no selectivity) will impair LES relaxation. Vagotomy usually used as part of gastric surgery to cure peptic ulcer.
 Abnormal gastric acid secretion:
- increased acid secretion: increased stimulus such as increased gastrin release by tumours and H.pylori gastritis or increased vagal stimulation
- decreased acid secretion: loss of parietal cells due to mucosal inflammation and atrophy, i.e. pernicious anemia or by vagotomy, removal of antrum (gastrin stimulus) and drugs that inhibit histamine and block proton pump
 Relationship of acid with ulceration: a strong correlation between acid presence and recurrent ulceration cases. Acid in the duodenum will cause necrosis of cells especially during the night where there are no pancreatic secretion (no food) to neutralize acid causing pain.
- Pepsin is active at pH 2 -4 so acid will prevent healing of ulcers as pepsin is active and degrading protein clots
 Inhibition of acid secretion:
- Inhibition of acetylcholine, gastrin or histamine produced partial incomplete acid secretion
- Inhibition of final pathway such as proton pump will produce near complete acid inhibition
 Peptic ulcer: necrosis and destruction of gut lining of the duodenum or stomach caused usually by the pathogen H.pylori. It is presented with a burning epigastric pain that intensify on an empty stomach and at night.
 Features of peptic ulcer:
- Gastric acid secretion is twice higher in duodenal ulcer patients due to destruction of S cells and loss of feedback inhibition, while in gastric ulcer, acid is lower than normal due to loss of parietal cells
- Plasma gastrin is elevated in patients with duodenal ulcer
- Inflammation of the stomach
- Urease test: testing for ammonia can indicate presence of H. pylorus as the bacteria produces ammonia to neutralize and protect against acid. The pathogen also resides close to the epithelial layer within the layer of neutral mucus containing bicarbonate secreted
- Increased incidence of peptic ulcer as increased nutrition causes increased gastric acid secretion
- Melaena: blood in the faeces due to haemorrhage of ulcers and dark appearance is of the oxidized iron in the ileum and colon (also there is acid modification of blood)
 Features of gastric ulcer:
- 70% of gastric ulcer is caused by H. pylori while 30% is due to anti-inflammatory drugs
- Located at the junction between body and antral mucosa
- Becomes more unstable and worsen with atrophic gastritis and intestinal metaplasia
 Background of H. pylori: H. pylori is adapted to live in the mucus layer of the antrum and causes gastritis with enzyme such as urease, degradation of mucus with inflammatory substance, and immune response with the bacterial lipopolysaccharide
- Infection is acquired in childhood and leads to life-long infection and chronic gastritis
- Risk of infection is related to living conditions
- Presently more adults are infected by H pylori than children due to changing in living standards and bacteria is no longer acquired
 Mechanism of ulceration: H pylori infection stimulates inflammatory cytokines which activates G cells to produce gastrin. Increased gastrin will lead to increased gastric acid secretion. Metaplasia of stomach and duodenum mucosa occurs and becomes unstable allowing the migration and colonization of the bacteria from antrum to the duodenal cap.
 Gastric ulcer and cancer:
- When H. pylori infect the entire stomach (pangastritis), atrophic gastritis will occur causing destruction of acid secreting body of the mucosa.
- Loss of acid (achlorhydria) allows bacterial colonization and formation of N-nitrosamines
- Bacterial carcinogens plus dietary factors gives higher risk for gastric cancer
 Features of gastric cancer:
- Intestinal: metaplasia of the mucosa to resemble that of the epithelium of intestine (i.e. containing goblet cells) occurring mostly at the antrum
- Diffuse: poorly differentiated tumour cells that produce large amount of mucus. Sporatic mutation of the E-cadherin gene can cause this.
- Linitis plastica: a type of diffuse cancer that has infiltrated into the submucosa and the stomach wall giving a leather bottle-like appearance


 Pathophysiological causes for diarrhea:
- Osmotic: malabsorption of carbohydrate (celiac disease) and lactose intolerance
- Secretory: cholera with electrolyte pumping and ileal resection (lack of bile salt absorption)
- Inflammatory: ulcerative colitis producing exudative diarrhea as fluid and electrolytes are lost across damaged epithelium
- Hypermotility: produced with vagotomy and rapid gastric emptying, and short bowel syndrome
- Steatorrhoea: malabsorption of fat
 Mechanisms of diarrhea:
- Virus invades the enterocyte and disrupts the Na+/glucose transport system and Na+/K+ ATPase. The gut is unable to absorb the glucose, electrolyte and water. Increased osmolarity of the lumen may even draw the water out paracellularly, e.g. enterotoxin by rotovirus uses this method.
- Death of enterocytes by virus can also reduce absorptive capacity
- Toxin absorbed in the gut can switch on cAMP in the cell and activate Cl- channels to pump chloride into the lumen and thereby pull water out of the body, e.g. enterotoxin produced by V cholera.
 Common clinical case of diarrhea:
- Cholera: high Na+ loss nearly double that of viral infections
- Rotovirus: cause of acute gastroenteritis and decrease in absorption of nutrients
 Features of diarrhea:
- Dehydration with lose of water and decreased ability to uptake food, loss of gut integrity can cause malnutrition
- Malnutrition can lead to decreased resistance to infection and lead to more diarrhea
- Lactose intolerance as lost of enterocytes reduce lactase production
 Pattern of gut absorption:
- Hypertonic solution worsen the situation as it draws water out from body
- Isotonic solution improves absorption
- Hypotonic solution is most effective to replenish lost water, hence used for oral rehydration therapy
 Limitation of oral rehydration therapy:
- Does not reduce volume, frequency or duration of diarrhea
- Cost to consumer may be prohibited in poorer countries
- Encourages the use of ineffective anti-diarrheal drugs
 Limitations of rice-based ORS:
- Variable carbohydrate content
- Low electrolyte
- Unpalatable
 Coeliac disease: inflammation and loss of villi in the duodenum and jejunum impairs absorption of nutrients, i.e. weight loss due to malnutrition and malabsorption of iron and folate also follows
- Evidence: loss of villi and hyperplasia of crypts with biopsy, iron and folate deficiency
- Clinical manifestation: tiredness, diarrhea and excessive flatulence over at least 2 years and weight loss
- Diarrhea mechanism: loss of brush-border enzyme that breaks down carbohydrates and endocrine cells that signals for pancreatic secretion (lipid digestion) produces osmotic diarrhea and steatorrhae. In addition hyperplasia of crypt increases secretion.
 Gastro-jejunostomy and vagtotomy: treatment for duodenal ulcer usually involve bypassing the duodenum and severing of vagal nerves to inhibit acid stimulation.
- Evidence: medical history of duodenal obstruction by ulceration and surgery
- Clinical manifestation: mild upper abdominal discomfort after meals and tendency to diarrhea
- Diarrhea mechanism: vagotomy causes loss of parasympathetic activity and increased secretion of electrolytes, small bowel motility (food moving too fast to be absorbed) and rapid influx of food into small intestine
 Ulcerative colitis: inflammation of the colon
- Evidence: blood and mucus and increased episode of diarrhea
- Clinical manifestation: frequent and urgent episodes of blood/mucus with pain
- Diarrhea mechanism: loss of absorption of colon due to damaged epithelium means water and electrolytes pass directly through. The kidney adjust to reabsorb as much Na+ as possible
- Treatment: ileostomy where a plastic pouch is connected to the end of the small intestine and help collect intestinal waste; take high salt diet and regular fluid supplementation
 Other causes of diarrhea:
- Campylobacter: similar to ulcerative colitis (but last only 7-10 days)
- Enterotexogenic E.coli: food poisoning and similar to V. cholera
- Giardia: parasites that colonize the duodenum and upper jejunum and cause mild villous atrophy. Carbohydrate malabsorption and bacterial metabolism of undigested food makes the faeces smelly and produce CO2
- Short bowel syndrome: resection of much of the bowel means special fluid and dietary intake is required. These include iso-osmolar fluid, low lactose and medium TG. TPN may be required
 Crohn’s disease
- Evidence: ileal surgery in which 150 cm of terminal ileum was resected due to the disease causing B12 and bile salt absorption to be significantly impaired.
- Clinical manifestation: diarrhea
- Diarrhea mechanism: decreased bile salt pool impair fat absorption and passes on to the colon along with bile irritation that increases colon secretion
 Normal ileostomy output:
- Volume: 600 mL
- Consistency: thick liquid
- Colour: dark green/brown – bile pigments
- Odourless: low bacterial count in small bowel
- Content: electrolyte concentration Na+ 140 mmmol/L, K+ 5 mmol/L, Cl- 60mmol/L – 60-80mmol per day

Inflammatory Disease of the Colon

 Inflammatory bowel disease: ulcerative colitis and Crohn’s disease are chronic inflammatory diseases of the gastrointestinal tract.
- smoking causes increased risk of Crohn’s disease and decreased risk of ulcerative colitis
 Aetiology:
- genetic factors: recent discovery of a gene called NOD2 that encodes for a protein involved in the immune response to intestinal bacteria LPS and products maybe related to Crohn’s disease by causing dyregulated immune response. First degree relative have 30 folds risk.
- Diet and psychological factors have no role
- Individual brought up in clean environment are vulnerable as they are not exposed to much pathogen and their underdeveloped immune system is hypersensitive
 Ulcerative colitis: infused disease limited to the large bowel and begins in the rectum and spreads continuously proximal. Usually only the mucosa is inflamed with a diffused granular surface, and there is atrophy and branching of crypts, loss of goblet cells and paneth cell metaplasia. Macroscopic ulceration only occurs with severe acute attacks.
 Symptoms of ulcerative colitis: minimal pain - some left lower abdominal pain prior to defecation and more constant sign in the case of severe disease
 Clinical features of ulcerative colitis:
- Relapsing diarrhea is the dominant symptom often with blood
- total colitis contribute to 25% of presentation while left sided colitis is 50%. The rest is proctitis
- ulceration at later stages with nodular pseudopolyps
- colon becomes shorter however in acute symptoms dilation of the colon can occur up to 10cm in diameter
- increased platelet and ESR level
 Treatment:
- suppressing inflammation with steroids administrated either locally or intravenously
- 5-ASA (5-aminosalycctic acids) is also used for anti-inflammatory activity
- Colectomy in which a large section of the large bowel is resected
 Crohn’s disease: can affect any part of the gastrointestinal tract and is typically discontinuous. The symptoms begins with aphtous ulcers (open ulcers from a break of the mucosal membrane) overlying lymphoid aggregates and later becomes fissuring and deeply penetrating (transmural inflammation) with all layers of the gut wall affected.
 Symptoms of Crohns: often lower abdominal cramping pain
 Clinical features of Crohn’s disease:
- mucosa is oedematous with cobblestone appearance
- small, non-caseating (does not decay into firm and dry mass) epitheloid granulomas
- small bowel infection: causes abdominal pain, nausea, diarrhea and weight loss
- terminal ileal disease: pain and localized tenderness in the right iliac fossa (may have subacute small bowel obstruction)
- peri-anal: abscess and fistulae causing pain and discharge
 Terminal ileal disease due to Crohn’s:
- Subacute bowel obstruction: mid abdominal cramping pain 30-60 mins after a meal. Larger meals associated with more pain due to abdominal distension. This condition may not be treated depending on degree of fibrosis
- Inflammatory pain: constant pain at the right iliac fossa unaffected by meal. Condition aggravated by movement, coughing or sudden joist and correlates more with inflammatory activity. Resolves with effective medical treatment.
 Complications of Crohn’s:
- fistulae: bowel to bowel, bladder, vagina, anterior abdominal wall
- nutritional deficiencies: occurs due to loss of villi in the duodenum where most of the nutrients is absorbed. Anaemias such as iron or folate deficiencies; hypoproteinaemia (loss of proteins); malabsorption of fat soluble vitamins; osteoporosis
- cholangitis: progressive bile duct narrowing
 Investigation: colonoscopy and ileoscopy, also possibly small bowel enema
 Medical management:
- nutritional deficiencies need to be treated
- steroids and 5-ASA containing drugs
- immunosuppressives such as azathioprine and methotrexate
- surgical resection of diseased segment of bowel relieves symptoms but disease reoccurs with a 50% rate after 5 years. This option is chosen when all other medicine fails

Hepatobilliary and Pancreatic Pathology 1

 Pancreas: a gland organ with both exocrine and endocrine secretory function
- exocrine: constituting 80% -90% of the gland. Acinar cells contains zymogen granules which are inactive precursors of digestive enzymes such as trypsin, chymotrypsin, lipase, elastase. Digestive enzymes are secreted along with pancreatic juice and activated by trypsin in the duodenum. Pancreas has trypsin inhibitor to protect against proteases.
- endocrine: producing hormones such as insulin and glucagon from islet of langerhans
 Clinical problems of the pancreas:
- acute and chronic hepatitis
- congential abnormalities
- non-neoplastic cysts
- cystic neoplasms
- pancreatic carcinoma
 Acute pancreatitis: inflammation of the pancreas associated with acinar cell damage.
 Etiology of acute pancreatitis:
- metabolic: alcohol toxins, genetics and drugs
- mechanical: blockage of duct by gallstones, trauma
- vascular: shock and vasculitis (reduced blood to pancreas)
- infection: mumps
 Mechanism of acute pancreatitis:
- damage to the acinar cells causes release of proenzyme which becomes activated by lysosomal hydrolase and initiate auto-digestion of the tissue. Inflammatory response also promoted by cell cytokines.
- pancreatic duct obstruction such as gallstones will increase intrapancreatic ductal pressure resulting in accumulation of enzyme rich interstitial fluid. Active lipase produces fat necrosis, and build up of fluid produces edema that can compromise blood flow.
- elastases digests the blood vessels leading to hemorrhage
 Testing:
- Increased level of serum amylase over 12 hours
- increased level of white blood cells due to inflammation
- CT scan to observe swelling of the pancreas
- Laparotomy where abdomen is opened up to observe the features (very rare now)
 Clinical manifestation of acute pancreatitis:
- severe pain in the epigastric region
- nausea and vomiting
- fever
- increased pulse rate and tenderness of abdomen over inflamed pancreas
 Management:
- intravenous fluid and nutrients
- analgesia (painkiller)
- monitoring of condition
 Complications:
- hypertension, shock, renal and respiratory failure due to massive release of proinflammatory cytokines
- jaundice (loss of digestion and thus no stimulation for bile secretion), hyperglycemia (loss of insulin function), low calcium
- pancreatic pseudocyst which is a pathological collection of fluid with a clear epithelium undergoing granulation and fibrosis
 Chronic inflammation: repeated episodes of inflammation with loss of pancreatic parenchyma and replacement by fibrous tissue (due to long term damage to normal tissue). There is an irreversible destruction of exocrine tissue.
 Etiology of chronic pancreatitis:
- 60% and 70% have heavy long term alcohol term
- Intraductal plugs – protein and cell debris
- Previous acute pancreatitis
- Severe malnutrition
- Hereditary/CFTR mutation
 Mechanism of chronic pancreatitis
- chronic damage causes fibrosis and hardening of the tissue with destruction of tissue
- atrophy of exocrine component while sparing the endocrine
- fibrous protein and calcification blocks the pancreatic duct hence prolonging inflammation
- cystic fibrosis also a mechanism of pancreatitis as there is a loss of chloride secretion and hence thick mucus develop and blocks the pancreas
- increased macrophages and cytokines attract more leukocytes causing damage
- continued release of pancreatic enzyme into normal tissue in addition with toxin
 Clinical features of chronic pancreatitis
- repeated attacks of abdominal pain usually brought about by alcohol
- more persistent with pain
- malabsorption, pseudocysts and rarely diabetes mellitus
 Testing:
- Clinical suspicion
- serum amylase but may not be elevated
- CT imaging
 Pancreatic carcinoma: cancer of the pancreas is the 4th most common cause of cancer death. It is not operable or responsive to chemotherapy. Prognosis is poor with only 5% surviving up to 5 years.
 Etiology of pancreatic carcinoma:
- smoking
- coffee drinking
- rare hereditary influence
 Mechanism of pancreatic carcinoma:
- production of pancreatic adenocarcinoma which are cancerous cells that have secretory properties
- 60-70% head, 5 -10%, 10-15% tail, 20% diffuse
- Cancer at head of the pancreas due to biliary obstruction, and invasion of ampulla by viruses. Carcinoma at body and tail are often silent, large and disseminated and can spread to nodes and adjacent organs
 Clinical features of pancreatic carcinoma: early presentations of the cancer is non-specific and can vary
- obstructive jaundice due to the growth of tumour which can occlude the common bile duct that partially runs past the head of the pancreas. Can progress to obstruct duodenum
- weight loss (malaabsorption)
- abdominal pain
- thrombophlebitis (vein inflammation due to blood clots)
 Testing:
- diagnosis usually made on imaging following CT and ultrasound
- no tumour marker identified
 Other tumours:
- pancreatic endocrine tumours: islet cell tumours are rare cancer cases that occur in the pancreas or peripancreatic tissue
- insulinoma: excessive secretion of insulin causing hypoglycaemia
 Cholelithiasis: the presence of gallstones in the gallbladder
- composition of gallstone: most of the gallstones contains more than 50% crystalline cholesterol and are called cholesterol stone while the remainder is made up of primarily bilirubin calcium salts and are called pigment stones.
- The dropping of gallstones into cystic duct can obstruct the bile flow leading to cholecystitis (inflammation of gallbladder)
 Mechanism of cholesterol stones: cholesterol is insoluble and only rendered soluble by aggregation of bile salt. When bile is supersaturated with cholesterol either due to lack of bile salt production or impaired expulsion of bile (stasis), gallstone will be promoted. Condition that favors this is microprecipitation of calcium salts.
 Etiology of cholelithiasis:
- increased risk in woman and age as estrogenic influences such as oral contraceptives, pregnancy, obesity and rapid weight loss all favors stone formation
- family history
- stasis
 Pigment stone risk factors: this is predominant in non-western countries due to infections and parasites
- chronic haemolytic syndrome (i.e. excessive bilirubin production from breakdown of heme)
- severe ileal dysfunction or bypass such as Crohn’s disease and ileotomy
- cystic fibrosis with pancreatic insufficiency
- bacterial infection of the biliary tree (cholangitis)
 Clinical consequences of gallstones: 70% to 80% are asymptomatic through lifetime. The last three symptoms are also associated with cholecystitis
- Acute/chronic cholecystitis with symptoms of pain
- Biliary colic due to choledocholithiasis which is obstruction of the common bile duct or the duct leading into it
- Empyema (pus within a body cavity)
- Obstructive cholestasis and pancreatitis
- Fistulae of biliary to gut
- Cholangitis infection
- Perforation of gallbladder with local abscess (collection of pus in a newly formed capsule) or peritonitis
 Acute cholecystitis: inflammation due to obstruction of the neck of the gallbladder or the cystic duct by gallstones. Chemical irritation appears to be the major factor with bacterial contamination possibly occurring later on.
 Clinical Features of Cholecystitis:
- right upper quadrant abdominal pain
- tender with guarding over gallbladder
- febrile (feverish)
 Testing:
- neutrophil leucocytosis (elevation in white blood cell count)
- raised bilirubin, ALP and GGT if stone common bile duct
- imaging - ultrasound
 Chronic cholecystitis: chronic cholecystitis results from long term association of gallstones and repeated bouts of mild to severe acute cholecystitis.
- the pathology is variable with wall thickened and gallbladder often contracted but can be normal size or enlarged
 Management of cholecystitis:
- initial acute event: conservative therapy such as intravenous fluid replacement and pain relief with up to 25% of cases requiring surgical intervention
- longer term: cholecystectomy using laparoscopic
 Cancer of the biliary system: cancer of either the gall bladder or the extrahepatic duct
 Carcinoma of gallbladder: late presentation in older patients. Increased risk with gallstones and chronic infections.
- Clinical features are very non-specific, i.e. similar to cholelithiasis – nausea, pain, jaundice, weight loss.
- Detection done with imaging
- Pathology involves development of adenocarcinomas and most would have invaded the liver by time of discovery and diagnosis
 Carcinoma of extrahepatic duct: uncommon adenocarcinomas that can involve the ampullary region along with carcinoma of the pancreas and adenoma of the ampulla of Vater
- presented with slow obstructive jaundice, pale stool, nausea and weight loss

Tests of Liver Function:

 Liver lobule structure: hexagonal shape and a portal triad located at 3 corners. Flow of bile passes from lobule outwards while blood flows inwards from triad to central vein.
 Liver enzyme patterns:
- hepatocellular: located within the lobules are the enzyme ALT and AST
- Biliary/cholestatic: located within the bile ducts are the enzyme GGT and ALP
 Alanine aminotransferase: catalyze the transfer of the amino group from alanine to alpha-ketoglutarate forming glutamate and pyruvate (involved in gluconeogenesis)
- sources: liver hepatocytes (the most liver specific enzyme) and muscles, heart and red blood
- processes: increase in ALT concentration due to hepatitis and inflammation in muscles cells produce a greater increase in ALT than AST
 Aspartate transaminase: transfer a amino group from aspartate to alpha-ketoglutarate to form glutamate and oxaloacetate
- sources: liver hepatocytes (less liver-specific than ALT) and other tissues such as muscles heart and red cells
- processes: increase in concentration due to cancer and alcohol poisoning (increase more than ALT) and also hepatitis. This provides clues about destructive infiltration of the liver.
 Alkaline phosphatase (ALP): transfers/hydrolysis phosphate groups. During puberty, ALP levels increases by several folds.
- sources: mainly the biliary system, osteoblasts, intestine and tumours
- processes: increases in concentration mainly during obstruction and inflammation of the billary system. Others include growing and remodeling of bone and inflammation of the intestine such as Crohn’s disease
 Gamma-Glutamyl Transferase: involves transferring of amino acid across cell membrane and glutathione metabolism
- sources: large single source is liver with others such as heart, pancreas, lung
- processes: inflammation and obstruction of the biliary system increase concentration and inducible substances such as alcohol (provide indication for alcohol problems) and drugs.
 Bilirubin metabolism: bilirubin is formed from haeme. It is insoluble and is carried in the blood mainly in the unconjugated form (85%) by albumin hence won’t get into urine. The liver absorbs bilirubin and solublize it by adding a glucoronic acid forming bilirubin-glucoronide (15%)
 Release of bilirubin: the liver stores the bilirubin and release it as bile.
- major pathway is release of bilirubin into the gut and transformed into urobilinogen (black pigmentation) and excreted along with faeces
- minor pathway is the “leakage” of bilirubin into the blood stream due to impaired excretion and loss of bilirubin in urine
- some urobilinogen is absorbed in the intestine into the blood and excreted through urine
 Clinical problem of bilirubin metabolism:
- haemolysis: increased degradation of heme produces excessive bilirubin level. The liver operates functionally but is overwhelmed nevertheless by bilirubin content forcing some overflow into the blood stream
- hepatitis/cancer: inflammation and tumour growth causes blockage of the hepatic canaliculi and flow of bile. The result is a reflux of almost all bilirubin content into the blood producing a dark urine but pale stool. Occurs also with pancreatitis.
 Causes of jaundice: increased bilirubin concentration in bloodstreams
- within circulation: Gilbert syndrome (inability to conjugation, so unconjugated bilirubin flow back into vessels) and haemolysis (increased bilirubin levels)
- intrahepatic: cholestasis (due to drugs, pregnancy or thyroid disease), obstruction such as hepatitis (swelling of the tight capsule increased intrahepatic pressure of the ducts), cirrhosis (destruction of ducts making it narrower) and liver masses (cancer)
- interhepatic: obstruction such as gallstones, biliary/pancreatic cancer and pancreatitis
 Albumin indication: normal concentration is 35-47g/L. The liver is the only source in adults. Albumin has a long half-life of 3 week thus can be misleading.
- processes: decreases in concentration with decreased synthesis usually due to shock or cirrhosis, increased loss through kidney, and redistribution
 Other indications:
- globulins: very high level with hepatitis and cirrhosis so reflect inflammation
- prothrombin ratio: raised ratio indicate vitamin K deficiency or liver failure (lack of synthesis)
- glucose: loss of homeostasis of glucose level in the blood
- ammonia: increased ammonia level due to loss of detoxification function of liver (occurs usually at end stage)
- CEA: carinoembryonic antigen, a marker for tumours. Increase in level indicate increased danger and malignancy of possible tumours
 Metastatic cancer (case 1):
- evidences: decreased albumin level, normal bilirubin but increased GGT and ALP which indicating the biliary tree is partly block but not all, normal AST meaning minimal inflammation and hepatocyte damage and finally incredibly high level of CEA shows presence of tumour
- clinical manifestation: history of bowel cancer, and rectal bleeding, right upper abdominal discomfort
 Gilbert syndrome (case 2):
- Evidence: normal range for all indicator except elevated level of bilirubin. Urine is not dark hence indicate raised level of unconjugated bilirubin (can’t escape in urine). There is no bile duct obstruction or hepatocyte injury.
- Clinical manifestation: persistent mild jaundice and rapid rise of bilirubin with fasting. No change in urine or faece colour.
 Hepatitis (case 3): chronic alcohol abuse
- evidence: history of excessive alcohol, decreased albumin and prothrombin ratio indicating malfunction of liver. Increased bilirubin with drastically elevated levels of AST and ALT and GGT and ALP suggesting severe damage to the hepatocytes and biliary system (very likely to be cirrhosis). Final serology test to insure viral infection
- clinical manifestation: nausea, vomiting and weakness
 Alcoholic liver disease (case 4): inflammation and alcoholic cirrhosis (scarring) causing obstruction of bile duct and blood flow. The result is portal hypertension and portal vein blood takes on a collateral route through small veins of the esophagus (esophageal varices)
- evidence: lowered albumin and prothrombin ratio shows damage to liver functions. Elevated AST and ALT indicate possible inflammatory response of the hepatocytes and obstruction (though non-specific). However the drastic increase in GGT, ALP and bilirubin concentration in blood underlines damage by alcohol toxins and tissue scarring.
- Clinical manifestation: long history of alcoholism, vomited blood
 Paracetamol poisoning and liver failure (case 5): accidental overuse of drug dose causes acute poisoning
- evidence: large overdose of paractetamol with above normal level for bilirubin, GGT and ALP and increased prothrombin ratio suggests damage to the function of the liver and inability to process bilirubin delivered into blood. Astronomical increase in level of ALT and AST strongly emphasize the severe injury to hepatocytes by toxic drugs
- clinical manifestation: tender enlarged liver and unconsciousness in 3 days and death in 5 days.

Hepatobiliary and Pancreatic Pathology 2

 Acini of the liver: the secretory lobule of a liver is split into three zones. Within the acini are chords of hepatocytes
- periportal: first 1/3 of the lobule closest to the porta hepatic
- mid-zonal: second 1/3 of the lobule located at the middle
- centrilobular: last 1/3 of the lobule located closest to the central vein
 Features of liver disease: most liver disease follows this pattern of progression
- hepatic injury
- hepatic failure
- cirrhosis
- portal hypertension
- jaundice
 Response to hepatic injury:
- degeneration of intracellular accumulation (substances)
- necrosis and apoptosis with severe damage
- inflammation causes by hepatitis virus
- regeneration of the tissues
- fibrosis of liver and leads to cirrhosis
 Hepatic failure: liver stops functioning due to sudden and massive destruction or at the endpoint of a chronic damage such as alcohol abuse.
- around 80-90% of capacity is lost
- high mortality due to hypoalbuminaemia (loss of synthetic functions) and elevated ammonia (loss of detoxifying function)
 Cirrhosis: healing and bridging damaged fibrous septae (tissue lining the portal tract around the porta hepatis region) with fibrotic tissue
- new proliferating parenchymal surrounded by fibrosis forming micro/macronodules leading to progressive loss of liver function
- overall scarring disrupts the entire architecture and reorganized, shunting the blood supply. Portal vein and hepatic artery bypasses functional liver cells due to this
 Causes of cirrhosis: mainly by alcoholic liver disease (60-70%) and minority viral hepatitis and biliary diseases etc
 Portal hypertension: increased resistance to portal blood flow due to three causes:
- prehepatic: obstructive thrombosis in portal vein
- postehpatic: severe right sided heart failure
- intrahepatic: cirrhosis (shunting of vessels by scarring)
 Consequences of portal hypertension:
- ascites: build up of pressure in the portal vein causes exudation and accumulation of fluid in peritoneum
- portosystemic venous shunts: rectum hemorrhoids (pressure buildup in portal circulation prevents flow of blood from lower veins), oesophageal varices
- congestive splenomegaly: enlargement of the spleen
- hepatic encephalopathy: bypassing of the liver filtration system allows toxin to travel in the blood directly to the brain without removal or modification and damage brain cells, i.e. impaired cognition and loss of consciousness
 Hepatitis A: benign self-limiting disease with an incubation period of 2-6 weeks. It does not cause chronic hepatitis.
- transmitted faecal-orally from person to person
- asymptomatic or have mild febrile illness and possibly jaundice
 Hepatitis B: initially acute hepatitis and progresses to chronic hepatitis producing cirrhosis of the liver. Incubation period between 4-26 weeks and requires infection of hepatitis D virus first.
- transmitted by blood and body fluid
- fulminant hepatitis in which onset is rapid and very deadly produces massive necrosis
 Hepatitis C: the major cause of liver disease in which liver inflammation causes the cytoplasm of hepatocytes to swells. Acute episodes are very rare and often asymptomatic, however most are chronic which can eventually lead to cirrhosis.
- transmitted by blood transfusions
 Alcohol liver disease: the leading causes of liver disease in western countries. There is a accumulation of fat in the liver cells observed as globules through a process called steatosis (reversible fatty change). In cases, patients may develop alcoholic hepatitis with necrosis and fibrosis of liver. Nodules of proliferating hepatocytes occur. Repeated alcohol abuse lead to cirrhosis.
 Haemachromatosis: autosomal recessive defect of the HFE gene that causes excessive accumulation of body iron and is deposited in the liver and pancreas. The iron stores in the tissue breaks down to form haemosiderin which is toxic to the liver, causing inflammation and micronodular cirrhosis.
 Intrahepatic Biliary Tract Disease:
- primary biliary cirrhosis: autoimmune disease of the liver marked by slow progressive destruction of the small bile duct within the liver leading to cholestasis, damage and ultimately cirrhosis. There is expansion of portal tract by infiltrate of lymphocytes and plasma cells (large granulomas)
- primary sclerosing cholangitis: inflammatory disease of the bile duct that leads to cholestasis (possibly an autoimmune response)
 Neoplasms of the liver: using ultrasound to monitor for cancer development and resection if possible. Adenocarcinomas are difficult to treat therapeutically.
- cavernous haemangiomas
- liver cell adenomas: benign liver tumours of glandular origin
- hepatocellular carcinoma: primary malignancy of the liver that is secondary to a viral infection or cirrhosis.
- Cholangiocarcinoma: cancer of the bile duct and the risk factors includes primary sclerosing cholangitis.

Pathology of Tumours of Colon and Rectum:

 Colonic cancer: adenocarcinoma of the large bowel which is the second most common cause of cancer death
 Polyps: circumscribed overgrowth or tumour which project above the surrounding mucosa
 Features of polyps:
- can classified as either sessile (flat) or pedunculated (elevated with a stalk)
- can be categorized as non-neoplastic with no malignancy or neoplastic adenomas that will progress into adenocarcinoma eventually
- examination: requires a biopsy and histological examination to determine nature of malignancy
 Non-neoplastic polyps:
- Hyperplastic polyps: usually very small and asymptomatic (don’t progress to carcinoma). Predominately found in rectum and sigmoid.
- Inflammatory: little overgrowth that occurs in inflammatory bowel disease, e.g. Crohn’s disease with little pseudopolyps scattered around the ulceration.
 Neoplastic polyps: benign adematous polyps with malignant potential consisting of proliferation of epithelial cell and shows dysplasia (abnormal growth). This is possibly an inheritance disorder and all 3 morphological types have the same malignant potential
- Tubular adenoma: most common with tubular glands
- Tubulovillous adenoma: villous projection, often large and sessile
- Villous adenoma: mixture of above two
 Adenoma to Carcinoma:
- Malignant risk is related to polyp size (greater than 1cm), histological architecture (when villous adenomas is greater than 4 cm) and severity of dysplasia
- Adenoma does not show malignancy if the submucosa is not invaded but will lead to carcinoma development
- Main risk is the maximum diameter of the polyp and matured
 Features of transformation to carcinoma: colorectal cancers are directly developed from adenomas. Evidence such as similar distribution of adenoma and carcinoma, frequent surrounding of carcinoma with adenoma, excision of adenoma reduced carcinoma incidence and finally molecular description of the process all support the development of adenoma into carcinomas
 Process of transformation: series of genetic step to cause activation of genes, e.g. mutations of the oncogenes or tumour suppressing gene to stimulate cancer
 Familial adenmatous polyposis: an autosomal dominant inherited polyposis where there is a mutation of the APC gene on chromosome 5q21. Colectomy is the only solution as you can’t remove individual polyps
- Study have confirmed the molecular pathology of the colorectal cancer
- There is multiple tubular adenoma on the colon
 Hereditary Nonpolyposis Colorectal Cancer: autosomal dominant cancer in which adenomas occur in low numbers but very early. Possibly due to inherited mutation in the DNA mismatch repair gene.
- goes through same stages as sporadic cancer
- mutation in the DNA repair gene causes microsatellite instability
- progression of adenoma to carcinoma with no increase in polyp size.
 Colerectal cancer:
- Risk factors: excessive dietary caloric intake, low fibers content, high intake of refined carbohydrates and red meant and finally low intake of vitamins A, C, E
 Pathology of colon cancer:
- Adenocarcinoma: large and almost round with rolled edges. Microscopy features include undifferentiated cells with big nucleus to cell ratio.
- Variable differentiation
- Found in all areas of the large colon
 TNM staging of Colorectal Cancer: system of classifying cancer by the extent of tumour spread at the time of diagnosis.
- T: refers to extent of invasion of layers of bowel wall
- N: number f involves lymph nodes
- M: presence and absence of metastases
- Example: T1N0M0 means tumour has invaded the submucosa but with no lumph node affected and metastases.
 Clinical features of colorectal cancer:
- Left-sided colon: involving the descending and sigmoid colon causing crampy abdominal pain from mucous discharge (large enough to cause blockage), PR bleeding and changes in bowel habit.
- Right-sided colon: right side of caecum and the ascending colon with symptoms of anemia, e.g. iron deficiency, weakness and fatigue as tumour is not large enough to show blood in faeces but capable of slow bleeding.
 Tumours of the appendix:
- Hyperplastic or adenomas polyps
- Adenocarinoma
- Carinoid tumour

Small Bowel Pathology

 Congenital abnormalities:
- Duplication: extra loose redundant tissue of the bowel
- Malrotation: lack of rotation of the gut tube
- Omphaloceole: failure of normal muscles development leading to herniantion of abdominal content
- Gastroschisis: lack of fusion of the abdominal wall producing herniation of the gut tube outside the abdomen
- Heterotopia of pancreatic tissue: displacement of the pancreatic tissue from its normal position
- Meckel diverticulm
- Hirschsprung disease
- Atresia./stenosis: complete and incomplete blockage respectively
 Meckel Diverticulum: congenital outpouching of the ileal bowel on the non mesentery side of the wall up to length of about 5-6 cm long. This is due to the lack of involution of the vitelline duct and affected 2% of the population.
 Features of Meckel Diverticulum:
- The diverticulum typically contains normal layers of the intestinal wall however in 50% of the cases the diverticulum contains ectopic pancreatic and gastric tissues. Secretion and collection of acid can cause bleeding and ulceration
- Normally asymptomatic but problems can occur and characterized by localized pain, bleeding, and herniation can obstruct blood supply producing ischaemia that mimics acute appendicitis
- Located around 85cm to the ileolcecal junction
 Hirshsprung disease: congenital or familial failure of the migration of neural crest cell into the developing gut, causing de-innervation of nerves usually around the rectum area. Consequentially loss of peristalsis will impair faecal movement and accumulation of materials proximally with dilate the gut tube (megacolon)
 Features of hirshsprung disease:
- Loss of ganglion in the submucosa and muscle layers
- Megacolon can reach 15 to 20 cm diameter
 Ischemic bowel disease: blockage of the blood supply to the bowel. Caused by:
- Vascular diseases such as atherosclerosis and thrombosis
- Emboli in the blood that can possible originate from the heart
- Venous obstruction that can increase pressure of capillary beds and decrease perfusion of the bowel
- Volvulus (twisting of the bowel) and herniation can also physically block the vessel but is very uncommon
 Features of ischemic bowel disease:
- patients experience profound shock and cardiac failure due to reduced perfusion
- resection depends on the extent of damage
- Mucosal infarction occurs only at mucosal surface. Necrosis later spreads outs. Mural infarction affects all layers except muscular while transmural infarction penetrates all layers.
- This may be later associated with infection
 Malabsorption syndrome: defective metabolic syndrome that impairs uptake of nutrients. Interruption at any level of the gut can cause malabsorption, e.g. blockage of pancreas or cystic fibrosis can stop enzyme release and produce chronic diarrhea
- Defective intraluminal digestion: pancreatic insufficiency
- Primary mucosal abnormality: lactase deficiency such as recovery from gastroenteritis which means lactose is degraded by bacteria instead
- Reduced small intestinal surface area: celiac diseases, short gut syndrome
- Lymphatic obstruction
- Infection
- latrogenic
 Celiac disease: inflammatory enteropathy in which hypersensitivity to gluten (protein gliadins) causes autoimmune reaction (damage to the mucosa is mediated by the T-cells). Loss of villus through mucosal lesions impairs absorption. Detection of the antibodies antigliadin or anti-endomysial supports the diagnosis.
- In infants, failure to thrive and diarrhea
- Variable symptoms in adults including FTT, diarrhea and weight, and fatigue
- Conditions improves on withdrawal of dietary wheat gliadins and related grain protein
- Cause of disease maybe genetically linked to HLA
 Histology of celiac disease:
- Appearance of fresh unfixed small intestinal mucosa that is flat showing diffuse atrophy and loss of villi
- Surface enterocytes show vacuolar denegation and loss of brush border
- As duodenum and proximal jejunum are exposed to the highest concentration of gluten, mucosal damage is significantly more in the proximal than distal small intestine
 Inflammatory bowel disease: chronic inflammatory conditions such as Crohn’s disease and ulcerative colitis
- Crohn’s disease: chronic relapsing autoimmune disease that can affect any portion of GI tract. Small intestinal wall becomes thickened and rubbery. Produces sharp unrestricted transmural inflammation and non-caseating granuloma. Later on develop fistulaes.
 Bowel obstruction: blocking of the gut tube producing abdominal pain and distention.
- Hernias
- Intestinal adhesions
- Intussusceptions
- Volvlus
- Tumors
 Herniation: weakness in the anterior abdominal wall, usually the inguinal region and location of surgery. The bowel protrudes through the hernia sack forming a bulge. The hernia can risk twisting on itself and blocking its lumen and blood supply.
- If hernia can’t be pushed back then it becomes a surgical emergency
 Intestinal adhesion: results of chronic inflammation and fibrous scarring through surgery, ruptured appendix, infection in abdomen (perforated ulcers) etc. Abnormal fibrous bands which are internal scar tissue may wrap around an intestine and prevent flow of the digestive tract.
- Clearing the adhesion can create more problems due to more cutting and inflammation required. Thus resting of bowel motion is a more appropriate treatment, i.e. aspiration of gastric fluid to decrease vomiting and bowel motions
 Intussusception: situation where the bowel is pushed into the distal segment (like a retracting telescope). Once trapped the invaginated segment is propelled further by peristalsis while dragging its mesentery along as well. This will eventually obstruct the blood supply producing infarction.
 Volvulus: complete twisting of the small intestine around its mesenteric origin producing obstruction and infarction.
 Adenocarcinoma of small intestine: tumours of the small bowel when enlarged enough can produce intestinal obstruction. If occurring in the proximal 2nd part of the duodenum, it can block pancreatic and bile duct.
- Commonest site is duodenum and increased risk with Crohn’s disease
- Often spread by the time of diagnosis
- Polyps can also occur with familial

Extra notes: AST higher than ALT = destructive infiltration process related to mitochondria destruction
Cirrhosis alcohol, and da cancer.

Fundal relaxation can cause gastrooesaphageal reflux

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