Gastrointestinal Pathology Lecture Notes PDF

Pathology 5.09 GI cancers Dr. Hurnik BMS 150 Week 14 Outline PATHOLOGY 5.09 Esophageal carcinomas Esophageal adenocarcinoma Squamous cell carcinoma Stomach Gastric polyps Gastric adenoma Gastric adenocarcinoma Gastric lymphoma I...

Pathology 5.09 GI cancers Dr. Hurnik BMS 150 Week 14 Outline PATHOLOGY 5.09 Esophageal carcinomas Esophageal adenocarcinoma Squamous cell carcinoma Stomach Gastric polyps Gastric adenoma Gastric adenocarcinoma Gastric lymphoma Intestines Colonic adenoma Adenocarcinoma of the colon Liver Hepatic adenoma Hepatic carcinoma Pancreas Ductal adenocarcinoma Learning outcomes Coming soon… Esophageal carcinomas - intro Two main variants: § Adenocarcinoma § Squamous cell carcinoma Relatively common, but deadly § FYI - 15,560 Americans diagnosed in 2007, 13,940 deaths that same year (number of deaths/year almost the same as number of new diagnoses!) Risk factors: § Squamous carcinoma: alcohol and tobacco use, poverty, caustic esophageal injury, achalasia, tylosis, Plummer-Vinson syndrome, and frequent consumption of very hot beverages § Adenocarcinoma: long-standing GERD and Barrett’s esophagus as well as tobacco use Diets rich in fruits and vegetables are protective Esophageal adenocarcinoma – etiology & pathogenesis Epithelial clones identified in nondysplastic Barrett metaplasia persist and accumulate mutations during progression to dysplasia and invasive carcinoma § Mutation or overexpression of p53 are present at early stages of esophageal adenocarcinoma § Additional genetic changes include amplification of c- ERB-B2, cyclin D1, and cyclin E genes, mutation of RB  Esophageal adenocarcinoma - pathology Usually occurs in the distal third of the esophagus and may invade the adjacent gastric cardia § Initially appears as flat or raised patches in otherwise intact mucosa § Large masses of 5 cm or more in diameter may develop, can infiltrate diffusely or ulcerate and invade deeply Microscopically, Barrett esophagus is frequently present adjacent to the tumor Tumors resemble intestinal cells and most Figure 17.10 Esophageal cancer. (A) Adenocarcinoma usually commonly produce mucin and form glands occurs distally and, as in this case, often involves the gastric cardia. Squamous cell carcinoma of the esophagus – etiology and pathology Etiology: § Loss of several tumor suppressor genes, including p53 and p16/INK4a Pathology: § In contrast to adenocarcinoma, half of squamous cell carcinomas occur in the middle third of the esophagus § Early lesions appear as small, gray-white, plaque-like thickenings § Progress over months to years to grow into tumor masses that may be polypoid or exophytic Can protrude into and obstruct the lumen or ulcerate and infiltrate § May invade surrounding structures including the respiratory tree, causing pneumonia; Figure 17.10 Esophageal cancer. aorta, causing catastrophic exsanguination; (B) Squamous cell carcinoma is mediastinum and pericardium most frequently found in the mid-esophagus, where it commonly causes strictures. Esophageal carcinomas – clinical features & prognosis Clinical features: § Dysphagia, odynophagia, obstruction First dysphagia to solid food is prominent, eventually leading to liquid dysphagia Weight loss and debilitation result from both impaired nutrition and effects of the tumor itself Hemorrhage and sepsis may accompany tumor ulceration Prognosis is exceptionally poor – 5 year survival is 10% - 25% (slightly better for adenocarcinoma) § Due to the frequency of metastases at diagnosis Stomach – Gastric Polyps 75% of all gastric polyps are either inflammatory or hyperplastic polyps § Are common between 50 and 60 years of age Usually develop in association with chronic gastritis, which initiates the injury and reactive hyperplasia that leads to polyp growth § The larger the polyp, the increased likelihood for presence of malignancy (polyps > 1.5 cm must be investigated) § Usually a smooth, ovoid growth that can exhibit superficial erosions and variable degrees of inflammation in the lamina propria Figure 17.17 Gastric polyps. (A) Hyperplastic polyp containing They look pretty normal, histologically corkscrew-shaped foveolar glands. Stomach – Gastric adenoma - intro Gastric adenoma make up 10% of all gastric polyps § Incidence increases progressively with age - males affected 3X more Usually 50-60 years of age § Gastric adenomas have a greater risk of cancer than colonic adenomas Etiology: § Adenomas in chronic gastritis are associated with gastric atrophy and intestinal metaplasia Stomach – Gastric adenoma Pathology § Usually solitary lesions < 2 cm in diameter Most commonly located in the stomach antrum (higher malignant potential if in fundus) § Risk of progression to adenocarcinoma is related to size of lesion (higher risk in lesions greater than 2 cm in diameter) Carcinoma in up to 30% of gastric adenomas when larger than 2 cm § Majority of adenomas composed of intestinal-type columnar epithelium Stomach – Gastric adenocarcinoma Intro § Classified based on their location and morphology Types: § Diffuse – diffuse infiltrative growth patterns § Intestinal - composed of glandular structures Epidemiology § Adenocarcinoma comprises 90% of all gastric cancers Highest incidence in Japan, Chile, Costa Rica, and Eastern Europe § 20-fold higher than in North America, Northern Europe, Africa, and Southeast Asia § Incidence in North America has dropped by 85% since 1930 Thought to be related to reduced rates of H. pylori infections & environmental factors Reduced consumption of of N-nitroso compounds and benzo[a]pyrene Gastric adenocarcinoma - pathophysiology Pathophysiology: § Tends to develop in the setting of chronic inflammation § Genes of interest: p53 mutations are common Diffuse - Loss of function of E-cadherin FYI – could be due to germline mutation of tumour suppressor gene CDH1 which encodes E-cadherin OR hypermethylation & silencing of CHD1 promotor § Review - What was the role of E-cadherin? Intestinal – mutations that increase signaling via the Wnt pathway  Gastric adenocarcinoma - pathology Pathology: § Advanced cancers are those that penetrate below the submucosa into the muscular wall § Described as either intestinal or diffuse variants Intestinal: § composed of malignant cells forming neoplastic intestinal glands resembling those of colonic adenocarcinoma Diffuse: § composed of gastric-type mucous cells that generally do not form glands but rather permeate the mucosa and wall as Figure 17.18 Gastric adenocarcinoma. (A) Intestinal-type adenocarcinoma consisting of scattered individual "signet-ring" cells an elevated mass with heaped-up borders or small clusters in an "infiltrative" and central ulceration. Compare to the peptic ulcer in Fig. 17.15A. (B) Infiltrative type growth pattern (linitis plastica) gastric cancer. The gastric wall is markedly thickened, and rugal folds are partially lost, but there is no dominant mass. Gastric adenocarcinoma – Clinical features Clinical features: § Symptomatically similar to PUD or chronic gastritis until it’s turned into advanced lesion What were these symptoms? § Advanced lesions: weight loss, anorexia, altered bowel habits, anemia, and hemorrhage Prognosis & progression: § If caught early, surgical resection results in 90% 5- year survival If advanced, 5-year survival is 20% § Common metastasis include the following locations: supraclavicular sentinel lymph node, ovaries Stomach – Gastric lymphoma - intro Most common site for lymphoma outside of lymph nodes § Arise at sites of chronic inflammation Most common cause of “pro-lymphomatous” inflammation in stomach is chronic H. pylori infection Gastric lymphoma – pathogenesis and pathology Originate in GI tract at sites of preexisting MALT, such as the Peyer's patches of the small intestine § More commonly within tissues normally devoid of organized lymphoid tissue Tend to be B-cell lymphomas § Dense lymphocytic infiltrate in lamina propria § Neoplastic lymphocytes infiltrate gastric glands focally to create diagnostic lymphoepithelial lesions § Reactive-appearing B-cell follicles present - some have plasmacytic differentiation Gastric Lymphoma - Prognosis Clinical Features: § Clinical findings are those of underlying B12 deficiency Why? § Fatigue, low-grade fevers, nausea, constipation, tarry stool, epigastric pain, weight loss, anemia, and SOB Prognosis: § Generally good – 90% 5-year survival if caught at an early stage, and 30-40% if discovered at more advanced stages Intestine – Colonic adenoma - intro Most common (and clinically important) neoplastic polyps are colonic adenomas Adenomas = intraepithelial neoplasms that range from small, often pedunculated polyps to large sessile lesions § Benign polyps that are precursors to colorectal adenocarcinoma § FYI - Other neoplastic polyps include carcinoid tumors, stromal tumors, lymphomas, and metastatic cancer (rare) Risk factors: § Present in nearly 50% of adults living in the Figure 17.45 Colonic Western world by age 50 - No gender preference adenomas. (A) Pedunculated adenoma § Precursors to colorectal cancer - recommended (endoscopic view). that all adults in the US undergo surveillance colonoscopy by age 50 Typically screened at least 10 years before youngest age at which a relative was dx Colonic adenoma – pathology & progression Pathology: § Adenomas exhibit epithelial dysplasia, but the majority of adenomas do not progress to adenocarcinoma Dysplasia = nuclear hyperchromasia, elongation, and stratification - accompanied by reduction in number of goblet cells § Epithelium fails to mature as cells migrate from crypt to surface § Range from 0.3 to 10 cm in diameter and can be sessile or pedunculated Progression to colorectal adenocarcinoma: § Size is the most important characteristic that correlates with risk of malignancy 40% of lesions > 4 cm in diameter contain foci of cancer Intestine – Adenocarcinoma of the colon Epidemiology: § Most common malignancy of GI tract and major cause of morbidity and mortality worldwide Small intestine is a relatively uncommon site for benign and malignant tumors 130,000 new cases and 55,000 deaths from colorectal adenocarcinoma - 15% of all cancer-related deaths Peak incidence: 60 to 70 years of age § < 20% of cases occur before age 50 Colorectal carcinoma most prevalent in United States, Canada, Australia, New Zealand, Denmark, Sweden, and other developed countries Adenocarcinoma of the colon - Etiology Etiology: § Dietary factors most closely associated with increased colorectal cancer rates Low intake of unabsorbable vegetable fiber and high intake of refined carbohydrates and fat § Reduced fiber content leads to decreased stool bulk and altered composition of intestinal microbiota § Deficiencies of vitamins A, C, and E (free-radical scavengers) compound damage caused by oxidants § High fat intake enhances hepatic synthesis of cholesterol and bile acids - converted into carcinogens by intestinal bacteria § COX-2 inhibitors may be protective  Adenocarcinoma of the colon - Etiology Etiology continued § Genes: FYI Adenocarcinoma of the colon - Pathogenesis Pathogenesis § Two distinct genetic pathways described: 1. APC/β-catenin pathway associated with WNT and the classic adenoma-carcinoma sequence 2. Microsatellite instability pathway associated with defects in DNA mismatch repair § Both pathways involve stepwise accumulation of multiple mutations - genes and mechanisms of mutation differ § BRAF mutations also common (proto-oncogene) Adenocarcinoma of the colon - Pathogenesis APC/β-catenin pathway 80% of sporadic colon tumors, typically includes mutation of APC early in the neoplastic process Both copies of the APC gene must be inactivated § APC is a key negative regulator of β-catenin, a component of the WNT signaling pathway The APC normally promotes degradation of β- catenin. With loss of APC function, β-catenin accumulates and translocates to the nucleus B-catenin activates MYC and cyclin D1, which promote proliferation additional mutations follow, including activating mutations in KRAS (which also promote growth and prevent apoptosis) & p53 loss of function (often due to chromosomal instability) late event Adenocarcinoma of the colon - Pathogenesis Microsatellite instability pathway: § Due to loss of mismatch repair genes, mutations accumulate in microsatellite repeats, a condition referred to as microsatellite instability § Usually silent because microsatellites are typically in noncoding regions § Some microsatellite sequences are located in the coding or promoter region of genes involved in regulation of cell growth: Type II TGF-β receptor Pro-apoptotic protein BAX  Figure 17.51 Adenocarcinoma of the Colorectal carcinoma. (B) Cancer of the colon - Pathology sigmoid colon that has invaded through the muscularis propria and is Pathology present within subserosal adipose tissue (left).Areas of § Distributed equally over entire chalky necrosis are length of colon present within the colon wall (arrow). § Can be palpable as firm masses § Tumors in proximal colon grow as polypoid, exophytic masses that Figure 17.51 extend along one wall of the viscus Colorectal carcinoma. (A) - rarely causing obstruction Circumferential, ulcerated rectal § Carcinomas in distal colon tend to cancer. Note the be annular lesions that produce anal mucosa at the bottom of the “napkin-ring” constrictions and image. luminal narrowing – can cause obstruction Adenocarcinoma of the colon – Clinical Features Clinical Features: § Insidious development Cecal and other right-sided colon cancers à bleeding leading to iron deficiency anemia, fatigue, & weakness Left-sided colorectal adenocarcinomas may cause occult bleeding, changes in bowel habits, or cramping left lower quadrant discomfort Prognosis: § most important prognostic factors are depth of invasion and the presence or absence of lymph node metastases § Liver is most common site of metastatic lesions - result of portal drainage of colon § Metastases may also involve regional lymph nodes, lungs and bones Liver – Hepatic adenomas Intro: Hepatic adenomas have clinical significance for three reasons: 1. When they present as an intrahepatic mass they may be mistaken for the more ominous hepatocellular carcinomas 2. Subcapsular adenomas have a tendency to rupture, particularly during pregnancy, causing life-threatening intraperitoneal hemorrhage 3. Rarely, they may transform into carcinomas § Usually they are well-differentiated and are almost always benign Epidemiology Hepatic adenomas tend to occur in young women who have used oral contraceptives; tumors generally regress if contraceptive use is terminated Although hormonal stimulation seems to be involved in causation, etiology is not clear Incidence of adenoma is approximately 1 in 100,000 Liver – Hepatic carcinoma Primary carcinomas of the liver: hepatocellular carcinoma (HCC) Epidemiology: § represent 20% to 40% of cancers in many other countries 82% of hepatocellular carcinoma cases occur in countries with high rates of chronic HBV infection § More common in southeast Asian and African countries - 52% of all HCC cases occur in China § relatively uncommon in North America and western Europe (0.5% to 2% of all cancers) § Liver is the most common site of metastasis for colon cancer In North America and in most of Europe malignancies in the liver are usually due to metastases, not primary hepatocellular carcinomas Hepatic carcinoma - Etiology Risk factors & etiology: Major risk factor is long-standing cirrhosis Chronic viral infection (HBV, HCV), chronic alcoholism, non- alcoholic steatohepatitis (NASH), and food contaminants (primarily aflatoxins) are common world-wide causes Aflatoxin is produced by the fungus Aspergillus flavus, which contaminates peanuts and grains Binds covalently with cellular DNA, mutates p53 Less commonly: alpha-1 antitrypsin deficiency & hemochromatosis Common driver mutations: Activating mutations in Beta-catenin genes TERT mutations – upregulated telomerase Inactivating mutations to p53 Hepatic carcinoma – Pathophysiology & Pathology Pathophysiology § Most HCC occur in setting of chronic liver disease with cirrhosis Repeated cycles of cell death and regeneration Thought that the accumulation of mutations during continuous cycles of cell division may damage DNA repair mechanisms and eventually transform hepatocytes § 15-20% arise in noncirrhotic livers Pathology § Relatively well-differentiated malignant tumour that can secrete bile Invades vascular structures early, with snakelike masses that can migrate along the portal vein or vena cava Tend to be less dependent on lymph Figure 18.52 Hepatocellular carcinoma. (A) Liver removed at autopsy showing a node infiltration for metastasis unifocal neoplasm replacing most of the right hepatic lobe. Hepatic carcinoma – Clinical Features Clinical features: § Ill-defined upper abdominal pain, malaise, fatigue, weight loss, and sometimes awareness of an abdominal mass or abdominal fullness § In many cases the enlarged liver can be felt on palpation Prognosis: § 5-year survival of large tumors is dismal, with the majority of patients dying within the first 2 years. § Screening procedures and advances in imaging can detect HCCs less than 2 cm in diameter, much better prognosis Pancreas – Neoplastic cysts A variety of cysts can arise the the pancreas § Majority are non-neoplastic pseudocysts § 5 – 15% are neoplastic cysts § (also have non-neoplastic congenital cysts) Neoplastic cysts can range from harmless benign cysts to pre-cancerous lesions Pancreatic cancer – Ductal adenocarcinoma Pancreatic cancer – also known as ductal adeno- carcinoma § Epidemiology 4th leading cause of cancer deaths § What three surpass it? Estimated that in 2008 approximately 37,000 Americans were diagnosed with pancreatic cancer, and that virtually all of them will die from their disease § Primarily a disease in the elderly, 80% of cases occurring between the ages of 60 and 80 Main risk factor is smoking Others: chronic pancreatitis and diabetes Pancreatic Cancer - pathophysiology 90% begin as pancreatic intraepithelial neoplasia § KRAS gene is the most frequently altered oncogene in pancreatic cancer Result in constitutively activation of Ras § Inactivation of CDKN2A, which encodes p16 § Inactivation of p53 gene Pancreatic Cancer - Pathology Pathology: § 60% arise in the head of the gland, 15% in the body, and 5% in the tail; in 20% the neoplasm diffusely involves the entire gland § Ductal adenocarcinomas that form glandular structures and secrete mucin Have two characteristic features § It is highly invasive § elicits an intense non-neoplastic host reaction composed of fibroblasts, lymphocytes, and extracellular matrix (aka “desmoplastic response”). As a result à Usually hard, stellate, Figure 19.13 Carcinoma of the pancreas. (A) Cross-section through gray-white, poorly defined masses the tail of the pancreas showing normal pancreatic parenchyma and a normal pancreatic duct (left) and a pale mass centered on the duct (right). Pancreatic Cancer - Progression Clinical features: § Typically silent until tumour causes obstruction or invades adjacent structures § Jaundice from obstruction of common bile duct which type of jaundice is this? Courvoisier sign – palpably enlarged, non-tender gallbladder + painless jaundice § Weight loss, anorexia, and generalized malaise and weakness tend to be signs of advanced disease Prognosis: § Poor - 5-year survival rate is less than 5% § Highest mortality rate of any cancer References Coming soon… Gastrointestinal Pharmacology Acid suppressors BMS150 Objectives With respect to acid suppressors: Relate their mechanism of action to their therapeutic effects Discuss any relevant adverse effects or contraindications Recognize given generic names or suffixes  Stomach acid review Select points (relevant to GI pharmacology): Acetylcholine Histamine M3-R H2-R Gastrin CCK-R Inhibitory PGE-R Prostaglandins Stimulatory G-protein G-protein Signalling Signalling K+ H+ Parietal cell K+ H+ Overview H2 Blockers Anticholinergic Drugs PPI’s Prostaglandin analogues H2-Blockers Mechanism of action Competitive block of H2-R on parietal cells Specific Agents Cimetidine (Tagametâ), Ranitidine ((Zantacâ), Famotidine (Pepcidâ) Note “tidine” endings Therapeutic uses: Ulcers Peptic ulcers Often associated with what type of infection? Common: “triple therapy” Also non-malignant gastric and duodenal ulcers H2-Blockers Therapeutic Uses continued Management of Zollinger-Ellison syndrome (?) What category of drug do you think would be even more effective for this, and why? Gastroesophageal reflux disease Antacids usually more effective for acute use – why? Anticholinergics Mechanism of action Block of ?-receptors on parietal cells Review: What NT normally acts on these receptors? Which nerve releases this NT at the level of the viscera? Specific agent FYI - Pirenzipine Therapeutic uses: ulcers Peptic, non-malignant gastric, duodenal PPI’s (proton pump inhibitors) Mechanism of action H+, K+-ATPase inhibition Specific agents Omeprazole, esomeprazole Note “prazole” endings PPI’s (proton pump inhibitors) Therapeutic uses As for H2-blockers Ulcers Common for first line use in peptic ulcer triple therapy GERD Management of Zollinger-Ellison syndrome Which do you think would be more effective, H2-blockers or PPI’s? Why? Prostaglandins: PGE1 analogues Prostaglandins (PGs) review (FYI this term except for “new” part): PG’s are considered eicosanoids. What are the two structural categories of lipids, and which one are eicosanoids based on? What specific lipid are most eicosanoids derived from? What are some physiological functions of PG’s you learned last term? New: Some PG’s can cause uterine contractions Prostaglandins: PGE1 analogues Mechanism of action: 2 parts 1) Decreased proton pump activity 2) Increased bicarbonate and mucous secretion Protective effect against acidity Specific PGE1 analogue Misoprostal Prostaglandins: PGE1 analogues Therapeutic use Most common = prevention of NSAID-induced ulcer/GI bleed Review: What is the connection between NSAID’s and PG’s, including the enzyme involved? Therefore, PGE1 analogues replace the gastro-protective PG’s that are decreased during NSAID use Contraindication: pregnant women Why? Gastrointestinal Pharmacology Motility and antinausea agents BMS150 Objectives With respect to motility and anti-nausea agents: Relate their mechanism of action to their therapeutic effects Discuss any relevant adverse effects or contraindications Recognize given generic names or suffixes Overview Agents that decrease motility Diphenoxylate-atropine (Lomotilâ) Loperamide (Imodiumâ) Agents that increase motility Laxatives Metoclopramide (Maxeranâ, Reglanâ) Domperidone (Motiliumâ) Overview Antinausea agents Anticholinergics Scopolamine Promethazine Dopamine-R blockers Metoclopramide Domperidone Decreased motility Diphenoxylate-atropine § Mechanism of action: diphenoxylate Opioid receptor agonist § Inhibits ACH release in enteric system at low doses What does ACH normally do to gut motility? Since opioids inhibit this effect, what do you think is a common adverse effect if someone takes an opioid for pain relief? Decreased motility Diphenoxylate-atropine § Mechanism of action: Atropine M-blocker - why is it part of the formulation? § 1) Synergistic effect with diphenoxylate to decrease effects of ACH on the gut § 2) Anticholinergic side effects discourage abuse potential Why does this drug have abuse potential? Anticholinergic side effects occur before euphoric opioid effects are felt Choose the correct common and annoying anticholinergic side effect: A – Dry mouth B – Excessive salivation Decreased motility Loperamide § Similar to diphenoxylate-atropine, but without the atropine Does not cross BBB, so general lack of CNS effects and therefore extremely low abuse potential § Note: Both these drugs are also relatively insoluble to prevent self-injection Increased motility Laxatives § Can be considered milder forms of cathartics, which are agents that cause evacuation of the bowels § Usually a secondary constipation treatment What might be a primary diet-based treatment? Increased motility Laxatives § Mechanisms fall into 4 main categories Bulking agents Osmotic laxatives Chemical stimulants Stool softeners Increased motility Laxatives: Bulking agents § Ex: Bran, psyllium § Non-absorbed agents that create bulkier stools and draw water into stools Bulkier stool: stimulates the bowel Softer stool: easier to move Increased motility Laxatives: Osmotics § Ex: Magnesium sulfate, magnesium hydroxide (“milk of magnesia”), lactulose § Not well-absorbed from the intestinal tract Results in an increase in osmotic pressure leading to retention of water in intestine, lumen extension, and increased bowel action Increased motility Laxatives: Osmotics § More on magnesium hydroxide Low doses: can neutralize stomach acid (antacid) High doses: too much bowel movement can cause diarrhea § Danger with too high dose of any laxative Increased motility Laxatives: Osmotics § More on lactulose Disaccharide (FYI galactose and fructose) that is not broken down well in the SI § Reaches colon, where it is broken down by bacteria to produce lactic acid Acidic conditions ionize ammonia to NH4+ Will this increase or decrease excretion of ammonia? Why? Remember, ammonia is neurotoxic Increased motility Laxatives: Chemical stimulants § Ex: Emodin (active ingredient found in Senna, aloe, cascara) § Irritate the gut to induce peristalsis and increase mucous production Increased motility Laxatives: Stool Softeners § Use water or oil to soften stools § Ex: Mineral oil, sodium docusate Mineral oil § Lubricates stools for easier passage § Do you think olive oil would work too? Sodium docusate § Detergent that allows water to penetrate stools Prevents hard, dry stools and allows for easier passage Increased motility Metoclopramide § Mechanism of action for increased motility: Block of peripheral D-receptors § Dopamine is inhibitory in the GIT, ACH is stimulatory Blocking dopamine effects allows ACH effects to predominate Increased peristalsis Increased tone of lower esophageal sphincter Increased motility Metoclopramide § Mechanism of action for anti-nausea/vomiting: Block of central D-receptors § Antiemetic action comes from block of D2-receptors in medulla § Therapeutic uses GERD (via peripheral D-receptor block) Diabetic gastric stasis (via peripheral D-receptor block) Prevention of nausea and vomiting with chemotherapy (via central D-receptor block) Increased motility Metoclopramide § Select adverse effects 1) What happens when you take the peripheral effects too far? 2) Hyperprolactinemia § Dopamine is also know as PIH = prolactin inhibitory hormone Blocking dopamine therefore causes increased prolactin Increased motility Domperidone § Similar to metoclopramide, but less likely to cross BBB or into breast milk § Off-label use: stimulation of milk production in lactating mothers Due to what action? Antinausea Anticholinergics § Block cholinergic transmissions between vestibular and vomiting centers in the CNS § Specific agents Scopolamine: M-blocker Promethazine: M-blocker and H1-blocker § Also used as an antihistamine and sedative due to the H1-block Antinausea D2-blockers (review from earlier today) § Antiemetic action from D2-block where? § Specific agents Metoclopramide, domperidone § Also used for?  Liver Pathology Part II Resources: Robbin’s and Cotran’s Pathologic Basis of Disease BMS 150 Chapter 18 Week 14 Harrison’s Principles of Internal Medicine Chapters 339, 342, 343, 346  Hepatitis Overview Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E Genome ssRNA dsDNA ssRNA ssRNA ssRNA Route of Fecal-oral Parenteral, Parenteral Parenteral Fecal-oral transmission (contaminated sexual food/water) transmission Incubation 2-6 weeks 2-26 weeks 4-26 weeks Same as HBV 4-5 weeks period Chronic liver Never 5 – 10% > 80% Ranges – 10 – Only in disease? 90% (90% with immuno- superinfection) compromised Diagnosis Serum IgM Hep B HCV RNA HDV RNA or HEV RNA or against HAV antigens – antibodies antibodies surface or against HDV against HEV core Syndromes of Hepatitis Infection Asymptomatic with recovery Acute symptomatic with recovery 1. incubation period 2. symptomatic preicteric phase 3. symptomatic icteric phase Icterus = jaundice 4. convalescence Chronic hepatitis ▪ Carrier state or low-grade symptoms Fulminant hepatic failure (rare) Long-term untreated HBV or HCV can progress to cirrhosis or hepatocellular carcinoma ▪ More common with HCV  Hepatitis A Common, especially in areas with poorer hygeine ▪ 30 – 50,000 new cases/year in US Transmission: Fecal-oral route Almost always self-limited and never enters a chronic carrier state, but very rarely can cause fulminant hepatic failure Clinical Features ▪ Usually fatigue, nausea, jaundice ▪ Often asymptomatic Hepatitis B Most prevalent form worldwide Transmission: through blood or sexual contact ▪ Most people worldwide living with hep B acquired at childbirth Clinical course can include: ▪ Acute hepatitis with recovery and clearance of the virus ▪ Nonprogressive chronic hepatitis ▪ Progressive chronic disease ending in cirrhosis Which can then progress to hepatocellular carcinoma ▪ Fulminant hepatitis with massive liver necrosis ▪ An asymptomatic carrier state Relatively low prevalence of chronic hepatitis in NA ( less than 2%) but can be very high in other regions of the world (>8%) Age is the best predictor of chronicity: children have almost 90% rate of chronicity while the number drops to about 5% in adults  Hepatitis B Clinical features of acute HBV: Nonspecific constitutional symptoms such as anorexia, fever Jaundice, upper right quadrant pain – 30% of acute hepatitis No symptoms (about 70%) Very rarely hepatic failure Hepatitis B: Serological Response Acute HBV that resolves – typical findings on blood labs (left) Chronic HBV – typical findings on blood labs (right) Viral Hepatitis: Hepatitis C 1.6% of the population, have chronic HCV infection Transmission: blood-blood Risk factors: IV drug use, blood transfusions Persistent infection and chronic hepatitis are the hallmarks of HCV infection (80 – 85%) ▪ Generally asymptomatic nature of the acute illness Viral Hepatitis: Hepatitis C Progression to chronic disease occurs in the majority of HCV-infected individuals In the past, cirrhosis eventually occured in 20% to 30% of individuals with chronic HCV infection ▪ Newer treatments have resulted in much better outcomes for those with chronic infection, however – chronic hepatitis C can now be cured Antiviral regimens are matched to genotype of HCV – most common genotype is 1a or 1b in North America ▪ Still most common indication for liver transplantation Hepatitis C: Serological Response Acute HCV that resolves (less common) – typical findings on blood labs (left) Chronic HCV that does not resolve (more common) – typical findings on blood labs (right) Viral Hepatitis: Hepatitis D & E Hepatitis D: Needs coinfection with hepatitis B for its life cycle ▪ Hepatitis B + D simultaneously can result in acute severe hepatitis ▪ In those with chronic hepatitis B infection, additional infection (superinfection) with HDV usually results in chronic infection with both Hepatitis E: ▪ Zoonosis that results in self-limited acute hepatitis ▪ Associated with a very high mortality in pregnant women (up to 20%) Other Hepatic Infections - FYI Bacterial – staph aureus, typhoid fever, syphilis ▪ Mild inflammation & cholestasis tend to occur Protozoal infestations can cause appearance of abscesses in liver (amebic, other protozoons) ▪ Abscesses are associated with fever and, in many instances, right upper quadrant pain and tender hepatomegaly ▪ Poor prognosis Alcoholic Liver Disease Three distinct but overlapping forms of alcoholic liver injury: 1) Hepatitis: Hepatocyte swelling and necrosis Mallory bodies Neutrophilic reaction 2) Hepatic steatosis Reversible 3) Steatofibrosis including cirrhosis Irreversible, looks just like cirrhosis from viral causes Only 10-15% of alcoholics develop cirrhosis Alcoholic Liver Disease: Major Pathologic Patterns Alcoholic Liver Disease: The Cellular Effects of Alcohol Causing Hepatitis Alcohol promotes movement of bacterial endotoxin from the gut into the portal circulation → liver inflammation Stimulates the release of endothelins from sinusoidal endothelial cells → vasoconstriction as well as contraction of activated stellate cells ▪ Endothelins are potent vasoconstrictors released from capillary endothelial cells ▪ leads to a decrease in hepatic sinusoidal perfusion Alcohol is metabolized to acetaldehyde (alcohol dehydrogenase, catalase, and microsomal activity) ▪ Acetaldehyde is toxic and can cause lipid peroxidation if concentrations rise too high ▪ More pathways next slide →  Metabolism of alcohol → decreased NAD+ NAD+ is necessary for fatty acid oxidation… therefore fat accumulation in the liver Metabolism of alcohol by CYP2E1 → free radical production Cirrhosis Typical micronodular cirrhosis of alcoholic liver disease Blue-staining fibrous tissue “traps” nodules of poorly-functioning heptatic tissue Alcoholic hepatitis – cellular findings Alcoholic steatohepatitis Hepatocytes “ballooned” by accumulation of fat in fat vacuoles (arrowheads) Red oval shows immune cells surrounding dead/dying hepatocytes ▪ Clusters of blue nuclei Inset shows an “empty” hepatocyte ▪ Brown staining is for particular keratins that are important components of the cytoskeleton ▪ Some hepatocytes prematurely ubiquinate keratin → collapse of the cytoskeleton Alcoholic Liver Disease Clinical Features: ▪ Non-specific symptoms are common: Malaise, anorexia, weight loss, upper abdominal discomfort, tender hepatomegaly ▪ Alcoholic hepatitis attends to appear acutely following bouts of heavy drinking ▪ Alcoholic steatosis usually does not have many symptoms and is usually reversible upon cessation of alcohol use Prognosis: ▪ 5-year survival approaches 90% in those who are free of jaundice, ascites, or hematemesis and abstain from alcohol ▪ Drops to 50%-60% in those who continue to drink Non-Alcoholic Fatty Liver Disease (NAFLD) Steatosis in the absence of significant alcohol consumption ▪ Most common cause of liver disease in US Forms include: ▪ Non-alcoholic steatohepatitis (NASH) Progresses to cirrhosis in 10 – 20% of cases In those that progress to cirrhosis, the incidence of liver cancer can be as high as 1-2% per year ▪ Simple hepatic steatosis and steatosis complicated by inflammation These show fewer long-term complications unless they progress to NASH Non-Alcoholic Fatty Liver Disease (NAFLD) Non-Alcoholic Steatohepatitis (NASH) Pathologic findings: ▪ Initially hepatocyte ballooning, lobular inflammation, and steatosis (fat accumulation in hepatocytes) ▪ With progressive disease there is steadily more fibrosis, eventually leading to cirrhosis ▪ Strongly associated with obesity and the metabolic syndrome Pathophysiology: ▪ “two-hit” model, involving 1) hepatic fat accumulation and 2) increased oxidative stress Free radicals cause lipid peroxidation of the accumulated intracellular fat ▪ Obesity seems to be associated with reduced intestinal barrier function → increased inflammation in the liver Movement of microbes from the gut into the portal circulation Non-Alcoholic Steatohepatitis (NASH) Non-Alcoholic Steatohepatitis (NASH) Clinical features: ▪ Usually asymptomatic until overt hepatic failure – clinical findings are due to atherosclerotic disease/diabetes that accompany NASH Cardiovascular disease is a frequent cause of death in those with NASH ▪ Fatigue and right-sided abdominal pain can occur in some, though ▪ Increases risk of hepatocellular carcinoma Diagnosis: ▪ Liver enzymes alone are poorly-reliable ▪ Scores calculated from age, BMI, fasting glucose, AST, ALT are helpful for gauging degree of inflammation and fibrosis ▪ Detection of fibrosis via imaging or biopsy for definitive diagnosis Drug and Toxin-Induced Liver Disease Most common cause of fulminant hepatitis ▪ But a wide range of pathological patterns and clinical presentations can result Insidious onset or rapid Hepatocyte necrosis, cholestasis, or insidious onset of liver dysfunction Hepatitis looks very similar histologically to viral hepatitis Toxins can: ▪ Be directly toxic ▪ Be converted by the liver into an active toxin ▪ Elicit an immune responses by acting as a hapten Most drugs or toxins affecting the liver can be classified as: ▪ Predictable hepatotoxins Dose-dependent, occur in most individuals ▪ Unpredictable or idiosyncratic hepatotoxins Independent of dose, rare Drug and Toxin-Induced Liver Disease Most common hepatotoxin causing acute liver failure is acetaminophen ▪ Main cause of acute liver failure necessitating liver transplant in the US ▪ So is Tylenol bad??? Not really – those with a long history of regular acetaminophen use, AS PER DIRECTED (i.e. not exceeding recommended dosages) very, very rarely have any significant hepatic damage Unfortunately it’s commonly used during suicide attempts and it’s in a lot of OTC medications, so unintentional overdose is surprisingly common Most common hepatotoxin causing chronic liver failure is alcohol Acetaminophen toxicity Low doses – conjugated and excreted in urine (95%) High doses – increased production of NAPQI ▪ If glutathione reserves are insufficient, then this reactive molecule damages hepatocytes FYI Autoimmune Hepatitis Etiology: ▪ unknown, though involves attack by cytotoxic T- lymphocytes ▪ Likely genetic, and can be triggered by certain medications (i.e. statins) or viral infections Epidemiology: ▪ Uncommon – 1-2/100,000/year m/c among white northern Europeans Most of those affected (78%) are female  Autoimmune Hepatitis Two types: ▪ Type 1 (most common): presence of ANA and anti- smooth muscle antibodies, HLA DR3 m/c in middle-aged to older individuals ANA = antinuclear antibodies (commonly found in autoimmune disorders such as lupus) ▪ Type 2 presence of anti-cytochrome antibodies (cytochrome p450) m/c in children and teenagers Autoimmune Hepatitis Prognosis: Many patients have relatively mild disease that can be treated conservatively with a “watch and wait” philosophy ▪ 10-year survival of all people with the disease is 80-90%, so a wide spectrum of severity Severe, untreated disease has a mortality of 40% ▪ Even with treatment, a large proportion go on to develop cirrhosis ▪ Recurs in up to 42% after liver transplant Portal Hypertension Caused by a combination of increased resistance to blood flow through the portal circulation, and a “hyperdynamic circulation” Causes include: ▪ Thrombosis and obstruction of the portal vein (prehepatic) ▪ Cirrhosis from any cause (intrahepatic) ▪ Severe right-sided congestive heart failure (post-hepatic) Blood accumulates in the hepatic veins → increased pressure in the portal system Typical complications: ▪ Ascites ▪ Formation of portosystemic venous shunts ▪ Congestive splenomegaly ▪ Hepatic encephalopathy Features of Portal Hypertension Hepatic encephalopathy Esophageal varices Splenomegaly Malnutrition Spider angiomas Caput medusae Ascites Hyperdynamic circulation → for reasons that are poorly understood, the overall blood flow through the intestines/stomach increases perhaps due to impaired liver clearance of vasodilatory substances Worsens pressures in the portal system Esophageal varices Portal hypertension results in the development of collateral channels at sites where the portal and caval systems communicate (i.e. distal esophagus) ▪ Collateral veins allow some drainage to occur, but result in enlarged, fragile, congested subepithelial and submucosal venous plexus within the distal esophagus (i.e. varices) develop in 90% of cirrhotic patients Cirrhosis and collateral circulation Why does cirrhosis result in portal hypertension and the development of varices? ▪ Think of the liver histology – blood flows from the portal triad (hepatic artery and portal vein) tributaries to the central vein ▪ If that pathway has increased resistance to flow, then pressures increase in the portal vein Cirrhosis causes necrosis and fibrotic “bridging” that interrupts the normal flow from triad to hepatic vein ▪ Anastomoses between the portal vein and the systemic circulation then get increased blood flow – it’s like blood is diverted from the liver to systemic veins nearby Look carefully at the diagram on the next slide Esophageal varices Esophageal varices How bad are they? ▪ May rupture causing massive hematemesis = medical emergency Inflammatory erosion of thinned overlying mucosa, increased tension in progressively dilated veins, and increased vascular hydrostatic pressure associated with vomiting contribute to it Treated by sclerotherapy (endoscopic injection of thrombotic agents); endoscopic balloon tamponade; or endoscopic rubber band ligation ▪ As many as half of patients die from the first bleeding episode Additional instances of hemorrhage occur in survivors in over 50% within 1 year - Each episode w/ similar rate of mortality Over half of deaths among individuals with advanced cirrhosis result from variceal rupture Intrahepatic biliary tract disease Affects the ducts and ductules within the liver ▪ Secondary biliary cirrhosis Secondary to uncorrected bile duct obstruction of the extrahepatic biliary tree (i.e. big bile ducts) ▪ Primary biliary cirrhosis (PBC) Autoimmune, non-supparative inflammation that destroys the intrahepatic bile ducts Portal inflammation leads to scarring and eventually cirrhosis ▪ Primary sclerosing cholangiitis (PSC) Intrahepatic and extrahepatic bile ducts become inflamed and the ducts become obliterated The unaffected areas dilate, leading to the appearance of ‘beads on a string’ PBC and PSC Primary biliary cirrhosis (PBC): Pruritus, fatigue, and abdominal discomfort are major initial presentations ▪ Eventually followed by skin pigmentation, xanthelasmas, steatorrhea, and vitamin D malabsorption ▪ osteomalacia and/or osteoporosis due to vitamin D malabsorption ▪ Cirrhosis, portal hypertension (+ variceal bleeding) and hepatic encephalopathy generally occur years - decades However, not all patients develop cirrhosis Pathogenesis is poorly understood ▪ Anti-mitochondrial antibodies against pyruvate dehydrogenase are usually found, as are T-cells that recognize this antigen Prevalence – 65/100,000 for women, 12/100,000 for men PBC and PSC Primary sclerosing cholangitis (PSC): Progressive fatigue, pruritus, and jaundice are major initial presentations ▪ Chronic liver disease → cirrhosis is the usual course weight loss, ascites, variceal bleeding, and encephalopathy Similar complications as PBC Median survival is ~ 12 years ▪ 7% develop cholangiocarcinoma ▪ Increased risk of colon cancer Pathophysiology is unclear but also likely autoimmune ▪ Associated with HLA-B8 and p-ANCA ▪ Thought that in those with ulcerative colitis, sensitized T-cells from the colon travel to the liver and cross-react with an as-yet unrecognized antigen Presents in early adulthood – middle-age ▪ 70% of patients are male, prevalence ~ 6/100,000 ▪ Greatly increased risk in those with ulcerative colitis General pathology of cholestasis - FYI In the parenchyma, cholestatic hepatocytes (1) are enlarged with dilated canalicular spaces (2). Apoptotic cells (3) may be seen, and Kupffer cells (4) frequently contain regurgitated bile pigments. In the portal tracts (triads) of obstructed liver there is also bile ductular proliferation (5), edema, bile pigment retention (6), and eventually neutrophilic inflammation. Surrounding hepatocytes (7) are swollen and undergoing degeneration. 42 Specific PSC and PBC pathologic findings PBC: ▪ Destruction of interlobular bile ducts due to lymphocytic inflammation +/- granuloma formation ▪ Patchy involvement, not all bile ducts affected to the same degree ▪ Severe cholestatic findings at the end-stages, accompanied by hepatomegaly Often end-stage cirrhosis → smaller, shrunken, scarred livers PSC: ▪ Large duct inflammation is similar to that seen in ulcerative colitis: acute, neutrophilic infiltration of the epithelium superimposed on a chronic inflammatory background; strictures can develop ▪ Smaller ducts often have little inflammation and show “onion skin” fibrosis around atrophic duct lumens ▪ Similar severe cholestatic findings at end-stage as PBC Acute cholecystitis One of the most common indications for abdominal surgery Acute inflammation of the gallbladder, precipitated 90% of the time by obstruction of the neck or cystic duct – It is the primary complication of gallstones and the most common reason for emergency cholecystectomy – Cholecystitis without gallstones = acalculous cholecystitis May occur in severely ill patients and accounts for about 10% of patients with cholecystitis Thought to be due to gallbladder ischemia Acute cholecystitis Results from chemical irritation and inflammation of the obstructed gallbladder ▪ Mucosal phospholipases hydrolyze luminal lecithins to toxic lysolecithins ▪ The normally protective mucus layer is disrupted, exposing the mucosal epithelium to the direct detergent action of bile salts ▪ Prostaglandins released and gallbladder distention cause inflammation, which results in gallbladder dysmotility ▪ Distention and increased intraluminal pressure compromise blood flow to the mucosa ▪ Bacterial contamination may occur later Acute cholecystitis Clinical Features Begins with progressive right upper quadrant or epigastric pain, frequently associated with mild fever, anorexia, tachycardia, sweating, nausea, and vomiting ▪ Most patients are free of jaundice; the presence of hyperbilirubinemia suggests obstruction of the common bile duct ▪ Rupture results in severe peritonitis as well as bleeding – the gallbladder can become gangrenous, which makes perforation worse Chronic cholecystitis Associated with cholelithiasis in >90% of cases Cause of chronic cholecystitis is obscure, in that it is not clear that gallstones play a direct role in the initiation of inflammation or development of pain – Supersaturation of bile predisposes to chronic inflammation – E. coli can be found in the bile in a significant minority (bile should be sterile) – Degree of inflammation found within the wall varies, from mild lymphocytic infiltration to more severe inflammation and fibrosis Chronic cholecystitis Clinical Features Recurrent attacks of either steady or colicky epigastric or right upper quadrant pain ▪ Nausea, vomiting, and intolerance for fatty foods are frequent accompaniments Complications include: ▪ Bacterial superinfection with cholangitis or sepsis ▪ Gallbladder perforation and local abscess formation or peritonitis ▪ Biliary enteric (cholecystoenteric) fistula, with drainage of bile into adjacent organs, entry of air and bacteria into the biliary tree, and potentially, gallstone-induced intestinal obstruction (ileus) ▪ Porcelain gallbladder = dystrophic calcification within the wall of the gall bladder, greatly increases risk of cancer Diseases of the extrahepatic ducts Cholangitis = bacterial infection of the bile ducts ▪ Cholangitis can result from any lesion that creates obstruction to bile flow, most commonly choledocholithiasis and biliary strictures ▪ Usually enteric gram-negative aerobes such as E. coli, Klebsiella, Enterococcus, or Enterobacter ▪ Acute onset of fever, chills, abdominal pain, and jaundice accompanied by acute inflammation of the wall of the bile ducts with entry of neutrophils into the luminal space ▪ Dangerous disorder that needs emergent referral Sepsis is the main concern – the patient can go into septic shock Intestinal Pathology Part II Liver Pathology Part II BMS 150 Week 14 Overview – Intestinal Obstruction 80% of obstructions are due to the following: ▪ Herniations (protrusion of a viscus through a defect in the abdominal wall) ▪ Adhesions (fibrotic bands that obstruct or entangle bowel) ▪ Intussusception (the bowel telescopes into itself) ▪ Volvulus (the viscus twists and obstructs) 10 – 20% are caused by tumours or infarcts ▪ Infarcts impair bowel motility The above are mechanical causes of bowel obstruction Intestinal Obstruction - Pathophysiology Distention of the intestine caused by the accumulation of gas and fluid proximal to and within the obstructed segment ▪ Gas is mostly swallowed air, poorly absorbed from the intestinal lumen ▪ Accumulation of fluid proximal to the obstruction from ingested fluid, saliva, gastric juice, biliary and pancreatic secretions as well as impairment of normal sodium and water transport Loss of fluids and electrolytes may be extreme → hypovolemia, renal insufficiency, and shock Fluid loss from: ▪ Vomiting ▪ accumulation of fluids within the lumen ▪ sequestration of fluid into the intestinal wall and peritoneal cavity (as a result of impairment of venous return from the intestine) Intestinal Obstruction Most mechanical obstructions occur in the small bowel Smaller lumen, smaller diameter As illustrated, the large bowel can also be involved Intestinal Obstruction: Hernias Weakness or defect in abdominal wall → protrusion of peritoneum ▪ Once the bowel becomes trapped → venous outflow obstructed → swelling of the bowel → increased intramural pressure → decreased arterial perfusion → ischemic bowel ▪ Named for the location - inguinal, femoral, umbilical ▪ Trapped bowel = incarceration; trapped and ischemic bowel = strangulated Incidence ▪ Common: occur in up to 5% of population ▪ Most frequent cause of obstruction worldwide Risk Factors ▪ Chronic cough ▪ Chronic straining ▪ Overweight Intestinal Obstruction: Hernias Clinical features can vary between patients: ▪ Acute pain or chronic pain Can be referred as well ▪ Bulges under skin ▪ Nausea and vomiting ▪ Constipation ▪ If severe (strangulation), ischemia of that portion of bowel → ischemia and shock, often severe abdominal pain Diagnosis – physical exam and ultrasound are often adequate Treatments ▪ Conservative – watchful waiting, hernia truss/belt, weight management ▪ Surgery General pathogenesis - obstruction Intussusception in adults usually occurs due to a tumour in the small bowel (lymphoma, adenocarcinoma) that disrupts motility ▪ Telescoping occurs where the tumour is located Adhesions are usually due to an inflammatory process that link two segments of bowel together or compress it from the outside – common cause of obstruction ▪ Crohn’s disease, diverticulitis ▪ Abdominal surgery, cancers, infections Volvulus tends to occur around a mesenteric point of attachment – both the vascular supply and the lumen are occluded at the site of twisting ▪ Less common cause of obstruction Obstruction – General Clinical Features Severe acute mechanical obstruction – similar symptoms to strangulated hernia ▪ Surgical emergency Long-term, milder obstructions can lead to chronic abdominal pain, change in bowel habits ▪ Vomiting and distention with worse obstruction ▪ If blood flow is impaired (i.e. volvulus) can cause mild hypoxia/ischemia and impaired function or food intolerance Functional obstructions Ileus = bowel experiences greatly decreased motility Similar clinical features mechanical obstructions, but tend to be less severe Causes include: ▪ Post-surgical (intraabdominal surgery) ▪ Intraabdominal inflammation, hemorrhage, ischemia ▪ Metabolic or electrolyte abnormalities, medications that impair bowel motility Common medications – opiates, antihistamines, anticholinergic agents ▪ Sepsis or peritonitis (even pneumonia) Usually managed conservatively, bowel rest and reduced oral intake ▪ Can complicate severe illnesses (i.e. sepsis) Intestinal Ischemia: General Overview Relatively uncommon GI disease, but can have very serious consequences Can be caused by: ▪ Atrial fibrillation, valvular disease, embolic disease – clots from within the heart occlude an intestinal artery ▪ Hypercoagulable states ▪ Global hypoperfusion (shock, MI) ▪ Severe atherosclerosis (uncommon, but increasing as incidence of severe atherosclerosis increases) ▪ Post-vascular surgery (one of the more common causes) Vascular compromise due to obstruction more common, but considered as a part of obstructive pathology Intestinal Ischemia: General Two phases: ▪ Hypoxic injury – epithelium, muscular layers are relatively resistant to ischemia, so damage is relatively limited early on ▪ Reperfusion injury – as blood supply is re-established, free radical production, neutrophil infiltration, and release of inflammatory mediators, such as complement proteins and TNF causes more severe damage Acute and complete arterial obstruction tends to cause transmural infarction ▪ Coagulative necrosis → perforation and inflammation of the serosa or peritoneum (peritonitis) Less severe infarction will not cause perforation (known as mural infarction) Vulnerable intestinal areas = watershed zones splenic flexure, where the superior and inferior mesenteric arterial circulations terminate sigmoid colon + rectum, where the inferior mesenteric, pudendal, and iliac arterial circulations terminate Intestinal Ischemia Clinical features: Tends to occur in older individuals with co-existing cardiac or vascular disease Acute transmural infarction typically presents with sudden, severe abdominal pain and tenderness, sometimes accompanied by nausea, vomiting, bloody diarrhea, or grossly melanotic stool ▪ Shock and vascular collapse within hours as a result of blood loss ▪ Bowel sounds absent, abdominal rigidity if peritonitis ▪ Signs overlap with those of acute appendicitis, perforated ulcer, and acute cholecystitis, therefore misdiagnosis is common ▪ As the mucosal barrier breaks down, bacteria enter the circulation and sepsis can develop; mortality may exceed 50% Mural infarcts have a better prognosis but may progress to more severe ischemic disease with time Angiodysplasia Malformed submucosal and mucosal blood vessels Occurs most often in the cecum or right colon ▪ Associated with aging; usually after the sixth decade of life Prevalence less than 1% in the adult population but accounts for 20% of major episodes of lower intestinal bleeding ▪ Intestinal hemorrhage may be chronic and intermittent or acute and massive Pathogenesis attributed to mechanical and congenital factors ▪ Normal distention and contraction may intermittently occlude the submucosal veins that penetrate through the muscularis propria and can lead to focal dilation and tortuosity of overlying submucosal and mucosal vessels. ▪ Cecum develops greatest wall tension ▪ Degenerative vascular changes related to aging may also have some role Angiodysplasia Pathology: nests of tortuous veins, venules, and capillaries ▪ Vascular channels may be separated from the intestinal lumen by only the vascular wall and a layer of attenuated epithelial cells; limited injury may therefore result in significant hemorrhage Clinical features: ▪ Hematochezia, melena, or iron-deficiency anemia ▪ Often asymptomatic if bleeding is mild Appendicitis Most common abdominal surgical emergency ▪ 11 cases per 10,000 per year ▪ between 7-9% of people will experience it during their lifetime peak age of onset between 10 and 19 years ▪ 70% before age 30 Major complication is perforation ▪ 20 cases per 100,000 per year perforate ▪ perforation more common younger than 5 years, older than 65 years Appendicitis Pathogenesis: unbelievably, the exact cause is not well characterized traditional model – a fecalith obstructs the lumen of the appendix, resulting in bacterial and mucous “build- up” ▪ leads to distention and ischemia as the tension in the wall builds – ischemia is severe enough that gangrene occurs ▪ neutrophils infiltrate the full thickness of the mucosa and pus can accumulate and fill the appendiceal lumen ▪ in cases of perforation, the wall “bursts” or leaks fecal material, mucous, bacteria into the peritoneum causing peritonitis Appendicitis Perforation can lead to: ▪ encapsulation of the appendix and leaked material → forms an abscess (greater omentum can encapsulate the “mess”) ▪ “free” perforation into the peritoneal cavity can cause 3rd-spacing, vascular collapse, sepsis terrible but rare complication of this is portal vein thrombosis with abscesses forming in the liver – prognosis is very poor ▪ Remember, though, only a minority perforate  Appendicitis Pathogenesis cont… If not a poo stone, then what? ▪ mesenteric adenitis (big lymph nodes) can obstruct the lumen inflammatory conditions (IBD for example) infections (maybe viral? hard to characterize) ▪ Cancer rarely also causes an obstruction The types of signs and symptoms vary – often because of variations in location of the appendix Appendicitis - Clinical Features Pain ▪ the classic picture – initial period of periumbilical pain (midgut structure being distended) → by RLQ pain at McBurney’s point inflamed appendix rubbing on the parietal peritoneum 12-24 hours later → temporary relief after the appendix bursts → decompensation with peritonitis and sepsis ▪ Only 50% of patients have the classic periumbilical → RLQ progression Often nausea and vomiting follow pain, almost all patients experience anorexia Appendicitis – Clinical Features Weird locations for the appendix: ▪ pregnancy – RUQ ▪ pelvic – inguinal or suprapubic pain accompanied by dysuria, urinary frequency, diarrhea, tenesmus ▪ retroperitoneal – flank pain Perforation - high temperature, hypotension (peritonitis) Rigid abdomen, sharp, well-localized pain – inflamed appendix rubbing on peritoneum ▪ McBurney’s point – 1/3 distance from ASIS to umbilicus (right side) ▪ Less common physical exam signs iliopsoas sign, Rovsing’s sign, obturator sign Appendicitis Signs and Symptoms  Diagnosis & Treatment Diagnosis: Ultrasound has a ~ 85% sensitivity and specificity, CT has a sensitivity and specificity of ~ 95% ▪ Abdominal X-rays fairly useless Treatment Immediate surgical removal if the patient is unstable Removal may be deferred until later if the abscess can be initially drained percutaneously MICROBIAL DISEASES OF THE DIGESTIVE SYSTEM GASTROINTESTINAL MICROBIOME, BACTERTIAL GASTROENTERITIS A N D I N TOX I C AT I O N Prepared by: BMS 150 Nick Inglis, Ph.D. IN A 24 HOUR PERIOD… ~200,000,000 people have gastroenteritis/day The amount of diarrheal water passed = the volume of water passing over Victoria falls in 1 minute 65,280,000L!!!!  1170 bacterial species!! GASTROINTESTINAL Viridans streptococci MICROBIOME ~free of microbes Anerobic environment; 30 trillion bacteria! Bacteroides Lactobacillus Eschericihia Enterobacter Proteus Klebsiella  1170 bacterial species!! GASTROINTESTINAL Viridans streptococci MICROBIOME ~free of microbes Anerobic environment; 30 trillion bacteria! Bacteroides Lactobacillus Eschericihia Enterobacter Proteus Klebsiella VIRIDANS STREPTOCOCCI Bacterial endocarditis  1170 bacterial species!! GASTROINTESTINAL Viridans streptococci MICROBIOME ~free of microbes Anerobic environment; 30 trillion bacteria! Bacteroides Lactobacillus Eschericihia Enterobacter Proteus Klebsiella CONSEQUENENCES OF INTESTINAL MICROBIOTA Review Microbial Antagonism Vitamin production (B12, folic acid, biotin and vitamin K) Produce 500mL/day of flatus BACTERIAL GASTROENTERITIS: COMMON FEATURES World-wide, endemic disease Associated with: poorly prepared foods, contaminated water, poor living conditions Common signs/symptoms: nausea, vomiting, diarrhea, loss of appetite, abdominal pain/cramping Diagnosis: signs/symptoms, nucleic acid test. BACTERIAL GASTROENTERITIS: TREATMENT Fluid replacement (drinking water, OTC electrolyte solutions like Gatorade) Some patients may need medication to suppress nausea if fluids can’t be taken (IV fluid sometimes required) Most symptoms disappear within hours or days; recovery from dehydration => 1 week GATORADE AS A MEDICATION?? BACTERIAL GASTROENTERITIS: PREVENTION BACTERIAL GASTROINTERITIS 1. CHOLERA Causative agent: Vibrio cholerae (vibrios, gram -ve) Portal of entry: ingestion of contaminated water, or raw/undercooked seafood Signs/symptoms: rice-water stool BACTERIAL GASTROINTERITIS 1. CHOLERA Incubation: 2-3 days Susceptibility: endemic areas with poor sewage treatment Treatment: fluid and electrolyte replacement, antimicrobials (e.g., tetracycline)  Intestinal lumen A Cholera toxin Water follows binds to B electrolytes into membrane lumen. of epithelial CHOLERA cell. TOX I N I N INTESTINAL CELLS Portion Epithelial Cyclic AMP cell of toxin A1 stimulates (part of A) cell to enters cell. secrete Cl−, Na+, and other electrolytes. A1 is an enzyme that Adenylate activates makes adenylate cyclic AMP cyclase. (cAMP). BACTERIAL GASTROENTERITIS: 2. SHIGELLOSIS Causative agent: Shigella (gram –ve bacillus) Starts as infection of small intestine, causing diarrhea, but eventually proceeds to large intestine Incubation: ~7 days Treatment: antimicrobial drugs, vaccine in development  Shigella Shigella attaches to epithelial cell of colon. Epithelial cell Nucleus THE EVENTS OF SHIGELLOSIS  Shigella Shigella attaches to epithelial cell of colon. Epithelial cell Nucleus THE EVENTS Shigella triggers endocytosis. OF SHIGELLOSIS  Shigella Shigella attaches to epithelial cell of colon. Epithelial cell Nucleus THE EVENTS Shigella triggers endocytosis. OF SHIGELLOSIS Shigella multiplies in cytosol.  Shigella Shigella attaches to epithelial cell of colon. Epithelial cell Nucleus THE EVENTS Shigella triggers endocytosis. OF SHIGELLOSIS Shigella multiplies in cytosol. Actin fibers Shigella invades neighboring epithelial cells, thus avoiding immune defenses.  Shigella Shigella attaches to epithelial cell of colon. Epithelial cell Nucleus THE EVENTS Shigella triggers endocytosis. OF SHIGELLOSIS Shigella multiplies in cytosol. Actin fibers Shigella invades neighboring epithelial cells, thus avoiding immune defenses. Mucosal abscess An abscess forms as epithelial cells are killed by the infection.  Shigella Shigella attaches to epithelial cell of colon. Epithelial cell Nucleus THE EVENTS Shigella triggers endocytosis. OF SHIGELLOSIS Shigella multiplies in cytosol. Actin fibers Shigella invades neighboring epithelial cells, thus avoiding immune defenses. Mucosal abscess An abscess forms as epithelial cells are killed by the infection. Blood vessel Phagocyte Shigella that enters the blood is quickly phagocytized and destroyed. No bacteremia. BACTERIAL GASTROENTERITIS: 3. SALMONELLOSIS/TYPHOID FEVER Causative agent: Salmonella enterica (2000 serotypes/strains) Serotypes Typhi and Paratyphi cause typhoid fever Enteridis and Typhimurium cause most N. American cases Exposure via consumption of food or water contaminated with feces of a carrier 1/3rd of chicken eggs contain S. enterica  (Slide 2) Salmonella Salmonella attaches to epithelial cells lining Epithelial the small intestine. cell Nucleus THE EVENTS OF SALMONELLOSIS  (Slide 3) Salmonella Salmonella attaches to epithelial cells lining Epithelial the small intestine. cell Nucleus THE EVENTS OF Salmonella triggers SALMONELLOSIS endocytosis.  (Slide 4) Salmonella Salmonella attaches to epithelial cells lining Epithelial the small intestine. cell Nucleus THE EVENTS OF Salmonella triggers SALMONELLOSIS endocytosis. Salmonella multiplies within food vesicle.  Salmonella Salmonella attaches to epithelial cells lining Epithelial the small intestine. cell Nucleus THE EVENTS OF Salmonella triggers SALMONELLOSIS endocytosis. Salmonella multiplies within food vesicle. Salmonella kills host cell, inducing fever, cramps, and diarrhea.  Salmonella Salmonella attaches to epithelial cells lining Epithelial the small intestine. cell Nucleus THE EVENTS OF Salmonella triggers SALMONELLOSIS endocytosis. Salmonella multiplies within food vesicle. Salmonella kills host cell, inducing fever, cramps, and diarrhea. Capillary (blood vessel) Bacteremia: Salmonella moves into bloodstream. TYPHOID FEVER AND SALMONELLOSIS Cells of serotype Typhi can enter blood Phagocytosed but not ingested Carried to liver, spleen, bone marrow, gall bladder Semi-permanent infection established Salmonella shed in feces TYPHOID FEVER: SIGNS AND SYMPTOMS Increasing fever, headache, muscle pains, malaise, loss of apetite (> 1 week) “Rose Spot” Rash on abdomen Repeated gastroenteritis bouts Life-threatening complications: intestinal hemorrhage, perforation, kidney failure, peritonitis BACTERIAL GASTROENTERITIS: 4. CAMPYLOBACTER DIARRHEA Causative agent: Campylobacter jejuni Lipopoylsaccharide/Lipid A Adhesins Cytotoxins (exotoxins) CAMPYLOBACTER DIARRHEA: PATHOGENESIS/EPIDEMIOLOGY 81% of chickens carry Campylobacter. Virulence factors specifically allow for colonization of the jejunum, ileum and colon. Incidence: 1.3 million people per year Mortality: ~75 Complications: Guillain-Barre Syndrome (GBS), Irritable Bowel Sydrome (IBS), arthritis. BACTERIAL GASTROENTERITIS: 5. ANTIMIICROBIAL-ASSOCIATED DIARRHEA Severe form of diarrhea caused by use of broad spectrum antibiotics Very common in hospitals Best case: 5-10 clear, watery, foul smelling stools passed each day Worst case: >10 bloody stools per day caused by formation of intestinal pseudomembranes INTESTINAL PSEUDOMEMBRANES Lesions CAUSATIVE AGENT: CLOSTRIDIUM DIFFICILE C. DIFF PATHOGENESIS BACTERIAL FOOD POISONING (INTOXICATION) Food poisoning Bacterial gastroenteritis Bacterial intoxications (toxifications) BACTERIAL INTOXICATION: SIGNS AND SYMPTOMS General symptoms (mild → severe): - Nausea, vomiting, diarrhea, cramps, discomfort, bloating, loss of appetite, fever - Less common: weakness, headache, breathing problems. Dehydration from fluid loss Most cases are self-limiting and last no more than 24 hours. S. AUREUS ENTEROTOXINS ENTERTOXIN STRUCTURE Superantigens! Can stimulate large populations of T-cells ENTEROTOXIN FUNCTION PATHOGENESIS AND EPIDEMIOLOGY Outbreaks usually associated with picnics, school cafeterias or large social functions Several hours at room temperature required for S. aureus to grow and produce toxins. Epidemiology: ???? MICROBIAL DISEASES OF THE DIGESTIVE SYSTEM VIRAL DISEASES OF THE DIGESTIVE S Y S T E M ( P L U S B O N U S D E N TA L C AV I T I E S A N D M U M P S ) Prepared by: BMS 150 Nick Inglis, Ph.D. OTHER BACTERIAL GI INFECTIONS: HELIOBACTER PYLORI AND PEPTIC ULCERS Ulcer: erosion of the lining of stomach or duodenum. Can be perforations Symptoms: Nausea, vomiting (with “coffee grounds” in vomit), tar-like stools Long-term: bowel obstructions, internal bleeding H. PYLORI IN ULCER FORMATION Helicobacter pylori (neutralizes stomach acid) Layer of mucus Nucleus Epithelial cell Mucus- in stomach lining secreting cell Red blood cells in capillaries Bacteria invade mucus and attach to gastric epithelial cells. UREASE H. PYLORI IN ULCER FORMATION Helicobacter pylori (neutralizes stomach acid) Layer of mucus Nucleus Epithelial cell Mucus- Neutrophil Lymphocyte in stomach lining secreting cell Red blood cells in capillaries Bacteria invade mucus and attach to Helicobacter, its toxins, and gastric epithelial cells. inflammation cause the layer of mucus to become thin. UREASE H. PYLORI IN ULCER FORMATION Helicobacter pylori (neutralizes stomach acid) Layer of mucus Acidic gastric juice Nucleus Epithelial cell Mucus- Neutrophil Lymphocyte in stomach lining secreting cell Ulcer Red blood cells in capillaries Bacteria invade mucus and attach to Helicobacter, its toxins, and Gastric acid destroys epithelial cells gastric epithelial cells. inflammation cause the layer of and underlying tissue. mucus to become thin. UREASE DENTAL CARIES/GINGIVITIS DENTAL CARIES – SIGNS/SYMPTOMS  Plaque DENTAL CARIES: CAUSATIVE AGENT Streptococcus mutans Dextran Dental plaque DENTAL CARIES DENTAL CARIES – DIAGNOSIS/TREATMENT Visual inspection during routine dental checkups Probing with sharp objects and X-rays can reveal cavities before observable pits form Treatment: remove the softened tissue from cavity and replace the hole with silver, gold, porcelain, or resin ROOT CANALS  DENTAL CARIES - EPIDEMIOLOGY N. American adults (20-64 y.o.) – 92% have had dental caries (to permanent teeth!); 42% of children (2-11) have at least one. Causes: - Diets high in sucrose (table sugar) - Continual snackingz Mumps Causative Agent: Rubulavirus (unenveloped, -ssRNA virus) Portal of entry: mucus membranes of upper respiratory tract Signs and Symptoms: parotitis, face pain, fever, headache, sore throat Incubation: 12-24 days LET’S BRING THE LECTURE BACK FULL CIRCLE! VIRAL GASTROENTERITIS ~200,000,000 people have gastroenteritis/day The amount of diarrheal water passed = the volume of water passing over Victoria falls in 1 minute 65,280,000L!!!! ROTAVIRUS primary cause of diarrheal illness in infants world-wide (30-50%) segmented dsRNA genome infects nearly every child in the world infections peak in winter 800k deaths/year (5% of all mortality < 5 yr old) GLOBAL DISTRIBUTION OF ROTAVIRAL DEATHS (~2014) R OTAV I R U S PATHOGENESIS OF ROTAVIRUS transmitted by fecal-oral contamination 10-100 infectious particles sufficient infants