Week 2 Flashcards
Prevalence of bacterial pathogens in causing gastroenteritis
- *which is the only one that reside in human? Other reside in animals
- what is most common 5
- Salmonella
- Campylobacter
- Shigella *** reside in humans
- Cryptosporidium
- ST producing E. Coli
- Vibrio
- YERSINIAE
- Listeria
Describe the 3 mechanisms for gastroenteritis
- Interference with the secretory and absoptive properties of intestine by adherence and/or enterotoxin, usually associated with effacement.
- Invasion of the mucosal enterocytes
- Penetration of organisms through the mucosa, where they multiply in cells of the mucosa- associated lymphoid tissue
Describe the link between CFTR and cholera toxin in causing the GI infections
Fluid secretion in GI tract (how?) How many CFTR mutations? (Differentiate class II vs class VI) ? What is the similarity of mutation in class II and VI
Fluid secretion in GI tract A. cAMP controls activity of CFTR – Na reabsorption. – the secretion of chloride and CFTR bicarbonate into the gut. B. Key points - Amount of Cl secreted = amount of water in GI - Gs or AC to increase Cl secretion - CFTR
- There are about 2000 types of CFTR mutations.
- They can be classified into six groups.
- 70% DF508
- Class II: Abnormal protein folding, processing, and trafficking.
- Class VI: Altered function in regulation of ion channels.
- The ΔF508 mutation is both a class II and class VI mutation (serve as ion channel regulator esp sodium channel)
**The functions of CFTR are tissue-specific
- Activity of epithelial SODIUM CHANNEL ENaC is linked with CFTR
In cystic fibrosis;
I) Lumen of sweat duct - increased Na+ and Cl-
II) Airway - dehydrated mucus
Identify toxin
- Impairs the normal absorption activity of the intestine.
- Activates adenylate cyclase which converts ATP to cAMP.
- CTX and other virulence genes are carried on a single stranded DNA phage.
**DESCRIBE TOXIN TRANSPORT and signalling
CHOLERA ENTEROTOXIN
Cholera RETROGRADE toxin transport and signaling
- B subunits binds to a ganglioside on cell surface.
- A subunit enters via endocytosis.
- In ER, A is reduced by protein disulfide isomerase (PDI).
- A is refolded in cytosol, and interacts with ADP ribosylation factor (ARF) to ribosylate and activate the stimulatory GSa protein
- Adenylate cyclase becomes locked in active state resulting in uncontrolled production of cAMP, causing massive flux of Cl, bicarbonate, Na
- *Ultimate result - watery diarrhea
Identify bacteria
- Gram negative
- Comma-shaped
- Facultative anaerobic
- Fermentative
- Oxidase positive
- Motile by a single polar flagellum (H antigen)
- Salt- or freshwater
**Identify toxins (differentiate the 2 toxins)
VIBRIO CHOLERA
• O antigens: 150 O groups.
• V. cholera O1 and O139: CLASSIC CHOLERA
• V. cholera O1 can be further subdivided into two biotypes: el tor and cholerae.
• O1 has three serotypes; (Ogawa, Inaba, and Hikojima).
• Serotype O139 is encapsulated.
O199 vs O1
Blot A; Pulsed-field electrophoresis gel
- O139 banding patterns differed from O1 banding
Blot B; southern blot
- O139 specific probe hybridized at the same position in O139 strains
- O1 strains did not hybridize
Identify pathogenesis of condition
Clinical manifestation
- Sudden onset of massive diarrhea.
- Very significant loss of protein- free fluid (patient can lose 20 liter of water per day).
- The loss of fluid lead to dehydration, acidosis and shock.
- The watery diarrhea is speckled with flakes of mucus and epithelial cells (“rice-water” stool) heavily loaded with vibrios.
Vibrio cholera
Pathogenesis
• Only 5µg of cholera toxin is needed to cause severe
symptoms.
• V. cholerae targets the intestine because the bacterium
requires low pH environment for proliferation.
• Can survive enzymatic activities of gastric secretions.
• Can survive the peristaltic action of the intestines.
Patho of cholera and ETEC • Enterotoxigenic E. coli two toxins differentiated based on heat stability • Colonization factor (Cfa) • Toxin-coregulated pilus (TcpA). • Cholera toxin (Ctx) • Labile toxin (LTA) • Adenylate cyclase (AC).
Identify other virulence factors and transmission of condition
Treatment
• Death is often due to severe dehydration and electrolyte imbalance. Treatment consists of prompt, adequate replacement of water and electrolytes, either orally or intravenously.
• It’s a self-limiting disease. As long as you can deal with dehydration. Within one week, it will clear itself.
• Doxycycline or tetracycline-adults.
• Furazolidone-pregnant women.
• Trimethoprim-sulfamethoxazole- children
• Vaccines are not effective (Need IgA - has 4 identical binding site to cross link toxin - specific for mucosal surface)**enterotoxin don’t usually have effective vaccines
Vibrio cholera
Other virulence factors
• TCP pili- toxin coregulated pili, occurs in bundles and are localized to one end of bacterial surface.
• Hemagglutinin that can act as an adhesins.
• Accessory colonization factor (chromsomal), membrane proteins (adhesion?)
• Other chromosomal virulence genes (zot and ace).
Transmission
• V. cholerae grow in estuarine and marine environment.
• Asymptomatic carrier.
• For colonization to occur, large numbers of bacilli are needed (one billion!).
• Gastric acidity reduced, infectious inoculum less.
Identify bacterial
**Primary septicemia skin lesions
• Rapidly progressive wound infections after exposure to contaminated seawater
• The wound infections are characterized by initial swelling, erythema, and pain followed by the development of vesicles or bullae and eventual tissue necrosis.
• Mortality: 50%
**common during what condition?
Acquired by eating what?
Result in what conditions?
Vibrio vulnificus
• V. vulnificus is most frequently implicated in the
outbreaks from the United States.
• V. vulnificus can be acquired by eating raw or
undercooked shellfish, or directly by contaminating open
wounds while swimming or cleaning shellfish.
• Results in Cellulitis, wound infection, or septicemia.
Identify condition
- typically causes gastroenteritis after
consumption of contaminated raw oysters and clams from
the northeastern and Pacific northwestern coasts of the
United States.
Less frequent results?
Pt with liver disease or immunocompromised?
Vibrio parahaemolyticus
• Less frequently, V. parahaemolyticus causes wound
infections that are generally less severe than V. vulnificus
wound infections.
• However, in persons with liver disease or
immunocompromising conditions, V. parahaemolyticus
wound infections can lead to death.
Identify bacteria
Aerobic Motile Non-encapsulated Spores Clinical Diseases: - Emetic food poisoning - Diarrhea food poisoning - Eye infections
**identify virulence factors and treatment
BACILLUS CEREUS
**re-heating Chinese friedrice
Virulence factors
- Spore formation:
- Enzymes:Lecithinase (phospholipase C)
- Enterotoxins-exotoxin
- Necrotic toxin:vascular permeability action, heat labile
- Cereolysin: a hemolysin which disrupts cholesterol of cell membrane
Treatment
- Fluid and electrolyte replacement if necessary
- Treatment with vancomycin, ciprofloxin and gentamycin
- Gram-positive, cluster-forming coccus
- Nonmotile, nonsporeforming facultative anaerobe
- Ferments glucose to produce mainly lactic acid
- Ferments mannitol (distinguishes from S. epidermidis)
- catalase positive; coagulase positive
- golden yellow colony on agar
- normal flora of humans found on nasal passages, skin and mucous membranes
- pathogen of humans, causes a wide range of suppurative infections, as well as food poisoning and toxic shock syndrome
- *identify enterotoxin (A-E, TST1)
- *which toxin is not food associated?
Staphylococcal Enterotoxins
A - most commonly associated with food poisoning
B - associated with staphylococca Enterocolitis (rare)
C - Rare, associated with contaminated milk products
D - Second most common, alone or in combination with A, associated with contaminated milk products
E - Rare, associated with contaminated milk products
TSST -1 ; toxic shock syndrome toxin, not food associated
- Typical antigen response< 1% T cells.
- Superantigens may stimulate up to 20% of T cells, leading to release of cytokines such as TNF, IL-1, IL-2, and IFN-g in such large amounts (cytokine storm).
- Massive vasodilation and shock.
- Enterotoxin A-E : acts on brain vomit center, inhibits intestinal water absorption.
- TSST-1 and GAS pyrogenic exotoxin A or C
Describe
- Enterotoxins - food positioning
- Exotoxins - Genetics
- Toxoid vaccines
- Enterotoxins - food positioning
- Food will not appear or taste tinten. **MEAN INCUBATION = 4 hrs
- last for 24 hrs severe vomiting, diarrhea (NON BLOODY)
- abdominal cramp or nausea NO FEVER
- only 30-50% of S.aureus strains producing them
2. Exotoxins - Genetics • Many exotoxin genes not part of chromosome • Plasmid-encoded - E.coli heat labile toxin • Bacteriophage-encoded - corynbacterium diphtheria - Strep pyrogens erythromycin - E.coli shiva-like toxin - botulinum toxin - cholera toxin
- Toxoid vaccines
- Toxoid = inactivated bacterial toxins
- Used for vaccination
- Used to prevent diphtheria and tetanus
- Part of DTaP combined immunization;
D - diphtheria
T - tetanus
AP - acellular pertussis
Describe liver blood flow
Weight
A. Toward liver
B. Within parenchyma
C. Away from liver
**Liver weight; 1400 - 1600 grams
Liver’s Blood Flow
- Dual blood supply to the liver through porta hepatis (hilum of liver)
a. Portal vein (60-70%)
b. Hepatic artery (30-40%) - Within the parenchyma branches travel in parallel through portal tracts vessels and sinusoids
- Away from the liver via central vein → hepatic veins → IVC
Hepatic architecture
- The hexagonal anatomical unit of the liver
- center vs periphery - The triangular functional unit of the liver
- center vs periphery
* *ZONE 1-3 (metabolic zones)
- which zone is first exposed to toxins
- which is more involved in bile synthesis
- which is the least oxygenated zone?
- which is susceptible to ischemia?
- closed to artery? Closed to vein?
- Lobule; HEXAGONAL anatomic unit
a. The central vein (or terminal hepatic venule) in the center
b. Portal tracts at the periphery - ACINUS; TRIANGULAR functional unit
- The portal tract at the center & central vein at the periphery
- Three metabolic zones in the acinus
(1) ZONE 1
(a) Immediately around the portal tract
(b) First area exposed to and affected by toxins
(c) Hepatocytes most specialized in drug detoxification
(d) MOST oxygenated zone
(2) ZONE 2: intermediate zone
(3) ZONE 3
(a) Immediately around the central vein
(b) Bile synthesized in this zone
(c) Hepatocytes most specialized in bile formation
(d) LEAST oxygenated zone; most susceptible to ischemia
Portal tract (portal triad)
What immediately surround portal tract?
a. Bile ducts
b. Hepatic arteriole (small muscular artery)
c. Portal venule (largest structure in the portal tract)
**Limiting Plate: hepatocytes immediately surrounding the PT
Liver parenchyma
Hepatocytes vs sinusoids vs space of disse vs bile canaliculi vs lymphocytes
- kupffer cells where?
- hepatic stellate cells where? (Responsible for fibrosis)
- bile canaliculi begin in what zone? Drain into?
LIVER PARENCHYMA
a. Hepatocytes
(1) Arranged in sheets, plates or cords
(2) Cords normally 1 to 2 cells in thickness
b. Sinusoids
(1) Vascular spaces between the hepatocyte cords
(2) Blood travels from the portal tract to the central vein
(3) Lined by a sheet of fenestrated endothelial cells
(4) Antigen presenting KUPFFER CELLS on the luminal aspect of the endothelium
c. Space of Disse
(1) Between the sinusoidal endothelial cells and the hepatocytes (2) Location of fat-containing HEPATIC STELLATE CELLS (Ito cells or perisinusoidal cells)
(a) Major source of collagen
(b) Activation into fibrogenic cells during hepatic fibrosis
d. Bile canaliculi
(1) Located in the grooves between the hepatocytes
(2) Begin in the centrilobular region (Zone 3)
(3) Separated from vascular space by tight junctions
(4) Drain into the ductular structures (canals of Hering) connecting the canaliculi to the portal terminal bile ducts (Zone 1) to hepatic ducts
e. Lymphocytes (up to 22% of cells other than hepatocytes)
Describe physiology of the liver
- Involved in glucose homeostasis
- Synthesizes most serum proteins
- Stores glycogen, triglycerides, iron, copper, lipid-soluble vitamins (A,D,E,K)
- Catabolizes hormones and proteins and detoxifies drugs and chemicals
- Excretes various products (conjugated bilirubin, bile salts, cholesterol and electrolytes) as bile
Features of hepatic disease
General
Mechanisms fo hepatic Injury and repair (list 4)
General
- Susceptible to circulatory, metabolic, microbial, neoplastic and toxic processes
- Usually slow process with signs/symptoms occurring weeks to years after injury
Mechanisms of Hepatic Injury and repair
- Hepatocyte necrosis and apoptosis
- Inflammation - HEPATITIS - injury to hepatocytes by an influx of acute and/or chronic inflammatory cells
- Regeneration
- Fibrosis (scar formation)
Mechanism of hepatic injury and repair
Types of hepatocyte necrosis and apoptosis (3)
A. Coagulative necrosis, macrophage cluster around
B. Shrunken eosinophilic acidophil bodies (e.g councilman bodies)
C. Cellular debris, macrophages (5)
- which zone around terminal hepatic venule ?
- piecemeal necrosis?
- from serious injury and may herald onset of cirrhosis (portal-to-portal, portal-to-central and central-to-central)
- involve most of liver?
a. Ischemia leads to coagulative necrosis, macrophages cluster around
b. Apoptosis: Shrunken eosinophilic acidophil bodies (e.g.Councilman bodies)
c. Patterns (zones) of necrosis (filled with cellular debris, macrophages)
(1) CENTRILOBULAR (around central vein) necrosis may be due to ischemia or various drugs or toxins
(2) INTERFACE HEPATITIS (PIECEMEAL NECROSIS) - immediately around the portal tract involving the limiting plate
(3) BRIDGING NECROSIS - from serious injury and may herald onset of cirrhosis (portal-to-portal, portal-to-central and central-to-central)
(4) SUBMASSIVE NECROSIS - involves entire lobe
(5) MASSIVE NECROSIS - involves most of the liver
Mechanism of hepatic injury and repair
- Hepatitis
- viral vs alcoholic? - Can hepatocytes regenerate?
- Inflammation - HEPATITIS - injury to hepatocytes by an influx of acute and/or chronic inflammatory cells
- neutrophils; alcoholic hepatitis
- lymphocytes - viral hepatitis - Regeneration
a. Via mitotic replication of hepatocytes adjacent to ones that have died
b. Hepatocytes are stem cell-like in their ability to regenerate
c. Hepatocytes may reach replicative senescence in long-standing chronic disease
Mechanism of hepatic injury
- what cells responsible for fibrosis
Fibrosis (Scar formation)
a. A response of hepatic stellate cells (Ito cells) to inflammation or toxins
b. The activated hepatic stellate cell becomes a myofibroblast
c. Scar deposition begins in and around portal tracts and central veins and extends into the sinusoids
d. Generally irreversible
e. Eventually fibrosis surrounds regenerating hepatocytes forming nodules
f. Regenerating nodules surrounded by dense scar tissue = cirrhosis
How much functional capacity of liver must be lost before hepatic failure occurs?
**definition and causes (3) of the following
Morphology
- Gross - small, shrunken liver (700g)
- Microscopic
- massive hepatic necrosis
- may or may not be scar formation and regeneration depending on length of time of development
Acute Liver failure; Approximately 80-90% of functional capacity must be lost before hepatic failure occurs
Definition; acute liver illness + encephalopathy + coagulopathy within 6 months of liver injury
Causes
- Drugs/toxins (acetaminophen [50% of cases of alf in US], halothane, rifampin, isoniazid, monamine oxidase, industrials, Amanita)
- Hepatitis A and B
- Autoimmune hepatitis
- Unknown etiology; lead to cryptogenic cirrhosis
Identify LIFE THREATENING CONSEQUENCES of the following (4)
Clinical
a. Jaundice and scleral icterus
b. Hypoalbuminemia
c. Hyperammonemia
d. Fetor hepaticus (odor of thiols on breath from portosystemic shunting of thiols into lungs in portal htn)
e. Impaired estrogen metabolism causing:
(1) Palmar erythema (local vasodilatation)
(2) Spider angiomas (central pulsating dilated arteriole with radiating smaller vessels)
(3) Hypogonadism and gynecomastia in males
ACUTE LIVER FAILURE
Life threatening consequences
1. Multisystem organ failure
- Coagulopathy with bleeding due to:
(a) Decreased synthesis of clotting factors
(b) DIC (when liver is unable to remove activated coagulation
factors from circulation) - Hepatic encephalopathy (elevated ammonia levels)
(a) Subtle behavior abnormalities to coma and death
(b) Neurological signs include rigidity, hyperreflexia and
ASTERIXIS (flapping, nonrhythmic tremor of the hand that occurs with dorsiflexion of the wrists)
(c) Can be reversed if underlying condition corrected - Hepatorenal syndrome
(a) Acute renal failure in patients with severe liver disease who
have NO intrinsic renal abnormalities
(b) Sodium retention, decreased renal perfusion and decreased glomerular filtration rate (GFR)
(c) Decreased renal perfusion secondary to systemic
vasodilation, vasoconstriction of the afferent renal arterioles and increased activation of renin-angiotensin axis causing vasoconstriction
(d) Decreased urine output initially with subsequent increasing blood urea nitrogen (BUN) and creatinine
(e) Median survival of ~ 2 weeks in the rapid form and ~ 6 months in the insidious form
(f) Treatment: liver transplantation
Identify liver condition
Morphology
a. 3 main morphologic features
(1) Bridging fibrous septa
(2) Parenchymal nodules (< 3 mm micronodules to macronodules) (3) Disruption of ENTIRE liver architecture
b. Varies among diseases
c. May correspond to Child-Pugh classification
d. Narrow fibrous septa separating large islands of intact hepatic parenchyma – less portal hypertension
e. Broad bands of fibrosis with less intervening parenchyma – more portal htn
f. Rarely, regression of cirrhosis may occur when underlying disease is cured
**list child Pugh classification? (3) - classify what?
CHRONIC LIVER FAILURE AND CIRRHOSIS
General
a. Primarily due to alcoholic liver disease, chronic hepatitis B, chronic hepatitis C, non-alcoholic fatty liver disease, biliary disease and iron overload
b. Not all cirrhosis leads to chronic liver failure and death
(1) Child-Pugh classification of cirrhosis
(a) Class A – well compensated
(b) Class B – partially compensated
(c) Class C – decompensated
Identify clinical features
Primarily due to alcoholic liver disease, chronic hepatitis B, chronic hepatitis C, non-alcoholic fatty liver disease, biliary disease and iron overload
CHRONIC LIVER FAILURE AND CIRRHOSIS
Clinical
a. May be clinically silent to symptomatic (anorexia, weight loss, weakness)
b. Jaundice and subsequent pruritus, sometimes severe
c. Impaired estrogen metabolism, hyperestrogenemia
(1) Palmar erythema (vasodilation)
(2) Spider angiomata
(3) In men: hypergonadism and gynecomastia
d. Advanced disease leads to death via:
(1) Same causes as acute liver failure
(2) Hepatocellular carcinoma (HCC)
(3) GI hemorrhage
(4) Bacterial infection
Identify liver condition
Due to sustained increased resistance to portal blood flow in sinusoids
a. Contraction of vascular smooth muscle cells and myofibroblasts (stellate)
b. Disruption of blood flow by scarring and parenchymal nodules c. Sinusoidal remodeling and anastomosis of arterial and portal system
(1) Causes shunting of arterial pressures to the low pressure venous system
(2) Disrupts metabolic exchange between sinusoidal blood and
hepatocytes
**Due to?
PORTAL HYPERTENSION
Due to ⭡ portal venous blood flow secondary to a hyperdynamic circulation
a. Due to arterial vasodilation in splanchnic circulation via nitrous oxide
b. Leads to increased splanchnic arterial blood flow → increased venous efflux into the portal venous system → ⭡ portal venous pressure
Identify 3 causes of condition
Major clinical consequences
a. Ascites
b. Portosystemic venous shunts
c. Congestive splenomegaly
d. Hepatic encephalopathy
PORTAL HYPERTENSION
*3 causes
A. Pre-hepatic causes
- Portal vein thrombosis
- Massive splenomegaly
B. Post-hepatic causes
- Severe right sided heart failure
- Constructive pericarditis
- Hepatic vein outflow obstruction (Budd-Chiari syndrome)
C. Intrahepatic cause - CIRRHOSIS (most common cause)
Identify consequence of portal hypertension
- *excess serous fluid in peritoneal cavity
- what does increased neutrophils suggest? Bloody fluid?
- pathogenesis
ASCITES; excess serous fluid in the peritoneal cavity
a. Increased neutrophils suggests secondary infection
b. Bloody fluid suggests disseminated intra-abdominal cancer
c. Pathogenesis
(1) Sinusoidal hypertension drives fluid into the space of Disse which is removed by hepatic lymphatics
(2) Movement of protein-rich hepatic lymph into the peritoneal cavity
(3) Splanchnic vasodilation and hyperdynamic circulation (decreased bp - release of vasoconstrictors, activation of renin-angiotensin, secretion of ADH - increased perfusion pressure of interstitial capillaries - extravasation of fluid into abdominal cavity)
Identify consequence of portal hypertension
**Increased pressure causes reverse of flow from portal to systemic circulation via collateral and new vessels
PORTOSYSTEMIC SHUNTS; increased pressure causes reverse of flow from portal to systemic circulation via collateral and new vessels
a. Rectum - causing HEMORRHOIDS (dilated veins)
b. Falciform ligament of the liver involving the periumbilical and abdominal wall collaterals - causing CAPUT MEDUSAE
c. Esophagogastric junction - causing ESOPHAGEAL VARICES (40% of pts with advanced cirrhosis)
Identify consequence of portal hypertension
**may cause thrombocytopenia or pancytopenia
SPLENOMEGALY
- SPLEEM can be up to 1000gm (normal - 150gm)
- may cause thrombocytopenia or pancytopenia
Identify condition of liver
- Included chronic liver disease, hypoxemia and intrapulmonary vascular dilation (IPVD)
- Vascular dilation - increased blood flow and decreased time for oxygen diffusion - V/Q mismatch - left to right shunting - hypoxemia, dyspnea
- Maybe due to increased nitrous oxide in the lung
HEPATOPULMONARY SYNDROME
**Another life threatening consequence of liver disease
Identify condition of liver
- Signs of acute liver failure in patients with stable, well-compensated advanced chronic liver disease
- Large volumes of functioning liver parenchyma are vulnerable because of borderline vascular supply
- Causes: superinfection with HepD in patient with chronic HepB, septic shock (decreased bp and perfusion), heart failure, drug or toxic injury etc
- Short term mortality is 50%
Acute on chronic liver failure
Memory pneumonic for CAUSES OF LIVER FAILURE
ABCDEF causes of liver failure
A - Acetaminophen, hepatitis A, autoimmune hepatitis, alcoholic liver disease
B - Hepatitis B
C - Hepatitis C, cryptogenic
D - Drugs/toxins, hepatitis D
E - Hepatitis E, esoteric causes (Wilson disease, Budd-Chiari)
F - Fatty change of the microvesicular type (fatty liver of pregnancy, valproate, tetracycline, Reye syndrome)
Summarize liver function tests (10
5 main LFTs
Other 5 - other test that evaluate liver status
- Albumin
- Bilirubin
- Alkaline phosphates
- GGT (gamma glutamyltransferase)
- Transaminases (AST and ALT)
- Ammonia
- Prothrombin time (PT) and activated partial thrombophlebitis time (aPTT)
- Serum globulin
- Urine urobilinogen levels
- CBC (complete blood count
Identify liver function test
- A. Decreased levels due to decreased synthesis in chronic liver disease
B. Also decreased in malnutrition, renal and GI diseases & severe burns - A. Serum levels are an indicator of hepatic uptake mechanisms, metabolism and excretory functions
- Albumin
Chronic liver disease
• Degree of hypoalbuminemia correlates with severity of chronic liver disease
• NOT a good indicator of acute hepatic dysfunction - Bilirubin
* *from heme degradation
What causes increased direct (6) vs indirect bilirubin (6)
Increased direct (conjugated) bilirubin
a. Hepatitis (viral or ischemic causes) or cirrhosis
b. Drug-induced and pregnancy-induced cholestasis c. Sepsis d. Inherited disorders (Dubin-Johnson, Rotor)
e. Biliary cirrhosis and sclerosing cholangitis
f. Obstruction (tumor, stone, etc.)
Increased indirect (unconjugated) bilirubin
a. Hemolysis or ineffective erythropoiesis
b. Prolonged fasting
c. Inherited disorders (Crigler-Najjar syndromes, Gilbert syndrome)
d. Sepsis
e. Hepatitis or cirrhosis
f. Drugs
Identify LFTs
A.
- Correlates with alkaline phosphatase activity & sensitive for alcoholic disease
- Greater sensitivity for hepatobiliary disease (biliary obstruction)
B.
- Elevated levels due to defective detoxification pathways and portosystemic shunting in severe liver disease
- Increased levels support the diagnosis of HEPATIC ENCEPHALOPATHY
C.
• Associated with cellular membranes
• Good indicator for cholestasis, biliary obstruction ( faster than bilirubin) and infiltrative diseases (cancer, granulomas)
• Other causes of levels: bone, kidney, GI, placental and WBC conditions
A. GGT (gamma glutamyltransferase)
B. Ammonia
C. Alkaline phosphatase
Identify LFT
Most indicative of HEPATOCELLULAR DAMAGE & correlates well with disease severity
a. Increased in viral hepatitis, toxic injury and hepatic vein obstruction
b. Also increased in biliary obstruction
* *describe 3 types
TRANSAMINASES
A. AST (formerly SGOT) and ALT (formerly SGPT)
B. ALT (8-20); more specific for LIVER INJURY than AST
C. AST (8-20); elevated more than twice as much as ALT in ALCOHOL INJURY (memory device: Another Scotch & Tonic)
ALT - liver injury
AST - alcohol injury
Identify LFTs
A. What are the changes in PT and aPTT
B.
- Increased levels often seen with chronic liver disease
- Marked increase with autoimmune hepatitis
C.
- Increased in hepatocellular damage
- Decreased in biliary obstruction
D. Changes in CBC
A. Prothrombin time (PT) and activated Partial thromboplastin time (aPTT)
- Prolonged interval due to various clotting factor deficiencies or inactivity
- Involves fibrinogen, prothrombin and factors V, VII, IX and X
- Prolongation due to severe widespread liver necrosis (hepatitis, cirrhosis)
B. SERUM GLOBULIN
C. Urine Urobilinogen levels
D. CBC
• Viral hepatitis may cause a relative or absolute lymphocytosis
• Increased MCV with liver disease
What makes up balanced diet (4)
**source of energy (3)
Balanced diet
- Energy; Carbohydrate + protein + Fat
- Essential and non-essential amino acids
- Fatty acids
- Vitamins and minerals
Diffentiate primary vs secondary malnutrition
- A diet lacking needed components of
nutrition can cause what type malnutrition? - In contrast, diarrhea resulting in too
little dietary absorption can cause what malnutrition?
- Primary malnutrition
2. Secondary or conditional malnutrition
Specify 6 causes of malnutrition
- Ignorance
- Infants on artificial milk need iron supplement
- Iodine deficiency common in areas remote from ocean; risk of goiter - Poverty
- Infections
- Chronic alcoholism
- Dietary deficiency, defective GI absorption, abnormal nutrient use and storage
- Common deficiencies: Thiamine, pyridoxine, folate and Vitamin A - Acute + Chronic illnesses
- BMR in many illnesses resulting in increased daily requirements for all nutrients - Self imposed dietary restriction
- Chronic alcoholics not uncommonly have
deficiencies in which of the following
vitamins? Check all that apply. A. Amino acids B. Carbohydrates C. Folate D. Pyridoxine E. Thiamine F.Vitamin A G. Vitamin C - A baby feed on a diet of only artificial milk is
susceptible to which deficiency? A. Aluminum B. Copper C. Iodine D. Iron E. Potassium F.Sodium G. Zinc
3. A man living in a remote area of Idaho has been hunting and trapping his own food for 25 years. He also grows potatoes. He only uses water from a local stream. He does not believe in dietary supplements. He goes to town only to buy supplies but no food. Recently he developed a neck mass. What nutritional deficiency is likely ? A. Aluminum B. Copper C. Iodine D. Iron E. Potassium F.Sodium G. Zinc
- Chronic alcoholic - deficiency;
Folate, Pyridoxine, thiamine, Vit A - IRON (baby on artificial milk)
- IODINE
Range of clinical syndromes characterized by inadequate dietary intake of protein and calories to meet the body’s need
**Identify ways to evaluate
PROTEIN-ENERGY MALNUTRITION (PEM)
** Malnutrition in children: defined as a child whose weight falls to less than 80% of normal weight.
Ways of evaluation mild or moderate PEM:
1. Body weight. Measured by body mass index (BMI). A BMI less than 16kg/m2 is considered malnutrition (normal range 18.5 to 25 kg/m2).
2. Fat stores skin folds.
3. Muscle mass circumference of the arm.
4. Serum protein adequacy of the visceral protein
(albumin and transferrin) reflect visceral protein compartment
- A Body-Mass Index below what
number is considered malnutrition? - The two ends of the protein-energy
malnutrition spectrum are: - PEM is functionally regulated by what two different protein compartments ?
4. A. Which protein compartment is most affected in marasmus? B. Which protein component is most affected in kwashiorkor?
- 16kg/m2
- A. Marasmus
B. Kwashiorkor
3. A. Somatic compartment - skeletal muscles - affected in MARASMUS** B. Visceral compartment (organs) - affected in KWASHIORKOR**
- A. Somatic - MARASMUS
B. Visceral - KWASHIORKOR
Identify condition that can result from global starvation
- diminished subcutaneous fat, decreased body weight
- growth retardation
- emanciated extremities, larger head
- increased risk of infections
- **NO EDEMA
MARASMUS
1. Global starvation
2. Somatic compartment is affected more severely
3. Diminished subcutaneous fat:
Decreased body weight (<60% for expected age)
4. Growth retardation - muscle wasting, wrinkled face.
5. Extremities are emaciated head looks larger than body (shrunken old person)
6. Increased risk of infections
7. Deficiencies of other required nutrients such as iodine and vitamins.
8. Hypoplasia of bone marrow: Anemia
9. Serum electrolytes and protein normal
10. No edema**
- Marasmus is associated with which of
the following? Check all that apply A. Anemia B. Increased risk of infection C. Loss of subcutaneous fat D. Severe hypoalbuminemia E. Thrombocytosis
- Anemia, increased risk of infection, loss of subcutaneous fat - MARASMUS
**NO EDEMA
Identify condition of malnutrition
⮚ More common in impoverished African and
southeast Asian children
⮚ Diet relatively high in carbohydrates & deficient in protein
⮚ Protein deprivation is associated with severe
loss of visceral protein compartment - DECREASED serum albumin - generalized edema and ascites.
- *
- characteristic skin lesions?
- hair changes?
KWASHIORKOR
Characteristic skin lesions; “FLAKEY POINT”
- alternating zones of hyper/hypo pigmentations
- desquamations
Hair changes – Overall loss of color or – Alternating bands of pale and darker hair (“flag sign”) – Fine texture. – Loss of firm attachment to the scalp.
- *Edema, ascities, skin changes
- Pitting edema/ascites characteristic of kwashiorkor;↓plasma oncotic pressure
- Caused by hypoalbuminemia leading to a loss of plasma oncotic pressure
Micro
- Loss of villi & microvilli Small intestinal Enzyme e.g Disaccharidase
- A 1 year old arrives to adopting parents from Haiti. He is found to be edematous with a protruding abdomen. He is normal weight. Which of the following nutritional history may explain the findings?
A.Protein deprivation is relatively greater than reduction in
calories
B. Protein deprivation is relatively less than reduction in calories
- Histology of kwashiorkor
- Which of the following may explain the ascites and edema?
A. Hypercalcemia B. Hyperkalemia C. Hypernatremia D. Hypoalbuminemia E. Hypocalcemia F. Hyponatremia - Why is the child normal weight
- State 4 features
- 2 indicate increased fluid
- skin changes?
- hair changes?
- Protein deprivation is relatively greater than reduction in calories (kwashiorkor)
- Kwashiokor
* *FATTY CHANGES; lipid vacuoles are holes in the cell cytoplasm - HYPOALBUMINEMIA
- The edema and ascites adds to the weight.
5. 4 features of kwashiokor A. Ascites B. Edema C. “Flaky paint” skin D. Alternating hair color (flag skin)
Identify condition of malnutrition
- Often develops in chronically ill, elderly, and bedridden patients.
- It is estimated that more than 50% of elderly residents in nursing homes in the United States are malnourished.
- Weight loss of more than 5% associated with PEM increases the
risk of mortality in nursing home patients by almost five-fold.
**Identify signs
In patients with AIDS or advanced cancers it is known as???
- controlled by?
SECONDARY PEM
Signs of secondary PEM
- Depletion of subcutaneous fat in the arms, chest wall, shoulders or metacarpal regions
- Wasting of the quadriceps femoris and deltoid muscles
- Ankle or sacral edema
- Bedridden or hospitalized malnourished patients have an increased risk of infection, sepsis, impaired wound healing and death after surgery
CACHEXIA
Secondary PEM in patients with AIDS or advanced cancers, and in these settings it is known as cachexia: It is controlled by;
- production of metabolic cytokines by the tumor, like TNF, IL-1, IL-6
- Protein energy malnutrition seen in cancer patient is known as?
- The bone marrow in a typical
malnourished child may be which of
the following? Select all that apply A.Hypercellular B.Hypocellular
- CACHEXIA
2. HYPOCELLULAR
Identify the following
- Self inflicted starvation - marked weight loss
* *Clinical features of #1
- findings related to thyroid levels?
- bone density ? - Condition where patient binge on food and then induce vomiting
- medical complications? (3)
- Anorexia Nervosa
• Clinical findings are similar to those seen in severe PEM.
• Amenorrhea: related to DECREASED secretion of
gonadotropin-releasing hormone (GnRH) - DECREASED LH and FSH.
• Anemia, lymphopenia, and hypoalbuminemia.
• Increased susceptibility to cardiac arrhythmia and sudden death (hypokalemia related).
• Finding related to decrease thyroid hormone levels:
– Cold intolerance.
– Bradycardia.
– Constipation.
– Changes in the skin and hair; Fine pale hair (lanugo).
• Bone density is decreased - LOW low estrogen levels & low Ca+ intake.
- Bulimia
** Occur in previously healthy young women with an
obsession of being thin!!
Huge amount of food (mainly carb) is ingested followed by induced vomiting. 1. Amenorrhea occur in 50% of patients. 2. Major medical complications relate to vomiting:
i. Electrolyte imbalances (hypokalemia) - cardiac arrhythmias.
ii. Pulmonary aspiration of gastric contents.
iii. Esophageal and gastric rupture.
- Which of the following can be seen in typical
anorexia nervosa? More than one answer A.Amenorrhea B.Constipation C.Dry skin
D. Heat intolerance E.Hypoalbuminemia F. Hypokalemia G. Osteopenia
H. Polycythemia I. Tachycardia - Sudden death in bulimia or anorexia
nervosa can be secondary to which
of the following A.Hypercalcemia B.Hyperkalemia
C.Hypernatremia D. Hypocalcemia E. Hypokalemia
F. Hyponatremia
3. A 23-year-old female patient presents complaining of amenorrhea. It normally did not bother her but now she wants to have kids. Her BMI is 12 kg/m2. Her heart rate is 56. Lab tests show an anemia, lymphopenia and hypoalbuminemia. What is the most likely cause of her amenorrhea? A.High levels of ADH B.High levels of Prolactin C.High levels of TSH D. Low levels of ACTH E.Low levels of GnRH F. Low levels of TSH
- A 22-year-old female has had 5 episodes of pneumonia
over the last year. She is enrolled at WVU and has a
4.0 grade average. In the past her BMI was 30
kg/m2 but now she is very proud of how much weight
she has lost over the last 16 months. She is having
irregular menses. Her current BMI is 16 kg/m2.
Physical exam is unremarkable. Laboratory tests are
all within normal limits. Which of the following is the
would likely explain her recurrent pneumonia?
A. Chronic diuretic use
B. Chronic laxative use
C. Gastric rupture
D. Immunodeficiency
E. IV drug abuse
F. Pulmonary aspiration
- ANOREXIA - low thyroid
- Amenorrhea, constipation, dry skin, hypoalbuminemia, hypokalemia, osteopenia - HYPOKALEMIA
- Amenorrhea - Low levels of GnRH
- Pulmonary aspiration (Pt has BULIMIA)
- how many vitamins necessary for health?
- endogenous synthesized vitamins?
- which vitamin cannot be synthesized endogenously
- 2 forms/mechanism of absorption
- Name the fat soluble vitamin s
Vitamins
⮚ Total thirteen vitamins are necessary for health
⮚ Necessary in trace amounts for metabolic functions
⮚ Endogenously synthesized vitamins (e.g. vitamin D and vitamin K and biotin, niacin from tryptophan)
⮚ Vitamin C , can’t be synthesized endogenously
need to be provided in diet.
2 absorption mechanisms ⮚ Vitamins A, D, E, and K: fat soluble ⮚ Vitamins C and B: water soluble ** Fat-soluble vitamins are more readily stored in the body, but they may be poorly absorbed in fat malabsorption disorders, caused by disturbances of digestive functions
- Fat soluble vitamins ; A,D,E,K
Identify vitamin deficiency
- Deficiency may occur as consequence of general undernutrition or as a secondary deficiency in individuals with conditions that cause malabsorption of fats
- Bariatric surgery and, in elderly persons, continuous use of mineral oil as a laxative may lead to deficiency
VITAMIN A DEFICIENCY
• In children, stores of vitamin A are depleted by infections, and the absorption of the vitamin is poor in newborn infants.
• Adult patients with malaborption syndromes, such as celiac disease, Crohn’s disease, and colitis, may develop vitamin A deficiency, in conjunction with depletion of other fat-soluble vitamins.
- Which of the following is associated
with vitamin A deficiency? Check all
that apply A.Celiac disease B.Chronic use of mineral oil C.Diet high in liver D. Gastric bypass surgery E. Inflammatory bowel disease F. Vegetarian diet - Most of the body’s vitamin A is located in which organ?
1. A. Celiac disease B. Chronic use of mineral oil D. Gastric bypass surgery E. Inflammatory bowel disease
- LIVER
Identify forms of vitamin A (4)
- transport form
- stored in perisinusoidal Ito cells
- affects growth regulation and differentiation
Forms of Vitamin A
- Retinol (transport from of vit. A)
- Retinol ester (storage form of vit.A 90% stored in liver in perisinusoidal stellate (Ito) cells)
- Retinol ester oxidized in vivo to retinal (form used in visual pigment)
- Retinoic acid -(affects growth regulation and differentiation)
- What carries retinol from the intestines to the liver?
- What binds retinol in the blood?
- What receptor on the liver uptakes retinol
- Which of the following is a vitamin A
provitamin? A.β-cadinene B.β-carboline C.β-carboxylic acid D. β-carotene E. β-catinin
- Chylomicrons
- Retinol binding protein
- Apolipoprotein E receptor
- Beta-carotene
State 6 functions of Vit A
- Maintenance of normal vision.
- Maintenance of specialized epithelia: Vitamin A and
retinoids play an important role in the orderly
differentiation of mucus-secreting epithelium;when a
deficiency state exists, the epithelium undergoes
squamous metaplasia, differentiating into a keratinizing
epithelium - Antioxidant
- Enhancement of immunity to infections:Vitamin A
supplementation can reduce morbidity and mortality from
some forms of diarrhea, and in preschool children with
measles - Plays role in Fatty acid metabolism: including fatty acid
oxidation in fat tissue and muscle, adipogenesis, and
lipoprotein metabolism - Retinoids are used clinically for the treatment of skin
disorders such as severe acne and certain forms of
psoriasis, and also in the treatment of acute promyelocytic
leukemia.
- What are the major functions of vitamin
A? Check all that apply A. Carbohydrate metabolism B. Epithelial growth and differentiation C. Fatty acid metabolism D.Maintenance of immune system E. Maintenance of normal vision F. Protein metabolism G.Purine metabolism
1. B.Epithelial growth and differentiation C. Fatty acid metabolism D.Maintenance of immune system E. Maintenance of normal vision
Identify consequences. Of Vit A deficiency
**Early vs Late eye lesions
Night blindness (earliest manifestation)
- rhodopsin reduced in rods
- reduced ability to see in dim light
Early eye lesions
I. Conjunctival xerosis ; conjunctiva becomes dry, thickened, wrinkled, pigmented, loses shiny luster
II. Bitot’s spot (build of keratin debris)
- bilateral, triangular, raised whitish plaques
- plaques appear as fine foam with bubbles
Late Eye lesions
I. Corneal xerosis
- begins with drying; hazy granular surface
- softening of cornea
- ulceration and necrosis
II. Corneal ulcers
- circular punched out
- leads to perforation and prolapse of iris
- keratoma alacia; loss of the eye
- child usually seriously ill with fever (~50% mortality)
- Identify condition in vit A deficiency patient
- bilateral, triangular, raised whitish plaques
- plaques appear as fine foam with bubbles - What are changes can occur in the eye in
a vitamin A deficiency? Select all that
apply? A. Bitot spots B. Corneal ulcer C. Excessive tearing (epiphora) D.Keratomalacia E. Myopia F. Night blindness G.Xerophthalmia H.Xerosis conjunctivae - Pathologic histo change with vit A deficiency
- What can occur to GU tract in VIT A def pt
A. Hematuria B. Hydronephrosis C. Nephritic syndrome D.Nephrolithiasis E. Nephrotic syndrome
**Summary of vit A def consequences (3)
- Bitot’s spot (build of keratin debris)
- bilateral, triangular, raised whitish plaques
- plaques appear as fine foam with bubbles
2. A. Bitot spots B. Corneal ulcer D. Keratomalacia F. Night blindness G. Xerophthalmia H. Xerosis conjunctivae
- Vit A deficiency - SQUAMOUS METAPLASIA
**decreased rhodopsin regeneration - night blindness
A. Conjunctiva - xeropthalmia
B. Cornea - keratomalacia BLINDNESS
C. Bronchitis - bronchopneumonia
D. Pancreatic ducts
E. Urinary tract - kidney stones
F. Follicular hyperkeratosis of skin - Genitourinary tract
A. Hematuria (secondary to nephrolithiasis)
B. Hydronephrosis (secondary to nephrolithiasis)
D. Nephrolithiasis
**VIT A DEF consequences
I. Night blindness
II. Xeropthalmia (dry eye)
III. Bitot spot
Identify vit toxicity
**vit deficiency
I. Night blindness
II. Xeropthalmia (dry eye)
III. Bitot spot
Vit A Toxicity
1. Acute toxicity; Headache, dizziness, stupor, blurred vision
- Chronic toxicity
a. Weight loss
b. Anorexia
c. Nausea and vomiting
d. Bone and joint pain
e. Increased risk of fractures - Teratogenic in pregnancy
Vitamin B complex
- water or lipid soluble?
- which is only gotten from animals?
All water soluble – widely availableVitamin B12 (animal
origin): only exception
▪ Vegan diet needs to supplemented with Vitamin B12
Identify vitamin
- found in fortified breads and cereals fish, lean meats and milk
⮚ Cofactor in biochemical reactions that produce ATP
⮚ Cofactors for transketolase in pentose phosphate pathway
⮚ Maintains neural membranes and normal nerve conduction (chiefly of peripheral nerve)
**causes of vit deficiency
THIAMINE (Vit B1) - thiamin pyrophosphate (TPP)
Causes of thiamine deficiency
• Chronic alcoholism (in the United States) is the most common cause.
• Diet of unenriched rice is the most common cause of deficiency in developing countries.
**
Wet beriberi; Dilated cardiomyopathy with biventricular heart failure and dependent pitting edema; cardiac muscle lacks ATP; IV thiamine reverses cardiomyopathy in some cases
40-year-old pedestrian is hit by an automobile and is brought to the
emergency department by ambulance. Laboratory studies completed immediately on arrival include normal complete blood count, serum glucose, and electrolytes. An intravenous line is inserted, and 5% dextrose and normal saline is administered. The patient has the smell of alcohol on his breath. While in the emergency department, he becomes confused and develops eye muscle weakness and horizontal nystagmus. The patient most likely has a deficiency of which of the following vitamins?
A. Folic acid
B. Niacin
C. Thiamine
D. Vitamin B6
E. Vitamin B12
THIAMINE
Identify vitamin
- Water soluble
- Unstable in sunlight
- Source: widely distributed, in meat, dairy product and vegetables
- **Function:Important role in ETC
Vitamin B2; RIBOFLAVIN
Identify vitamin
- Can be synthesized endogenously from Tryptophan
- food source; diary, poultry, fish, lean meat, nuts and eggs
**function? Complication of deficiency
NIACIN
Function
- Essential component of NAD & NADP
- Used in the treatment of hypercholesterolemia (lowers plasma LDL level by reducing hepatic synthesis of VLDL)
Complication of niacin deficiency
- Patients who have corn-based diets commonly develop niacin deficiency(pellagra) because the niacin in corn is in a bound form that cannot be reabsorbed, and corn is deficient in tryptophan.
- Why do vitamin supplements during pregnancy typically not include vitamin A?
2. This finding in a patient with a vitamin C deficiency is due to which of the following A.Anemia B.Fragile vessels C.Hypofibrinogenemia D. Low clotting factors II, VII, IX and X E. Thrombocytopenia
- Vitamin A supplementation can be TERATOGENIC
2. Vitamin C - fragile vessels
The deficiency state is scurvy, ⮚ not very common ä Still sometime encountered in:
• Elderly individuals.
• Alcohol addicts.
- *functions of vitamin?
- *consequences of deficiency?
Vitamin C functions - Antioxidant: may retard atherosclerosis (by reducing oxidation of LDL) - Collagen formation: - Aids in the absorption of iron
Consequences of Vit C deficiency
1. Impaired wound healing
2. Hemorrhages from fragile vessels due to weak collagen: for example gingival mucosa
3. Characterized by bone disease in children; defective formation
of osteoid matrix (due to impaired synthesis of
hydroxyproline and hydroxylysine)
4. Swelling of the large joints with inflammation and subperiostal
hemorrhages: May results in “pseudo paralysis” with
characteristics frog-legged positioning
- Skin lesions: perifollicular, hyperkeratotic papular rash
- purpura and ecchymoses on the skin
- Note the marked hematomas due to capillary hemorrhages in the legs of the patient with scurvy.
Identify vitamin
- Fat soluble; steroid hormone
- Major dietary source include fortified milk, liver, fish, butter and eggs.
**origin? 2 forms? Another name
VITAMIN D
90% of the vitamin D requirement is endogenously derived from photochemical conversion of 7- dehydrocholesterol present in the skin.
2 forms
1) Vitamin D3 (cholecalciferol, derived from 7-dehydrocholesterol present in skin)
2) Vitamin D2 (ergocalciferol derived from plant ergosterol).
**Vitamin D3 is also known as CHOLECALCIFEROL
Explain the metabolism of Vitamin D
- *1-OHas
- activity increased how?
- how is activity affected through PTH
- Photochemical synthesis of vitamin D from Vitamin D precursors in the skin and absorption of vitamin D from foods and supplements in the gut
- Binding of vitamin D from both of these sources to
plasmaα1-globulin(D-binding protein or DBP)and
transport into the liver - Conversion of vitamin D into 25-hydroxycholecalciferol (
25-OH-D) in the liver, through the effect of 25-Ohases - Conversion of 25-OH-Dinto 1,25-dihydroxyvitamin D,in
the kidney, the most active form of vitamin D, through
the activity ofα1-hydroxylase (1-OHase)
1-OHas
- Activity increased in;
- hypophosphatemia
- increases in PTH hormone level
- Changes in calcium affect activity through PTH
1. The role of the liver in vitamin D metabolism is to A. Convert 1,25 (OH)2D to 25(OH)D B. Convert D3 to 1,25 (OH)2D C. Convert D3 to 25(OH)D D. Convert D3 to cholecalciferol
- Place the following locations in sequence of
the formation from Pre-D3 to 1,25(OH)
2D: _____ to ______ to_______ Choices: 1. Kidney 2. Liver 3. Skin - Which vitamin D is made in the skin from
photosynthesis A. D1 B. D2 C. D3 - Which enzyme converts Vitamin D in the
kidney to the most active form? A. 1-OHas
B. 12-OHase C. 21-OHase D. 22-OHase E. 24-Ohase F. 25-OHase
- C. Convert D3 to 25(OH)D
- SKIN to LIVER to KIDNEY
- D3
- A. 1-OHas
- Major function of vitamin D active form
2. Identify effects of vitamin D on homeostasis fo 2 othe rminerals (4)
- Major Function of 1,25-dihydroxyvitamin D ( Vitamin D active form)
- Maintenance of normal plasma level of calcium/phosphate - Effects of Vitamin D on Calcium and Phosphorus Homeostasis
- Stimulation of intestinal calcium absorption.
- Stimulation of calcium reabsorption in the kidney.
- Interact with parathyroid hormone (PTH) in the regulation
of blood calcium.
i. Together, they enhance the expression of RANKL (receptor
activator of NF-κB ligand) on osteoblasts.
ii. RANKL binds to its receptor (RANK) located in preosteoclasts
, inducing the differentiation of these cells into mature osteoclasts - Mineralization of bone
i. It contributes to the mineralization of osteoid matrix and
epiphyseal cartilage in the formation of both flat and long bones in the skeleton
ii. It stimulates osteoblasts to synthesize the calcium-binding
protein osteocalcin, involved in the deposition of calcium during bone development.
Vitamin D deficiency states (5)
Vit D deficiency in HYPOCALCEMIA (4)
Vit D deficiency states
- Insufficient vitamin D in diet
- Insufficient production of vitamin D in skin due to limited exposure of sunlight (heavily veiled women)
- Inadequate absorption (fat malabsorption syndromes)
- Abnormal conversion of Vitamin D to its active form (Liver disease and chronic renal failure)
- Renal disorders causing decreased synthesis of 1,25-dihydroxyvitamin D
Vit D deficiency in HYPOCALCEMIA (4)
- Increase PTH secretion
- Increase osteoclast activity
- Increase renal phosphate excretion
- Decrease renal calcium excretion
Consequence of vitamin D deficiency
- Children vs adults
- Milder forms?
- An excess of unmineralized matrix.
A. Rickets- Children
B. Osteomalacia- Adult - Milder forms of vitamin D deficiency leading to an
increase risk of bone loss and hip fractures are quite common in the elderly in the United States and Europe
Identify condition
- Most common during the first year of life
- An excess of osteoid producesfrontalbossingand
asquaredappearancetothehead. - Deformation of the chest results from overgrowth of
cartilage or osteoid tissue at the costochondral junction, producing the“rachiticrosary.” - The weakened metaphyseal areas of the ribs are
subject to the pull of the respiratory muscles and thus bend inward, creating anterior protrusion of the sternum(pigeon breastdeformity).
RICKETS
** When an ambulating child develops rickets,
deformities are likely to affect the spine, pelvis, and tibia, causinglumbarlordosisandbowingofthelegsshort stature
**BOWING OF LEGS, RACHITIC ROSARY
- In a child with rickets, what chest deformity
can occur? - What can occur to the spine in rickets?
- In adults, vitamin D deficiency leads to
which bone disease?
In a child with rickets, what chest deformity
can occur? PIGEON BREAST DEFORMITY
What can occur to the spine in rickets? LORDOSIS
In adults, vitamin D deficiency leads to which bone disease? OSTEOMALACIA
IDENTIFY condition
• Newly formed osteoid matrix is inadequately mineralized - excess of persistent osteoid is characteristic.
• Bone is weak and is vulnerable to fractures, usually affecting:
– The vertebral bodies.
– Femoral neck.
• Persistent failure of mineralization - lead to osteopenia (loss of skeletal mass).
OSTEOMALACIA - Adult
- The main function of vitamin D is to regulate
which of the following? There may be more
than one answer. A. Bicarbonate homeostasis B. Calcium homeostasis C. Cholesterol homeostasis D. Creatinine homeostasis E. Magnesium homeostasis F. Phosphate homeostasis G. Potassium homeostasis - What directly increases the 1-OHase activity in
the conversion of 25(OH)D to 1,25 (OH)2D.
More than one answer. A. High levels of 1,25 (OH)2D B. Hypercalcemia C. Hyperphosphatemia D. Hypophosphatemia E. Increases in parathyroid hormone level F. Renal disease - The main effect of 1,25 (OH)2D on the
kidney is: ______________ The main effect of 1,25 (OH)2D on the
intestines is: _____________ - The main effect of 1,25 (OH)2D in
combination with PTH on bone
metabolism is to do which of the following: A. Increase RANK expression on
osteoblasts B. Increase RANK expression on osteocytes C. Increase RANKL expression on
osteoblasts D. Increase RANKL expression on
osteoclasts E. Increase RANKL expression on
osteocytes - 1,25 (OH)2D in bone metabolism stimulates
osteoblasts to make which calcium binding
protein?
- Vitamin D regulate
B. Calcium homeostasis
F. Phosphate homeostasis - What increase 1-OHase activity
D. Hypophosphatemia
E. Increases in PTH hormone level - A. The main effect of 1,25 (OH)2D on the
kidney is: INCREASED CALCIUM REABSORBTION
B. The main effect of 1,25 (OH)2D on the intestines is: INCREASED CALCIUM ABSORPTION - Main effect of 1,25 (OH) 2D in combination with PTH on bone metabolism
C. INCREASE RANKL EXPRESSION ON OSTEOBLASTS - OSTEOCALCIN
A. What direction do each of the following go
in hypocalcemia with a vitamin D
deficiency.
1. PTH: Increase or decrease
2. Osteoclast activity: Increase or decrease
3. Renal phosphate excretion: Increase or
decrease
4. Renal calcium excretion: Increase or
decrease
B. Patients with ostemalacia are more prone to
fractures because of which of the
following: A. Osteopetrosis B. Paget disease C. Persistent osteoid D. Type 2 collagen defect E. Type 1 collagen defect
A. HYPOCALCEMIA and Vitamin D deficiency
- PTH: Increase
- Osteoclast activity: Increase
- Renal phosphate excretion: Increase
- Renal calcium excretion: Decrease
B. Osteomalacia patients
***PERSISTENT OSTEOID (NON-CALCIFIED BONE)
Identify condition
- Calcifications of soft tissues
– Bone pain
– Hypercalcemia
Vitamin D toxicity (Megadoses)
**Cannot get toxic from prolonged sun exposure
** hypervitaminosis D is from the deposit of what material in the soft tissue? Calcium
Obesity
- Histology of adipose tissue
- Definition of obesity
- Adipocyte numbers
- Central obesity
- Histology of adipose tissue
- Each clear space corresponds to the fat vacuole in a single adipocyte. When making slides of fat, the tissue is placed through alcohol which dissolves the fat leaving a clear space.
2. Definition of obesity; BMI >30 kg/m2 – Other methods to measure: • Triceps skinfold thickness • Mid-arm circumference • Ratio of waist and hip circumferences – Central (visceral) obesity: Fat accumulates in trunk, mesentery and around viscera
- Adipocyte numbers
– Total number established by adolescence
– In adults, numbers remain constant - Central obesity (or visceral obesity)
- in addition to fat in subcutaneous tissue, fat is also around the ORGANS
- fat accumulate around trunk and in abdominal cavity
State 4 adipocyte hormones
1.
– From ob gene
– Secretion stimulated by abundant fat stores
2.
– Concentration inverse to fat stores (high fat stores
have low concentration; lean have high concentration)
– Increases insulin sensitivity
- Made in stomach and hypothalamus
– Increases before meals; falls 1-2 hours after
meals
– Postprandial decrease is attenuated in obese
– Increases food intake
- Made in stomach and hypothalamus
4. – Made in ileum and colon – Low during fasting and increase after food intake – Reduces energy intake
1. LEPTIN from fat cells – Effects: • Increase energy expenditure and heat generation • Stimulates physical activity • Decreases food intake – If no ob gene, cannot make leptin • Leads to early onset severe obesity – Leptin receptor (OB-R) is from db (diabetes) gene • If no db gene, also see severe obesity
2. ADIPONECTIN from fat cells – Concentration inverse to fat stores (high fat stores have low concentration; lean have high concentration) – Fatty acid metabolism • Directs fatty acids to muscle for use • Decreases fatty acid uptake in liver • Decreases glucose production by liver – Increases insulin sensitivity
- GHRELIN
- PYY
- Identify the leptin gene and the leptin
receptor gene 1. db 2. erb 3. Her2/neu 4. ob 5. rb - LEPTIN is synthesized by which cells?
- Which will have a higher leptin level, a BMI
of 18 kg/m2 or a BMI of 30 kg/m2? - Increased leptin will do which of the
following? • Increase or decrease energy expenditure • Increase or decrease heat production • Increase or decrease food intake - Will an animal lacking the ob gene given unlimited food become obese or anorexic?
- Db - LEPTIN receptor gene
ob - LEPTIN gene - LEPTIN - synthesized by fat cells
- BMI of 30 has higher LEPTIN levels than BMI 18
- Increased LEPTIN
A. INCREASE energy expenditure
B. INCREASE heat production
C. DECREASE food intake - OBESE
- Which of the following are true about Adiponectin.
There may be more than one answer. A. It decreases sensitivity to insulin. B. It is lower in concentration in an obese person
as compared to a lean person C. It is mainly secreted by muscle D. It is mainly secreted by the pituitary gland E. It stimulates fatty oxidation in muscle F. It suppresses fatty oxidation in muscle - What happens to ghrelin level after Meal
- PYY levels after meal
- B. It is lower in concentration in an obese person as compared to a lean person
E. It stimulates fatty oxidation in muscle - GHRELIN DECREASES after meal
- PYY INCREASES after meal
State consequences of obesity (11)
• Type 2 diabetes with insulin resistance and hyperinsulinemia
• Metabolic syndrome:
– Includes visceral adiposity, Type 2 diabetes, hypertension, dyslipidemia
• Increased risk of atherosclerosis
• Non-alcoholic fatty liver disease
• Cholelithiasis with high concentration of cholesterol in stones
• Hypersomnolence and Hypoventilation Syndrome (Pickwickian
Syndrome)
– Associated with sleep apnea and polycythemia
- Osteoarthritis
- Increased cancer risk for multiple locations
- Steroid metabolism: Changes in androgen and estrogen balance • Dyslipidemia: Increase triglycerides with decrease HDL
- Hypertension
- What arthritis is associated with obesity
- What Diabetes is associated with obesity
- Type of liver disease associated with obesity
- Gallbladder disease associated with obesity?
- What happens to HDL in obesity
- What may explain polycythemia in a
severely obese person?
- Osteoarthritis
- Type 2 DM (insulin resistant)
- NONALCOHOLIC FATTY LIVER DISEASE
- CHOLELITHIASIS (gallstones)
- HDL decreases in obesity
- Polycythemia in severely obese person
* *HYPOVENTILATION SYNDROME
Obesity associated with; increased risk of cancer, hypersomnolence, high conc cholesterol (obesity associated gall stones)
Summarize common polyps vs colorectal neoplasia
Common polyps
- Hyperplastic
- Colonic adenomas — > Sporadic Colonic adenocarcinoma
- Inflammatory Polyps
- Hamartomatous polyps: Sporadic and Syndromic
Colorectal Neoplasia
- Sporadic
- Familial: (FAP, MYH-associated, Lynch syndrome)
- Colitis (Ulcerative Colitis and Crohn Disease); Associated Neoplasia
Identify colon condition
• Most common colonic polyp (75 - 90% of colon polyps)
• Most commonly found in the left colon
• Typically <5 mm in diameter
• Singly, frequently multiple (sigmoid colon and rectum)
• Histologically, composed of mature goblet and absorptive
cells (delayed shedding of these cells leads to crowding that
creates the serrated surface architecture)
**what is the CHIEF SIGNIFICANCE?
Microscopic vs gross
HYPERPLASTIC POLYPS (Non-neoplastic)
Micro
Serrated surface architecture (morphologic hallmark); typically restricted to the upper third, or less, of the crypt
Gross: Smooth, nodular protrusions of the mucosa, often on the crests of mucosal folds
A) Polyp surface with irregular tufting of epithelial cells
B) Tufting results from epithelial overcrowding
C) Epithelial crowding produces a serrated architecture when
crypts are cut in cross- section
Identify colon condition
• Low-grade epithelial dysplasia
• Small, often pedunculated, polyps to large sessile lesions.
• Small male predominance
• Present in ~30% of adults living in the Western world by age 60
• Recommended: all adults in the United States undergo
surveillance by age 50
• Patients at increased risk, including those with a family
history of colorectal adenocarcinoma: typically screened
colonoscopically at least 10 years before the youngest
age at which a relative was diagnosed
- *
- do they progress to malignancy?
- S&S?
- 4 types
COLONIC ADENOMA
• Majority of adenomas do not progress to become adenocarcinomas
• S/S: Most adenomas are clinically silent with
- large polyps that produce occult bleeding and
anemia
- rare villous adenomas that cause hypoproteinemic
hypokalemia by secreting large amounts of protein
and potassium
• Four types: Tubular adenoma, Tubulo-villous adenoma,
Villous adenoma and Serrated adenoma
Describe pathology of colonic adenoma
**Types
A. A smooth surface and rounded glands. Active inflammation occasionally present in adenomas, in this case, crypt dilation and rupture can be seen at the bottom of the field
B. Long, slender projections that are reminiscent of small intestinal villi
C. with an increased nuclear-to- cytoplasmic ratio, hyperchromatic and elongated nuclei, and nuclear pseudostratification. Compare to the nondysplastic epithelium below.
D. lined by goblet cells without cytologic features of dysplasia.
A. Tubular adenoma
B. Villus adenoma
C. Dysplastic epithelial cells
D. Sessile serrated adenoma
COLONIC ADENOMA
• Size: 0.3 to 10 cm in diameter
• Pedunculated or sessile
• Having a texture resembling velvety or smooth
• Histologically:
**• Nuclear hyperchromasia (hallmark of epithelial dysplasia) and
elongation, and stratification , changes easily appreciated at the
surface of the adenoma
- Cytologically: prominent nucleoli, eosinophilic cytoplasm, and a reduction in the number of goblet cells
- Pedunculated adenomas have slender fibromuscular stalks
containing prominent blood vessels derived from the submucosa :
usually covered by nonneoplastic epithelium, but dysplastic
epithelium sometimes present
Identify colon condition
A) The dilated glands, proliferative epithelium, superficial erosions, and inflammatory infiltrate are typical of an inflammatory polyp. However, the
smooth muscle hyperplasia within the lamina propria suggests that mucosal prolapse has also occurred.
B) Epithelial hyperplasia.
C) Granulation tissue-like capillary proliferation within the lamina propria caused by repeated erosion.
INFLAMMATORY POLYPS (Non-neoplastic) • Mixture of epithelial and stromal components admixed with inflammatory cells • Often related: - Inflammatory bowel disease (Crohn's disease or ulcerative colitis) - Anastomosis - Ischemic colitis - Infection
Identify colon conditions
- Composed of tissue elements normally found at that site, but growing in a disorganized manner
- Sporadically (non-neoplastic)
- Components of various genetically determined
or acquired syndromes. Some are neoplastic: - In the polyp, - Some are intestinal and extraintestinal site of malignancy
- Hamartomatous polyps
2. Colonic Hamartomatous polyps
Summarize different GI polyposis syndromes
**What are the 2 most important
- Juvenile polyposis **
- Peutz-Jeghers syndrome **
- Cowden syndrome, Bannayan-Ruvalcaba-Riley syndrome
- Cronkhite- Canada syndrome
- Tuberous sclerosis
- Familial adenomatous polyposis (FAP)
* *classic FAP, attenuated FAP, Gardner syndrome , Turcot syndorme, MYH-associated polyposis
Identify colon condition
• Focal malformations of the epithelium and lamina
propria
• Sporadic or syndromic; histologically same
• Mostly <5 years, may at older ages ; Most in the rectum:
• S/S: typically rectal bleeding; some cases :
intussusception, intestinal obstruction, or polyp prolapse
JUVENILE POLYPS
A. Sporadic juvenile polyps (retention polyp): Usually
solitary lesions
B. Juvenile polyposis syndrome (Autosomal Dominant): - (3 -100) hamartomatous polyps - Require colectomy to limit the chronic and sometimes
severe hemorrhage associated with polyp ulceration
Identify condition, genetic mutations?
Gross; Pedunculated, smooth-surfaced, reddish lesions with characteristic cystic spaces apparent after sectioning • Microscopic examination:
- Cysts to be dilated glands filled with mucin and inflammatory debris
- Remainder of the polyp is composed of lamina propria
expanded by mixed inflammatory infiltrates
- Muscularis mucosae may be normal or attenuated
**
A. Surface erosion and cystically dilated crypts
B. Inspissated mucous, neutrophils, and inflammatory debris can accumulate within dilated crypts.
JUVENILE POLYPS
- Dysplasia is extremely rare in sporadic juvenile polyps**
- Dysplasia associated with Juvenile polyposis syndrome,
both within the juvenile polyps and in separate
adenomas - 30% to 50% of pts with juvenile polyposis develop colonic adenocarcinoma by age 45
AUTOSOMAL DOMINANT
• A minority cases: polyps in stomach and small bowel
that undergo malignant transformation
• Pulmonary arteriovenous malformations and other
congenital malformations
• Mutation identified: <50% cases
- Most common: SMAD4, which encodes a cytoplasmic intermediate in the TGF-β signaling pathway
- Others: BMPR1A, a kinase that is a member of the
TGF-β superfamily, may be mutated in other cases
- Other responsible genes: remain to be discovered!!!!!! (MAY BE YOU ARE ONE OF THEM TO DISCOVER☺ )
Identify colon condition
A. surface (top) overlies stroma composed of smooth muscle bundles cutting through the lamina propria
B. Complex glandular architecture and the
presence of smooth muscle are features that distinguish it from another
**pathogenesis
Peutz-Jeghers polyps
**differentiate from juvenile polyps
Pathogenesis
• Germline heterozygous loss-of-function mutations in the
gene STK11: ~50% familial Peutz-Jeghers syndrome and a subset of sporadic Peutz-Jeghers syndrome
• STK11 is a tumor suppressor gene that encodes a kinase
that regulates cell polarization and acts as a brake on growth and anabolic metabolism
• Loss of fu
Identify condition
• Median age of 11 years with multiple GI hamartomatous polyps and mucocutaneous hyperpigmentation
• Mucocutaneous hyperpigmentation: - Dark blue to brown macules on the lips, nostrils, buccal mucosa, palmar surfaces of the hands, genitalia, and perianal region - Similar to freckles, but presence in the buccal mucosa.
• Polyps– > intussusception, occasionally fatal
• Markedly increased risk of malignancies:
Lifetime risk: ~ 40%
• Regular surveillance at beginning of birth:
- beginning at birth for sex cord tumors of the testes
- late childhood for gastric and small intestinal cancers
- second and third decades of life for colon, pancreatic,
breast, lung, ovarian, and uterine cancers
**Identify clinical features
Peutz-Jeghers Syndrome: Clinical Features
• Most common in SMALL INTESTINE> stomach and colon >bladder and lungs
• Morphology of Peutz-Jeghers polyps overlap with that of
sporadic hamartomatous polyps
• Diagnosis:
- Multiple polyps in the small intestine
+ mucocutaneous hyperpigmentation
+ a positive family history
• Detection of STK11 mutations can be helpful, particularly
diagnostically in patients with polyps who lack
mucocutaneous hyperpigmentation.
• Absence of STK11 mutations does not exclude the
diagnosis
Identify 3 FAMILIAL colorectal neoplasia
- Familial Adenomatous Polyposis (FAP)
- MYH-associated Polyposis Syndrome
- Hereditary Nonpolyposis Colorectal Cancer (HNPCC) (Lynch syndrome )
Identify colorectal condition
- AUTOSOMAL DOMINANT
- develops numerous colorectal adenomas as teenagers
- 100% of untreated patients develop COLORECTAL ADENOCARCINOMA often before age 30 and nearly always by age 50
- standard therapy; prophylactic colectomy
- *how many needed for diagnosis?
- *morphology similar to what?
- *micro?
- what prevent colorectal cancer?
- manifestations?
Familial adenomatous polyposis (FAP)
• At least 100 polyps are necessary for a diagnosis of
classic FAP, but as many as several thousand may be
present
• Morphologically indistinguishable from sporadic adenomas; flat or depressed adenomas are also prevalent in FAP
• Microscopic adenomas, consisting of only one or two dysplastic crypts, are frequently observed in otherwise normal-appearing mucosa
• Colectomy prevents colorectal cancer, but patient remain at risk for neoplasia at other sites:
- Adenomas elsewhere in GI tract, particularly adjacent to the ampulla of Vater and in the stomach
• Associated with a variety of extraintestinal manifestations :
- Congenital hypertrophy of the retinal pigment
epithelium, which can generally be detected at birth
Identify pathogenesis of colorectal condition
**Therapy - COLECTOMY
• Colectomy prevents colorectal cancer, but patient remain at risk for neoplasia at other sites:
- Adenomas elsewhere in GI tract, particularly adjacent to the ampulla of Vater and in the stomach
• Associated with a variety of extraintestinal manifestations :
- Congenital hypertrophy of the retinal pigment
epithelium, which can generally be detected at birth
Familial adenomatous polyposis (FAP)
Pathogenesis
- Mutations of the adenomatous polyposis coli, or APC, gene, a key negative regulator of the Wnt signaling pathway
- Approximately 75% of cases are inherited, remaining appear to be caused by de novo mutations
- Specific APC mutations associated with the development of other extraintestinal manifestations of FAP and partly explain variants such as Gardner syndrome and Turcot syndrome
Identify colorectal condition
- Autosomal recessive disorder
- Colonic phenotype is similar to attenuated FAP
- Polyp development at later ages
- Polyps: fewer than 100 adenomas
- Delayed appearance of colon cancer, often at ages of 50 or older.
MYH-associated Polyposis Syndrome
• Bi-allelic mutations of the base-excision repair
gene MYH ( MUTYH)
• Serrated polyps, often with KRAS mutations, are frequently present in MUTYH-associated polyposis
Identify colorectal condition
Originally described based on familial clustering of cancers at several sites including - Colorectum - Endometrium - Stomach - Ovary - Ureters - Brain - Small bowel - Hepatobiliary tract - Pancreas - Skin
- what percent of colorectal cancers?
- what part of colon?
- what age?
- Inherited mutations
- what 5 repair genes
(HNPCC)= Lynch syndrome
• Account for 2% to 4% of all colorectal cancers, most
common hereditary colorectal carcinoma syndrome
• Colon cancers in HNPCC patients occur at younger ages
than sporadic colon cancers
• Often located in the right colon
• Inherited mutations in mismatch repair (MMR ) genes (encode proteins responsible for the detection, excision, and repair of errors that occur during DNA replication, particulary seen in microsatellite regions)
- At least five mismatch repair genes:
Majority of patients: mutations in MSH2 or MLH1; less commonly MSH6 or PMS2; others: PMS1, EPCAM
Identify colon condition
**Presentation? Screening? Markers?
Epidemiology
• Most common malignancy of the GI tract
• Major cause of morbidity and mortality worldwide
• Approximately 1.2 million new cases, and 600,000 associated
deaths, occur each year worldwide
• Responsible for nearly 10% of all cancer deaths • Incidence : highest in North America: - In US: ~10% of worldwide cases ; 15% of all cancer-related deaths in the US , second only to lung cancer. • Other counties with high incidence: Australia, New Zealand,
Europe, and, with changes in lifestyle and diet, Japan,
• Lower Incidence: South America, India, Africa, and South
Central Asia
• Peaks at 60 to 70 years of age, with fewer than 20% of cases
occurring before age 50
COLONIC ADENOCARCINOMA
• Per rectal bleeding
• Screening: at age 50 years (colonoscopy and occult blood testing)
• Presentation:
- Proximal colon: Polypoid and exophytic; rarely obstruct lumen; Iron deficiency anemia (fatigue and weakness)
- Distal colon: Annular lesions that produce “napkin ring” constructions and luminal narrowing - obstruction;
- Presentation; occult bleeding, changes in bowel habits, or cramping and left lower quadrant discomfort
- *Associated with STREPTOCOCCUS BOVIS ENDOCARDITIS
- *Serum tumor marker; CEA for treatment response and follow up; NOT FOR SCREENING
• Associated with Streptococcus bovis endocarditis • Serum Tumor Marker: CEA for treatment response
and follow-up; not for screening
- *IDENTIFY
- dietary factors? Theories?
COLONIC ADENOCARCINOMA
• Dietary factors: most closely associated with colorectal cancer;
- Low intake of unabsorbable vegetable fiber and high
intake of refined carbohydrates and fat
- Theorized:
a. Reduced fiber content leads to decreased stool bulk and altered composition of the intestinal microbiota - increase synthesis of potentially toxic oxidative by products of bacterial metabolism, remain in contact with the colonic mucosa for longer periods
b. High fat intake also enhances hepatic synthesis of cholesterol and bile acids, which can be converted into carcinogens by intestinal bacteria
Colon condition
High expression enzyme cyclooxygenase-2 (COX-2):
~90% of colorectal carcinomas and 40% to 90% of adenomas
**Pharmacologic chemoprevention???
COLONIC ADENOCARCINOMA
** Pharmacologic chemoprevention:
a) Some NSAIDs cause polyp regression in FAP patients in
whom the rectum was left in place after colectomy. It is
suspected that this effect is mediated by inhibition of
the enzyme cyclooxygenase-2 (COX-2)
b) COX-2 is necessary for production of prostaglandin E2,
which promotes epithelial proliferation, particularly
after injury
c) COX-2 expression is regulated by TLR4, which recognizes
lipopolysaccharide and is also overexpressed in
adenomas and carcinomas
2 genetic pathways of colonic adenocarcinoma
- Molecular events: heterogeneous and includes genetic and epigenetic abnormalities
- Involved at least two genetic pathways:
1) APC/β-catenin pathway, which is activated in the classic
adenoma-carcinoma sequence (80% of sporadic ) and
2) Microsatellite instability pathway, which is associated with
defects in DNA mismatch repair and accumulation of
mutations in microsatellite repeat regions of the genome
- Both pathways involve the stepwise accumulation of
multiple mutations, but differ in the genes involved and the mechanisms by which mutations accumulate - EPIGENETIC EVENTS (methylation-induced gene silencing)
– > enhance progression along either pathway
SUMMARIZE 4 PATHOGENESIS OF COLORECTAL CARCINOMA
- CLASSIC ADENOMA - CARCINOMA Sequence
- DNA mismatch repair deficiency, mutations accumulate in microsatellite repeats, a condition referred to as microsatellite instability
- A subset of MICROSATELLITE UNSTABLE colon cancers without mutations in DNA mismatch repair enzymes demonstrate the CpG island hypermethylation phenotype (CIMP):
- MLH1 promoter region is typically hypermethylated, thereby reducing MLH1 expression and repair function
- BRAF mutation
- No KRAS and TP53 mutation - A small group of colon cancers display increased CpG island methylation in ABSENCE OF MICROSATELLITE instability.
DESCRIBE Pathogenesis (main one)
A, Circumferential, ulcerated rectal cancer. Note the anal mucosa at the bottom of the image.
B, Cancer of the sigmoid colon that has invaded through the muscularis propria and is present within subserosal adipose tissue (left). Areas of chalky necrosis are present within the colon wall (arrow).
COLORECTAL CARCINOMA - PATHOGENESIS
- CLASSIC ADENOMA - CARCINOMA SEQUENCE
• Typically includes mutation of APC early in the neoplastic
process
• Normally APC protein binds to and promotes — > degradatio
Histology types
A. Note the elongated, hyperchromatic nuclei. Necrotic debris, present in the gland lumen, is typical.
B. forms a few glands but is largely composed of infiltrating nests of tumor cells.
C. with signet-ring cells and extracellular mucin pools.
**Metastasis?
Colorectal carcinoma
A. Well-differentiated adenocarcinoma
B. Poorly differentiated adenocarcinoma
C. Mucinous adenocarcinoma
Metastatic colorectal carcinoma.
A, Lymph node metastasis. Note the glandular structures within the subcapsular sinus.
B, Solitary subpleural nodule of colorectal carcinoma metastatic to the lung.
C, Liver containing two large and many smaller metastases.
Identify colon condition
A, Dysplasia with extensive nuclear stratification and marked nuclear hyperchromasia.
B, Cribriform glandular arrangement in high- grade dysplasia.
C, Colectomy specimen with high-grade dysplasia on the surface and underlying invasive adenocarcinoma. A large cystic, neutrophil- filled space lined by invasive adenocarcinoma is apparent (arrow) beneath the muscularis mucosae. Also seen are small invasive glands (arrowhead).
**Risk factors? (3)
COLITIS ASSOCIATED DYSPLASIA
Colitis associated Neoplasia
• Incidence of CRC in patients with IBD: Six times higher
>general population
RISK OF DYSPLASIA related to several factors;
- Duration of the disease; risk increases sharply 8-10yrs after disease onset
- Extent of the disease; pancolitis are at greater risk than those with only left-sided disease
- Nature of the inflammatory response; Greater frequency and severity of active inflammation (characterized by the presence of neutrophils) confers increased risk
Surveillance programs in colitis associated dysplasia/neoplasia
• Typically enrolled in surveillance programs :
- screening starts ~8-10 years after diagnosis of IBD
and surveillance colonoscopy recommended every 1 to 2 years thereafter
• IBD and primary sclerosing cholangitis:
- generally enrolled for surveillance at the time of
diagnosis.
• Surveillance requires regular and extensive
mucosal biopsies:
- Low-grade dysplasia
- High-grade dysplasia
Summary causes of gastroenteritis (stomach flu)
- transmission (how is it spread?)
- incubation period?
- how do you get disease symptoms (diarrhea?)
Gastroenteritis (stomach flu) is caused by a number of bacteria and viruses. Viral gastroenteritis is especially widespread worldwide in infants and children with the most severe disease seen in underdeveloped countries where nutritional deprivation is a primary factor. The spectrum and severity of disease depends of the virus itself as well as the underlying health of the individual. Most virus- caused gastroenteritis (GE) have symptoms of diarrhea, nausea, vomiting, fever and abdominal pain and resolves without clinical intervention after several days.
Recovery requires bed rest and supportive therapy, especially administration of fluids. In more severe cases of GE, especially those caused by rotavirus infection of infants, aggressive rehydration therapy may be required.
The viruses are spread by the fecal-oral route via contaminated water and food and by personal contact. The incubation period for GE is usually 2-4 days. Recall discussions about Enteroviruses within Picornaviridae.
In order to produce disease symptoms, the virus merely infects the cells lining the lumen of the GI tract. Lysis of these cells leads to disruption of the salt and ion flow and an electrolyte imbalance ensues. This process leads to diarrhea, which in severe cases, can lead to dehydration, especially in children who are malnourished. See Jan. 11 lecture for the specifics of Adenoviruses.
Viruses that cause gastroenteritis (stomach flu) - 7
**virueses - family - polarity - DNA or RNA
- Rotavirus ; reoviridae ; double stranded RNA genome, segmented genome
- Calicivirus ; caliciviridae ; + polarity RNA
- Norovirus (genotypes 1,2) ; caliciviridae; + polarity RNA
- Coronavirus ; cornaviridae; + polarity RNA
- Astrovirus ; astroviridae ; + polarity RNA
- Adenovirus types 40,41 ; adenoviridae ; double stranded DNA genome
- Picornaviruses (enteroviruses - Coxsackie A) ; picornaviridae ; + polarity
IDENTIFY virus causing stomach flu
- An orphan virus was originally isolated before corresponding disease was determined, Recall ECHO virus
- characteristics?
REOVIRIDAE (reo =respiratory enteric orphan)
Characteristics of reovirus particles
a. 60-80 nm
b. Usually naked virion (for our purposes it is non-enveloped)
c. stable to acid and in the environment
d. Structural features of the virus particle: Two concentric icosahedral capsids –
* External capsid + internal capsid, the latter is commonly designated “core”
* Tubular structures originates from the vertices of the core (internal capsid) and extend through the vertices of the external capsid
e. RNA dependent RNA polymerase + capping enzymes are located inside of core (internal capsid)
f. Double stranded RNA genome in 10-12 segments (depending on the reovirus), genome segments classified based on length of genome segment: L = large, M = medium, S = small
g. mRNA and (+) strand of DS RNA are capped at 5’ end
