gross appearance alteration (white and cheesy) in necrotic area
tissue structure obliterated
granulmatous inflamation seen microscopically
What is necrosis? What are the 2 essential concurrent processes that are involved?
Premature death of cells caused by infection/interruption of blood supply
requires enzymatic digestion of cells, and denaturation of proteins
What is liquefactive necrosis?
Often associated with bacterial or fungal infections
Accumulation of inflamatory cells as well as digestion of dead cells and the presence of pus (white goop)
Compare hypoxia and ischemia
hypoxia: oxygen deficiency
ischemia: lack of oxygen delivery due to lack of blood flow
2 branches of consitutional disease? 3 branches of environmental disease?
Hereditary vs non-hereditary
Dietary, living external agents, non living external agents
What is metaplasia?
Reversible change in which one differentiated cell type is replaced by another
What is coagulative necrosis?
Dead tissue is preserved for a span of time (ex. myocardial infarction)
Characterized by intracellular acidosis (resulting in denaturation of proteins and enzymes but not proteolysis
essentially cells are dead but remain undigested
localized area of coagulative necrosis is called an infarct
what are the 4 types of necrosis?
coagulative
liquefactive
caseous
fat
How does excess cytosolic calcium impact the cell?
increases activity of ATPase (decreased ATP)
phospholipase (decreases phopholipids)
proteases [these first 3 lead to membrane damage]
incudces endonuclease release by ER (chromatin damage)
Why are depleted levels of ATP problematic for cells?
Decrease in membrane transport-> Swelling of cell
Decrease in protein synthesis (ribosomal detachment)
Increase in anaerobic glycolysis (decreased pH, decreased glycogen)-> the decrease in pH will clause clumping of nuclear chromatin
Explain some components of the progression of apoptosis, from earliest to latest
cell shrinkage
chromosome condensation
formation of cytoplasmic blebs and apoptotic bodies (cell fragments)
phagocytosis of apoptotic cells or cell bodies
What are some biochemical changes in apoptotic cells?
protein cleavage (activated caspases)
DNA breakdown (by activated endonucleases)
protein cross-linking (activated transglutaminase which cross-links cytoplasmic proteins-> leads to cell shrinkage)
phagocytic recognition (phospatidylserine expressed on outer membrane of apoptotic cells is recognized by macrophage)
What are some ways genes are altered in their pattern of expression?
DNA methylation, histone acetylation, RNA interference
What are the three forms of colour blindness?
Monochromacy: no cones
Dichromacy: one one is missing
Anomalous Trichromacy: one cone has altered spectral sensitivity
Which gene is linked to colour blindness?
16 genes on 19 chromosomes, though most commonly is x-linked
What is the life-expectancy of patients with Down's Syndrome?
75% of patients will die in utero
15% will die within one year of birth
35% of those who were born will die before age 50
What are 3 types of tests that can be done to detect for Down's syndrome?
Amniocentesis/chonrionic sampling (invasive)
HCG/hormonal sampling (week 15-20)
Ultra sound (week 12)
usually you combine 2+3 to get a high detection rate while staying non-invasive
What is thallasemia, and how is it transmitted?
Missing or defective genes of HB resulting in anemia
usually single gene defect (both copies affected=homozygotes will have severe thalassemia)
What is sickle-cell disease, and how is it transmitted? what are the four crises in sickle cell disease?
people are homozygous for HbS subunit gene.
vaso-occlusive crisis: caused by cells blocking blood flow, leading to necrosis, pain, and ischemia
splenic sequestration crises: filtration function of the spleen is compromised; splenectomy or death
sickle-cell crisis: parvovirus B19 shuts down erythrocyte production for 2-3 days, potentially fatal in sickle-cell patients (treatment: blood transfusions)
Hemolytic crisis: rapid loss of erythrocytes, particularly in G6PD patients (treatment: blood transfusions)
What is PKU, and how is it transmitted? Why might it have been selected for?
absence of penylalanine hydroxylase (Phenylalanine -> Tyrosine)
additional symptoms at birth: albinism, seizures, mousy odor
single gene, thus both parents must be carriers
Confers protection in damp areas by protecting against fungal toxins (elevated phenylalanine levels confer protection)
What are the two forms of PKU, which is most prevalent? What is the treatment?
PAH enzyme deficiency (98%): patient must restrict phenylalanine intake
Biopterin-deficient PKU (2%): missing co-factor; supplement with biopterin-> no dietary restrictions
What is cystic fibrosis?
Mutation in cystic fibrosis transmembrane conductance receptor (CFTR)
people with CF produce overly sticky and thick mucous resulting in continuous lung infection
heterozygotes may be protected from cholera
medications can only control symptoms
patients usually die from infection, thus treat patient until they become resistant to antibiotics
How should you alter the diet of a patient with cystic fibrosis?
High fat, protein, calories and fat soluble vitamins
-due to thick digestive mucous that can prevent pancreatic secretion -> decreased fat absorption
What is muscular dystrophy?
group of genetic mutations that cause progressive weakness in voluntary muscles
multiple recessive genes (however Duschene muscular dystrophy is x-linked)
Duschenne Muscular dystrophy
leads to muscle degeneration (ultimately resulting in loss in ability to breathe-> death)
caused by dysfunctional dystrophin gene (which maintains muscle fiber)
death by late teens~mid 20s
What are two common problems associated with neural tube defects?
Spina bifida-> neonatal death of life-long paralysis
Anencephaly-> miscarriage, still born, or brief live birth
tough to conclusively diagnose beforehand (measure a-fetoprotein, which varies during development)
Calcium's atomic number? molecular weight? valence #? Abundance in nature?
20
40
+2
5th most
What are the three most important functions of calcium?
stability of biological membranes
subcellular signalling
bone (least important)
How does calcium confer membrane stability?
Ca2+ interacts with negative phosphoric part of phospholipid, which anchors lipids, making membranes more permeable.
As a general rule, higher [Ca] will make it more difficult for membranes to depolarize
This is why low calcium causes random neural firing (spasticity of muscles)
2 bed-side tests to check for low [Ca]
Chvostek sign: touch angle of jaw to see if face twitches
Trousseau sign: cut off bp in arm, wait for hand to spazz
How is extracellular calcium regulated?
Calcitonin (increases bone formation)
PTH [fast response](increases bone resorption->osteoclasts + increases renal Ca reabsorption)
serum osteocalcin: non-collagen bone peptide, reflects rate of bone protein synthesis by osteoblast
amino and carboxy terminal propeptides of collagen: (PINP and PICP)
How are bone markers important in diagnosis
baseline markers are higher in osteoporosis patients compared to healthy controls
BMD expected to be inversely proportional to bone marker levels
However, substantial overlap between osteoporosis and normal subjects
How can you predict future bone loss?
Culmination of bone markers + BMD
BMD predicts 50% of fracture risk (but not the rate of bone loss)
Bone markers shown to be predictive of bone loss
What are some limitations of bone marker usage?
Rates of bone turnover vary widely over a range
large overlap between disease and normal state
few studies connecting bone histology with markers of bone turnover
What are some things that affect bone marker levels?
Bone markers do not change with age in men
Bone markers are elevated during menopause, and remain elevated (in women)
as a general rule of thumb: if some bad shit happens to the bone-> increase in markers; if good shit is happening[i.e. exercise]-> decrease in markers
Why is it good to get 1000mg of calcium?
Calcium protects intestinal mucosa by binding compounds (excess calcium excreted in stool)
You get a net =0 if you get 1000mg, compared to 200mg eating=-5 net loss
How can you measure BMD?
dual energy x-ray absorptiometry
ultrasonography -> predictive of fracture risk, but threshold yet to be determined
What is osteomalacia?
Equivalent to childhood rickets
Caused by little vitamin D or little calcium
Can treat with calcium supplementation + VitD
Lots of collagen, but no calcium deposition. thus soft bones
What can you do to facilitate absorption of calcium?
Take with food (to increase their ionization)
only ionized calcium is absorbed
What's the metabolic pathway of calcitriol?
7-dehydrocholesterol->
Vitamin D3(also dietary)-> this step occurs in liver
25-(OH)D-> this steps occurs in kidney
1,25(OH)2D
Half-lives of compounds in the calitriol pathway
Vitamin D3=~a day (stored in muscle and fat due to a carrying protein OR converted to 25 (OH)D
25(OH)D-long half-life (~2months)-> this is usually what's measured for indicating Vit D deficiency
1,25(OH)D-stimulated by PTH and lowering of Calcium levels; thus serum levels are not directly affected by vit D
What does 1,25(OH)2 D do? how is its production stimulated? where is it made?
Increase gut absorption of calcium
Increased PTH or decreased [Ca]
it's made in multiple tissues, however the place where it is released as a hormone is in the kidney
What is asthma? What is the most important risk factor?
Chronic inflammation leading to airway hyperresponsiveness, leading to widespread but variable airflow obstruction that is reversible
Genetics is the most important risk factor.
What is the trend of asthma incidence and mortality in Canada over the last 20 years
What is the worldwide prevalence?
Incidence increased by 15-20%, however mortality has decreased by 50%
300 million cases worldwide
What is asthma decompensation? What are some triggers for asthma decompensation?
Not adequately controlled asthma
----------------------
Non-compliance
Respiratory tract infections
Allergens
Irritants
Drugs (NSAIDs/B-Blockers)
Preservatives (sulfites, MSG)
GERD, anxiety, cold air/exercise
What are some characteristics of high risk asthmatics?
Lack of consciousness during attack, intubation, frequent ICU/ER visits
frequent use of B-agonists without anti-inflammation treatment
night-time symptoms (2-4am you get further constriction of airways-> exacerbated in asthmatics)
limited respiratory reserve (symptoms when FEV<60%)
How has asthma control changed over the last decade? What percentage of people have successfully controlled their asthma? What percentage of people believe their asthma is under control? % of people who are concerned about ICS? % of patients who did not plan to fill their ICS prescription? Of those that did fill it, what percentage did not take the medication?
No real change over the last decade
About 55%
97%
75%
33%
20%
What is atopy?
predisposition towards developing certain allergic hypersensitivity
Why is ciclesonide advantage over traditional ICS?
lower systemic side-effects
high protein binding+high first pass+rapid bile elimination +requires activation in lung
Routine Liver Tests
Bilirubin
marks functioning of hepatocytes and billiary tract distal to the site of metabolism
metabolic product of heme metabolism
Routine Liver Tests
Alkaline phosphatase
Not specific to liver injury
Marker of open billiary tract-> cholestasis
Routine Liver Tests
Transaminases
Found elevated when liver is injured, and the enzymes leak into blood
AST-less specific (found in many other tissues)
ALT-more specific for liver injury(but also found in other tissues)
Routine Liver Tests
Gamma-glutamyl transferase
Tends to be elevated in all liver disorders (particularly useful for alcoholic abuse)
Routine Liver Tests
Albumin
synthesized in the liver, long turnover rate (3 weeks)
indicative of liver synthesizing ability chronically
Routine Liver Tests
PT
Clotting factors synthesized in liver
Shorter half-life, thus more acute marker of liver synthesizing ability
Specific liver tests
Ammonia
Breakdown product of amino acids
Metabolized to urea in liver, which is excreted in urine
Indicative of liver metabolic insufficiency
Specific liver tests
a-fetoprotein
fetal albumin
increase in a-fetoprotein is indicative of primary hepatoma (not metastatic cancers)
Specific liver tests
LDH (Lactate dehydrogenase)
increased if there's general metastasis into liver or congested blood flow of liver.
Specific liver tests
5'Nucleotidase
Increased in cholestasis
Specific liver tests
a1-antitrypsin
shuts off proteases
if diminished in capacity or amount-> cirrhosis
Specific liver tests
caeruloplasmin
important in copper metabolism (Wilson's disease)
thus decrease can detect copper overdose ???
Specific liver tests
TIBC (total iron binding capacity), Ferritin, [Fe]
TIBC: assesses transferrin levels (increased when iron is low)
Ferritin: assesses iron stores (increased when iron is high)
Specific liver tests
Viral Antigens and antibodies
helpful in detecting hepatitis
Specific liver tests
Immunoglobulins
IGG, IGA, IGM may be elevated in chronic liver disorders
not very specific
Specific liver tests
Autoantibodies
usually antibodies to smooth muscle or mitochondria
not specific to liver but useful in autoimmune disorders
What type of bilirubins and their derivatives get into urine?
Conjugated bilirubin
bilinogens (which are then called urobillinogens)
Low cellular energy of liver selectively affects:
secretion
then it affects metabolism
thus lower cellular energy will more readily
What are the four different types of billiary obstructions?
Drug induced: diffuse throughout liver
Autoimmune: slow, chronic, process of destruction of billiary tracts
Focal obstruction: billiary tract is obstructed in the vicinity of a metastatic module
extrahepatic obstruction (cholidocholithiasis, cancer in pancreatic head, scar tissue from operations, gall bladder inflammation)
What markers will be elevated in diffuse billiary tract obstruction?
ALP, 5'NTD, GGT (10-20X)
conjugated bilirubin
Acute: negative immune markers
Longer duration: Increase in AST and ALT
Chronic (AKA primary billiary cirrhosis): immune markers will be positive (especially to mt); destruction of billiary tree leading to metabolic insufficiency
How can you identify focal billiary tract obstruction?
Increase in cholestatic marker enzymes (ALP, 5'NTD, GGT)
Not as much of an increase in bilirubin (as it can still be metabolized in other parts of the liver)
Note that AST may be normal or slightly elevated, and a-fetoprotein may be normal or slightly elevated
How can you identify hepatocellular jaundice?
(AKA sick hepatocytes or end-stage liver failure)
greater increase in bilirubin (especially in unconjugated bilirubin, compared to conjugated) compared to cholestatic markers (5'NTD, ALP, GGT)
Identifying acute viral hepatitis
Biggest three things are :
a) AST and ALT are highly increased
b) ALT>AST
c) positive immune markers
note that prothrombin (even though acute), may not necessarily decrease
also note that peak height is not related to disease severity
What can immunoglobulins tell you about an infection?
IgM mounts the initial immune response (will rise as ALT is starting to fall). IgG mounts a life-long immunity(thus you had Hep A sometime in the past)
Identifying Toxic hepatitis
AST>ALT (note how it's not ALT>AST, thus not acute viral hepatitis)
Increase in Bu and Bc
you would also see liver insuffiiciency (prothrombin, ammonia, Bu>Bc)
No viral serology
thus toxic insult by exlcusion (ex. halothane)
Chronic viral hepatitis
a)waxing and waning of AST and ALT
b) AST>ALT (one of 3 instances where this occurs)
c) immune markers (IgG, mitoantibodies, muscle antibodies)
d)late-stage-> a-fetoprotein
Identifying Gilbert's syndrome
loss of function in conjugating enzyme (Glucoronide transferase)
would see a decrease in bilirubin in urine (as conjugated bilirubin is filtered)
urobilinogen will seem normal (even though it's actually reduced, due to urinary dipstick shortcomings)
liver cell is otherwise healthy
Identifying alocoholic hepatitis
How to determine if alcoholic hepatitis is severe?
How to determine chronicity?
AST>ALT (~10fold elevation, but AST:ALT = 2:1)
Increase in GGT, lesser increase in ALP
can determine severity if:
Bilirubin increases 5X
PT increases
Can determine chronicicty if:
albumin is low
What are 3 conditions in which AST>ALT, but they are both elevated?
Alcoholic hepatitis (2:1 ratio)
Acute Toxic hepatitis
cirrhosis (ability to make/release ALT is impaired more than AST)
Chronic viral (although he didnt say it)
Why are women more susceptible than men to alcoholic liver disease?
More alcohol consumed/kg
Less ADH
Alcoholic liver disease is the _____ leading cause of death. Rate?
Alcoholic liver disease is the _____ leading cause of liver disease in NA. How many of these patients are infected with Hep C
ALD requires daily drinking of ____g of alcohol
10-12th
4.4/100,000
2nd
25%
80g
Why is acetaldehyde toxic?
Produces protein adducts (which produce antibodies) leading to impairment of mitochondrial function and glutathione function
3 factors that are altered after continuous alcohol intake
Increased gut permeability-> chronic inflammation
Decreased antioxidants
Increased acetaldehyde
What are two important genes that may prove useful in preventing Alcoholic liver disease
PNPLA3 (lipid storage protein)-> if defective, increases ALD
TNF-a-> if defective, increases ALD
What is the earliest sign of alcoholic fatty liver progression
redox imbalance due to metabolism of ethanol -> acetate leading to increased lipogenesis
can be seen in biopsys very early
Describe alcoholic hepatitis
infiltration of liver with neutrophils and lymphocytes
AST + ALT increase (AST>ALT)
35-40% mortality if severe presentation, or continued drinking
Prednisone improves outcome, especially if presentation includes encephalopathy
Pentoxifylline (anti-TNFa) may be helpful
What is liver cirrhosis?
Diffuse process characterized by fibrosis and nodules
Requires biopsy to diagnose (unless portal hypertension+accompanying symptoms present)
fibrosis is reversible, but the nodules are not
90% 5 year survival=compensated patients
70% 5 year survival=continued drinking patients+clinical compensation
30%=no compensation+continued drinking
best treatment is abstinence+transplant
will eventually lead to hepatoma
3 types of liver cirrhosis
active cirrhosis: increased ALT/AST, increased PT, increased Bili, decreased Alb
inactive cirrhosis: no, or minore liver function test abnormalities
end-stage cirrhosis: normal ALT/AST, but everything else is fucked
True or false: most heavy, long-term drinkers will develop cirrhosis
True or false: coffee confers a dose-response adverse effect on alcoholic cirrhosis
false; most will not develop cirrhosis
false; dose-response protective effect
What do the major complications of liver cirrhosis stem from?What are the major complications of liver cirrhosis?
Portal hypertension
Ascites, esophageal varices, encephalopathy
Explain ascites:
Fluid buildup in peritoneum, leading to fluid infection, breathing difficulty, hepatorenal syndrome
Caused by splanchnic vasodilation due to accumulation of NO
very poor survival rate without transplant (30-40% without, 75% with)
Treatment: Na restriction, paracentesis, diuretics, and antibiotics
Esophageal Varices
a)engorgement of veins in esophageal and stomach mucosa because of blood shunting away from liver
b)thrombocytopenia due to spleen enlargement
management:
sclerosing and or banding
somatostatin/octreotide
b-blockers
Hepatic encephalopathy due to alcoholic liver cirrhosis
accumulation of CNS toxins (ammonia) and increased sensitivity to GABA
can only do a bed-side diagnosis (people will flap their hands when their arms are up arhythmically)
management: enema, laxatives, protein restriction (to decrease ammonia)
What are the 4 rules of body fluid compartments
1. Water goes to where particles are
2. ECF volume is determined by Na+ content
3.Water crosses cell membranes rapidly to equalize osmolarity of ECF+ICF
4.Volume of cells depends inverse on ECF somolarity
What are the three effects of ANG II?
Increase reabsorption directly (PT) and indirectly (aldosterone)
Increase vasoconstriction
Increase thirst and ADH
What are three ways in which the body responds to a loss in ECF volume? What is the body trying to prevent?
RAAS
SNS
ADH
Shock due to low perfusion of vital organs
What are four causes of excessive ECF volume?
Renal failure
Nephrotic syndrome (filtration of proteins)
CHF (low CO causes increase in SNS, RAAS, ADH)
liver cirrhosis: causes very vasodilated circulation, leading to increased SNS RAAS ADH
What are the three diuretics that were learned in kidney section?
Furosemide: acts in ascending limb of loop of henle where it binds NKCC and inhibits its action (no reabsorption of NKCC)
Hydrochlorothiazide: acts in distal convoluted tubule, where it binds NaCl transporter (mimics chlorine)
Spironolactone: binds to aldosterone receptor in collecting duct (decreases reabsorption of sodium) (potassium sparing)
What are some major causes of water excess? Treatment?
Severely reduced GFR
ADH not being inhibited
-cancers (lung cancers)
-patient with severe diarrhea only replaces with water (baroreceptor mediated increase in ADH)
-patient with congestive heart failure (baroreceptor mediated)
-ecstasy
What are some major causes of water deficit? Treatment?
Increases loss of water without accompanying NaCl
Diabetes insipidus
Give water orally, or as Dextrose (D5W)
What is diabetes insipidus? What can it cause?
Lack of ADH effect due to either
a) ADH not being made (treat by giving DDAVP)
b) ADH not detected by kidney (usually due to lithium)
What can affect potassium balance?
Na/K atpase
insulin (facillitates potassium entry into cell)
B2 agonist (facillitates potassium entry into cell)
Bicarbonate
Aldosterone (increased sodium reabsorption receptor expression, which facillitates potassium loss) (note also that ACE-i and ARB will affect this too!!!!)
What are some causes of hypokalemia
Increased insulin
Increased beta agonism
NaHCO3 administration
Anabolism
What are the symptoms of hyperkalemia? Hypokalemia?
Hyperkalemia-> mostly cardiac symptoms
Hypokalemia-> Cardiac arrhythmias, and skelatal muscle weakness and rhabdomyolysis
How can you produce new bicarbonate?
Kidneys: glutamine->ammonia+HCO3-
Liver: Lactate-> HCO3-
What is respiratory acidosis
increase in [H+] due to increase in [CO2] (hypoventilation)
newplasm: a new growth/tumour (with unco-ordinated growth which persists after stimuli that evoked the change)
oncology: study of neoplasms
dysplasia: disordered growth (precursor to cancer, thus can detect dysplasia to prevent cancer)
What does -oma signify? Carcinoma? Sarcoma?
oma: benign tumours
sarcoma: malignant stromal tumours
carcinoma: malignant epithelial tumours
What are the four phases of tumours?
Transformation
Growth
Local invasion
Distant Metastases
the last 2 are only characteristic of malgnant tumours
How might a cancer undergo distant metastases?
1) direct seeding of body cavities and surfaces
2) lymphatic vessels
3) blood vessels
What are the three categories of hereditary predisposition to cancer (and give examples)
Autosomal dominant inherited cancer syndromes (inheritance of single mtant gene that increases cancer risk; mutant rb gene-> retinoblastoma+ osteosarcoma)
Defective DNA repair syndromes-defective dna repair genes (MSH/MLH/MSH-> HNPCC syndrome [colon cancer-most common predisposition syndrom]
Familial cancers
What is the normal cell division cycle signalling process, and what are the proteins that regulate it?
Binding of growth factor on cell surface
Signal transduction
Transmission to nucleus
activataion of dna transcription
cyclins
cyclin-dependent kinases
inhibitors of cyclins and CDK (ex. RB and CDK-Inhibitors)
What is the function of RB? What is the function of p53?
Tumour suppressor genes that :
enforces the S-> G1 checkpoint (RB)
G1 and G2 arrest and induces DNA repair and then apoptosis (if repair fails) (P53)
How do cancer cells maintain a limitless replicating potential?
Reactivation of enzyme telomerase-> relengthens telomeres
How might cancer cells invade and metastasize?
Produce VEGF (gives cells access to vasculature)
Cancer cells lose their intercellular junction (E-cadherin)
Cancer cells bind surrounding tissue (laminin + fibronectin)
Define cancer cachexia. Define Paraneoplastic syndromes
Cancer cachexia: loss of body fat and muscle with weakness and anorexia and anemia due to cytokine production by tumour and host cells (also produces abdominal striae)
Paraneoplastic syndromes: symptoms that present due to tumour presence, but not because of the actual tumour
What is Cushing's syndrome? What condition might it be seen in?
Cushing's syndrome may be seen secondary to lung cancer-> increased ACTH-> Increased cortisol
Compare and contrast staging and grading
staging: based on TNM (size of primary TUMOUR, spread to regional lymph NODE, METASTASIS to distant site); a measure of spread
Grading: based on degree of differentiation, number of mitoses, acrhitectural features; a measure of the appearance of cancer
What are some ways in which you can diagnose cancers?
Histology: tumour samples looked under light microscope to determine subtype/grade/prognosis
Immnohistochemistry: antibodies to categorize poorly differentiated/anaplastic malignant tumours, determine site of origin, and molecules of prognostic significance
