Lectures Pathophys Questions Flashcards
What are the consequences of Chronic Right Heart failure
Systemic Congestion - Hepatomegaly, Splenomegaly, Renomegaly
Skin cyanosis
Acites
What are the consequences of Chronic Left Heart failure
Congestion of the Lungs
Heart Failure cells in sputum
Dyspnea
Definition of Shock
State of significant Hypo-perfusion resulting in a cell Injury due to Hypoxia and lack of waste metabolites removal
Short term effects of Shock
Syncope, Orthostatic collapse, Carotis Hyperesthesia, Electric shock, Spinal cord Injury
Stages of shock
Compensated - maintaining perfusion.
Progressive - Inadequate perfusion levels start to show.
Irreversible - Cell and tissue damage, Multi-organ failure.
Pathophysiology of Shock - Progression of events in the various stages
Stage 1 - Pathogenesis causes low CO or low TPR, Hypotension compensated.
Stage 2 - Decreased perfusion and Major end-organ dysfunction, Hypotension Decompensated.
Stage 3 - Microcirculatory failure and endothelial damage leading to cellular membrane Injury and death.
Clinical markers of shock
Brachial systolic BP - less than 100mmHg Sinus Tachycardia Metabolic Acidemia Hypoxemia Low urine output and High respiratory rate.
Classification of shocks
Hypovolemic shock - Loss of blood or body fluids
Obstructive shock - Embolism
Cardiogenic Shock - Heart failure
Distributive Shock - Neurogenic, Anaphylactic, Septic
Shock Index
SI = RR Interval divided by Pulse
Should be 2 a Normal conditions.
It is lower than 1 in case of shock.
Further classification of Irreversible and Progressive stages of shock
Subacute reversible - Oxygen delivery could overtime return to normal with medical attention
Subacute Irreversible - with time and medical care no normal oxygen delivery could be achieved, although an initial improvement may appear.
Acute Irreversible - No Improvement whatsoever and only deterioration of the supply and demand of oxygen ratio.
Hypovolemic shock - causes
Hemorrhage, Vomiting or Diarrhea, Diabetes or Diuretics, Burns or Inflammation of skin, Loss of interstitial fluids
Hemorrhagic shock Initial Compensation - Neural
Alpha Adrenergic- Vasoconstriction of GI, Muscle, Adipose, KIdney vessels
Beta Adrenergic- Bronchodilation and cardiac stimulation
Pale skin, Decreased Diuresis, Muscle weakness
Hemorrhagic shock - Progressive Compensation efforts, Humeral
Blood Glucose elevation and Capillary pressure lowering.
ADH and Renin-Angiotensin- Aldosterone sys
Hemorrhagic Shock - Irreversible stage
Cell death metabolites diffuses easily to systemic circulation due to high vasodilation causing irreversible damage and death
Cardiogenic shock cause and possible treatment
Heart (pump) Failure - 40% of Myocardium damaged by AMI
Alternative Pumping - Transplant or Synthetic Device
Distributive Shock - symptoms
Normovolmia Normotension Low TPR High CO Redness fever
Distributive Shock
Septic
Causes and Events
The same events of Anaphylactic shock occur due to overwhelming infection reactions.
Distributive Shock
Anaphylactic
Causes and Events
Immunogenic Inappropriate Vasodilation causes fluid shift into cells from capillaries.
Micro clots are formed and hazardous SMC contraction occurs like Bronchospasm.
Distributive Shock
Neurogenic
Causes and Events
Spinal cord Lesion, Poisoning or Drug abuse causing inability of NS to maintain Vascular tone.
Hyperdynamic stage of Distributive Shock
Accumulation of Lactic Acid
Changes in Amino acid metabolism - Tyrosine becomes Octopamine that inhibits alpha receptors
Increased NO - By cytokines
Relative oxygen deficits - Cardiac failure
Obstructive Shock causes
Pulmonary Embolism - Blocked pulmonary Circulation
Tension Pneumothorax - Increased Intrathoracic Pressure
Cardiac Temponade - Pressure on Myocardium, Decreased Preload
Possible Reperfusion Injury problems in order
Hypoxia - Tissue Injury (Endothelial cells)
Liberation of Mediators - Inflammatory Cytokines or Calcium elevation in cells
Free radicals and iNOS activation.
Role of Muscles in Shock
Release of Amino acids, Pyruvate and Lactate to Circulation.
Roles of Lungs in Shock
Overreaction of Immune response - ARDS
Liquid sequestration in alveoli
Adipose tissue Role in Shock
Negative factor - Centralized due to high alpha 1 receptors
Causes of ARDS
Alveolar Membrane damage, DIC, Overreacted Immunogenicity response
Possible Negative Feedback mechanism allowing for compensation in Trauma
Baroreceptor reflexes Chemoreceptors reflexes Cerebral Ischemia Reabsorption of Tissue fluids Endogenous Vasoconstrictors Renal conservation of Water
Role of the Liver in shock
Hyperglycemia
Amino acid release
Coagulatory, Complement and Fibrinilytic proteins
Acute phase reaction proteins and C-reactive Protein
What is NOT a cause of Ketosis? ● fasting, starvation ● cocaine ● untreated DM type 1: DKA ● alcoholism ● ketogenic diet ● vomiting (mostly in children)
cocaine will not cause Ketosis
List the chronic malnutrition disease and the abnormal eating diseases accordingly: Anorexia, Cachexia, Kwashiorkor, Bulimia ,Pica, Marasmus.
Abnormal eating diseases - Bulimia and Pica
Chronic malnutrition diseases - Anorexia, Cachexia, Kwashiorkor and Marasmus
Symptoms of Cachexia
loss of muscle mass and of subcutaneous fat tissue
Cachexia causes
Malignant tumors, Anorexia with increase of catabolic processes - IL6, TNF-alpha and PIF cause UPS overactivation.
What is a key way to differentiate between Marasmus and Kwashiorkor?
Kwashiorkor involves Edema and Ascites and Marasmus doesn’t.
Kwashiorkor Symptoms
●low albumin level ● fatty liver ● ascites, edema ● hair and skin symptoms ● infections ● apathy
When is the usual onset of Anorexia and what is the treatment?
Anorexia onset is in puberty and the treatment is psychotherapy which is in 90% of cases saves lives.
What are the lab findings in general Malnutrition?
● low albumin level ● low transferrin level ● lymphocyte count < 1 G/l ● low Zn, Mg plasma level ● BMI < 18,5 kg/m2
BMI Calculation and Normal Range
body mass [kg] / (height [m])^2
18.5-24.9 is the Normal Range
What are the components of the Metabolic Syndrome ?
Central Obesity Insulin Resistance High Blood Pressure High Triglycerides Low HDL Cholesterol Hypertension
Pathogenesis of obesity:
● Genetic background ● Simple overeating ● Imbalance in energy expenditure ● Socioeconomic factors ● Defective thermogenesis ● Leptin ● Thrifty gene hypothesis ● Intestinal flora
What is the precentages of primary and secondary hyperlipidemia
Primary - 10-40%
Secondary - 60-90%
What is the right sequence of lipoprotein molecule based on their size?
CHY-VLDL-IDL-LDL-HDL
Which Apolipoproteins are found on Chylomicrons?
Apo-B48, Apo-A, Apo-C, Apo-E
Which Apolipoproteins C-2’s Job?
Activation of LPL
Function of Apo-C2
Activation of LPL
Lipoproteins containing Apo-E?
CHY, VLDL, IDL, and LDL
Function of Apo-A1
LCAT Activator
Function of Apo-B100 and Apo-B48
Structural for all Lipoproteins (Except HDL), LDLR bind
Mutant Gene, Frequency and Inheritance of Familial Hypercholesterolemia:
LDLR
1/500
Autosomal Dominant
Mutant Gene, Frequency and Inheritance of Familial Combined Hyperlipidemia:
Not Known yet
1/100
Autosomal Dominant
Mutant Gene, Frequency and Inheritance of Familial Type 3 Hyperlipidemia:
Apo E
1/10,000
Autosomal Recessive
Genetic Deficiency and Symptoms of Familial Hyperchylomicronemia (Type 1 Dyslipidemia):
LPL or Apo-C2
Severe elevation of TGs - Lipemia Retinalis, Eruptive Xanthomata, Hepatosplenomegaly, Pancreatitis Risk.
Genetic Deficiency and Symptoms of Familial Hypercholesterolemia (Type 2 Dyslipidemia):
Most commonly LDLR but PCSK9 or ApoB as well.
Tendon and Tuberous Xanthomas, Eyelid Xanthelasma, Elevated risk for Cardiovascular Diseases.
Genetic Deficiency and Symptoms of Dysbetalipoproteinemia (Type 3 Dyslipidemia):
Apo-E2 - Both Cholesterol and TG increased
Xanthomas (Palm, Tuberous), Premature Atherosclerosis.
Renal Diseases that Cause of Secondary Hyperlipidemias:
Nephrotic Syndrome
Chronic Renal Failure
Endocrine Causes of Secondary Hyperlipidemias:
Diabetes Mellitus
Thyroid Disease (Hypothyroidism)
Pituitary Disease (Cushing Syndrome)
Pregnancy (Transient)
Hepatic Diseases that Cause of Secondary Hyperlipidemias:
Cholestasis
Hepatocellular Diseases
Cholelthiasis
Immunoglobulin Excess that Cause of Secondary Hyperlipidemias:
Myeloma Multiplex
Macroglobulinemia
SLE
Metabolic Disorders that Cause of Secondary Hyperlipidemias:
Hyperuricemia
Glycogen Storage Diseases
Lipodystrophies
Nutritional factors that Cause of Secondary Hyperlipidemias:
Obesity
Alcohol
Anorexia Nervosa
How is obesity Linked to Secondary Hyperlipidemias?
Increased Adipose Tissue and High Carbohydrates Intake causes Liver to Produce more VLDL and TG and Less HDL. Metabolic X syndrome: Central Obesity and Insulin Resistance.
How is DM Linked to Secondary Hyperlipidemias?
DM-I : Only if Untreated, Ketone and FFA ↑
DM-II : Insulin Resistance; LPL Activity↓, VLDL↑, FFA ↑ - Metabolic X Syndrome.
How is Hypothyroidism Linked to Secondary Hyperlipidemias?
LDLR Synthesis and Activity↓ Leading to LDL↑, IDL↑, CHY↑
How is Alcohol Linked to Secondary Hyperlipidemias?
Cause of Ethanol Metabolism - Beta Oxidation↑ leads to TG↑.
Activity of LPL↑ leads to HDL↑.
How are Nephrotic Syndrome and Chronic Renal Failure Linked to Secondary Hyperlipidemias?
Hypoalbuminemia - Apo-B Synthesis↑ - Hyperlipidemia.
How are Liver Diseases Linked to Secondary Hyperlipidemias?
Serum Cholesterol↑
How is Pregnancy Linked to Secondary Hyperlipidemias?
Estrogen↑ leads to Synthesis of VLDL↑ and Hepatic Lipase↓
How is Cushing Syndrome Linked to Secondary Hyperlipidemias?
Cortisol↑ leads to Synthesis of VLDL↑ (Central Obesity in long term Stress).
How is Von-Gierke-Disease Linked to Secondary Hyperlipidemias?
Glucose-6-Phosphatase Deficiency- Glucose Release↓ - Compensation Eflux of FFA↑ leads to TG Synthesis↑
Causes of Primary Hypoalphalipoproteinemias
Rare Hereditary Diseases:
Tangier-Disease, Familial Type, Fish-Eye Disease, LCAT Def.
Causes of Secondary Hypoalphalipoproteinemias
Obesity and Physical Inactivity DMII Smoking Excess Carbohydrates Beta-Blockers, Anabolic Steroids and Other drugs
Causes of Primary Hypobetalipoproteinemias
Hereditary Diseases:
Bassen-Kornzweig-Disease (All ApoB containing lipoproteins are Missing) , ApoB Def.
Causes of Secondary Hypobetalipoproteinemias
Liver diseases Hyperthyroidism Malnutrition Malignancy(CML) Rheumatic Arthritis or SLE (Inflammatory Diseases) Fever
What is Lipidosis?
Any Disorder of lipid Metabolism involving abnormal accumulation of lipids in the reticuloendothelial cells.
4 Examples for Genetic Disorders that cause Lipidosis:
Prognosis of Each
Tay-Sachs Disease - Death at age of 4 from Infections
Gaucher’s Disease -May Reach Adulthood
Niemann-Pick Disease -Neuro. Disorders Premature Death
Fabry Disease - CVD Premature Death
What are the 4 Major Phases of Atherosclerosis and what are their corresponding symptomes?
1) Fatty Streak (Teenage years) - Silent Clinically
2) Fibrous Plaque - Effort Angina Claudication
3) Occlusive Atheroscleric Plaque - Effort Angina Claudication
4) Plaque Complications - MI/Unstable Angina/Stroke
What are the Most common locations for Atherosclerosis to develop?
1) Coronary Arteries
2) Abdominal Aorta
3) Carotid Arteries
Non-Modifiable Risk Factors for Atherosclerosis
Age
Gender - (Male more then Female up to 60 years)
Family History
Potentially Controllable Risk Factors for Atherosclerosis
Hyperlipidemia Hypertension Cigarette Smoking Diabetes Mellitus Elevated Homocysteine Infections; Chlamydia/Herpes/Pneumoniae Obesity, Inactivity, Stress
What are the components of the Fibrous Cap in atherosclerotic plaques?
SMCs Macrophages Foam cells Lymphocytes Collagen and Elastin
What are the components of the Necrotic Center in atherosclerotic plaques?
Cell Debris
Cholesterol Crystals
Foam cells
Calcium
Atherosclerosis Thrombogenic Theory: In short
Micro Injuries develop on vascular Intima - Vasoactive substances from Adhesed platelets (TXA and PGI) Promote Lipid Infiltration.
Atherosclerosis Mesenchymal Theory: In short
Hyaluronic Acid↓ causes BM permeability↑ and Lipid infiltration↑ = which causes Metabolic Functions in wall↓
Heparan sulphate↓ - Anti-thromic Activity↓
Atherosclerosis Monoclonal Theory: In short
Proposing that atherosclerotic lesions are benign SMC Tumors -G6PD Monoclonality checked. Therefore Risk factors: Smoking,Age,Free radicals,Infections all apply.
Atherosclerosis Inflammation Theory: In short
“Pathogen Burden” Cytokines↑ cause eventual Cross Reactivity with Self Antigens and Autoimmunity.
Atherosclerosis “Response to Injury” (Unifying) Theory: Possible causes of Endothelial Dysfunction?
LDL/ Modifed LDL↑
Genetic Alteration
Plasma Homocysteine ↑
Herpes Viruses/Chlamydia Pneumoniae Infections
What are the Effects of Homocysteine?
Endothelial Injury
Prothrombotic
Increase synthesis of collagen
Free Nitric Oxide ↓
What are Circulating EPCs?
Endothelial Protecting Cells in bloodstream:
CD34+, CD133+ and VEGF2R+ (Mononuclear WBCs)
Repair of Vascular or Myocardial Injury (Angiogenesis)
Which two organs play fundamental roles in the pathogenesis of fever?
a. Brain
b. Blood vessels
c. Skeletal muscles
d. Brown adipose tissue
c. Skeletal muscles
d. Brown adipose tissue
Which inflammatory signs help discriminate bacterial and viral infections?
a. Leukocytosis
b. Raised CRP
c. Raised ESR
d. Response to treatment
Raised CRP- low in Viral
also Response to treatment
What proves the essential role of the body in the development of inflammation?
a. That bacterial infections trigger an inflammatory response
b. The heredity of LPS resistance
c. The efficacy of bactericidal antibiotics
d. The efficacy of bacteriostatic antibiotics
The heredity of LPS resistance
What are the earliest laboratory markers of severe inflammation?
a. Decreased serum albumin level
b. Raised CRP
c. Increase in the number of neutrophil leukocytes in the blood
d. Raised ESR
Increase in the number of neutrophil leukocytes in the blood,Raised CRP and Raised ESR
How does the body recognize tissue damage?
a. Lymphocytes recognize the damage via foreign antigens presented on the surface of MHC II molecules
b. Proteins and DNA molecules released by damaged cells activate the macrophages and the dendritic cells
c. Proteins released by the damaged cells bind to cell surface receptors and activate the immune sentinel cells
d. Tissue damage changes the cellular ATP concentration that is sensed by the macrophages
Proteins and DNA molecules released by damaged cells activate the macrophages and the dendritic cells
+
Tissue damage changes the cellular ATP concentration that is sensed by the macrophages
How do polymorphonuclear cells kill pathogens?
a. Neutrophils form a net using their nuclear material to trap bacteria or fungi
b. Neutrophils phagocytose bacteria and in the intracellular compartment kill them via
mitochondrial oxidants
c. Neutrophils secrete proteolytic enzymes, hydrogen peroxide and perchloric acid
that can damage extracellular pathogens
d. Neutrophils activate specific killer cells of the body: the natural killer (NK) cells and the cytotoxic lymphocytes
Neutrophils form a net using their nuclear material to trap bacteria or fungi and secrete proteolytic enzymes, hydrogen peroxide and perchloric acid
Which statements are true about the initiation of inflammation?
a. Inflammation is primarily a vessel reaction, which is followed by a cellular phase that involves the activation of inflammatory cells
b. The activation of neutrophils (neutrophilia) is the primary event that is followed by the extravasation of monocytes and finally leads to the activation of macrophages
c. Chemokines derived from the vessels attract inflammatory cells to the site of the injury and they trigger the inflammatory response
d. Resident macrophages and dendritic cells initiate the inflammation via the secretion of cytokines
Resident macrophages and dendritic cells initiate the inflammation via the secretion of cytokines.
Inflammation is primarily a vessel reaction, which is followed by a cellular phase that involves the activation of inflammatory cells.
(A and D)
Why don’t we see any difference between the clinical presentation of sepsis caused by Gram positive and that of Gram negative bacteria?
a. Because the body shows the same reaction to LPS released from the cell walls of Gram positive and Gram negative bacteria
b. Because the inflammatory reaction shows convergence at the level of intracellular signaling, they both share the same signaling events
c. Because they equally trigger the release of damage associated molecular pattern (DAMP) molecules
Because the inflammatory reaction shows convergence at the level of intracellular signaling, they both share the same signaling events
How does the immune system detect a viral infection?
a. Viral RNA molecules are recognized via intracellular receptors
b. Intracellular receptors detect viral DNA molecules via their alternative methylation pattern
c. Viral capsids are recognized by cell surface receptors
d. Viruses are not sensed directly, but an indirect recognition system is in effect, which relies on cell and tissue damage (e.g. cell death of infected cells)
Viral RNA molecules are recognized via intracellular receptors and Viruses are not sensed directly, but an indirect recognition system is in effect, which relies on cell and tissue damage (e.g. cell death of infected cells)
Which statements are true about the blockage of TNF-α?
a. Anti-TNF-α therapy (Infliximab, Remicade) is ineffective in sepsis, because TNF-α is an early cytokine, and its serum level is normalized by the time symptoms occur
b. Anti-TNF-α therapy (Infliximab, Remicade) is effective in autoimmune inflammatory diseases (e.g. IBD, Rheumatoid arthritis), because it blocks TNF-α that
is released during tissue injury
c. Anti-TNF-α therapy (Infliximab, Remicade) cannot be used in chronic inflammatory diseases (e.g. in IBD, Rheumatoid arthritis), because TNF-α is an early
mediator
d. Anti-TNF-α therapy (Infliximab, Remicade) should not be used in sepsis, because it completely blocks the immune system of the body and may promote a fulminant infection
Anti-TNF-α therapy (Infliximab, Remicade) is effective in autoimmune inflammatory diseases (e.g. IBD, Rheumatoid arthritis), because it blocks TNF-α that
is released during tissue injury and Anti-TNF-α therapy (Infliximab, Remicade) should not be used in sepsis, because it completely blocks the immune system of the body and may promote a fulminant infection
Which statements are true about high-mobility group box-1 (HMGB-1)?
a. HMGB-1 is a transcription factor that induces late cytokine response
b. HMGB-1 precursor is activated by the inflammasome and the active HMGB-1 is released by the cells
c. HMGB-1, as a prototypical PAMP (pathogen associated molecular pattern), activates the inflammatory cascade the same way as LPS does
d. Inactivation or binding of HMGB-1 suppresses the inflammatory responses
HMGB-1, as a prototypical PAMP (pathogen associated molecular pattern), activates the inflammatory cascade the same way as LPS does.
Inactivation or binding of HMGB-1 suppresses the inflammatory responses.
Which treatment modalities may have a significant anti-inflammatory effect?
a. Surgical interventions
b. Antibiotics
c. Non-steroidal anti-inflammatory drugs and steroids
d. Anti-cytokine (e.g. anti-TNF-α) therapy and immunomodulatory drugs
Anti-cytokine (e.g. anti-TNF-α) therapy and immunomodulatory drugs.
Non-steroidal anti-inflammatory drugs and steroids.
Which statements are true about monocytes and macrophages?
a. Tissue macrophages originate from circulatory monocytes and play a role in the late phase of inflammation; they phagocytose pathogens and remove the injured cells
b. The reticuloendothelial system (RES), or with other words the mononuclear phagocyte system (MPS), is the term that describes all monocytes and macrophages
of the body, because these cells have a common precursor and they are functionally almost identical
c. Monocytes make up 4-10% of the total amount of white blood cells
d. Monocytes (similarly to the neutrophil cells) develop in bone marrow but they remain in the circulation for a longer period than the neutrophils
The reticuloendothelial system (RES), or with other words the mononuclear phagocyte system (MPS), is the term that describes all monocytes and macrophages
of the body, because these cells have a common precursor and they are functionally almost identical.
Monocytes make up 4-10% of the total amount of white blood cells.
Which statements are true about the natural killer (NK) cells?
a. NK cells constitute approximately 10% of circulatory lymphocytes
b. NK cells are not true lymphocytes, because they do not express a T cell receptor, therefore we call them lymphoid cells instead
c. NK cells possess an immune effector function: they kill infected or damaged cells
d. NK cells produce TNF-α and IFN-γ and they play a role in the regulation of immune responses
NK cells possess an immune effector function: they kill infected or damaged cells.
NK cells are not true lymphocytes, because they do not express a T cell receptor, therefore we call them lymphoid cells instead.
Inhibition or deficiency of which molecules disrupt the LPS-induced cytokine (TNF-α) response?
a. LPS binding protein (LBP)
b. glucocorticoid steroids
c. Myeloid differentiation-2 (MD-2)
d. MyD88 (Myeloid differentiation primary response 88)
e. CD14
f. I-kappaB
g. Toll like receptor 5 (TLR5)
h. Toll like receptor 3 (TLR3)
LPS binding protein (LBP) MyD88 (Myeloid differentiation primary response 88) Toll like receptor 5 (TLR5) Toll like receptor 3 (TLR3) CD14 (LPS Binding)
Prevelance of DM?
8 to 9%
Genes play a strong role in the development of - DM Type 1 or 2?
DM type 2
What Percentage of health care costs is spent on diabetes care?
15%
Cause of the late complications
Diabetes is the likely diagnosis if Fasting blood glucose is greater than?
7 mMole/L
Treatment goal for HbA1c in DM is ? (Value)
<7%
Reason for polyuria in DM?
Osmotic Diuresis from elevated plasma glucose
Possible complications of DM?
6
Retinopathy Nephropathy Stroke Cardiovascular Neuropathy Cancer
How many diabetic patients die from Cardiovascular diseases?
80%
Causes of weight loss in DM?
Fat and Muscle catabolism is increased
Causes of Coma in Dm?
Dehydration or Ketonemia
MODY
Maturity onset diabetes in the young
LADA
Latent autoimmune diabetes in adults
Type 2 DM
Why is it not called NIDDM anymore?
Some Type 2 DM patients needed Insulin treatments which confused the NON INSULIN DEPENDENT term.
More complex than the old categorization.
Percentage of DM types in overall cases?
1 - 5,10%
2 - 90,95%
Insulin Production in each type of DM?
1 - low or abscent
2 - High or Normal
Ketosis in each DM type? (Presence)
1 - Common to have ketosis
2 - Rare to have Ketosis
Obesity prescience in each DM type?
1 - Not a characteristic
2 - Common to have obesity
Presence of Autoantibodies and HLA involvement in each DM type?
1 - common to have Autoantibodies and HLH involvement
2- Not related
Characteristic of DM type 1A ?
Autoimmunity (majority of cases)
Characteristics of DM type 1B?
Idiopathic - No known cause
Mostly in Asian or African origin patients
Symptoms of DM type 1 (A) ?
Polyuria and Polydipsia Weight loss Weakness Ketosis Ketoacidotic coma
Probable reasons for the Autoimmunity in DM type 1?
Gene predisposition (30%) Viral infection
Honeymoon period of treatment of DM1 ?
Episodic halt of Beta cells destruction upon constant administration of Insulin. But it continues afterwards unfortunately.
Age distribution for DM type 1
No actual definitive appearance in juvenile!
Abrupt onset could happen at any age.
How long until DM1 shows symptoms after autoimmunity?
May take years, variable
Is there always eradication of the beta cells in DM1A?
Not always
DM Type 2 - important characteristic
Insulin Resistance - Less of an effect of the same dose of Insulin in a healthy person
IFG and IGT appear in which phase of DM2 development?
Prediabetic stage
What Is the mathematical relationship between Insulin sensitivity and Secretion?
Hyperbolic
Gestational Diabetes - Major risk, time of termination
Congenital abnormalities and complications as well as DM2 for the mother.
Terminated after birth.
Why Insulin resistance in DM2 is believed to be Enviormental and life style related?
Out of the 19 genes related to DM2 only 1 is related to Resistance
Genes related to DM2
Try to remember at least 3
GCK - Glucokinase Wolframin - Ca transporter IGF2BP2 - Protein binding to IGF2 mRNA SLC30A8 - Zinc transporter KCNJ11 - ATP sensitive K channel
Monogenic forms of DM
MODY
MIDD
Insulin receptor defects
Etiology of DM2
Monogenic factors - 3% Polygenic - most Obesity Lifestyle Fetal malnutrition
Prevention of DM
Lifestyle activity and Metformin
Possible causes of Beta cells failure in late DM2?
Still in speculation
Genetic
Obesity
Glucose toxicity
Glucose toxicity
Glycation of Proteins leading to Microangiopathy
How much does Incretins effect the insulin response?
Examples for Incretins?
GIP and GLP - Decreased in DM2
70% of the insulin response
Twin cycle of Insulin Resistnace - Hypothesis
Positive energy balance leads to fatty liver that leads to eventual visceral fat increase and Beta cells increase in TGA and De-differentiation of them.
What determines the reversibility of DM2?
Length of the disease progression
The genes that cause DM2 are mostly responsible for
Decreased ability to secrete insulin
What is the share of the CO received by the liver?
Why?
25%
Filter and Important enzymatic functions
Exocrine functions of the liver
Cholesterol
Bilirubin
Copper
Storage done by the liver?
Glycogen
Iron
Why Detoxification not a proper term for the liver function?
Bio transformation is a process that can cause formation of harmful substances (ROS) out of drugs or other xneobiotics. Not always safe entirely.
Zone of the Lobules of liver
Zone 1 - Outermost
Good oxygenation
Gluconeogenesis and Urea cycle
Sensitive to Direct toxin
Zone of the Lobules of liver
Zone 3 - Innermost
Poor Oxygenation
Glycolysis and Lipogenesis
Sensitive to secondary toxins and circulatory problems or bile obstruction
What is the percent of all tissue residual macrophage represented by Kupffer cells? Why?
80%
High CO percentage allows attack on Microbes infections
SBP - What is it and in which patients?
Spontaneous bacterial Peritonitis
Happens more commonly in liver disease patients (Kupffer cells shortage)
What happens if Activation and Hydroxylation are not coupled correctly in the bio transformation pathway? What patients experience that?
Increase in Reactive substances - TIssue Damage
Alcoholics
What carbohydrate metabolic pathway is inhibited in alcoholics?
Gluconogensis
What are the crucial protein productions damaged in Liver disease?
Albumin
Coagulation Factors
Chronic Liver disease causes symptoms that are related to hormonal metabolism - which are they?
Estrogen metabolism - Hairless skin and Gynecomastia on males
Physical Examination of Liver disease patients
Palpable, Tender liver, Splenomegaly
Jaundice, Palmar Erythema, Spider Navi
Foetor Hepatis
Portal Hypertension symptoms
Acites
Caput Medusae
Esophagial Varices
Hepatocellular liver disease clinical appearance
Parenchyma
Acute liver Injury - Atrophia Hepatis Flava
Chronic Hepatitis
Cirrhosis - Can progress to liver cancer
Hepatobilliary (Cholestatic) liver disease clinical symptomes
Obstructive Jaudice
Why are ASAT and ALAT could be elevated in blood?
Parenchymal Liver damage
Liver cells die and release it
Cytotoxicity of Alcohol or the Acetaldehyde Metabolite
Cirrhosis, Cardiomyopathy, PNS and CNS damage, Oral cancer, Gastritis, Anemia
Which hepatocellular system is activated in alcoholics?
MEOS - Microsomal ethanol oxidizing system
Effects of the NADH/NAD ratio elevation of Alcoholics in liver
Lactic acidosis
Hypoglycemia
TCA and Beta oxidation inhibition
Why is it common for anesthesiologists to know if a person is alcoholic or not?
In sober state the Biotransformation of Barbiturates is elevated .
Anesthesia is could be tolerated.
What is the difference in sensitivity to alcohol doses between men and women?
Maximal dose causing Cirrhosis-
Men - 240 g/d
Women - 81 g/d
What is the most common cause for acute liver injury?
Paracetamol Poisoning
HepA Virus and HepE Virus
Fecal oral and Water
Never chronic
Vaccine possible
HepB and HepD Virus
Precutaneous, Perinatal, Sexual
Can progress to Chronic - Cirrhosis and cancer ultimately
Vaccine is available
HepC
Precutneous
More than 50% of cases become chronic!
No vaccine
Cholestatic problem enzymes elevated
GGT and ALP
How can we diagnose cirrhosis ?
Ultrasound (used to be only Biopsy)
NAFLD
Consequence
Non alcoholic fatty liver
Could progress to Hepatitis and ultimately to Cirrhois
Clinical consequences of Cirrhocis
Portal Hypertension
Loss of liver Parenchyma
Hepatorenal syndrome and Hepatocellular Carcinoma
Hepatorenal Syndrome
Perfectly functioning kidneys (if transplanted in healthy person)that can not function in the liver diseased patient.
Gastritis - Possible Causes
- Alcoholic
- Viral
- Bacterial (H. Pylori)
- Drug induced
Common Symptoms of Gastric Diseases
- Vomiting
- Epigastric pain
- hyperacidity (reflux)/ hypoacidity
- bleeding - Melena (in stool)
- Vitamin-B12 deficiency
Etiology of Peptic ulcer disease (PUD)
- Helicobacter pylori infection
- NSAIDs consumption
- Viral Infections
- Gastrinoma (Zollinger-Ellison S.)
Where does H.Pylori attack in infections?
Antrum of Stomach
How does Aspirin causes Peptic Ulcers?
Causes inhibition of PGE2 formation by COX1 therefore less activation of the PGE2R on Parietal Cell - Increased HCl production!
Complications of Peptic Ulcers
- GERD
- Bleeding
- Perforation of Bowel Wall
- Gastric Cancer in rare cases
Secondary lactose malabsorption:
- Small intestinal bacterial overgrowth or Infectious
- Celiac disease
- IBD (especially Crohn)
- Drug-induced enteritis
- Irradiation induced enteritis
Primary lactose malabsorption:
- Acquired primary lactase deficiency
- Developmental lactose malabsorption
- Congenital lactase deficiency
Celiac disease - Prevalence Correlates with:
Genetic Predisposition: HLA-DQ2>HLA-DQ8
Lifestyle Predisposition: High wheat consumption
Celiac disease - Serum autoantibodies:
IgA anti-gliadin
IgA anti-tTG(tissue transglutaminase)
Celiac - Classic symptoms: (6)
- Diarrhea, abdominal pain
- Growth failure in children, weight loss in adults
- High temperature
- Severe anemia
- Neurologic disorders from deficiencies of B vitamins
- Osteopenia from deficiency of vitamin D and calcium
Celiac - Subclinical disease symptoms (3)
- fatigue
- borderline iron deficiency
- unexplained elevations in serum aminotransferases
Non-GI manifestations of Celiac:
- Arthritis
- Iron deficiency
- Metabolic bone disease
- Kidney Disease: (glomerular IgA deposition in 33% of patients)
Celiac Associated - Dermatitis herpetiformis:
Autoantibodies against epidermal transglutaminase (homologue to tTG). Responses to Gluten Withdrawal!
Celiac Associated - DM type 1:
Share the genetic Risk region - HLA-DQ
Celiac Associated - Selective IgA Deficiency:
Celiac disease is found in 8% of them
Celiac Associated - Down Syndrome:
20x risk of developing Celiac Disease
Celiac Associated - Hashimoto:
Increased Incidence in Celiac
Celiac Associated - IBD:
10x risk of developing IBD
Celiac Disease Terminal Conditions:
Increased Risk of Lymphoma, GI Cancer and General Mortality .
What is the dominant Cytokine appearing in IBD (UC,CD)?
IL17
GI Clinical Manifestations of Ulcerative Colitis:
- Diarrhea, usually associated with blood
- Colicky abdominal pain, urgency, tenesmus, and incontinence.
- Frequent Discharge of blood and mucus.
- Systemic Symptoms: fever, fatigue, weight loss
Non-GI Clinical Manifestations of Ulcerative Colitis:
- Arthritis (most frequent)
- Uveitis and Episcleritis
- Skin lesions
- Hepatobiliary: primary sclerosing cholangitis, fatty liver
- autoimmune liver disease
- Venous And arterial thromboembolism
- Autoimmune hemolytic anemia
Hallmarks of Crohn Disease:
- Fatigue
- Prolonged Diarrhea with crampy abdominal pain
- Weight loss and malabsorption(steatorrhea)
- Fever
- Occult Bleeding (gross bleeding is infrequent).
Pathological Findings on Intestine (commonly on distal ileum) in Crohn’s:
- Fat Wrapping around
- Muscle Hypertrophy
- Cobblestone Appearance
- Fissures
Crohn’s Differential diagnoses:
- IBS
- Lactose Intolerance
- Infectious Colitis
- UC
Irritable bowel syndrome (IBS) diagnosis:
Exclusion of other GI diseases!
Symptoms of Irritable bowel syndrome (IBS) :
Chronic abdominal pain and Altered bowel habits
Risk Factors for Colorectal Cancer:
- APC chromosome 5.: Germline mutations - 5% of cases
* IBD, obesity, smoking, irradiation, alcohol, diabetes, infectious agents and Kidney Transplantation.
Familial adenomatous polyposis (FAP):
- <1%of CRC(!)
- Numerous colonic adenomas appear in childhood.
- First symptoms at age of ~16 years
- Colon cancer in 90%of untreated patients by the age of 45.
Role of APC in CRC initiation:
Transcription Factor that Prevents the WNT - Beta Catenin pathway from causing transcribing Cell proliferation and Migration.
Hereditary risk factors of CRC:MAP - MUTYH associated polyposis
MUTYH repairs oxidative DNA damage
•APC gene is susceptible to oxidative damage
•MUTYH failure leads to somatic mutations in APC, and to a polyposis phenotype.
Hereditary risk factors of CRC: Lynch syndrome
Genetic defect in one of the DNA mismatch repair genes - Increased risk of multiple cancer kinds.
Protective factors from CRC: Mannyyy
- Physical activity
- Diet high in fruits and vegetables (50% lower risk!!!!)
- Higher fiber intake:10 g/day increase in dietary fiber reduces CRC risk by 10%(!)
- Fish consumption: omega-3 fatty acids
- Folate intake:inhibits pathogenesis of cancer
- Vitamin B6 intake: ~20% decrease in CRC risk
- Vitamin D:Vitamin D and its metabolites inhibit CRC.
- NSAID regular use: reduces risk of colonic adenomas and CRC by 20-40%
Anaphylaxis
Sensitized Individual exposed to Antigen triggers an IgE mediated activation of Mast cells - Histamine and Other Inflammatory Cytokines are getting involved.
High inflammatory response causes Bronchoconstriction and Peripheral Vasodilation
