Physiology Flashcards
How do pancreatic fluid secretions change with flow rate? What controls / secretes this?
Fluid is isotonic and secreted by pancreatic ductal (NOT acinar cells, which are in control of enzymes)
Low flow rates -> High Cl- levels (in the absence of secretin), low HCO3- levels
High flow rates -> High HCO3- levels, low Cl- levels (stimulated by secretin)
Na+ is high and K+ is low (like plasma ultrafiltrate), and this remains constant. #6574
How are salivary gland secretions affected by flow rate?
Low flow rates -> more contact with acinar cells, Na/Cl is resorbed, K+ is secreted more
High flow rates -> saliva becomes more like an ultrafiltrate of plasma because there’s no time.
What does CO * TPR =
Change in P = MAP - RAP
Where Mean arterial pressure = 1/3 systolic + 2/3 diastolic, since diastole is usually 2x as long as systole.
What happens to the pulse pressure in the elderly and why?
Increased arterial stiffness -> decrease compliance -> decreased ability to smooth out the systolic / diastolic BP differential -> increased pulse pressure (greater difference between systolic / diastolic pressure)
What determines afterload?
DIASTOLIC BP -> the force that the heart must push against
How do Beta1 receptors improve cardiac output?
Via action of Protein Kinase A
-> phosphorylation of L-type calcium channel -> improved Ca+2 entry -> improved contractility
-> phosphorylation of phospholamban -> increases active SERCA activity -> faster relaxation to improve diastolic filling
What is the formula for wall stress? What increases / decreases it?
Wall stress = (Pressure x Radius) / 2(wall thickness)
-> force with cardiomyocytes must push against
Increased by greater radius from center to wall of ventricle, and systolic pressure (afterload)
Stress is decreased via increasing wall thickness
Why is afterload approximated by mean arterial pressure?
Afterload is actually wall stress -> Force per unit area the heart must push against
However, we assume that ventricular radius and wall thickness are pretty much constant, so pressure (in the numerator of wall stress equation) is a pretty good proxy.
Pressure = Force per area
Radius = length (i.e. cm)
Wall thickness = length (i.e. cm)
(F/A * cm) / cm = F/A, Laplace’s law
How does wall stress change during ejection?
It decreases because
- The size of the LV cavity decreases -> Radius decreases
- LV wall thickness increases -> more sarcomeres pushed together (think of flexing your bicep)
What is wall tension? How does it relate to oxygen demand?
Pressure (MAP) * radius
-> it’s the numerator of the wall stress equation
Force you’re pushing against * the radius of the circular ventricle cavity
Increasing wall tension will increase oxygen demand (related to afterload)
How does blood velocity relate to cross-sectional area?
Remember P = CO*TPR
CO = Q
Q = flow rate
Volumetric flow rate (m^3/s) = flow velocity (m/s) * cross-sectional area (m^2)
Increasing the cross-sectional area for a given flow rate / cardiac output will decrease the flow velocity.
Thus, blood travels fastest in the aorta and slowest in the capillaries (largest total cross-sectional area)
How is resistance dependent on hematocrit?
Resistance = 8viscositylength / (pi* r^4)
Viscosity is mostly dependent on hematocrit
- > viscosity increased in polycythemia
- > viscosity also increase in hyperproteinemia state
Viscosity decreased in anemia (lower hematocrit)
What should you think of Total Peripheral Resistance as in order to get questions right? How will it affect cardiac output and venous return?
Arteriolar resistance -> since most of the resistance is at the level of the arterioles
Decreasing TPR -> decreases arteriolar resistance
- > more blood reaches veins = increased venous return
- > less pressure to push against = decreased afterload -> increased cardiac output
What is the median systemic pressure? What changes the x-intercept of the venous return vs right atrial pressure graph?
X intercept represents the median systemic pressure -> pressure in veins / arteries if there was no cardiac output
Increasing volume or venous tone -> increased RA pressure at 0 cardiac output (X-intercept)
Decreasing volume or venous tone -> decreased RA pressure at 0 cardiac output
Remember that venous tone is what maintains venous return and RA pressure (prevents pooling of blood in veins due to too much compliance)
How does an AV fistula affect TPR and what will it do to median systemic pressure overtime?
Lowers TPR -> increased cardiac output and venous return, since you have a low resistance system to push thru
Despite increased CO, most CO is going thru fistula -> decreased systemic perfusion -> decreased kidney perfusion
Activation of RAA system by kidney -> fluid retention, increasing median systemic pressure over time (X-intercept)
Waves of jugular venous pulsation:
a wave -> Atrial contraction, corresponds with s4
c wave -> RV Contraction, with tricuspid valve bulging into right atrium, corresponds to just after s1
x descent -> downward displacement of closed tricuspid valve during rapid ventricular ejection
v wave -> “villing” of right atrium against closed tricuspid valve
y descent -> RA emptYing into RV before next cardiac cycle (absent in cardiac tamponade -> cannot fill, prominent in constrictive pericarditis, with abrupt stop)
When does the physiologic delay in splitting happen?
Inspiration -> P2 happens even later due to increased venous return. It is normally after A2 anyway, just becomes more prominent.
What causes wide split vs paradoxical split heart sounds?
Wide split - right BBB, pulmonic stenosis -> delayed RV ejection, slow P2 closure
Paradoxical split - splitting on expiration, none or smaller on inspiration - left BBB, aortic stenosis -> delayed LV ejection, slow A2 closure
What causes fixed splitting / why does it happen?
Equalization of left and right atrial pressures with an atrial septal defect
-> elimination of respiratory variation in splitting.
How does increasing afterload affect an aortic stenosis murmur?
Decreases it
-> will decrease the transvalvular gradient, lessening the murmur
How does a Valsalva manuever destroy a supraventricular tachycardia?
Inhale / strain -> preload is reduced as blood is held in lungs -> reflex tachycardia
Release -> massive rush of blood from lungs to heart -> increased preload / contractility -> reflex bradycardia
-> massive parasympathetic input terminates the SVT
How does squatting affect preload / afterload?
Increases preload -> you get closer to the ground and also use muscles to force blood back into your heart
Increases afterload -> much like a handgrip, muscle contraction increases load you must push against.
How does squatting affect aortic stenosis murmur?
Increase in preload is more significant than the increase in afterload
-> increases aortic stenosis murmur
Remember that preload is necessary to maintain perfusion in patients with aortic stenosis -> cardiovert if they have AFib
When is a PDA the loudest?
At S2
-> highest blood flow at end of systole
What channel in cardiac pacemakers do ACh / adenosine and symphathetic nervous system modify?
I-funny channel, nonselective Na/K channel
- > ACh / adenosine decreases firing
- > Ne / E increases firing
-> affect the phase 4 slow diastolic depolarization
Normal times for PR interval, QRS compelx, and QT interval?
PR interval: <200 ms (1 big box)
QRS complex: <120 msec (3 small boxes)
QT interval: <450 ms
What’s the J point?
Junction of the end of the QRS (ventricular depolarization) and start of ST segment (sustained ventricular depolarization)
What electrolyte imbalances can precipitate torsades?
Hypokalemia (impaired repolarization), hypomagnesiemia (explains why Mg+2 can treat the arrhythmia)
What does WPW syndrome do to the QRS and PR intervals? What is the tachycardia which can result?
QRS - widens it (delta wave via bundle of kent)
PR - shortens it (Due to premature appearance of delta wave before Q wave)
Tachycardia - atrioventricular re-entrant tachycardia
How can you tell if the pace of the ventricles in 3rd degree heart block is set by the AV node or the His Purkinje system?
AV node - pace is 45-55 bpm with narrow QRS
Purkinje system - pace is <40 bpm with wide QRS
What is the mechanism of the natriuretic peptides?
Signal by increasing cGMP levels -> vasodilation
Also dilate the afferent arteriole of the kidney and constrict the efferent arteriole -> increase GFR
What drug is a recombinant natriuretic peptide?
Nesiritide -> BuMP the GruMP, it is necessary to turn the tide
What nerves transmit blood pressure information to the brain, and where do they signal to?
Aortic arch - via vagus nerve (X) -> nucleus solitarius of medulla
Carotid sinus - via glossopharyngeal nerve (IX) -> nucleus solitarius of medulla
What is the mechanism of the Cushing reflex?
Increased ICP -> poor perfusion adn increase pCO2 with decrease pH. Body senses the need to increase cerebral perfusion
Increase SANS -> hypertension + tachycardia (phase 1)
Phase 2 -> hypertension sensed by peripheral baroreceptors -> induce increased parasymphatetic tone
-> bradycardia with hypertension (sympathetic mediated vasoconstriction with vagal bradycardia)
Phase 3 -> increased pressure on medulla induces irregular respirations
Where are the peripheral chemoreceptors located? Do they respond to O2?
Located in carotid / aortic bodies (With barorceptors)
Peripheral ones respond to O2 and CO2.
Oxygen response is really only important in COPD where hypoxemia drives respirations. Correction of hypoxemia -> decreased respiratory drive in these patients, as they become desensitized to hypercapnia.
Central = Co2 only = located in the medulla.
What is the rule for remembering total body water, intracellular and extracellular volume?
60-40-20 rule
60% of total body weight = water
40% of total body weight = ICV
20% of total body weight = ECV
i.e. Intracellular volume is twice the extracellular volume
Extracellular volume = plasma volume (~5 L) + interstitial fluid (~10 L)
What would be the approximate volume of distribution of a drug that distributes to total body water? How can it be higher than this?
70 kg (average person) * 0.6 (60% = TBW) = 42 L
Around 42L is a hydrophilic molecule which is uncharged and can spread out.
Can be higher than this if lots of drug is administered and it collects in tissues, with a low measured plasma concentration (highly lipophilic)
What is the mechanism of pulsus paradoxus in cardiac tamponade?
Decreased area for RV to fill up in inspiration (increased venous return) leads to an exaggerated bowing of IV septum into the LVOT -> limiting stroke volume / CO of LV.
> 10 mmHg drop during inspiration #1782
How do you tell apart LV enlargement from mitral regurg vs hypertension?
Mitral regurg - will be ECCENTRIC hypertrophy (to accommodate volume overload) -> no increased thickness of wall, just increased chamber volume
Hypertension - CONCENTRIC hypertrophy to deal with greater afterload -> increased wall thickness #181
How does left heart failure lead to right heart failure?
Back of blood in the lungs actually leads to leakage of proteins into interstitium / endothelial dysfunction -> decreased NO, increased endothelin -> development of pulmonary hypertension -> RV failure #198
Does insulin cross the placenta?
NO!
Fetal macrosomia is due to endogenous production of insulin in response to maternal high blood sugar
What does GLUT5 transport?
Fructose
What two signalling pathways are utilized by insulin and which one is unaffected in Type 2 diabetes, mediating increased cell growth?
- PI3K/Akt/mTOR pathway, also known as PKB pathway -> controls GLUT4 / anabolic effects
- RAS/MAPK pathway -> responsible for cell growth, DNA synthesis. Unaffected in Type 2 diabetes -> accounts for how diabetes is associated with cancer.
How does glucagon affect insulin levels?
Glucagon STIMULATES insulin release -> to allow target tissues to take up sugar.
What cancer types release PTHrP?
Q + urinary tract + BRCA
Women and men have similar levels of testosterone in circulation. Why don’t women have hirsutism?
Women have increased SHBG relative to men.
What stimulates secretin, what releases it, and what are its actions?
Acidic chyme in duodenum stimulates release by S cells
Actions - increase pancreatic and Brunner’s glands bicarbonate secretions, decrease gastric acid secretion
How does bilirubin get made and transported to the liver?
Made in reticuloendothelial system (i.e. spleen)
Heme -> biliverdin = open chain form of heme porphyrin ring. (Via heme oxidase)
Unconjugated bilirubin made from biliverdin, and transported via albumin in blood (UCB is water insoluble, needs to be conjugated)
What is the fate of bilirubin once it enters the intestine?
Bacteria in the gut deconjugate it to urobilinogen.
Urobilinogen can be excreted in stool after being made into stercobilin -> gives the stool its brown color.
Some urobilinogen is reabsorbed -> can be excreted again in bile, or transported to kidneys where it is oxidized to urobilin -> gives the urine its yellow color.
What are the embryonic globins?
Zeta and Eta chains -> produced in fetal yolk sac
Who is the universal donor and recipient of plasma?
Universal donor -> AB (no anti-RBC antibodies in plasma)
Universal recipient -> O (can handle any anti-RBC antibodies in donor plasma)
Order of migration distance in hemoglobin electrophoresis?
Accelerates - farthest - HbA
Fast
Slow
Crawls
What effect does estrogen have on the myometrium?
Increases endometrial excitability via upregulation of gap junctions -> ripens it for labor during pregnancy
What type of estrogen has the greatest increase in pregnancy?
Estriol -> indicator of fetal well-being
Increase of what hormone indicates ovulation has occurred?
Progesterone -> since it is secreted by corpus luteum, which only forms if there has been ovulation
Two phases of oocyte arrest?
Pre-ovulation - Prophase 1 of Meiosis 1
Until it meets sperm, post-ovulation - Metaphase 2 of Meiosis 2
What allows lactation post-pregnancy?
Disinhibition of prolactin via a fall in progesterone
-> estrogen induces hyperplasia of lactotrophs, and progesterone must fall to allow lactation to begin
How does hCG maintain pregnancy?
It is an LH analog -> maintains corpus luteum
What function does oxytoxin have in lactation?
Similar to inducing uterine contractions, it has a contractile function in allowing milk letdown
What vitamin do exclusively breastfed infants need?
Vitamin D - it is actually poorly supplied in human breastmilk
Does breastfeeding help the mom in any way?
yes - reduces her risk of ovarian and breast cancer.
Who tends to have early menopause?
Smokers
What is the source of estrogen in menopause, and what are the general symptoms to remember?
Peripheral conversion of androgen to estrogen. (LH stimulates the theca cells). These increased androgens can lead to hirsutism.
Remember HAVOCS:
Hot Flashes
Atrophy of ->
Vagina
Osteoporosis (first three from decreased estrogen)
Coronary Artery Disease
Sleep Disturbances (from hot flashes and night sweats)
What is premature ovarian failure? What type of disorder is it?
Menopause before age 40
This is primary ovarian insufficiency -> hypergonadotrophic hypogonadism
Due to premature atresia of ovarian follicles
What is the inspiratory capacity?
IRV + TV = (TLC - FRC)
Air that can be breathed in after a normal respiration
How do you calculate alveolar ventilation?
VA = (VT-VD) x RR
Tidal volume - dead space volume = Alveolar volume (amount that is actually hitting the alveoli)
Multiple Alveolar volume times respiratory right to get the alveolar ventilation
What is minute ventilation?
VE = (VT) x RR
Just tidal volume multiplied by respiratory rate
How does the compliance of the lung vs chest wall differ at lower volumes?
Lung - Slope of volume / pressure curve is very steep = high compliance
(easily change volume because it wants to collapse inward towards minimum volume)
Chest wall - Slope of volume / pressure curve is very shallow = low compliance
-> chest wall does not want to decrease in volume any more (has strong outward elastic recoil)
How does the compliance of the lung vs chest wall differ at higher volumes?
Chest wall - Compliance is greatly increased as it is happy pulling outward
Lung - Compliance decreases as it expands
Eventually both chest wall / lung are too overpulled -> compliance of the system becomes very low and they want to collapse back down to FRC.
How do you determine the point the lung / chest wall would be happy at if they weren’t attached to eachother?
Look at their respective pressure / volume curves. Wherever pressure = 0, that volume on the X axis is where they are happy resting at.
For the chest wall, that is higher than FRC (Since it springs outward).
For the lung, that is lower than FRC (since it collapses inward) -> that volume is = minimum volume.
How does carboxyhemoglobin affect oxygen content and oxy-hemoglobin dissociation curve?
Decreases oxygen content (more hemoglobin loaded with CO)
Dissociation curve - left shift, due to decreased oxygen unloading in tissues
How does cyanide poisoning affect PaO2, SaO2, and CaO2? How does this explain the presenting blood color?
They will all be normal. Cyanide poisoning just binds to complex IV -> prevents utilization of oxygen.
-> Thus a-v oxygen difference will be increased (venous blood will be closer to arterial blood due to lack of oxygen usage) -> explains why venous blood is cherry red.
What explains the presenting blood and skin color of methemoglobinemia?
Cyanosis with chocolate colored blood
- > oxidation of iron leads to brownish tinge (like spoiled meat)
- > also poor oxygenation -> turning blue (vs cyanide poisoning where oxygenation is OK, tissues just can’t use it)
What’s the skin color for carboxyhemoglobinemia?
Cherry red, just like cyanide poisoning. God knows why. Probably cuz PaO2 is normal, and O2 just can’t unload. Just remember the forensics lecture.
What is done for the acute and chronic treatment of acute intermittent porphyria?
Acute - IV dextrose and heme
Chronic - avoidance of all CYP inducers which will worsen the condition, i.e. anti-epileptics, alcohol, smoking, OCPs
What is the primary cell type involved in formation of the fibrous plaque of atherosclerosis?
Vascular smooth muscle cells of the media which invade the intima and adopt a myofibroblast-like phenotype -> secrete collagen, elastin, and other extracellular proteins #443
What can happen to patients with undiagnosed pheochromocytoma who go under anesthesia?
A catecholamine surge can be induced -> flash pulmonary edema, atrial fibrillation, and hypertensive crisis #15105
Is CO uptake diffusion or perfusion limited?
Diffuse limited -> reason why we can use the diffusion limitation of CO to determine how easily O2 is diffusing across the membrane
Is O2 normally perfusion or diffusion limited? In which cases will it become the other?
Normally perfusion limited (i.e. equilibrates before the end of the capillary)
Becomes diffusion limited (i.e. speed of diffusion is rate-limiting) with things which reduce its diffusion (i.e. emphysema, fibrosis)
Is CO2 or O2 closer to diffusion limitation?
O2 -> CO2 equilibrates significantly faster than O2.
Why is pulmonary vascular resistance lowest around FRC?
High volumes -> alveoli compress and collapse bloood vessels
Low volumes -> positive intrapleural pressure and lack of radial traction collapses blood vessels
What is Hypoxia vs Hypoxemia vs Ischemia?
Hypoxia - Loss of O2 delivery to tissue
Hypoxemia - Loss of PaO2
Ischemia - Loss of blood flow
Is V/Q high or low at the apex / base of the lung?
Apex - High (wasted ventilation, more ventilation than perfusion)
Base - Low (wasted perfusion, more perfusion than ventilation, explains why A1AT affects bases mostly)
Is ventilation greater at the top of the bottom of the lung?
Overall, the greatest ventilation still occurs at the base of the lung. V/Q is just higher at the apex RELATIVE to perfusion.
What would cause a V/Q ratio of infinity vs 0 and will 100% O2 improve each condition?
Infinity - Blood flow obstruction (V»_space; Q) - 100% O2 improves it by increases PaO2. Occurs in i.e. pulmonary embolism
0 - Airway obstruction (V<
What are the three major zones of the lung with respect to perfusion?
Towards apex - Zone 1
PA > Pa > Pv -> Alveolar pressure at apex exceeds blood flow, and alveoli is not perfused
Middle - Zone 2
Pa > PA > Pv -> Arterial side of capillary exceeds alveolar pressure, but venous side does not. Blood flow is determined by the arterial-alveolar pressure difference
Bottom - Zone 3
Pa>Pv>PA -> Blood flow is complete, and perfusion is even better than ventilation. At the very base, the extraalveolar capillaries may even collapse due to lack of negative intrapleural pressure
What are the three forms in which CO2 can be stored?
- Dissolved HCO3- - 70-90%
- Carbamino hemoglobin - 4% in arterial blood, 24% in venous blood -> deoxygenation favors this formation
- Dissolved CO2 - 5-9%
How does venous O2 and CO2 content change with exercise?
CO2 - increases (producing more)
O2 - decreases (extracting more)
How does lung V/Q ratio change with exercise?
V/Q ratio from apex to base becomes more uniform
What techniques are used to measure plasma volume and ECF volume?
Plasma volume (25% of ECF volume) - radiolabeling albumin (cannot leak into tissues)
ECF volume - inulin or mannitol (stay outside the cells)
Volume = (amount of tracer given) / (concentration of tracer)
What are the parietal and visceral layers of Bowman’s capsule?
parietal - Outside of Bowman’s space
Visceral - also known as the epithelial layer of the glomerular filtration barrier -> podocytes
What type of capillary does the kidney use? Where is the diaphragm?
Fenestrated capillary, but WITHOUT a diaphragm
Epithelial side (podocytes) uses a slit diaphragm between podocytes
What is the basement membrane of the kidney made of?
Basement membrane is negative charged with Type IV collagen + heparin sulfate -> repels negatively charged particles like albumin
How do you calculate renal blood flow?
RPF / (1-Hct)
RPF estimated by clearance of PAH
What is splay?
Splay -> variation around “threshold” plasma concentration at which glucose doesn’t get excreted linearly more with increases in plasma concentration, due to heterogeneity of tubules
Why is glycosuria / aminoaciduria seen in pregnancy?
Due to increased filtered load of glucose and amino acids in fetus -> normally try to go to placenta
How does artifactual hyponatremia occur and what are two disorders responsible for this?
Since Na only dissolves in the plasma water content, and not the 7% of undissolved solids, situations where there are elevated undissolved solids can make the measured Na+ be low relative to the whole volume of plasma pulled from the lab, while the Na+ / plasma WATER is relatively normal.
Examples:
Hyperlipidemia
Hypergammaglobulinemia (i.e. multiple myeloma)
-> patient will be measured as hyponatremic when they are normal
What is the concentration of injected normal saline and why?
154 mmol/L, since all the NaCl is dissolved in pure water.
154*0.93 = 140 mmol/L, the concentration we are used to, since 7% of plasma is normally undissolved solids
-> we just measure the sodium / liter with our instruments, when really we want the osmolality, which is mol Na / kg water, not L solution.
What is hyperosmolal hyponatremia and when does it occur? How can this be corrected?
In hyperglycemia due to uncontrolled diabetes mellitus, plasma osmolality truly rises because insulin is not present to bring glucose into the cells. As water exits cells into the ECF, the ECF [Na] goes down, causing pseudohyponatremia. Na cannot simply move across the membrane.
When the hyperglycemia is corrected with insulin, the [Na] will renormalize.
-> note that this same effect does not occur with elevated urea in renal failure since urea freely diffuses throughout the compartments
How does angiotensin 2 promote contraction alkalosis in the proximal tubule?
Stimulates Na/H exchange
-> HCO3- gets reabsorbed
How does PTH act on the proximal and distal convoluted tubule?
Proximal - inhibits Na/PO4 cotransporter
Distal - Upregulates NCX - increases calcium absorption. Also upregulates TRPV5 on principle cell surface for more calcium reabsorption
What is thought to be the underlying mechanism of Fanconi’s syndrome?
Defect in cellular energy metabolism resulting in a decrease in ATP levels -> impairing secondary transport mechanisms
What are the inherited causes of Fanconi’s syndrome?
- Cystinosis
- Wilson’s disease
- Tyrosinemia
- Glycogen storage diseases
What are the acquired causes of Fanconi’s syndrome?
Lead poisoning
Multiple myeloma
Ingestion of expired tetracyclines
Tenofovir / other nephrotoxic drugs
How does Cl- reabsorption change during the proximal tubule?
Early PCT -> poor Cl- reabsorption, gets left behind like urea to some extent
Late PCT -> chemical concentration gradient allows it to become reabsorbed at the same rate as Na+ / K+, plateaus off in terms of tubular fluid / plasma ratio (being absorbed isotonically later on)
What type of RTA do NSAIDs cause and how?
Type IV RTA -> prostaglandins are required for proper renin secretion
-> hyperkalemic hypoaldosterolism results
Which cells of the kidney help make 1,25-vitamin D?
Proximal convoluted tubule cells
What effect will hyperosmolarity have on blood potassium levels and why?
Hyperosmolarity - increased K+ levels
- > Osmotic drag = K+ leaves the cells with water
- > Decreased water inside cells also concentrates K+, passive movement out of cells
What other things cause hyperkalemia by shifting K+ out of cells?
Basically, just remember all the conditions seen in diabetes pretty much lead to hyperkalemia
- > acidosis
- > high blood sugar
- > low insulin levels (since insulin is needed to stimulate Na/K ATPase)
Is the hyperkalemic effect of metabolic acidosis worse with mineral or organic acids?
Worse with mineral acids, since the anions can’t enter the cell and must stay in the blood (i.e. H2SO4)
Organic acids can be transported into the cell so the effect of hyperkalemia will be less dramatic
How does a beta adrenergic agonist like albuterol induce hypokalemia?
Increases Na+ / K+ ATPase activity -> brings more K+ into cells
What are the symptoms of hypercalcemia to remember?
- Stones - nephrolithiasis (kidney stones due to hypercalciuria), renal failure (post-renal azotemia)
- Thrones - Polyuria (with volume depletion and dehydration)
- Groans - abdominal discomfort from kidney stones, acute pancreatitis, nausea/vom, gastric ulcers (calcium increases gastrin)
- Bones - osteitis fibrosa cystica
- Psychiatric overtones: Coma, altered mental status
- Metastatic calcification (of normal tissues, i.e. nephrocalcinosis)
What is the major way to distinguish between Bartter and Gitelman syndrome based on labs?
Bartter - high urine calcium (loop diuretic)
Gitelman - Low urine calcium (thiazide diuretic)
How does SIADH affect aldosterone?
Decreases it -> blood volume will be normal / elevated, no reason to activate the RAA system
- > Body increases ANP/BNP, and decreases aldosterone to incresae urinary Na+ secretion
- > normalization of ECF volume = EUVOLEMIC HYPONATREMIA
How does the urinary anion gap change if the kidney is properly responding to normal plasma anion gap metabolic acidosis and why?
Normal response would be to increase renal tubule acid secretion in the collecting duct. This is done by increasing ammonia excretion. Since ammonia will be excreted as a positive cation, the Cl- in the urine will also increase to counteract this cation in the urine. This will be measured as an increase in urine chloride.
Thus, normal UAG response to metabolic acidosis is:
UAG = normal Na + Normal K+ - HIGH CL-
Urinary anion gap is VERY negative, reflecting high ammonia concentration.
-[NH4+] = UAG
What does it mean if UAG is zero or positive in the presence of normal plasma anion gap metabolic acidosis?
It means ammonia is not being excreted properly -> distal tubule renal tubular acidosis
Type I renal tubular acidosis
What is the urinary pH in Type I RTA and how does it change with plasma HCO3-? What pathophys mechanism accounts for this?
Distal renal tubular acidosis, associated with pH > 5.5 even with very low plasma [HCO3-], due to impaired ability to secrete H+ by alpha intercalated cells
- > decreased titratable acid and trapping of NH4+ -> decreased net acid secretion
- > impaired reabsorption of HCO3-, urine remains basic
What are the causes of RTA Type I?
Congenital abnormalities:
Obstruction - damages collecting duct
Hereditary mutation in H+-ATPase
Drugs:
Amphotericin B, tenofovir -> nephrotoxic, increase H+ permeability, allowing diffusion of H+ back into the cell (urine cannot be acidified)
What is RTA Type II? What will the urine characteristics be? Include pH and anion gap.
RTA Type II - proximal RTA
Impaired bicarbonate reabsorption in the proximal tubule leads to increased bicarbonate loss in urine
Urine pH will still be low (<5.5) as alpha-intercalated cells are functioning properly and can secrete H+ into urine via increasing ammonia production + increased H+ secretion.
UAG will be very negative (normal response to acidosis) since cells are responding properly
What are the causes of Type II RTA?
- Fanconi syndrome - proximal tubule transporters don’t work at all, leading to loss of all types of things in urine (Type 2 RTA loss of bicarbonate is just one consequence)
- > caused by drugs like ifosfamide, cisplatin, tenofovir, expired tetracyclines
- > cystinosis, tyrosinemia - Carbonic anhydrase inhibitors - i.e. acetazolamide
- Osteopetrosis - defective Carbonic Anhydrase isoform
What will happen to blood potassium levels in Type I and Type II RTA and why?
Type I - decreased ability to use H+/K+ antiporter inhibits K+ reabsorption -> hypokalemia
Type II - increased delivery of non-absorbable anions to principle cells -> increased negative luminal charge and K+ wasting -> hypokalemia
What is the pathogenesis of Type IV RTA?
Hypoaldosteronism leads to hyperkalemia
Hyperkalemia causes impaired NH4+ generation by PROXIMAL tubule (from glutamine) -> impaired excretion of acid
-> hyperkalemic renal tubular acidosis
What conditions or drugs can lead to the development of hypoaldosteronism / Type IV RTA?
- Diabetic hyporeninism - kidney damage of the JG apparatus
- ACE inhibtors, ARBs, NSAIDs which are needed for renin production
- Heparin - toxic to zona glomerulosa, adrenal insufficiency
- Cyclosporine - nephrotoxic
- Trimethoprim or pentamidine (PJP pneumonia) - competitive inhibitor of ENaC
Why does uremia cause increased anion gap metabolic acidosis?
Associated with renal failure, which means decreased net acid excretion in general (urea formed from ammonia which was failed to be excreted) -> acidosis
Why is methanol ingestion toxic?
Step 1: Formaldehyde - toxic to optic nerve, causes blindness
Step 2: Formic acid (analagous to lactic acid of ethanol) - causes acidosis
What are the non-renal loss of HCO3- causes which induce a hyperchloremic metabolic acidosis?
Diarrhea - Rich in HCO3- and K+. Kidney will compensate well with acid secretion and K+ reabsorption.
Small bowel or pancreatic drainage - loss of HCO3- secretions
What are situations where “HCl” could be added to induce hyperchloremic (normal anion gap) acidosis?
Parenteral nutrition - formulas contain excess cations -> arginine-Cl or lysine-Cl -> chloride rises and arginine / lysine are acid cations which need to be buffered
Eating HCl or NH4Cl -> ammonium chloride used to be used as a diet pill
Does metabolic acidosis happen early or late into salicylate overdose?
Late
Early you tend to see respiratory alkalosis due to stimulation of the respiratory centers
What is the differential diagnosis of metabolic alkalosis based off of?
Based on urine [Cl-] -> low concentration of Cl- implies that bicarbonate is being reabsorbed largely because there is a deficit in Cl- to run Na/Cl- cotransporter -> HCO3- transporter goes in its place. -> kidney is focusing on ECF depletion, its #1 priority
What are the two categories of metabolic alkalosis?
- Saline responsive: Urinary [Cl-] < 20 mEq/L
- > ECF depletion is the issue - Saline unresponsive: Urinary [Cl-] > 20 mEq/L
- > ECF is normal or expanded
What are two common causes of saline responsive metabolic alkalosis?
Diuretics, especially loop diuretics -> volume depletion, loss of chloride and sodium(NKCC)
Vomiting -> HCl loss, volume depletion
What are two types of diarrhea which cause a metabolic alkalosis rather than metabolic acidosis?
- Villous adenoma -> secretes Cl- and K+ into bowels
2. Congenital chloride losing diarrhea
What are the two usual broad causes of saline unresponsive metabolic alkalosis?
Excess mineralocorticoids -> will cause K+ wasting
Severe K+ depletion -> increased acid secretion to reabsorb K+. Hence hypokalemia is associated with alkalosis and vice versa.
Why does non-hyperparathyroid hypercalcemia cause metabolic alkalosis?
When bone is broken down, calcium carbonate is released. This is normally stimulated by PTH, whhich also signals to excrete bicarbonate in urine to prevent alkalosis.
If PTH is not accompanying the hypercalcemia, the release of bone bicarbonate will not accompany bicarbonate excretion -> alkalosis.
What are the metabolic alkaloses causes where base is ingested faster than it can be excreted?
Excess alkali intake (baking soda) or milk-alkali syndrome
