W2 Hypo/HyperCALcemia (Joey) Flashcards
Calcium
● Calcium is a bivalent metal ion with a 2+ Charge
● Calcium is the most abundant metal in the body, so abundant that it is utilized and stored in several
locations throughout:
○ The bones (~99% in the bones complexed with phosphate into a matrix struct known as “hydroxyapatite” Ca10(PO4)6(OH)2 which in itself makes up about 60-65% of the bone in total)
○ Extracellularly in the serum and interstitial fluids (~0.99%):
■ In the serum it actually exists in two main forms: bound to serum proteins (“bound calcium”) and as ionic calcium: Ca++ (free calcium)
○ Intracellularly (~0.01%): with notably higher concentrations in certain organelles like the mitochondria and smooth endoplasmic reticulum (in muscles: the sarcoplasmic reticulum - remember the erectile phys pathway ?, when it dumps Ca++ into the cytoplasm, causes construction, NO erection)
■ Appropriate intracellular Ca++ balance is incredibly important, as too high of intracellular Ca++ levels leads to profound cellular dysfunction and may lead to cell death. The cell keeps intracellular Ca++ levels in check via two main mechanisms:
● Ca++ is stored intracellularly in the mitochondria and smooth ER (SR in muscles)
● The cell also is constantly working very hard to appropriately pump Ca++ out …
This is just FYI reading
● Appropriate intracellular Ca++ levels are extremely important for many intracellular fnxs,
pathways, receptor activities, storage and release of macromolecules intracellularly and
extracellularly - exs of extracell release? (abnls in storage & release of macromolecules = bad)
● In order to keep the cell safe and functioning normally, there is a great deal of energy put into
constant intensive efflux of Ca++ ions through 2 types of channels imbedded into the cell
membrane:
○ ATP-Dependent Ca++ Channels (highly prevalent across all somatic cell types)
■ ATP used to open up these channels and pump the Ca++ out of the cells
○ Na+ / Ca++ Exchange Transporters (also highly prevalent across all somatic cells)
■ Swap 2-3 Na+ in, for 1 Ca++ out (simplified explanation, the true mechanism involves multiple ion transporters, don’t worry about this too much for nephro, point is this process is ionically driven rather than primarily ATP-dependent)
● Ca++ also stored in the mitochondria and the smooth ER (or SR), which serve as Ca++ reservoirs for rapid calcium-dependent intracellular processes when needed…
○ What’s a men’s health example of when SR calcium dumping occurs?!?! (Losing an erection, detumescence)
● Ok now with all that work being done to keep Ca++ out of the cell, how does Ca++
make its own way into the cells? Through 2 other types of channels imbedded into
the cell membrane:
○ Ligand Gated Channels (highly prevalent across all somatic cell types)
■ Typically agonised by neurotransmitters, hormones, and other signalling
molecules, which then leads to temporary opening of the Ca++ channels
and allows for temporary Ca++ influx into the cell
○ Voltage Gated Channels (also diffusely prevalent, however are found much
more commonly and in abundance on nerve and muscle cells)
■ These channels typically open and allow Ca++ into the cell once a specific threshold of change in the electrical cell membrane potential is reached
● Reminder: a membrane potential is made by differences in ionic balance between intra and extracellular space
Two types of calcium
Which takes part in cellular processes?
What calcium is seen on a BMP?
Extracellular Calcium Exists in 2 forms:
● Free Calcium ( “free” meaning “non-protein bound” ): Ca++ that is able to pass through membranes (either via channels or pumps - more common, or via diffusion following a gradient - less common)
○ “Ionized Calcium” This is Ca++ that is able to be physiologically active for cellular processes, meaning
able to participate in and potentiate (exs): neuronal action potentials, pro-coagulation pathways (by both platelet and factor VIII activation), acting as a ligand for particular channels (notably for ones that end up down stream promote hormone release)
■ Ionized Calcium is a lab occasionally drawn in practice when assessing serum Ca levels if there is concern that the Ca++ on your BMP / CMP (which tells you about total Ca in blood) is not reflective of current suspected physiology
⭐️The standard calcium value you see on a BMP or CMP is the value of TOTAL serum Ca (not just free Ca++)
⭐️ Ionized Ca++ lab tells you how much Ca++ in the blood is actually available for physiologic processes
○ Complexed Calcium: This is Ca++ that is ionically bound to other smaller negatively charged molecules like oxalate, the complex of which still exists as a small molecule that can easily cross many cell
membranes / barriers via diffusion or channels
■ Complexed Calcium is often a net neutral compound, and cannot be used for normal Ca++ processes
● Bound Calcium (bound meaning protein-bound): Ca++ that is bound to large proteins & unable to cross barriers
○ Ca++ / Albumin complexes in the serum are a great example of “bound calcium”
■ Bound Ca++ also cannot be used for normal Ca++ cellular processes
Calcium and parathyroid gland
● Serum Calcium levels as a whole are monitored and regulated primarily by the Parathyroid Gland
○ The parathyroid gland has surface receptors called the “calcium sensing receptor” (CaSR)
The Parathyroid Gland…
● Increases release of Parathyroid Hormone (PTH)
in the setting of low serum Ca++ levels (ionic), and decreases release of PTH in s/o higher serum Ca++ (ionic)
● PTH is responsible for:
promoting Ca++ leaching from the bone, promoting renal retention of Ca++, and promoting renal conversion of calcifediol → calcitriol (active Vitamin D)
Calcium on the CMP
● The calcium level you see on a BMP or CMP (the total serum calcium) is unfortunately just an estimated sum of all forms of calcium that exist in the subject’s serum (which are each approximated in their own right as the test is often assuming: normal physiologic status, normal pH, norm hydration and serum osmolarity / osmolality, normal albumin levels, etc):
○ Free Calcium (meaning in ionically unbound form → ca++) = approx 40% - 45% of total serum
calcium normally
○ Complexed Calcium = approx 15% of total serum calcium normally
○ Bound Calcium = approx 40 - 45% of total serum calcium normally
● Because the sCa level you see on a BMP if a reflection of the estimated sum of 3 different types of calcium, the values you get on a BMP or CMP is often misleading in regard to how much Ca++ is actually available in the serum a given moment for physiologic processes
● Measurement of ionized Ca++ is the true gold standard for assessing Ca++ status from a physiologic perspective (but it isn’t the way we actually screen Ca off the bat)
○ “So why don’t we just get iCal all the time?” → It’s more expensive, while BMPs/CMPs are cheap, in general most people’s Ca levels are truly normal, and the NNTT just isn’t there to offset the increased cost of ical screening
unless it’s deemed necessary in particular clinical setting (like true concern for presentation / s/sx being related to too low or too high of physiologically available Ca++ levels)
For your own reading, great UTD article that well explains the above:
Situations where the balance serum Ca++ levels are a bit beyond the control of the PTG
While the Parathyroid Gland does a very good job at tightly regulating total serum Ca++ levels (which downstream should keep total sCa levels b/t ~8.5 - 10.2), there are certain situations where the balance serum Ca++ levels are a bit beyond the control of the PTG, leading to (often temporary) changes in available free ionized Ca++ (cal available for physiologic processes)
● Ex1: Changes in serum pH, affecting the overall net charge and available binding sites of Ca++ to albumin
(albumin in aqueous solutions, like the serum and interstitial fluid, tends to be negatively charged on its surface d/t its outward facing hydroxyl groups on the glutamate and aspartate amino acids that exist in the albumin chemical structure - the deprotonated hydroxyl groups in aqueous solution is where Ca++ tends to bind to albumin to become “bound calcium”):
In settings of serum alkalosis (high pH), less H+ ions are
available in the serum to competitively bind to the negatively
charged hydroxyl groups on glutamate & aspartate amino
acids that exist in the albumin chemical structure, leading to
more free available binding sites for Ca++ ions, which leads to more Ca++ binding to albumin, decreasing the levels ionized Ca++
○ Serum acidosis is the same thought process, just the opposite (increase in free ionic calcium, too much) Ex 2: Changes in serum protein levels as a whole (like in setting of hypoalbuminemia)
○ Much easier thought process on this one, less albumin = less available binding sites for Ca++, leads to increased levels of serum ionized Ca++, done (except not done because then the PTG senses this > ionized Ca++ level and then decreases its output of PTH and the ionized Ca++ lvs normalize)
HyPOcalcemia
Definitions:
● Hypocalcemia = Low Calcium Levels in the Blood (serum ← note: extracellular )
● Laboratory definition of Hypocalcemia being a total serum Ca of < 8.5 mg/dL.
● Ca level on a BMP is a measure of total Ca (so bound, free, complexed)
In situations of hypocalcemia with concomitant acute hypoalbuminemia, you can determine if you are dealing with “true” hypocalcemia vs a “false” hypocalcemia by screening the performing the “Corrected Calcium” equation:
- In pts w/ severe illness, CKD, chronic hypoalbuminemia however the “corrected calcium” is far less useful than just jumping to the ionized Ca (in modern practice if you’re acutely concerned you can typically just jump to screening iCal as it’s universally more helpful)
Signs & Symptoms of Hypocalcemia however tend to present when there are decreased levels of ionized Ca++ (makes sense, right? as there would be less available Ca++ for normal physiologic processes) Point here being: Total serum Ca++ levels are clinically < important than ionized serum Ca++ levels
HyPOcalcemia
“True hypocalcemia”
General laboratory definition of Hypocalcemia is a serum Ca of < 8.5 mg/dL.
● Because of the total vs free/bound Ca++ mechanistic balances that we previously discussed,
true (free) hypocalcemia tends to occur in the following settings (just some examples, others do occur)
a. Serum alkalosis ( see prior slides re: albumin binding sites )
b. Decreased Ca++ entering the serum:
this is the most common cause of hypocalcemia):
■ Ex1: Hypoparathyroidism (more on this in endo, but think < PTH lvls), which may occur in s/o:
● Autoimmune attack on parathyroid (or thyroid)
● In the setting of surgical resection of the parathyroid (like when you have a thyroidectomy, unfortunately the parathyroids are often removed as well) Other exs include: blood
● In setting of hypomagnesemia (Mg++ is needed for PTH production) transfusions d/t
○ This is a reason why you always want to avoid giving Mg++ in pts w/ hyperCa additives chelating
■ Ex2: Decreased GI Absorption (many focal exs: < intake, malnutrition, diarrhea, IBD) serum Ca++, systemic
● Hypovitaminosis D3 - think cirrhosis and CKD! Why is this again…? inflammatory states leading to more
c. Excessive Ca++ loss from the serum negatively charged free
■ Ex: Excessive Ca++ excretion in the kidneys! Where in the nephron does Ca++ excretion tend to occur?
particles / radicals
● This is a SECOND mechanism by which hypocalcemia may occur in CKD (inability to resorb
Ca++)
d. Excessive Ca++ being bound up by other molecules in the serum
■ Ex: like in cellular lysis, leading to dumping of intracellular PO4^3- into the serum →
hyperphosphatemia, which leads to PO4^3- binding to free Ca++ ions (forming calcium phosphate
molecules - note that these are insoluble), which then decreases free serum Ca++ levels
● > serum phos is a THIRD mech by which hypocalcemia may occur in CKD (CKD a/w > sPhos*)
Hypocalcemia
Signs and symptoms
Low serum ionized Ca++ (aka true hypocalcemia, the better definition in your brains of “hypocalcemia”) may lead to dysfunction of several biological processes at the cellular level:
● As you may remember from cardiology, the resting state of Na+ channels on neuronal cell membranes is
regulated by net membrane potential, which is partially driven by [ ] of extracellular Ca++ ions (these are Na+ channels that typically remain CLOSED in presence of normal extracellular Ca++ levels)
○ If the extracellular Ca++ levels are too low, then the Na+ channels may open, leading to Na+ influx into the cell, leading to more rapid and frequent depolarization events, w/ a few of the clinical results of this phenomenon outlined below and on the following slide…
Signs of Hypocalcemia (exs):
● Tetany: Involuntary Muscle Contraction (a hallmark of hypoCa)
● Seizures!!!! In extreme hypocalcemia Symptoms of Hypocalcemia (exs)
● Muscle cramps, generalized and muscle fatigue, malaise, abdominal pain, palpitations (many of these
similar to <K)
● Perioral and oral paresthesias (the classic wording is “perioral tingling” associated w/ hypocalcemia)
HyPOcalcemia
Signs, Symptoms, Clinical Findings & Some Mechanisms By Which They Occur
Common Clinical Findings of Hypocalcemia:
● Physical Exam & Objective Findings (variable b/o acuity and severity of < Ca)
○ Vitals changes (in severe hypoCa): ⭐️Bradycardia (think b/c of > Na influx, depolarization happens more
profoundly, so then repolarization is more difficult → < HR), hypotension (if significantly < cardiac inotropy)
○ ⭐️+ Chvostek Sign: involuntary facial muscle contraction / twitching after tapping of an upstream aspect of the facial nerve (like below the zygomatic process)
○ ⭐️+ Trousseau’s Sign: involuntary wrist flexion when applying a BP cuff to pt’s arm (causes compression of
brachial artery → compression of the brachial nerve, which then leads to stimulation and the nerve fires → anterior forearm contracts)
● EKG:
○ Hypocalcemia may show on EKG as prolonged QT interval (also similar to hypoK), prolonged ST segment, or in severe cases arrhythmias like a fib & v tach (including potential → torsades)
● Labs (this is your initial workup! - values you get here may help you identify the cause of hypoCa):
○ Lower serum Ca++ and low ionized Ca++ (ionized Ca++ very commonly screened in pts w/ hypocalcemia
and hypoalbuminemia to assess what their “true” available Ca++ is for the cells)
○ PTH: May be low
○ Magnesium: May be low (note: if Mg is low and PTH is low, might be < PTH 2/2 < Mg)
○ Phos: May be high (or high-normal if most is bound to Ca++)
○ Vitamin D3 (calcitriol): May be low
Hypocalcemia
Treatments
● Step 1: Try to identify the cause!
○ Step 1 sub a: Fix it :) ← see step 3
■ This workup actually takes a while, and more severe cases of hypocalcemia (which is often how pts first clinically present) can be a tenuous and dangerous clinical situation, so while your workup is occurring, after you draw your labs you typically are immediately jumping to step 2
● Step 2: Replete the Ca++ !
○ Acute Repletion: IV Calcium Gluconate is standard of care for initial acute repletion
○ Non-acute repletion / maintenance: PO Ca++ supplement (often via PO Calcium Carbonate - TUMS)
● Step 3: Once you have identified your cause, do what you can to remedy it/them to prevent the hypocalcemia event from happening next time
○ If low PTH, you’re somewhat stuck, typically we then use: daily PO supplementation +/- thiazide diuretics as
PTH supplementation is not cheap or readily available in hospital setting
○ If vitamin D levels are low, replete their vitamin D via vitamin D supplementation
■ Question: how might you change how you replete vitamin D in pts w/ liver failure vs renal failure vs
both? Type could be different, higher up in the pathway, more expensive
○ If Mg++ levels are low and PTH is low, try repleting the Mg and trend your Ca++, Mg++, PTH
○ What about pts who have both hypocalcemia and hypoalbuminemia… would albumin repletion be good
here? No, replete calcium first, if you give albumin first, it’ll tank their iCal levels!!
Hypercalemia
Definitions:
● Hypercalcemia = High Calcium Levels in the Blood (serum ← note: extracellular)
● Laboratory definition of Hypercalcemia being a total serum Ca of > 10.2 mg/dL.
For reference: hypercalcemia
Hypercalcemia
Signs & Symptoms and clinical findings
High serum ionized Ca++ (aka true hypercalcemia, the better definition in your brains of “hypercalcemia”) may lead to dysfunction of several biological processes at the cellular level:
● As you may remember from cardiology, the resting state of Na+ channels on neuronal cell membranes is
regulated by net membrane potential, which is partially driven by [ ] of extracellular Ca++ ions (these are Na+ channels that typically remain CLOSED in presence of normal extracellular Ca++ levels)
○ If the extracellular Ca++ levels are too high, then the Na+ channels may stay shut longer, leading to
decreased Na+ influx into the cell, leading to slower and less frequent depolarization events, w/ a few of the clinical results of this phenomenon outlined below and on the following slide…
Signs of Hypercalcemia (exs):
● Muscle Weakness
● Altered Mental Status
Symptoms of Hypercalcemia (exs)
● Muscle cramps, generalized and muscle fatigue, malaise, constipation, palpitations (starting to see a pattern
here with the electrolyte imbalances?), confusion / altered mental status
Hypercalcemia
Clinical findings
EKG
Labs
Common Clinical Findings of Hypocalcemia: ● Physical Exam & Objective Findings:
○ Vitals changes: Bradycardia, hypotension (if significantly < cardiac inotropy), orthostatic
hypotension (typically from dehydration related to Ca++ urine dumping and H2O following)
○ ⭐️Slower, diminished, or absent reflexes (the classic PE finding of hypercalcemia)
● EKG:
○ Hypercalcemia may show on EKG as shortening QT interval, AV block, bradycardia
● Labs (this is your initial workup! - values you get here may help you identify the cause of hypoCa):
○ High ionized Ca++ +/- high total serum Ca++
○ UA: May show elevated urine Ca++ (trying to excrete the extra Ca++), as well as possible showing calcium oxalate crystals
○ Vitamin D (calcitriol) may be high
○ Albumin may be high
○ Phos may be low or low normal
○ Mg++ may be high (elevated Mg++ may lead to elevated PTH levels) or norm
○ PTH may be high
○ PTHrP may be high (this would raise suspicion for malignancy)
Hypercalcemia
> calcium associated w/ which malignancy ?
● Hypercalcemia can unfortunately be associated with several malignancies (>Ca is often an eventual
complication of approx 10 - 30% of cancers) and is considered one of the “paraneoplastic syndromes”
● Hypercalcemia of malignancy can occur via a few mechanisms, the 3 primary examples include:
1. Tumor production of PTHrP: Inappropriate creation and ectopic secretion of PTHrP (an analogue of PTH that functions similarly to normal PTH in many tissues) by the tumors cells themselves as an inherent dysfunction and poor differentiation of that cell line. Downstream this leads to → >serum Ca levels.
a. Common cancers that can create and secrete PTHrP are:
i. lung, breast, RCC, lymphomas, mult myeloma, squamous cell carcinomas
- Osteolytic metastases → mets lead to destruction of bone via invasion and local cytokine release → increased bone breakdown and serum resorption of constituents (including
calcium) → >serum Ca levels - Tumor production of 1,25-Dihydroxy Vitamin D (less common) → increased intestinal Ca absorption and bone resorption → >serum Ca levels
● In pt’s w/ malignancy and > Ca, should screen iCal, PTH, PTHrP, vit D levels to help rule in that the
malignancy is a contributor to the > Ca
● In pt’s w/ malignancy-associated hypercalcemia, overall prognosis is often poor (guesses why?)
Hypercalcemia
Treatments
● Step 1: Try to identify the cause!
○ Step 1 sub a: Fix it :)
■ This workup actually takes a while, and more severe cases of hypercalcemia (which is often how pts
first clinically present) can be a tenuous and dangerous clinical situation, so while your workup is
occurring, after you draw your labs you typically are immediately jumping to step 2
● Step 2: Lower the serum Ca++ !
○ This is typically done by first rehydrating the patient (NS is common) to dilute out the >serum Ca++, but more
importantly to increase the GFR which in the end should lead to increased Ca++ excretion by kidneys, and
serially monitoring Ca levels via CMP q4 hours
■ Can be done via gentle boluses, infusions, dose and rate depends on severity and concom. dz states
○ Loop diuretics (help prevent Ca++ reabsorption in the LOH)
■ Which diuretic class do you NOT want to give in these pts?
○ Stop meds that can promote Ca++ retention (like?) ○ Give steroids to < GI absorption of Ca++ ○ In severe > Ca++, promote osteoclast inhibition by giving patients bisphosphonates +/- calcitonin,
denosumab
● Step 3: Once you have identified your cause, do what you can to remedy it/them to prevent
the hypocalcemia event from happening next time (exs below)
○ Stop the > PO vitamin D supplementation ○ Treat the cancer (complicated)
You will get more detailed review of electrolyte derangement treatments in pharmacology, but this is a great place to start :)
