This chapter is relevant to Section I3(ii) of the 2017 CICM Primary Syllabus, which expects the exam candidates to "describe the function, distribution, regulation and physiological importance of sodium, chloride potassium, magnesium, calcium and phosphate ions". It is difficult to know where to put this material, as it could just as easily be classified as endocrinology. Calcium the electrolyte has appeared multiple times in the past papers, and the questions have generally been asking about its distribution and regulation in the body fluids, but a lot of the answers depended on whether or not the candidates knew what the regulatory hormones did and where they came from.
Calcium-related SAQs were:
- > 99% of total body calcium is in bone and not easily accessible
- Less than 1% is in the extracellular fluid (~20-30mmol total)
- Minimal intracellular concentration (second messenger)
- In the plasma:
- 40-45% of calcium circulates bound to albumin
- 10-15% is bound to other anions such as lactate and phosphate
- 40-45 % is free and ionised
- Regulation of calcium intake
- Absorbed by combination of paracellular and transcellular transport in the ileum
- Transcellular route carefully regulated by hormones
- intestinal absorption increased by calcitriol and PTH,
- decreased by calcitonin
- Regulation of bone resorption of calcium
- Normal daily flux in and out of bone is 12-13 mmol
- Bone is reabsorbed by osteoclasts; this liberates calcium
- Osteoclast activity is increased by PTH and decreased by calcitonin
- Calcitriol has mixed effects; in vitro increased osteoclast activity, and in vivo protective effects in the treatment of osteoporosis
- Regulation of renal elimination of calcium
- 70% is reabsorbed in the proximal tubule
- 20% is reabsorbed in the thick ascending limb
- 10% is reabsorbed in the distal convoluted tubule by a mechanism that is regulated by PTH calcitriol and calcitonin:
- Calcitonin decreases the reabsorption of calcium and phosphate
- PTH and calcitriol increase the reabsorption of calcium and phosphate
- Calcitriol increases the activity of calbindin, TRPV5 and TRP
- Main hormones involved
- PTH is a polypeptide hormone secreted by the parathyroid glands
- Stimulus for release: hypocalcemia, hypophosphatemia
- Inhibitory factors: calcitriol, hypermagnesemia
- Actions: increases plasma calcium by increasing its renal reabsorption and osteoclast activity
- Also increases Vit D conversion into calcitriol
- Calcitriol is the metabolic product of Vit D, a fat-soluble vitamin
- Stimulus for release: hypocalcemia, hypophosphatemia, PTH
- Inhibitory factors: decreased sun exposure, decreased functional renal mass, elevated calcium and phosphate levels
- Actions: increases plasma calcium by increasing its gut absorption and renal reabsorption
- Inhibits the production of PTH; conflicting effects on osteoclast activity
- Calcitonin is a polypeptide hormone secreted from parafollicular cells of the thyroid
- Stimulus for release: hypercalcemia, gastrin
- Inhibitory factors: hypocalcemia, somatostatin
- Actions: decreases plasma calcium by decreasing its renal reabsorption, as well as inhibiting osteoclast activity
If the time-rich reader wanted to lose a few hours, their tumble into the calcium rabbit-hole would likely begin with an article like Mundy & Guise's "Hormonal Control of Calcium Homeostasis" (1999). One would likely follow with Daniel Bickle's 2014 treatment of Vitamin D, a definitive resource that happens to be freely available online.
You have about 360mmol/kg of calcium in your body; that makes about 25 moles of calcium. A 70kg male has about 25 moles of calcium, or about 1000g. Of this, over 99% is locked up in bone. Some absolute minimum amount is present in cells, and about 20-30 mmol of calcium is in the extracellular fluid. The proportion of circulating calcium is slightly higher than what might be expected from the usual distribution of extracellular fluid, because it is bound to albumin, of which the interstitial compartment has less. Thus, in your 10 or so litres of extracellular fluid, you have about 10-15mmol of mainly ionised calcium, and then a further 7.5-10 mmol of calcium in the plasma of the blood.
In the circulation 40-45% of calcium circulates bound to albumin, 10-15% is bound to other anions such as lactate and phosphate, and 40-45 % is free and ionised, which is the only biologically useful form.
Most serious review literature on this subject starts with some kind of statement about how much calcium enters the adult human body, and how much leaves, and by which means it does so. Classically, this is represented in the form of a diagram where a length of bowel, a bone and a kidney are depicted as sources reservoirs and final destinations for calcium. Often, these diagrams are labelled Americanly, describing the flux of calcium in milligrams. In the Australian healthcare system, the ICU registrar and resident tasked with the duties of replacing calcium will usually do so by ordering calcium in millimoles, and so the author here takes liberties with some classical anatomy art to reframe calcium flux into this familiar metric scheme.
Unlike potassium and sodium, which enter the body uninvited and just lounge around until the kidneys eliminate them, calcium is a carefully selected guest. Calcium absorption takes place in the duodenum by some active transcellular process, and passively along the rest of the gut (Bronner, 2003). Because the duodenum is a brief and unremarkable pitstop along a food boluses' tour of the bowel, the transcellular uptake only plays a major role when dietary calcium intake is very low; which in the ICU probably correlates with periods of prolonged fasting or ileus. When calcium uptake is high or normal, paracellular passive uptake accounts for the majority of the gastrointestinal absorption. In addition to unabsorbed dietary calcium, some additional calcium is excreted as part of digestive secretions and shed gut mucosa (Davies et al, 2004); some of this becomes trapped in the gut by binding to dietary phosphate to form an irreversible bond and an insoluble compound. The net absorbed calcium (about 3.75mmol/day) is matched by the daily renal excretion of calcium (again 3.75 mmol/day).
As you might have noticed, the pool of mobile calcium is small. The exchange of ionised calcium between the extracellular fluid, the soft tissue and the bone therefore has to be very finely controlled, as changes that might appear small will have a significant impact on the extracellular calcium concentration. Whenever you give somebody a 6.8 mmol ampoule of calcium chloride, you are essentially giving them two days worth of dietary calcium intake, rapidly increasing their total extracellular calcium content by one-third. Similarly, small changes in calcium binding to protein which make it more or less bioavailable can produce observable clinical change.
This is a topic large enough for a whole chapter all to itself. In brief summary:
|increased albumin = decreased ionised calcium|
|increased pH = decreased ionised calcium|
|increased lactate = decreased ionised calcium|
|increased phosphate = decreased ionised calcium|
|increased bicarbonate = decreased ionised calcium|
|increased citrate = decreased ionised calcium|
|Presence of heparin in the sample = decreased ionised calcium|
Free fatty acids
|Increase in free fatty acids = decreased ionised calcium|
The paracellular diffusion of calcium is not something you can control. However the transcellular mechanism is tightly regulated. This mechanism has three steps:
Apparently, almost 90% of this occurs in the ileum, mainly because the residence of the intestinal content is longer. The following regulatory influences are involved:
Bone represents a massive and essentially unavailable locked reservoir of mineral calcium, from which (and into which) there is a constant trickle of calcium exchange. The job of controlling this calcium trickle is performed by osteoblasts and osteoclasts which form or destroy bone, respectively. Bruzzaniti & Baron (2006) do an excellent job of discussing the detail of this, so that we do not need to revisit it here. The most important examinable elements are the hormonal influences:
Question 7 from the first paper of 2008 asked the candidates to "outline the mechanism of action of bisphosphonates". These drugs are analogs of pyrophosphate, containing an oxygen instead of a carbon atom. Their main effects are described in more detail by Fleisch et al (2002) and Rogers et al (2020). In a form condensed for a short written exam answer:
Renal handling of calcium consists of three main processes:
The transcellular reabsorption in the distal convoluted tubule is where all the fine control of plasma calcium concentration occurs. Like with the intestinal absorption, there are the same three steps here:
The regulatory influences on renal reabsorption, from Jeon (2008), consist of:
PTH is this 84-amino acid peptide that comes from the chief cells of the parathyroid gland. All tetrapods appear to have some sort of parathyroid glands (but fish do not, and their PTH-equivalent is secreted by their gills). The actual PTH hormone and its receptors are actually rather ancient, being traced genomically to some point before the protosome-deuterostome split (i.e. pre-Cambrian). This makes sense, because the need to control extracellular calcium is fairly fundamental to the secondary messenger systems which use it, and those are common to all good god-fearing multicellular organisms.
Palaeontological digressions aside, PTH is probably the most important regulator of calcium homeostasis and ends up being the first test you do to investigate a deranged calcium value. Its secretion is regulated by extracellular calcium levels, but in a manner that is not completely linear. High calcium concentrations can never completely suppress PTH secretion, and in severe hypocalcemia, the parathyroid gland does not appear to react proportionally to the existential threat of the frighteningly low calcium concentrations. This is illustrated by the graph below, which was shamelessly misappropriated from Felsenfeld et al (2007) and lightly modified to address the transPacific gap in results reporting (mg/dL instead mmol/L) and the unholy use of "z" in "ionised".
In short, PTH secretion is stimulated by falling calcium levels, and reaches some sort of peak at an ICU-able ionised calcium concentration of around 0.90 mmol/L. A sensible reaction to such hypocalcemia would be to mobilise endogenous calcium stores, prevent its loss in urine and increase its absorption in the gut. All of these are effects produced by PTH. Within minutes of the onset of hypocalcemia, the rising level of PTH causes osteoclasts to pump calcium ions out of bone fluid and into the extracellular fluid pool. Then, over hours, changes in gut absorption and renal excretion increase the calcium levels further. Lastly, osteoclastic digestion of existing bone contributes more and more calcium from the massive (roughly 1.0kg) skeletal stores of calcium.
So, PTH ends up being the first test you order, when investigating calcium disturbances. If the calcium is low, one might expect PTH to be high, and so when one finds that it is not, the blame falls on the parathyroid gland. Similarly, when the serum calcium is high, one would not expect the PTH to also be high, unless something is fundamentally broken in the parathyroid glands. Conversely, when the PTH is reacting to the calcium level appropriately, that virtually rules out the parathyroid glands as the cause of the derangement. In those situations, one ends up looking at the Vitamin D level next.
It seems like a shame to waste the reader's time with something as pointless as the "physiological role" of an intrinsic building block of life. Unfortunately "the diverse roles of calcium" were 70% of the marks in Question 4 from the first paper of 2011.