Podcast - Understanding low calcium: causes, symptoms and treatment

The video version of this podcast can be found here:

·      https://youtu.be/pxOeszuHRsI

This episode makes reference to guidelines produced for NHS Greater Glasgow and Clyde and Liverpool University Hospitals NHS Trust. Please note that the content on this channel reflects my professional interpretation/summary of the guidance and that I am in no way affiliated with, employed by or funded/sponsored by them.

My name is Fernando Florido and I am a General Practitioner in the United Kingdom. In this episode, I go through the management of hypocalcaemia, in particular, we will look at the guidance on the management of hypocalcaemia in NHS Greater Glasgow and Clyde and in Liverpool University Hospitals NHS Trust, always focusing on what is relevant in Primary Care only.  

I am not giving medical advice; this episode is intended for health care professionals; it is only my summary and my interpretation of the guidelines and you must use your clinical judgement.  

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https://youtube.com/@practicalgp?si=ecJGF5QCuMLQ6hrk 

The resources consulted can be found here:

The guidance on the management of hypocalcaemia by Liverpool University Hospitals NHS Trust can be found here:

·      https://pathlabs.rlbuht.nhs.uk/Guideline%20for%20Treating%20and%20Monitoring%20Hypocalcaemia%20for%20non-critical%20areas%20of%20Trust.pdf

The guidance on the management of hypocalcaemia by the Adult Therapeutics Handbook for the NHS Greater Glasgow and Clyde can be found here:

·      https://handbook.ggcmedicines.org.uk/guidelines/electrolyte-disturbances/management-of-hypocalcaemia/

Calcium – The Lancet - Bushinksy DA, Monk RD. Calcium. Lancet 1998; 352 (9124): 306-311:

·      https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(97)12331-5/abstract 

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Transcript

If you are listening to this podcast on YouTube, for a better experience, switch to the video version. The link is in the top right corner of the video and in the episode description. 

Hello and welcome, I’m Fernando, a GP in the UK. Today we are going to go through the management of hypocalcaemia, in particular, we will look at the guidance on the management of hypocalcaemia in NHS Greater Glasgow and Clyde, and in Liverpool University Hospitals NHS Trust, always focusing on what is relevant in Primary Care only. The links to their guidelines and the other sources consulted are in the episode description. 

Right, without further ado, let’s jump into it. 

As a quick overview of calcium metabolism, I will simply say that it is tightly regulated by vitamin D and the parathyroid hormone or PTH. Active vitamin D or calcitriol enhances intestinal calcium absorption and PTH both enhances calcium reabsorption in the kidneys, and releases calcium from the bones by increasing osteoclast activity and bone resorption. 

Both phosphate and magnesium can also affect calcium levels. For example, a low magnesium can impair PTH secretion and action, resulting in hypocalcaemia.  

On the other hand, a high phosphate, like seen in CKD, can lead to the precipitation of calcium with phosphate and the consequent reduction in serum calcium and hypocalcaemia.

Right, now that we have done this review, let’s now look at hypocalcaemia itself.

The reference range for adjusted serum calcium is 2.2 - 2.6mmol/L.

Symptoms of hypocalcaemia, typically develop when serum adjusted calcium falls below 1.9mmol/L. However, this threshold varies and symptoms also depend on the rate of fall. 

So, we will talk of hypocalcaemia when we have an adjusted serum calcium less than 2.2 mmol/L, although you should always take into account your local path lab reference range.  

The cause of hypocalcaemia may be varied depending on whether we are talking about acute or chronic hypocalcaemia. And we must remember that hypocalcaemia is far less common than hypercalcaemia because of the role of the bones as a calcium reserve to maintain homeostasis. 

So, let’s look at causes of acute hypocalcaemia first. The most common cause is hyperventilation which induces transient hypocalcaemia with normal serum total calcium levels normal. Let’s quickly see why this is the case. 

• When a person hyperventilates, they breathe out excessive CO₂ which leads to a decrease of carbonic acid, and respiratory alkalosis.
• Alkalosis causes more calcium to bind to albumin, reducing the concentration of free (ionized) calcium. Given that the ionized form is the physiologically active form, this decrease leads to symptoms of hypocalcaemia.
• However, despite the decrease in ionized calcium, the total serum calcium remains normal because this value includes the calcium bound to albumin. 

Other less common causes are:

·      Other forms of alkalosis.

·      Medications, for example post IV bisphosphonate or denusomab treatment

·      A high phosphate. We have to remember that phosphate and calcium often behave like two parts of a seesaw, where changes in one can inversely affect the other. Therefore, hypocalcaemia can be seen in clinical situations where phosphate is high, like in:

• rapid tumour lysis – like e.g. during cytotoxic treatment of leukaemia or
• in excessive phosphate intake – like for example excessive phosphate containing enemas.
• And finally, another less common cause of hypocalcaemia is acute pancreatitis. 

Let’s now look at the causes of chronic hypocalcaemia. And the most common cause is a decrease in levels of active vitamin D. This could be because there is:

• An overall vitamin D deficiency, like in dietary causes, malabsorption, and lack of sunlight or
• A reduction in the active form of vitamin D or calcitriol, due to poor renal conversion as seen in CKD

Less common causes are:

• hypoparathyroidism which can be post-surgical, autoimmune, genetic, idiopathic etc.
• hypomagnesaemia, because low magnesium impair the secretion and function of PTH, giving rise to a functional hypoparathyroidism.
• Pseudohypoparathyroidism, which is a rare, genetic disorder characterized by the body’s resistance to PTH despite normal or elevated PTH levels and finally
• low plasma albumin caused by, for example, malnutrition, or liver disease. However, it is worth mentioning that a low plasma albumin can lead to low total calcium levels but it does not cause true hypocalcaemia (understood as a low ionized or free calcium). Instead, it leads to pseudohypocalcaemia, where only the bound calcium is reduced, so patients typically do not experience symptoms of low calcium unless their ionized calcium is also low.

It is also worth mentioning that dietary lack of calcium intake is a very rare cause of hypocalcaemia. 

What are the symptoms and signs of hypocalcaemia?

Well, the clinical features of hypocalcaemia are connected to its effects on the nerves and muscles. Typical features include: 

·      Effects on the nervous system like:

• Paraesthesia
• convulsions which may occur because hypocalcaemia lowers the seizure threshold, and
• psychiatric effects, from general malaise to overt psychosis in chronic hypocalcaemia
• Effects on the muscles like:
• painful cramps
• tetany, which may result in spontaneous muscular spasms largely precipitated by exercise
• laryngeal spasm causing stridor, and obstructive respiratory symptoms and
• latent tetany, which may be demonstrated by Trousseau's and Chvostek's signs. Let’s quickly have a look at them:

For Trousseau’s sign, a blood pressure cuff is inflated usually about 20 mm Hg above the systolic BP, and it is left inflated for about 3 minutes. A positive sign is indicated by involuntary contraction of the muscles in the hand and fingers, known as carpal spasm or "Trousseau’s phenomenon." 

On the other hand, Chvostek's sign is performed by tapping on the facial nerve just in front of the ear, at the angle of the jaw, which is the area where the facial nerve crosses the masseter muscle. A positive sign is indicated by twitching of the facial muscles on that same side.  

Both Trousseau's and Chvostek's signs are indicative of increased neuromuscular excitability, which is often associated with hypocalcemia, although not exclusively. 

Other features of chronic hypocalcaemia depend on the underlying cause. They can be very varied so I will mention only a few like:

• candidiasis
• nail dystrophy
• alopecia, and
• rickets or osteomalacia - from chronic vitamin D deficiency

What investigations should be carried out in primary care if we find hypocalcaemia? And we are obviously talking about mild asymptomatic hypocalcaemia because patients with severe or symptomatic hypocalcaemia should be referred to hospital. 

Initial investigations should include as a minimum: 

• A repeat serum adjusted calcium and phosphate
• Parathyroid hormone (PTH)
• Urea and electrolytes
• Magnesium
• Vitamin D and
• A 12-lead ECG as there is a significant likelihood of QT prolongation, in which case cardiac monitoring may be required.

We should monitor calcium concentrations regularly to judge response and review treatment. Serum bone profile should be checked regularly according to clinical judgement, perhaps weekly or fortnightly depending on the case until concentrations are stable. 

Let’s now have a look at the treatment of hypocalcaemia. 

The treatment depends on the severity of symptoms and underlying condition: 

• treatment generally invovles administration of calcium. How calcium is administered and the need for additional agents such as vitamin D depends on the acuity and severity of the hypocalcaemia as well as the underlying cause.
• Severe Hypocalcaemia, that it, a serum adjusted calcium <1.9mmol/L and/or symptomatic hypocalcaemia should be treated as a medical emergency because it can be life-threatening. So, these patients should be referred to hospital for the administration of IV calcium.
• Chronic, Asymptomatic Mild Hypocalcaemia, that is, serum adjusted calcium between 1.9 - 2.2mmol/L is treated with oral calcium and often vitamin D supplements.
• Because calcium binds with dietary phosphate and oxalate we should advise patients that calcium is better absorbed when taken between meals.
• oral calcium is given to increase its availability and, often, vitamin D to enhance absorption.
• calcium carbonate is widely available in tablet form and we should aim for a daily dose of 1-2.6 g and then adjust according to response.
• Examples of calcium carbonate supplements are adcal and calcichew.
• NHS Greater Glasgow and Clyde recommend starting Calcichew Forte Chewable, 2 tablets twice a day, which is an unlicensed dose, and adjust the dose according to the patient’s requirements. As soon as it is appropriate, we should prescribe the licensed dose of 1 tablet daily.
• Alternatively, Liverpool Hospitals recommend starting oral calcium and vitamin D supplements such as Adcal D3 (2 to 4 tab daily) with monitoring and adjustment.
• calcium citrate and calcium phosphate should be avoided because they may cause problems, especially in patients with renal failure.
• If the patient is vitamin D deficient, we will start oral vitamin D supplementation with loading doses of colecalciferol as per the NICE guideline on vitamin D deficiency.
• vitamin D2 or ergocalciferol and vitamin D3 or colecalciferol at doses of 400 units a day are adequate to avoid nutritional deficiency, although higher doses may be needed in malabsorption.
• However, they require conversion to the active form calcitriol and therefore they are not suitable if the alpha-hydroxylation process is impaired, like for example in renal failure. In these cases, we should be guided by the renal team.
• Other general principles that apply to the management of hypocalcaemia are:
• magnesium levels should be checked and corrected if low. If patient has hypomagnesaemia, we should stop any precipitating drug and admit the patient to hospital for the administration of IV magnesium.
• patients on digoxin should be monitored carefully because administration of calcium may lead to digoxin toxicity and death
• Patients with hypoparathyroidism have decreased renal calcium reabsorption and oral calcium supplementation, may lead to hypercalciuria with possible nephrocalcinosis or kidney stones. Therefore, in hypoparathyroidism, the treatment should be guided by endocrinology.
• If hypocalcaemia is secondary to post-thyroidectomy, we will also seek specialist advice.
• When calcium is given to patients with hyperphosphataemia, there is a risk of soft-tissue calcium phosphate precipitation, so we should get specialist advice on the use of phosphate binders. Calcium supplements may have to be delayed until phosphate levels come down.

Right, so that is it. We have come to the end of this episode. Remember that this is not medical advice and it is only my summary and my interpretation of the guidelines. You must always use your clinical judgement.  

Thank you for listening and goodbye.