Podcast - The calcium puzzle: how to handle high levels - Primary Care Guidelines | Lyssna här

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This episode makes reference to guidelines produced for the Maidstone and Tunbridge Wells NHS Trust, and NHS Greater Glasgow and Clyde. 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 guidance on hypercalcaemia produced by the Maidstone and Tunbridge Wells NHS Trust, and the guidance in NHS Greater Glasgow and Clyde, 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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The resources consulted can be found here:

The guidance on the treatment of hypercalcaemia in adults by the Maidstone and Tunbridge Wells NHS Trust can be found here:

· https://www.formularywkccgmtw.co.uk/media/1629/treatment-of-acute-hypercalcaemia-in-adults.pdf

The guidance on the management of hypercalcaemia 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-hypercalcaemia/

Other guidance can be found here:

Joshi D, Center JR, Eisman JA. Investigation of incidental hypercalcaemia. BMJ. 2009;339:b4613

· http://www.ncbi.nlm.nih.gov/pubmed/19933303

Carroll MF, Schade DS. A practical approach to hypercalcemia. Am Fam Physician. 2003;67(9):1959-66

· http://www.ncbi.nlm.nih.gov/pubmed/12751658

Smellie WS et al. Best practice in primary care pathology: review 11. J Clin Pathol. 2008;61(4):410-8

· http://www.ncbi.nlm.nih.gov/pubmed/17965216

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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 guidance on hypercalcaemia produced by the Maidstone and Tunbridge Wells NHS Trust, as well as other general guidance on the subject, always focusing on what is relevant in Primary Care only. The links to the information consulted can be found in the episode description.

Right, let’s not waste any more time so let’s jump into it.

Before we start, let’s quickly have an overview of calcium metabolism.

Calcium is one of the most abundant electrolytes in the body, and levels are tightly controlled by parathyroid hormone and vitamin D. Serum calcium is bound to albumin, and measurements should be adjusted for it, so we should be primarily concerned about corrected calcium levels.

Calcium is mostly absorbed in the small intestine and active vitamin D (or calcitriol) enhances calcium absorption.

Parathyroid Hormone (or PTH) is also important. When blood calcium levels drop, PTH is secreted, which enhances calcium reabsorption in the kidneys, and also stimulates osteoclasts in the bones, breaking down bone tissue and releasing calcium into the blood stream. This is precisely the opposite effect of calcitonin, which inhibits osteoclast and reduces bone resorption and calcium levels.

So, from a pathophysiological perspective, a high calcium or hypercalcemia can be seen in, for example, hyperparathyroidism, malignancy, or excessive vitamin D intake.

There are also pathophysiological interactions between calcium and levels of phosphate and magnesium.

For example, a high calcium can suppress magnesium renal absorption, leading to hypomagnesaemia. Equally, a high calcium also often leads to a low phosphate due to its effect on PTH.

Right, having had this overview, let’s now have a look at hypercalcaemia itself. It is generally defined as a corrected calcium level greater than 2.6 on two occasions, although we will need to take into account our local path lab reference range.

About 90% of cases are due to either primary hyperparathyroidism or malignancy.

Other rarer causes of hypercalcaemia include:

· Chronic granulomatous diseases like sarcoidosis or pulmonary Tb

· Paget's disease with bed rest

· Immobilisation

· Vitamin A and/or vitamin D toxicity

· Drugs like thiazide diuretics and lithium

· Familial hypocalciuric hypercalcaemia

· Non-parathyroid endocrine diseases (e.g. thyrotoxicosis, Addison's disease, and phaeochromocytoma)

· Milk-alkali syndrome

· Chronic kidney disease and

· Tertiary hyperparathyroidism. By the way, if you want to know more about tertiary hyperparathyroidism, stay until the end because I will give you a brief pathophysiological explanation of it.

The possible sign and symptoms of hypercalcaemia are often summarised by "stones, bones, thrones, abdominal groans and psychiatric overtones". Let’s see where these come from:

· "Stones" refer to kidney stones.

· "Bones" refer to skeletal symptoms such as bone pain, osteoporosis, and fractures associated with underlying bone disorders like in hyperparathyroidism or pathological fractures in malignancy.

· "Thrones" refers to polyuria and constipation

· "Abdominal groans" refer to gastrointestinal symptoms such as nausea, vomiting, anorexia, weight loss, abdominal pain, pancreatitis and peptic ulcer. By the way, peptic ulcers can be an effect of increased gastric acid secretion caused by hypercalcemia.

· "Psychiatric overtones" refer to effects on the central nervous system such as lethargy, fatigue, depression, confusion, irritability, memory loss, psychosis, ataxia, delirium, and coma.

· Other: obviously this list of symptoms is not exhaustive. There are others not included, such as flushing, itching and cardiovascular complications, like hypertension, cardiac conduction abnormalities and arrhythmias.

In general, hypercalcaemia can be classified as:

mild – if corrected calcium levels are between 2.6 – 3.00 mmol/l. It is often asymptomatic and does not usually require urgent correction.

moderate – if between 3.00 – 3.40 mmol/l and it may be well tolerated if it has risen slowly, but it may also be symptomatic and require prompt treatment and

severe – if it is more than 3.40 mmol/l, which requires urgent correction due to the risk of dysrhythmia and coma. The most common cause of severe hypercalcaemia is malignancy.

What initial investigations should we consider in Primary Care for a patient with a high corrected calcium? I am obviously referring to mild hypercalcaemia, given that the more severe cases we will be referring to secondary care for immediate management.

So, as investigations, we should organise Blood Tests in order to check:

· An FBC

· Renal function tests, as hypercalcemia can cause renal impairment.

· Sodium and potassium to assess for electrolyte imbalances that may coexist.

· To check a repeat corrected calcium to ensure it is not a lab error.

· Also to check phosphate levels. and

· Alkaline phosphatase which may suggest bone involvement, such as in malignancy or Paget’s disease.

· Also to test for Vitamin D levels to assess for vitamin D intoxication or deficiency.

· To check magnesium levels: As magnesium abnormalities, usually hypomagnesaemia can also be associated to hypercalcaemia.

· To measure PTH to determine whether the hypercalcaemia is PTH-dependent or PTH-independent. For example,

o A low PTH in the context of hypercalcaemia suggests a non-PTH-mediated cause, such as malignancy, excess vitamin D, granulomatous disease, or drug-induced causes. On the other hand,

o A high or normal PTH in the context of hypercalcaemia suggests primary or tertiary hyperparathyroidism or familial hypocalciuric hypercalcemia (FHH). Please note that Familial hypocalciuric hypercalcemia has an inappropriately normal or elevated PTH because the calcium-sensing receptors in the parathyroids glands are less sensitive due to genetic reasons and this tricks the body into believing that the calcium levels are lower than they are.

· The blood test is also to check thyroid function tests given that hyperthyroidism can also cause hypercalcaemia and we should also

· Check serum protein electrophoresis if multiple myeloma is suspected.

We should consider additional tests depending on the clinical context such as:

· A Chest X-ray to screen for granulomatous disease, TB or malignancy

· An ECG to look for shortened QT intervals or other conduction abnormalities

· A 24-hour urinary calcium excretion if we need to differentiate between primary hyperparathyroidism and familial hypocalciuric hypercalcemia, which has a low urinary calcium and a

· Serum cortisol if Addison’s disease is suspected

In terms of treatment, we should get specialist advice and treat the underlying cause.

We should consider:

· Immediate referral or same day hospital admission in cases of severe hypercalcaemia, that is, with a corrected calcium >3.4 mmol/L. We should also do so, regardless of the level of hypercalcaemia, for symptomatic patients, if there is a suspicion of a serious underlying condition, such as malignancy or a parathyroid crisis, or if there is worsening renal function.

· Non-urgent outpatient referral would be reserved for patients with mild hypercalcaemia, that is, a corrected calcium less than 3, as long as they are asymptomatic and otherwise stable. We should carefully monitor calcium, renal function, and other relevant tests while awaiting secondary care input. And finally, what do we do with patients with moderate hypercalcaemia? Well,

· From a primary care perspective, the management of patients with moderate hypercalcaemia, that is, levels between 3.00 and 3.40 mmol/L, is controversial but, in general, it may also be safer to err on the side of caution, and many guidelines recommend immediate hospital referral in these cases too.

Other obvious measures that we should instigate in Primary Care would be to stop drugs associated with hypercalcaemia, such as thiazide diuretics, encourage hydration and, if possible, avoid immobilisation.

I will not indulge in secondary care treatment as this is outside our hands, but one of the limitations is that there are no national guidelines for the management of hyerpcalcaemia, and practice varies widely across UK Hospitals. The acute management in secondary care generally involves:

· Rehydration:

· And then assess if IV bisphosphonates such as pamidronate or zolendronic acid are required, followed by the definitive treatment of the underlying cause, like, for example, parathyroidectomy in primary hyperparathyroidism.

Now, as promised, I am going to tell you more about tertiary hyperparathyroidism.

And before I can explain tertiary hyperparathyroidism, we probably need to go through the definitions of primary and secondary hyperparathyroidism first.

Primary hyperparathyroidism is when the parathyroid glands produce excessive amounts of parathyroid hormone (or PTH) without any external trigger, that is, it is an intrinsic problem within the parathyroid glands and the most common cause is a benign tumour or adenoma.

In Secondary hyperparathyroidism, the parathyroid glands overproduce PTH as a compensatory response to low calcium levels in the blood and it is the body's attempt to normalise calcium levels. Possible causes of secondary hyperparathyroidism are chronic kidney disease and vitamin D deficiency.

And, finally, tertiary hyperparathyroidism involves the autonomous overproduction of PTH due to hyperplastic parathyroid glands that no longer respond to normal regulatory feedback, generally seen after prolonged secondary hyperparathyroidism in patients with CKD.

Let’s quickly examine the pathophysiology of tertiary hyperparathyroidism:

In CKD, the kidneys lose their ability to excrete phosphate, leading to hyperphosphatemia.

In CKD, the kidneys also produce less active vitamin D, resulting in decreased calcium absorption and hypocalcemia.

Both hypocalcemia and hyperphosphatemia stimulate the parathyroid glands to produce more PTH to maintain calcium levels. This is the secondary hyperparathyroidism stage.

However, over time, the continuous stimulation of the parathyroid glands leads to glandular hyperplasia and, as hyperplasia progresses, the parathyroid glands become less responsive to normal feedback mechanisms.

So, in some patients, particularly in those after prolonged and severe secondary hyperparathyroidism, the parathyroid glands can become autonomous, meaning they secrete PTH independently of blood calcium levels. At this stage, even when the initial cause of secondary hyperparathyroidism is corrected (e.g., after a kidney transplant), the overactive parathyroid glands continue to produce excessive PTH which will lead to hypercalcemia. This is when we talk about tertiary hyperparathyroidism.

So that is it, a quick review of the different types of hyperparathyroidism.

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.

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