A 44-year-old patient is admitted post thyroidectomy for Graves’ disease. Seven years ago, she had gastric bypass surgery for obesity. Shortly after admission, her serum biochemical findings are:

Parameter

Patient Value

Adult Normal Range

Sodium 

136 mmol/L

135 – 145

Potassium  

5.0 mmol/L

3.5 – 5.0

Chloride 

103 mmol/L

95 – 105

Bicarbonate 

23.0 mmol/L

22.0 – 26.0 

Glucose 

5.8 mmol/L

3.5 – 6.0

Urea 

5.5 mmol/L

3.0 – 8.0

Creatinine  

80 μmol/L

45 – 90 

Magnesium

0.60 mmol/L*

0.75 – 0.95

Albumin 

35 g/L

35 – 50 

Protein 

74 g/L

60 – 80

Total bilirubin 

12 μmol/L

< 26

Aspartate aminotransferase (AST) 

34 U/L

< 35

Alanine aminotransferase (ALT)

40 U/L*

< 35

Alkaline phosphatase (ALP)

188 U/L*

30 – 110

γ-Glutamyl transferase (GGT)

45 U/L*

< 40

Calcium corrected 

1.80 mmol/L*

2.12 – 2.62

Phosphate 

0.7 mmol/L*

0.8 – 1.5

  1. Give two potential explanations for the abnormalities seen.               (10% marks)
  2. What clinical features might be associated with these abnormalities?       (20% marks)
  3. Outline your management.                                                              (40% marks)

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College answer

a) Give two potential explanations for the abnormalities seen. 
Vit. D deficiency 
Hypoparathyroidism 
 
b) What clinical features might be associated with these abnormalities  

Hypocalcaemia is classically associated with 
Paraesthesias in perioral and acral areas 
Chvostek and Trosseau’s signs 
Muscle cramps, laryngeal spasm 
Irritability, confusion, seizures 
Prolonged QT, arrhythmias 
 
Hypomagnesaemia – some of above, also muscle weakness 
Hypophosphatemia – mild, unlikely to be associated with clinical features 
 
c) Briefly describe how you will manage this condition                     

IV Cal chloride or gluconate, IV Magnesium PO4 replacement 
Monitor ionised Ca level, if available. Check ECG for prolonged QT 
Avoid alkalosis – as it worsens neuromuscular irritability 
Oral Vitamin D3 (cholecalciferol) as soon as oral intake is allowed 
Oral Cal supplement (up to 1.5 – 2.0 grams/day) – preferable as Ca citrate Not Ca carbonate Oral Magnesium supplements 
If recalcitrant hypoCa, consider s/c parathyroid hormone (confirm adequate vit D level)

Check TFT, TSH – replacement T4 as needed. 

Discussion

Unlike a normal data interpretation question which asks the candidate to mindlessly produce a shopping list of abnormalities, this one expects a little more. The shopping list and salient features from the question are:

  • Post-thyroidectomy
  • Gastric bypass (thus, possible malabsorption)
  • Low magnesium, calcium and phosphate
  • Raised alkaline phosphatase, suggestive of increased bone turnover

The thyroidectomy story raises the possibility of hypoparathyroidism, which is an easy mark. To produce another differential, one might need to think somewhat laterally.  Possibilities relevant to this case might include:

  • Hypomagnesemia (after all, it is low)
  • Vitamin D deficiency due to malabsorption

More remote possibilities may include:

  • Consumption by osteoclastic bone metastases (alk phos)
  • Consumption of calcium by coagulopathy (from a massive transfusion? thyroidectomy can be a bloody surgery)

Clinical features, they ask?

Clinical Manifestations of Hypocalcemia

Mild hypocalcemia

  • Generalised myalgia
  • Twitching, fasciculations
  • QT prolongation
  • Chvostek’s sign
  • Confusion, delirium, psychosis

Severe hypocalcemia

  • Carpopedal spasm (Trousseau’s sign)
  • Tetany and seizures
  • Papilloedema, raised intracranial pressure
  • Cardiac arrhythmias, esp. Torsades
  • Hypotension

Clinical Features of Hypomagnesemia

Symptoms

Physical signs

  • Confusion
  • Delirium
  • Tremors
  • Seizures
  • Tachyarrhythmias (particularly VT and VF)
  • Tetany
  • Chvostek sign
  • Trousseau sign

ECG changes

  • Widening QRS complexes
  • Peaking T-waves (which vanish in very severe hypomagnesemia)
  • Prolonged PR interval

Associated biochemical abnormalities

  • Hypokalemia, refractory to replacement
  • Hypocalcemia
  • Low parathyroid hormone levels (in spite of hypocalcemia)
  • Low Vitamin D levels
Clinical Features of Hypophosphataemia

Neurological manifestations

  • Irritability
  • Hallucinations
  • Delirium
  • Seizures
  • Coma
  • Increased risk of osmotic demyelination

Cardiovascular manifestations

  • Impaired cardiac contractility, cardiomyopathy
  • Propensity towards arrhythmias

Biochemical abnormalities

  • Hypercalciuria
  • Increased bone resorption
  • Increased calcitriol (1,25-dihydroxyvitamin D)

Musculoskeletal manifestations

  • Weakness
  • Proximal myopathy
  • Dysphagia
  • Ileus
  • Slowed ventilator weaning
  • Rhabdomyolysis
  • Osteopenia and rickets (long term)

Haematological abnormalities

  • Decreased red cell 2,3-DPG levels (a left shift)
  • Increased RBC rigidity, and propensity to haemolysis
  • Impaired clot retraction
  • Leukocyte dysfunction
  • Thrombocytopenia

Management of hypocalcemia might seem as straightforward as replacing the calcium, but the college examiners make the fair point that this process can be more involved and occasionally requires extra thinking. A structured approach might resemble the following, which was borrowed from an excellent article by  Cooper and Gittoes (2008):

Acute replacement

  • IV replacement of calcium salt
  • Calcium chloride or gluconate, doesn't matter
  • Ensure magnesium and phosphate are replaced at the same time 

Medium term replacement

  • Oral calcium replacement
    • The college specifically recommend calcium citrate, "Not Ca carbonate",   in spite of the fact that the citrate appears to have lower oral bioavailability (Wang et al, 2014). According to UpToDate, both choices are available in exactly the same dose of elemental calcium. One possible reason for this (otherwise unexplainable) preference is the need for normal gastric pH to dissolve calcium carbonate tables, i.e. it is to be taken with food whereas calcium citrate is more suitable to an otherwise fasted post-operative patient. 
  • Vitamin D replacement
  • With intact parathyroid function:
    • Cholecalciferol (which is then converted to calcitriol in the kidney, provided parathyroid function is normal)
  • With impaired parathyroid function:
    •  Calcitriol, the hormonally active version of Vitamin D (without PTH around the oral cholecalciferol supplements will not be effective)
  • Both drugs will have positive effects:
    • Improve gut absorption
    • Improve release of calcium from bone
    • Decrease renal excretion

So, what might one do if in spite of ongoing calcium infusion the ionised calcium keeps dropping? That would probably be the "recalcitrant hypoCa" described by the examiners, who were presumably too busy to type "hypocalcemia" for the purposes of this model answer. "Recalcitrant hypoCa" is actually a real phenomenon which tends to occur in patients who have previously had gastric bypass procedures (Moore et al, 2013), as the patient in this question has done. It has no scientific definition, but some authors (eg. Ballal et al, 2017) seem to characterise it as a hypocalcemia which fails to respond to either vitamin D supplementation or intravenous calcium. Therre arre some treatment options open to these people:

  • Thiazide diuretics (which increase the renal reabsorption of calcium)
  • recombinant PTH 

References

Cooper, Mark S., and Neil JL Gittoes. "Diagnosis and management of hypocalcaemia." BMJ 336.7656 (2008): 1298-1302.

Wang, Haiyuan, Peter Bua, and Jillian Capodice. "A comparative study of calcium absorption following a single serving administration of calcium carbonate powder versus calcium citrate tablets in healthy premenopausal women." Food & nutrition research 58.1 (2014): 23229.

McKenzie, Travis J., et al. "Recalcitrant hypocalcemia after thyroidectomy in patients with previous Roux-en-Y gastric bypass." Surgery 154.6 (2013): 1300-1306.

Ballal, Devesh Sanjeev, et al. "Persistent recalcitrant hypocalcemia following total thyroidectomy: a management challenge." Malta Medical Journal 29.02 (2017).