Calcium Disorders Diagnosis and Management PDF

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Diagnosis and Management of Calcium Disorders Department of Medicine LEARNING OUTCOMES 1. Define hypercalcemia and hypocalcemia​ 2. Explain the pathophysiology of hypercalcemia and hypocalcemia​ 3. List the cardinal...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Diagnosis and Management of Calcium Disorders Department of Medicine LEARNING OUTCOMES 1. Define hypercalcemia and hypocalcemia​ 2. Explain the pathophysiology of hypercalcemia and hypocalcemia​ 3. List the cardinal symptoms and signs of hypercalcemia and hypocalcemia​ 4. Explain how each symptom and sign is caused in hypercalcemia and hypocalcemia​ 5. Develop a differential diagnosis for hypercalcemia and hypocalcemia​ 6. Outline the overarching principles of investigation and management in calcium disorders LEARNING OUTCOME 1 Define hypercalcemia and hypocalcemia​ HYPERCALCAEMIA Corrected serum calcium of > 2.6mmol/L​ Mild hypercalcaemia 2.6–3.0 mmol/L​ Moderate hypercalcaemia 3.0–3.5 mmol/L​ Severe hypercalcaemia >3.50 mmol/L LIFE THREATENING MEDICAL EMERGENCY Corrected Calcium: Serum Ca + 0.02 x (Normal Albumin – Patient Albumin) Units: Calcium in mmol/L & albumin in g/L HYPOCALCEMIA Corrected serum calcium of < 2.2mmol/L​ Corrected Calcium: Serum Ca + 0.02 x (Normal Albumin – Patient Albumin) Units: Calcium in mmol/L & albumin in g/L Clinical Tip: always look at the corrected calcium, which is the calcium corrected for albumin. Calcium binds to albumin, if the albumin levels are low, the calcium may actually be normal but under-reported. LEARNING OUTCOME 2 Explain the pathophysiology of hypercalcemia and hypocalcemia CALCIUM HOMEOSTASIS Parathyroid hormone (PTH) regulates serum calcium levels. Vitamin D also important Calcium level is regulated by 3 main processes: Bone turnover Intestinal absorption Renal excretion PTH, calcium & vitamin D are closely linked and changes in one of these will invariably affect the others CALCIUM HOMEOSTASIS PTH is secreted by the 4 parathyroid glands that lie posterior to the thyroid The parathyroid glands are controlled via negative feedback related to calcium levels i.e. PTH is secreted in response to hypocalcemia. When serum calcium levels rise, a negative feedback mechanism causes decreased release of PTH from parathyroid glands CALCIUM HOMEOSTASIS E.g. in case of HYPOCALCEMIA: PTH secreted (in response to low calcium levels) Decreases renal excretion of calcium due to stimulation of calcium reabsorption in the distal tubule Increases calcium resorption from bone Increases intestinal calcium absorption mediated by increased renal production of 1,25-dihydroxyvitamin D COMPLEX SYSTEM LEARNING OUTCOME 3 List the cardinal symptoms and signs of hypercalcemia and hypocalcemia​ SYMPTOMS AND SIGNS Important to know that ionised calcium plays an important role in: Bone formation and turnover Muscle contraction Nervous system function Coagulation cascade Intracellular signalling for secretion of many hormones Symptoms and signs can depend on the severity and the acuity/chronicity of the hypercalcemia/hypocalcemia HYPERCALCEMIA SYMPTOMS AND SIGNS May be asymptomatic Memory aid for symptoms of hypercalcemia: ‘bones, stones, abdominal moans and psychiatric groans’ Bones: bone pain, pathological fractures Renal stones: abdominal pain, haematuria, fever, etc Abdominal: abdo pain, nausea, vomiting, constipation, pancreatitis Psych: confusion, hallucinations, lethargy, depression Other: sluggish reflexes, polydipsia and polyuria, palpitations ECG: shortened QT interval - can progress to complete AV nodal block and cardiac arrest HYPOCALCEMIA SYMPTOMS AND SIGNS May be asymptomatic Acute: tetany, papilledema, seizures, psychological symptoms, cardiac manifestations (hypotension, heart failure and arrhythmias) Chronic: ectodermal and dental changes, cataracts, basal ganglia calcification, extrapyramidal disorders NB: tetany characterised by neuromuscular irritability and can be mild (paraesthesia periorally or in hands or feet, muscle cramping) or severe (carpopedal spasm, laryngospasm, seizures) Trosseau’s sign – inflation of sphygmomanometer above systolic BP for 3 minutes leads to involuntary contraction of hand/wrist (carpal spasm) Chvostek’s sign – tapping of facial nerve anterior to ear causes ipsilateral contraction of facial muscles (may be twitching lip or spasm of all facial muscles) ECG: may see QT prolongation – can progress to Torsades de pointes and cardiac arrest Chvostek's Sign Trosseau's Sign QTc prolongation to Torsades de Pointes LEARNING OUTCOME 4 Explain how each symptom and sign is caused in hypercalcemia and hypocalcemia​ HYPERCALCEMIA – PATHOPHYSIOLOGY OF SYMPTOMS AND SIGNS Musculoskeletal manifestations – bone pain due to reduction in cortical bone mass Kidney manifestations – commonly: polyuria, nephrolithiasis, and acute and chronic kidney insufficiency. Polyuria results from decreased concentrating ability in the distal tubule. Chronic hypercalcemia associated with hypercalciuria can lead to nephrolithiasis or nephrocalcinosis due to formation of calcium crystals and subsequently stones GI manifestations – commonly: constipation, anorexia, and nausea. Constipation possibly related to reduced smooth muscle tone and/or abnormal autonomic function. Pancreatitis less frequent and possibly due to deposition of calcium in pancreatic duct and calcium activation of trypsinogen within pancreatic parenchyma Cardiovascular manifestations – acute hypercalcemia shortens myocardial action potential (seen as shortened QT interval on ECG). Arrhythmia has been reported in patients with severe hypercalcemia due to changes in cardiac conduction. Longstanding hypercalcemia (as seen in primary hyperparathyroidism) can lead to other cardiac disease -> deposition of calcium in heart valves, coronary arteries, and myocardial fibers; hypertension; and cardiomyopathy. HYPOCALCEMIA – PATHOPHYSIOLOGY OF SYMPTOMS AND SIGNS Tetany – hyperexcitability of peripheral neurons. Repetitive, high- frequency discharges sent after a single stimulus Trousseaus and Chvosteks sign – caused by increased neuromuscular excitability due to hypocalcemia Seizures: EEGs of patient with seizures secondary to hypocalcemia show both spikes (convulsive effect) and bursts of high-voltage, paroxysmal slow waves Cardiovascular: mechanism of myocardial dysfunction undefined but calcium plays key role in excitation-contraction coupling and is needed for epinephrine-induced glycogenolysis in the heart. Prolongs QT by prolonging cardiac action potential LEARNING OUTCOME 5 Develop a differential diagnosis for hypercalcemia and hypocalcemia​ HYPERCALCEMIA DIFFERENTIALS NB: over 90% of cases of hypercalcemia due to either primary hyperparathyroidism or malignancy Hyperparathyroidism (primary and tertiary) Malignancy (myeloma, bone metastases, paraneoplastic syndromes – increased bone resorption) Excess vitamin D (supplements, sarcoidosis, tuberculosis) Renal disease Drugs (lithium, thiazide diuretics) Familial hypocalciuric hypercalcemia Dehydration HYPOCALCEMIA DIFFERENTIALS NB: Hypocalcemia can occur when PTH secretion is insufficient (hypoparathyroidism). If parathyroid glands and PTH functioning normally, other causes of hypocalcemia (eg, vitamin D deficiency) are characterized by high PTH (secondary hyperparathyroidism). So can characterize hypocalcemia as associated with low PTH or high PTH Drugs: – bisphosphonates, denosumab, calcium chelating medication, chemotherapy Hypocalcemia with decreased PTH (hypoparathyroidism): – postsurgical, autoimmune hypoparathyroidism, inherited disorders such as familial hypocalcemia, infiltrative disease such as haemochromatosis (iron deposits) and Wilsons disease (copper deposits) and metastatic disease HYPOCALCAEMIA DIFFERENTIALS CONTINUED Hypocalcemia with high PTH: – Vitamin D deficiency – secondary to reduced nutritional intake, reduced UV light exposure, decreased activation in liver and kidney, increased metabolism to inactive metabolites – Chronic kidney disease – causes decreased renal production of 1,25-dihydroxyvitamin D. Does not occur until end stage renal disease and has associated hyperphosphatemia secondary to reduced phosphate excretion – Hyperphosphatemia – may be secondary to CKD or excessive tissue breakdown in rhabdomyolysis or tumor lysis syndrome. These can cause acute presentations of hypocalcemia – Osteoblastic metastases – secondary to deposition of calcium in newly formed bone around tumor – Acute pancreatitis – associated with precipitation of calcium soaps in abdominal cavity – Sepsis, severe illness, surgery – due to impaired secretion of PTH, reduced production of calcitriol, end-organ resistance to PTH – Hypomagnesemia – reduction in Mg can lead to PTH resistance and therefore hypocalcemia. Magnesium must be replaced for treatment to be effective HYPOCALCEMIA DIFFERENTIALS LEARNING OUTCOME 6 Outline the overarching principles of investigation and management in calcium disorders HYPERCALCEMIA INVESTIGATION Key points: Verify serum calcium result with a corrected calcium level. Then check PTH to see if hypercalcemia is PTH dependent or independent Remember primary hyperparathyroidism and malignancy are most common causes (>90% of cases). However, must consider all causes Patients with hypercalcemia of malignancy usually have higher calcium concentrations and are more symptomatic from hypercalcemia than individuals with primary hyperparathyroidism HYPERCALCEMIA MANAGEMENT Prevention: regular medication review and management of underlying cause General principles – the degree of hypercalcemia and the rate of rise of serum calcium concentration often determines symptoms and urgency of therapy Mild hypercalcemia – those with asymptomatic or mildly symptomatic hypercalcemia don’t require immediate treatment. Advise to avoid aggravating factors: thiazide diuretics, lithium carbonate therapy, volume depletion, prolonged inactivity, calcium supplements, vitamin D supplements, high-calcium diet (>1000 mg/day)) Moderate hypercalcemia – asymptomatic or mildly symptomatic individuals with chronic moderate hypercalcemia may not require immediate therapy, but should avoid aggravating factors listed above. However, an acute rise to these levels may cause changes in sensorium, which requires treatment as described for severe hypercalcemia. Severe hypercalcemia – those with severe or symptomatic (eg, lethargy, stupor) hypercalcemia need aggressive therapy. Initial therapy includes simultaneous administration of intravenous isotonic saline, subcutaneous calcitonin, and a bisphosphonate (usually IV zoledronic acid) HYPOCALCEMIA INVESTIGATION HYPOCALCAEMIA MANAGEMENT Prevention: regular medication review and management of underlying cause Treatment varies based on severity and underlying cause Severe acute hypocalcemia If severely symptomatic (carpopedal spasm, laryngospasm, bronchospasm, seizures, decreased cardiac function, prolonged QT interval), rapid correction of calcium levels with intravenous calcium therapy is required IV calcium therapy also suggested in asymptomatic patients with acute decrease in serum corrected calcium to ≤1.9 mmol/L IV calcium not warranted as initial therapy in patients with CKD who are asymptomatic or who have chronic stable hypocalcemia with only mild symptoms (eg, paresthesias) -> correction of hyperphosphatemia and of low circulating 1,25-dihydroxyvitamin D usually the primary goals here Mildly symptomatic or chronic hypocalcemia If mild symptoms of neuromuscular irritability (paresthesias) and corrected serum calcium concentrations >1.9 mmol/L, initial treatment with oral calcium supplementation sufficient. If this does not improve symptoms then IV calcium infusion required. IV calcium also indicated to prevent acute hypocalcemia in patients with milder degrees of hypocalcemia or chronic hypocalcemia (due to hypoparathyroidism) who become unable to take or absorb oral supplements (this can occur after complex surgical procedures requiring prolonged recuperation) If hypocalcemia caused by hypoparathyroidism or vitamin D deficiency, administration of calcium only transiently effective (as long as the infusion continues), and oral calcium may not be well absorbed. In this setting, addition of vitamin D is required, which often permits a lower dose of calcium supplementation Concurrent hypomagnesemia In patients with concurrent hypocalcemia and magnesium deficiency, hypomagnesemia should be corrected first, to effectively treat KEY POINTS Verify serum calcium result with a corrected calcium level Hypercalcemia and hypocalcemia can affect multiple systems Is PTH elevated/normal/reduced? The treatment of hypercalcemia and hypocalcemia can be dictated by a number of factors Don’t forget to investigate for and manage underlying cause RESOURCES UpToDate Geeky medics