History

Fact Explanation
History of secondary hyperparathyroidism eg:- Chronic kidney disease Tertiary hyperparathryoidism is where excessive autonomous secretion of parathyroid hormone occurs after a longterm history of secondary hyperparathyroidism and resulting in hypercalcemia. [3] This can also defined as secondary hyperparathyroidism not settling with renal transplantation. Patient may be having a history of chronic secondary hyperparathyroidism as in Chronic kidney disease, dietary vitamin D deficiency and rickets. Vitamin D is important in absorption of calcium from the gastrointestinal tract, tubular reabsorption of calcium and resorption of bone. Rickets is mainly due to lack of vitamin D and calcium. When the vitamin D is lacking, low calcium triggers parathyroid glands to increase the secretion of parathyroid hormone causing secondary hyperparathyroidism.
Renal colic Hypersecreted parathyroid hormone acts on kidney, and reduce the excretion of calcium via urine. Increased calcium can precipitate as stones. [1] This nephrocalcinosis causes loin to groin pain. Most of them are calcium oxalate and occasionally calcium phosphate.
Skeletal problems Renal osteodystrophy is the term used for the bone problems associated with chronic kidney disease. [2] Parathyroid hormone causes bone resorption, leading to abnormal bone mineralization, bone pain, pathological fractures osteomalacia [3] and osteoporosis. Tertiary hyperparathryoidism can present with or without parathyroid bone disease. [3]
Anorexia, nausea, vomiting, constipation, polyuria and polydypsia Due to hypercalcaemia. [1,4]
Skin pruritus This may be due to calcium depositions in the skin. Sometimes this may be a chronic problem. [5]
Confusion, drowsiness These are neurological symptoms of hypercalcaemia. [4]
Ansomnia, depression and poor memory, irritability and impatience There can be abnormalities in calcium transport across the cell membrane due to hypercalcaemia and this can cause psychiatric and neurological manifestations. [6]
References
  1. ASSADI F. Hypercalcemia: an evidence-based approach to clinical cases. Iran J Kidney Dis [online] 2009 Apr, 3(2):71-9 [viewed 24 June 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/19395781
  2. SNIVELY CS, GUTIERREZ C. Chronic kidney disease: prevention and treatment of common complications. Am Fam Physician [online] 2004 Nov 15, 70(10):1921-8 [viewed 10 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/15571058
  3. DAVIES DR, DENT CE, WATSON L. Tertiary Hyperparathyroidism Br Med J [online] 1968 Aug 17, 3(5615):395-399 [viewed 19 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1986316
  4. RALSTON SH. Medical management of hypercalcaemia. Br J Clin Pharmacol [online] 1992 Jul, 34(1):11-20 [viewed 19 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1381369
  5. ABBOUR SA. Cutaneous manifestations of endocrine disorders: a guide for dermatologists. Am J Clin Dermatol [online] 2003, 4(5):315-31 [viewed 25 June 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/12688837
  6. PYRAM R, MAHAJAN G, GLIWA A. Primary hyperparathyroidism: Skeletal and non-skeletal effects, diagnosis and management. Maturitas [online] 2011 Nov, 70(3):246-55 [viewed 24 June 2014] Available from: doi:10.1016/j.maturitas.2011.07.021

Examination

Fact Explanation
Pallor Is seen in chronic kidney disease. Osteitis fibrosa in renal osteodystrophy [1] can aggravate the marrow fibrosis and worsen the anemia.
Skin pigmentation, peripheral oedema Due to underlying chronic kidney disease. [1]
Features of rickets: Widening of wrist and ankle joint, [2] bowing of the legs, rickety rossery, curvature of the spine, softening of skull bones. Rickets can be cause for the long term secondary hyperparathyroidism. [2]
Scratch marks Pruritus due to secondary hyperparathyroidism [3] and underlying chronic kidney disease.
Ballotable kidneys Polycystic kidneys are an aetiological factor for tertiary hyperparathyroidism. [4]
Ataxia Neurological manifestations of hypercalcaemia. [5]
Irregular pulse rate Arrhythmia due to hypercalcaemia. [5]
Corneal calcifications, conjunctivitis Eye manifestations due to hypercalcaemia. [5]
References
  1. SNIVELY CS, GUTIERREZ C. Chronic kidney disease: prevention and treatment of common complications. Am Fam Physician [online] 2004 Nov 15, 70(10):1921-8 [viewed 10 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/15571058
  2. JANCAR J. Rickets with Secondary Hyperparathyroidism in a Severely Subnormal Child Arch Dis Child [online] 1963 Aug, 38(200):412-414 [viewed 11 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2018945
  3. YONOVA D. Pruritus in certain internal diseases Hippokratia [online] 2007, 11(2):67-71 [viewed 11 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2464269
  4. DAVIES DR, DENT CE, WATSON L. Tertiary Hyperparathyroidism Br Med J [online] 1968 Aug 17, 3(5615):395-399 [viewed 19 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1986316
  5. RALSTON SH. Medical management of hypercalcaemia. Br J Clin Pharmacol [online] 1992 Jul, 34(1):11-20 [viewed 19 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1381369

Differential Diagnoses

Fact Explanation
Primary hyperparathyroidism There is an autonomous production of parathyroid hormone by the parathyroid glands which leads to elevated serum parathyroid hormone and hypercalcemia/normocalcemia. [3] Normocalcemic primary hyperparathyroidism is a variety that incidentally diagnosed with reduced bone mineral density. [1] They can also present with hypercalcaemic emergencies.
Secondary hyperparathyroidism This usually occurs in disease conditions such as chronic kidney disease and malabsorption. [1] This usually develops in response to hypocalcaemia, Calcium will be low or normal and parathyroid hormone level will be high. [1]
Familial hypocalciuric hypercalciuria This is an autosomal dominant condition. The problem is in the calcium sensing receptors in the parathyroid glands. There will be low urinary calcium in 24h urine, and calcium/creatinine clearance ratio is decreased. [1] Secondary hyperparathyroidism also has low urinary calcium levels. Fasting urinary calcium excretion is done to confirm the condition. [2]
Drugs Reduced renal calcium excretion by thiazide diuretics [2] and lithium can cause hypercalcaemia [1]. This will respond to discontinuation of medication.
Malignancy They can present with hypercalcaemia and parathyroid hormone level is usually low in these conditions. [1]
References
  1. MART¡NEZ CORDELLAT ISABEL. Hyperparathiroidism: Primary or Secondary Disease?. Reumatolog¡a Cl¡nica (English Edition) [online] 2012 September, 8(5):287-291 [viewed 11 July 2014] Available from: doi:10.1016/j.reumae.2011.06.002
  2. RALSTON SH. Medical management of hypercalcaemia. Br J Clin Pharmacol [online] 1992 Jul, 34(1):11-20 [viewed 19 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1381369
  3. CARNEVALE V, ROMAGNOLI E, PIPINO M, SCILLITANI A, D'ERASMO E, MINISOLA S, MAZZUOLI G. [Primary hyperparathyroidism]. Clin Ter [online] 2005 Sep-Oct, 156(5):211-26 [viewed 24 June 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/16382970

Investigations - for Diagnosis

Fact Explanation
Serum parathyroid hormone level Elevated PTH secondary is seen. This is the most important investigation to differentiate the causes of hypercalcaemia. [3] PTH level > 450 pg/dl is associated with advanced bone turnover.
Serum calcium Serum calcium levels will be within reference range or even elevated. [2] Should get corrected to the serum albumin level. [3]
Serum phosphate Phosphate renal clearance is high. [2]
Alkaline phosphate level May be high due to bone resorption. [2]
X-ray Bone resorption can be seen in several locations in the bones. Bone resorption, periosteal reaction, osteoporosis, osteosclerosis, osteomalacia [2] are the frequent pathological features seen in tertiary hyperparathyroidism. Other changes would be osteopenia, 'salt-and-pepper' appearance on skull x-ray with trabecular resorption, subperiostal bone resorption and patchy diffuse areas of osteoclerosis.
References
  1. CUNNINGHAM J.. Achieving therapeutic targets in the treatment of secondary hyperparathyroidism. Nephrology Dialysis Transplantation [online] 2004 August, 19(suppl_5):v9-v14 [viewed 10 July 2014] Available from: doi:10.1093/ndt/gfh1050
  2. DAVIES DR, DENT CE, WATSON L. Tertiary Hyperparathyroidism Br Med J [online] 1968 Aug 17, 3(5615):395-399 [viewed 19 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1986316
  3. RALSTON SH. Medical management of hypercalcaemia. Br J Clin Pharmacol [online] 1992 Jul, 34(1):11-20 [viewed 19 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1381369

Investigations - Fitness for Management

Fact Explanation
Arterial blood gas Hyperchloremic metabolic acidosis occur in hyperparathyroidism. [1,3]
HbA1c, fasting blood sugar CKD patients may have underlying diabetes mellitus that needs follow up. [2]
References
  1. ASSADI F. Hypercalcemia: an evidence-based approach to clinical cases. Iran J Kidney Dis [online] 2009 Apr, 3(2):71-9 [viewed 24 June 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/19395781
  2. SNIVELY CS, GUTIERREZ C. Chronic kidney disease: prevention and treatment of common complications. Am Fam Physician [online] 2004 Nov 15, 70(10):1921-8 [viewed 10 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/15571058
  3. RALSTON SH. Medical management of hypercalcaemia. Br J Clin Pharmacol [online] 1992 Jul, 34(1):11-20 [viewed 19 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1381369

Investigations - Followup

Fact Explanation
Serum PTH Will get reduced with the parathyroidectomy. [1]
Serum calcium level Will become normal after surgery. [1]
References
  1. DAVIES DR, DENT CE, WATSON L. Tertiary Hyperparathyroidism Br Med J [online] 1968 Aug 17, 3(5615):395-399 [viewed 19 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1986316

Investigations - Screening/Staging

Fact Explanation
DEXA scan (Dual-emission X-ray absorptiometry) This is to detect osteoporosis and Z -score <-2.0 forearm is suggestive of osteoporosis . [3]
Renal function tests(blood urea, serum creatinine, serum electrolytes, glomerular filtration rate) Patients with chronic kidney disease need regular assessment of renal functions. [1]
Ultrasound scan of neck Parathyroid adenoma may be associated with tertiary hyperparathyroidism. [2]
References
  1. SNIVELY CS, GUTIERREZ C. Chronic kidney disease: prevention and treatment of common complications. Am Fam Physician [online] 2004 Nov 15, 70(10):1921-8 [viewed 10 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/15571058
  2. DAVIES DR, DENT CE, WATSON L. Tertiary Hyperparathyroidism Br Med J [online] 1968 Aug 17, 3(5615):395-399 [viewed 19 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1986316
  3. VERA LARA, DOLCINO MARA, MORA MARCO, ODDO SILVIA, GUALCO MARINA, MINUTO FRANCESCO, GIUSTI MASSIMO. Primary hyperparathyroidism diagnosed after surgical ablation of a costal mass mistaken for giant-cell bone tumor: a case report. Array [online] 2011 December [viewed 25 June 2014] Available from: doi:10.1186/1752-1947-5-596

Management - General Measures

Fact Explanation
Prevention of falls As the patients are having osteoporosis [2], they are vulnerable to fractures, therefore measures should be taken to prevent falls and fractures.
Management of chronic kidney disease and its complications Hypertension, dyslipidaemia, anaemia, diabetes mellitus, uremia and cardiovascular complications need appropriate management. [1]
Rehydration This would be one of the earliest step in managing hypercalcaemia. [3]
References
  1. SNIVELY CS, GUTIERREZ C. Chronic kidney disease: prevention and treatment of common complications. Am Fam Physician [online] 2004 Nov 15, 70(10):1921-8 [viewed 10 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/15571058
  2. ASSADI F. Hypercalcemia: an evidence-based approach to clinical cases. Iran J Kidney Dis [online] 2009 Apr, 3(2):71-9 [viewed 24 June 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/19395781
  3. LYELL VERONICA, KHATAMZAS ELHAM, ALLAIN THERESA. Severe hypercalcaemia and lymphoma in an HTLV-1 positive Jamaican woman: a case report. J Med Case Rep [online] 2007 December [viewed 14 September 2014] Available from: doi:10.1186/1752-1947-1-56

Management - Specific Treatments

Fact Explanation
Parathyroidectomy Tertiary hyperparathyroidism needs surgical removal of the autonomous parathyroid gland. [1] Total parathyroidectomy with autotransplantation or subtotal parathyroidectomy is indicated. Hypercalcaemia, osteomalacia and osteitis fibrosa are responding only to the surgery.
Management of hypercalcaemia with phosphate Phosphate therapy can be used to correct hypercalcaemia as an oral or parentaral therapy. This would be the choice in managing patients with hypercalcaemia after failed parathyroidectomy. [2] 1-3g of phosphorous per day is given with checking Ca daily in the initial period. Acute hypercalcaemia can be managed with intravenous phosphate therapy [4] specially if the patient is in coma situation. This improves the calcium soon, but patient should be started on oral phosphate as soon as possible.
Management of hypercalcaemia with Sodium ethylene diamine tetraacetate This is a calcium chelating agent. [2] Given as an intravenous infusion.
Management of hypercalcaemia with furosemide Helps in excretion of calcium. [2] Contraindicated in kidney failure.
Management of hypercalcaemia with calcitonin Inhibits the bone turn over and reduce the renal tubular absorption of calcium for a certain extent. Important in managing severe hypercalcaemia. [3]
References
  1. DAVIES DR, DENT CE, WATSON L. Tertiary Hyperparathyroidism Br Med J [online] 1968 Aug 17, 3(5615):395-399 [viewed 19 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1986316
  2. PATERSON CR. Drugs for the treatment of hypercalcaemia Postgrad Med J [online] 1974 Mar, 50(581):158-162 [viewed 19 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2495534
  3. RALSTON SH. Medical management of hypercalcaemia. Br J Clin Pharmacol [online] 1992 Jul, 34(1):11-20 [viewed 19 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1381369
  4. LYELL VERONICA, KHATAMZAS ELHAM, ALLAIN THERESA. Severe hypercalcaemia and lymphoma in an HTLV-1 positive Jamaican woman: a case report. J Med Case Rep [online] 2007 December [viewed 14 September 2014] Available from: doi:10.1186/1752-1947-1-56