Hypercalcemia: Colorado ACP Meeting February 2017 David Tanaka MD FACP

Hypercalcemia
Colorado ACP meeting

February 2017
David Tanaka MD FACP
Disclosures
None
Objectives
• Be able to effectively and efficiently evaluate hypercalcemia
• Be able to counsel patients on their diagnosis and prognosis
• Be able to counsel patients on their options for treatment
60 yo woman – evaluation of fatigue
• Anxiety, hypothyroidism, hypertension, obesity
• Levothyroxine, venlafaxine, HCTZ, losartan
• No recent illness
• Some increased stress
• Snores
• Fatigue is worse for 1+ year but most noticeable for 1-2 months
60 yo woman – evaluation of fatigue
• Weight is stable, exam is normal
• Labs 9 months previous TSH 4.16, prior 2.97
• Glucose 84, creatinine 0.66, CBC and LFT’s normal
• Calcium 10.6
What do you order to evaluate her
hypercalcemia
• Calcium, ionized calcium, PTH, PTHrp, Phosphate, creatinine, vitamin
D(25-OH and 1,25 OH), 24 hr urine calcium and creatinine
• Calcium, phosphate, creatinine, PTH
• Calcium, creatinine, PTH, vitamin D (25OH)
• All of the above + sestamibi scan of neck
Etiology and Differentiation of Hypercalcemia
Calcium PTH Vitamin D
Primary Hyperparathyroidism Elevated High normal or elevated Normal or low
Malignancy Elevated Low (<20 ng/dl) Depends on malignancy
60 yo woman – lab evaluation
• Calcium 11.1, Creatinine 0.65, PTH 73 (12-88)
• 24 hour urine Calcium 3.0 mg/dl X 1266 cc = 38 mg / d
• 24 hour urine Creatinine 118 mg / dl X 1266 = 1481 mg / d
60 yo woman - differential diagnosis
• Primary hyperparathyroidism
• Hydrochlorothiazide causing hypercalcemia
• Familial hypocalciuric hypercalcemia
• All of the above
Familial hypocalciuric hypercalcemia
• Autosomal dominant – caused by inactivating mutations in the gene
for calcium-sensing receptor (CaSR or CaR)
• Parathyroid gland is less sensitive to calcium, higher calcium
concentration is required to reduce PTH.
• Kidney – this leads to increase in tubular calcium and magnesium
reabsorption
• Benign natural history
• Parathyroidectomy does not cure disorder
Differentiating PHP from FHH
• PHP – 10% will have ”normal PTH” and FHH – 15-20% will have
elevated PTH
• Other causes of low calcium excretion – vitamin D deficiency and/or
very low calcium intake, thiazide diuretics, lithium
• Ca/Cr clearance ratio – (24h ur calcium X serum creat) / (serum Ca X
24 h ur creat)
• Ca/Cr ratio < 0.01 in FHH (>80%) and PHP (<20% most with vit D def)
• Ca/Cr ratio >0.02 essentially excludes FHH
• Ca/Cr ratios 0.01-0.02 may benefit from genetic testing for FHH
60 yo woman – lab evaluation
• Calcium 11.1, Creatinine 0.65, PTH 73 (12-88)
• 24 hour urine Calcium 3.0 mg/dl X 1266 cc = 38 mg / d
• 24 hour urine Creatinine 118 mg / dl X 1266 = 1481 mg / d
• Repeat labs off HCTZ – calcium 10.4, PTH 110, 24 hr urine calcium 158
mg / day, 24 hr urine creatinine 1566 mg / day
• Ca/Cr clearance ratio = (158 X 0.65) / (1566 X 10.4) = 0.006
• Previous serum calcium 2012 9.5; 2011 9.4; 2009 9.6
60 yo woman - differential diagnosis
• Primary hyperparathyroidism
• Hydrochlorothiazide causing hypercalcemia
• Familial hypocalciuric hypercalcemia
• All of the above
Figure 1. Schematic Diagram of Calcium Set Points in Healthy Individuals Compared With
Individuals With Primary Hyperparathyroidism and Hypothetical Relationship to Parathyroid
Adenoma Size
JAMA 2005 293:1773

What are the target organ effects of PHP?
• Bone loss, nephrolithiasis / renal failure, psychiatric / cognitive,
increased mortality
• Nephrolithiasis / renal failure, psychiatric / cognitive, no change in
mortality, improvement in bone – fewer fractures
• Bone loss, nephrolithiasis / renal failure, psychiatric / cognitive, no
change in mortality
• None of the above, “its all too confusing”
PHP and Bone
• Osteitis Fibrosa Cystica – severe hyperparathyroidism
PHP and Bone
• Osteoporosis – commonly seen
• Parathyroid hormone – main effect on cortical bone (radius)
increasing fracture risk slightly, less effect on trabecular bone (spine)
• Hyperparathyroidism is associated with about 50% increase in bone
turnover – the loss of cortical bone is more marked than increase in
trabecular bone
• Therapeutically PTH injected daily – stimulates new bone formation
and leads to increased bone mineral density and decreased fracture
risk
PHP and kidney
• Serum creatinine, 24 hr urine calcium, imaging to identify urolithiasis
• 24 hr urine evaluation was not able to predict nephrolithiasis in PHP
in prospective study
PHP and the brain
• Fatigue, weakness, depression and memory problems are associated
with PHP
• RTC of surgery versus observation for asymptomatic PHP, 53 patients,
post-op difference in SF-36 social function and emotional role
functioning (P<0.007 and <0.012 respectively)
Surgery 2000; 128:1031

Medical treatment of PHP
• Calcium and in patients with low vitamin D replacement of vitamin D
• Estrogen
• Bisphosphonates for osteoporotic patients
• Cinacalcet
Surgical treatment of PHP
• Cure approximately 95% of cases
• Complications
• Re-exploration
• Laryngeal paralysis
• Hypoparathyroidism
• Benefits of surgery
• Reduces incidence of nephrolithiasis by 90%
• Bone mineral density improves by 10% in 10 years
• Nonspecific symptoms may improve
Indications for surgery PHP - Fourth
International Workshop guidelines 2013
• Serum calcium (> upper limit of normal) 1.0 mg/ dl (0.25 mmol/L)
• BMD by DXA: T score < -2.5 or Vertebral fracture
• Creatinine clearance <60 ml/min, 24 hr urine calcium >400 and
increased stone risk by biochemical stone risk analysis, presence of
nephrolithiasis
• Age <50
• Surgery is also indicated for whom medical surveillance is neither
desired or possible and in patients opting for surgery, in the absence
of meeting any guidelines, as long as there are no medical
contraindications
60 yo woman with fatigue and PHP
• She was seen by Endocrinologist
• He agrees that this is PHP
• He discussed the diagnosis, prognosis and treatment with the patient
and she has elected to see thyroid surgeon to have neck exploration
Surgeon Beware : many pts are misdiagnosed
• 324 pts were referred for PHP surgery
• 265 (82%) diagnosis confirmed
• 60 (19%) were misdiagnosed
• 54 had secondary hyperparathyroidism
• 6 had hypercalcemia but no increase in PTH
• 70% had localization studies and of those 57% suggested positive finding
Surgery 2012: 152:635

The correct diagnosis
• Familial Hypocalciuric hypercalcemia 0 cases
• Vitamin D deficiency 37 cases
• Roux-en-Y bypass surgery 4 cases
• Celiac disease 2 cases
Secondary Hyperparathyroidism
• Renal failure
• Decreased calcium intake
• Calcium malabsorption
• Vitamin D deficiency
• Bariatric surgery
• Celiac disease
• Pancreatic disease
• Renal calcium loss
• Idiopathic hypercalciuria
• Loop diuretics
• Inhibition of bone reabsorption
• Bisphosphonates
• Hungry bone syndrome
Normocalcemic Primary Hyperparathyroidism
• These cases are found when patients are being evaluated for
osteoporosis or nephrolithiasis
• There are no guidelines directed at these patients
• Case series suffer from selection bias towards patients with end organ
disease
Surgery at UCH for Primary Hyperparathyroidism
Robert McIntyre, Jr MD
24 years of experience, 100 parathyroid surgeries per year
Primary surgery
Eucalcemia 94%, Hypercalcemia 2%, Hypocalcemia –temp
25%, long term 4%
Secondary surgery
Eucalcemia 75%, Hypercalcemia 11%, Hypocalcemia 14%
Complications rate 1% hoarseness, 0% operative mortality

Surgery at UCH for Primary Hyperparathyroidism
Robert McIntyre, Jr MD
Estimate of the asymptomatic / minimally symptomatic patients who meet

the 4th International Workshop guidelines for the management of
asymptomatic primary hyperparathyroidism criteria?
50%
Any points that you would like to pass on to an audience of internists:

95% of patients have symptoms based on a careful history and
95% of patients report significant improvement in those symptoms.
Conclusions
• Hypercalcemia is common and the most common causes are primary
hyperparathyroidism and malignancy (90%)
• The initial evaluation should include calcium, creatinine, PTH, vit D
• If parathyroid level is elevated then order 24 hr urine calcium and
creatinine, consider xray to look for nephrolithiasis / vertebral
compression fracture, BMD
• There is no current recommended medical therapy. Correct vitamin D
deficiency. Calcium intake of 1,000 mg daily is recommended.
Conclusions
• Surgery is curative in 95% of patients with PHP
• Surgical complications vary by volume of surgeries
• 3.76% for those < 15 cases annually
• 1.48% for those > 50 cases annually
• Surgery at UCH equals or exceeds this national data
• Localization studies should be ordered when the decision to proceed
to surgery has already been made. They are not helpful in making the
diagnosis.

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Hypercalcemia

Colorado ACP meeting

JAMA 2005 293:1773

Surgery 2000; 128:1031

Surgery 2012: 152:635

Complications rate 1% hoarseness, 0% operative mortality

Estimate of the asymptomatic / minimally symptomatic patients who meet

Any points that you would like to pass on to an audience of internists:

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