Case presentation of primary
• 44 yrs old lady not known to have any chronic illness before
presented with history of bone pain (lt hip joint pain) of
unknown duration , she saught medical advice and managed
conservatively with bed rest ( ?? Hip bone fracture )
• returned to her physician again after 3 mths with unresolved
symptoms where he requested for a set of blood
investigations that showed a high s.calcium !!!!
• What is the differential diagnosis of hypercalcemia ?
• PTH-mediated (high , normal PTH )
- Primary hyperparathyroidism (sporadic)
-Familial MEN-I and -IIa
-Tertiary hyperparathyroidism .
• PTH-independent (low PTH )
-Hypercalcemia of malignancy
-Vitamin D intoxication
-Chronic granulomatous disorders
-Medications (Thiazide diuretics ,Lithium ,Teriparatide ,Excessive
Vitamin A , Theophylline toxicity )
• Whats the most clinical presentation of primary
hyperparathyroidism ? ~ 80 %
asymptomatic hypercalcemia detected by routine biochemical
Biochemical screening tests that include measurements of
serum calcium currently account for the identification of at least
80 percent of patients with primary hyperparathyroidism (PHPT)
in western countries
• Is it diffenent in eastern region ?
in comparison with eastern countries where there is a greater
prevalence of vitamin D deficiency , they present with clinically
significant disease, including larger adenomas, higher
concentrations of PTH, increased bone turnover, and more
frequent fractures .
• "bones, stones, abdominal moans and
Classic presentaion of PHPT divided to .“osteitis
fibrosa cystica < 5 % in USA and
What is the Osteitis fibrosa cystica?
• is characterized clinically by bone pain and radiographically by
subperiosteal bone resorption on the radial aspect of the middle
phalanges, tapering of the distal clavicles, a "salt and pepper"
appearance of the skull, bone cysts, and brown tumors of the
long bones. Brown tumors(hemosiderin deposition.)
• Osteitis fibrosa cystica is now very rare in the United States. It
occurs more typically in patients with severe disease, especially
those with ( parathyroid carcinoma with secondary
hyperparathyroidism due to chronic renal failure )
• In a review of 97 cases of mild PHPT, as an example,
conventional radiography revealed signs of bone disease in only
occurs in approximately 15 to 20 percent of patients with
PHPT , conversely, about 5 percent of patients with
nephrolithiasis have hyperparathyroidism.
• What is the composition and mechanism of stone formation?
• Most stones in patients with PHPT are composed of calcium
oxalate, although a slightly alkaline urine may favor the
precipitation of calcium phosphate stones.
• A contributing factor for stone formation in PHPT is
- increase in filtered calcium due to hypercalcemia,
-high serum calcitriol concentration (PTH stimulation of renal
hydroxylation of 25-hydroxyvitamin D )
Clinical manifestations of hypercalcemia
Polyuria ,Polydipsia ,Nephrolithiasis ,Nephrocalcinosis ,Distal renal
tubular acidosis , Nephrogenic diabetes insipidus ,Acute and chronic
Anorexia, nausea, vomiting Bowel hypomotility and constipation
Pancreatitis Peptic ulcer disease
Muscle weakness ,Bone pain ,Osteopenia/osteoporosis
Decreased concentration ,Confusion , Fatigue ,Stupor, coma
Shortening of the QT interval, Bradycardia ,Hypertension (unknown )
Different patterns of presentation of primary hyperparathyroidism in three
different time periods. The latest survey shows that 80 percent of patients are
asymptomatic and discovered incidentally on routine blood screening; bone
disease (osteitis fibrosa cystica), on the other hand, has virtually disappeared
as a presenting symptom. Bone disease was assessed by x-rays and bone
• How can the diagnosis of PHPT made ?
• The diagnosis of primary hyperparathyroidism is usually made
by finding a frankly elevated PTH concentration or one that is
within the normal range but inappropriately elevated given the
• Measurement of PTH — The accurate measurement of serum
PTH has been greatly simplified by the use of
immunoradiometric (IRMA) ,These tests measure intact PTH by
using antibodies directed simultaneously at both the N– and
the C–terminal regions of the PTH molecule.
(normal range 10 to 60 pg/mL)
Return to the case :
The patient lab result showed high ca , high PTH
PHPT ( most likely )
MEN I ,II
FHH ( could be)
tertiary hyperparathyroidism (unlikely )
How can we differentiate between PHPT & FHH ?
measuring 24 hr urinary calcium excretion
• Measurement of urinary calcium excretion — Measurement of 24-hour urine
calcium excretion is required for distinguishing PHPT from familial
hypocalciuric hypercalcemia (FHH)
• Approximately 40 percent of patients with PHPT are hypercalciuric, and most
of the remaining patients have normal values , An elevated urinary calcium
concentration (>400 mg/24 hours) essentially excludes FHH.
• If calcium excretion is low,; about 75 percent of affected persons with FHH
excrete less than 100 mg of calcium in urine daily .
• A Ca/Cr clearance ratio, which is equivalent to the fractional excretion of
calcium, also may be helpful. This ratio is calculated from 24-hour urinary
calcium and creatinine and total serum calcium and creatinine
concentrations using the following formula:
• Ca/Cr clearance ratio = [24-h Urine Ca x serum Cr] ÷ [serum Ca x 24-hr
• A value below 0.01 in a vitamin D replete individual is highly suggestive of
FHH rather than hyperparathyroidism (ratio usually >0.02).
• What about values from 100 – 200 mg/day ?
familial hypocalciuric hypercalcemia (FHH, or
hyperparathyroidism with concomitant vitamin D deficiency are
• To differentiate FHH from mild primary hyperparathyroidism
with concomitant vitamin D deficiency in individuals with
elevated serum PTH and calcium and low 24-hour urinary
calcium excretion, we typically measure 25OHD. In the latter
patients, urinary calcium excretion increases with vitamin D
repletion, thereby distinguishing it from FHH.
What Other lab investigation should be sent in PHPT?
• UEC: The development of renal insufficiency in PHPT is related
to the degree and duration of hypercalcemia (two to three years
• S.phos : ( PTH inhibits the proximal tubular reabsorption of
phosphate, leading to increased phosphate excretion)
• Mg : (Renal tubular reabsorption of magnesium is stimulated by
PTH but inhibited by hypercalcemia)
• 25OHD : Due to the significant prevalence of vitamin
D insufficiency in individuals with PHPT, the Third International
Workshop on Asymptomatic Primary Hyperparathyroidism
recommends measuring 25OHD in all patients with PHPT
(defined as ≤20 ng/mL [50 nmol/L]
• Bone mineral density :
Patients with PHPT may have decreased bone mineral density
(BMD), in particular at more cortical sites (forearm and hip) as
compared with more cancellous sites (spine). Randomized trials
have demonstrated increased BMD following
Measurement of BMD is an essential part of the management
of the disease, and BMD should be measured at the spine, hip,
and distal one-third forearm sites
• Do we need imaging to diagnose primary hyperparathyroidism
The diagnosis of primary hyperparathyroidism is established
by appropriate biochemical testing.
we need them for Localizations , However, they are commonly
used now, along with intraoperative PTH monitoring, to facilitate
unilateral exploration and minimally invasive surgery in those
with probable single gland disease.
Primary hyperparathyroidism is usually caused by a solitary benign
adenoma (80 to 85 percent), but can also be due to double
adenomata (2 to 5 percent), diffuse or nodular hyperplasia (10
to 15 percent), or parathyroid carcinoma (<1 percent)
• (99mTc-sestamibi or MIBI). Sestamibi
scintigraphy (methoxyisobutylisonitrile 99mTc-sestamibi ) is
taken up by the mitochondria in thyroid and parathyroid tissue.
• DISADVANTAGES :
-parathyroid hyperplasia, multiple parathyroid adenomas, and in
those with coexisting thyroid disease (unrevealing ) .
-falsely negative scans can also be caused by calcium channel
blockers that interfere with the take up of the isotope by
parathyroid cells .
-Other gland characteristics that can increase the likelihood of a
negative scan include small size, superior position, and a paucity
of oxyphil cells.
Sestamibi scanning for parathyroid tissue can be enhanced by
combination with three-dimensional imaging (SPECT)
• SPECT — Sestamibi-single photon emission computed
tomography (SPECT or MIBI-SPECT) is a three-dimensional
sestamibi scan that provides higher resolution imaging and
improves the performance of sestamibi scannig.
• ADVANTAGE :
SPECT imaging substantially reduces the likelihood of missing
multiglandular disease compared to planar imaging
• Subtraction thyroid scan :
Even with the addition of SPECT, distinguishing abnormal
parathyroid glands from thyroid pathology can be difficult. If
necessary, a subtraction thyroid scan can be obtained by using
two radiotracers (dual isotope scintigraphy). The use of
technetium plus a second radiotracer such as(thallium) permits
selective imaging of the thyroid gland.
(99mTc-sestamibi or MIBI) shows the parathyroid glands, while
thallium shows both the thyroid and parathyroid glands . The
technetium image is then subtracted from the thallium image.
Neck ultrasonography (USS) :
Sonographic characteristics of parathyroid adenomas include
homogeneous hypoechogenicity and an extrathyroidal feeding vessel with
peripheral vascularity seen on color Doppler imaging .
- US is highly sensitive in experienced hands
inexpensive, noninvasive, and reproducible in the operating room.
_ helpful for the characterization and evaluation of any thyroid pathology,
facilitating operative planning. This is a common problem, since concurrent
thyroid pathology is present in up to 30 percent of patients with primary
-the sensitivity of ultrasound for parathyroid adenoma localization is
reduced in patient With thyroid nodule.
Ultrasound views of parathyroid adenomas.
(A) Sagittal image of the upper pole of the right lobe of the thyroid gland,
demonstrating a hypoechoic parathyroid adenoma posterior to the thyroid
(B) Sagittal image of the lower pole of the lower pole of the left lobe of the thyroid
gland with an adjacent hypoechoic parathyroid adenoma measuring 9 mm in greatest
• Magnetic resonance imaging
Parathyroid adenoma characteristics on magnetic resonance
imaging (MRI) include intermediate to low signal intensity on T1
imaging and high intensity on T2 imaging.
Cervical lymph nodes can also have similar imaging
characteristics, which limits the accuracy of MRI.
Invasive localization (venography , arteriography ):
-prior neck surgery
-whom noninvasive testing has been unrevealing.
Selective venous sampling : A 1.5 to 2-fold increase in parathyroid
hormone levels obtained from representative cervical vein
drainage locations (inferior, middle, superior thyroid, thymic,
and/or vertebral veins
Selective arteriography positive localization is considered an
increase in the parathyroid hormone level to 1.4 times the
baseline or a blush seen on arteriography
• (MIBI SCAN)( Sestamibi scintigraphy) combined with sestamibi
single photon emission computed tomography (SPECT) has the
highest positive predictive value of the available imaging
techniques and some prefer this as the localizing procedure of
choice for initial surgery .
• However, SPECT is not available at all centers and some use
planar sestamibi as the initial localizing study.
• Non-localizing imaging studies should not preclude initial
surgery for patients with biochemically confirmed primary
hyperparathyroidism who meet operative criteria. In such
patients, a single adenoma is still the most likely intraoperative
finding (62 to 77 percent)
Return to the case :
The patient underwent MIBI scan which revealed parathyroid
adenoma in Rt parathyroid gland .
What is Next step ?
• What are the Patient criteria for parathyroidectomy ?
The Third International Workshop guidelines concluded that
surgery is indicated in asymptomatic patients who meet any of
the following conditions:
-Serum calcium concentration of 1.0 mg/dL (0.25 mmol/L) or more
above the upper limit of normal.
-Creatinine clearance that is reduced to <60 mL/min.
-Bone density at the hip, lumbar spine, or distal radius that is more
than 2.5 standard deviations below peak bone mass (T score <-
2.5) and/or previous fragility fracture.
-age less than 50 years.
Our patient indications for surgery:
S.Ca = 11-12 mg/dl
Age= 44 yrs
T score= -3.2
Patient undewent parathyroidectomy of Rt upper and
lower glands .
Bilateral parathyroid exploration :cure rates (95 to 99 percent).
-For patients with negative (non-localizing) preoperative imaging studies or
when bilateral foci are detected.
-Most forms of hereditary hyperparathyroidism are an indication for bilateral
parathyroid exploration due to the predictable involvement of multiple
-Concomitant thyroid disease requiring surgical resection, such as biopsy proven
papillary thyroid cancer, necessitates bilateral exploration.
-pregnant patients due to the radiation required for some localization studies.
However, if ultrasound expertise is available and the results show an
apparent single adenoma, a focused approach can be planned.
-lithium associated hyperparathyroidism has a higher incidence of being
associated with multiple gland involvement and may require bilateral
• Focused parathyroid exploration
When combined with use of intraoperative PTH monitoring,
minimally invasive parathyroidectomy techniques result in
excellent outcomes that are comparable to a traditional bilateral
The smaller incisions and less extensive dissection lead to
reduced postoperative pain and a lower incidence of
hypocalcemia from ischemia of other glands.
-imaging suggesting unilateral pathology.
-no suggestion of concomitant, thyroid disease requiring
-no family history of multiple endocrine neoplasia.
use of intraoperative PTH monitoring:
A baseline PTH value is obtained at the start of the procedure,
PTH levels are then measured at following removal of the
suspected adenoma .
A reduction of at least 50 percent from the baseline following
excision of the hyperfunctioning gland is an accepted standard
for intraoperative confirmation of success.
Returning to the case :
The patient readmitted to the hospital in less than one month as a
case of symptomatic hypocalcemia , s .ca was ranging from 4 to
• What are the Complication of parathyroidectomy ? :
-Postoperative hypocalcemia ( transient , hungrey bone syndrome )
-Recurrent laryngeal nerve injury
-Hyperthyroidism (31 to 43%)
The hypocalcemia is generally transient , Transient hypoparathyroidism
may be due to manipulation of the blood supply to or removal of one
or more parathyroid glands during surgey .
In some cases, however, the postoperative hypocalcemia is severe and
prolonged despite normal or even elevated levels of parathyroid
hormone (PTH). This phenomenon, called the hungry
most often occurs in patients who have developed bone disease
preoperatively due to a chronic increase in bone resorption induced
by high levels of PTH (osteitis fibrosa).
Hypocalcemia after parathyroidectomy
Time course of development of hypocalcemia in 25 patients
following parathyroidectomy for primary hyperparathyroidism.
Most of the fall in the plasma calcium concentration occurred in
the first 24 hours after surgery. To convert plasma calcium
concentration from mg/dl to mmol/L, divide by 4.
D/D for the patient hypocalcemia ?
-Hungrey bone syndrome (PTH level ).
-Vitamine D deficiency.
-Permanent hypoparathyroidism (injuried glands )( low PTH ).
What are the Criteria for diagnosis of hungrey bone
serum calcium concentration below 8.5 mg/dL (2.13 mmol/L) and the
serum phosphate postoperative conentration below 3.0 mg/dL (0.96
mmol/L) on the third day post op.
Who are patients at risk ?
1-Volume of the resected adenoma.
2-Preoperative blood urea nitrogen concentration.
3-Preoperative alkaline phosphatase concentration.
Preoperative serum calcium and PTH levels did not provide
additional predictive information.
Presentation of hungrey bone syndrome :
The decrease in bone resorption and increase in bone
formation that occurs after parathyroidectomy can also
lead to hypophosphatemia.
-Hypomagnesemia : refractory hypocalcemia.
-Hyperkalemia (80 percent) ( unknown ).
How it can be prevented ?
-starting oral calcium 2 to 3 grams per day two days prior to surgery,
even in patients who are hypercalcemic.
-intravenous calcitriol : in Vit D deficiency , CRF
(vitamin D2) (1000 IU per day or more depending on level) in vit D def
pts , (2 mcg at the end of each hemodialysis treatment) in HD pts ,
begun three to five days prior to surgery and continued
postoperatively may be helpful in preventing marked hypocalcemia.
How it can be treated ?
Treatment is aimed at each of the abnormalities that can occur:
hypocalcemia, hypomagnesemia, hypophosphatemia, and
the serum calcium concentration should be measured two to four times
per day for the first few postoperative day .
the time of greatest risk , Oral calcium supplementation (2 to 4 g of
elemental calcium [50 to 100 mmol] per day) should be started as
soon as the patient is able to swallow.
If the serum phosphorus is normal or low, calcium should be
administered between meals to maximize intestinal absorption and
minimize phosphate binding.
Intravenous calcium is indicated if the patient develops a rapid and
progressive reduction in serum calcium or symptoms related to
hypocalcemia, including frank tetany, latent tetany (Chvostek's or
Trousseau's sign), or a plasma calcium concentration below 7.5
mg/dL (1.9 mmol/L).
the administration of phosphate to reverse hypophosphatemia is
generally avoided in patients with hungry bone syndrome, since
phosphate can combine with calcium and further reduce the plasma
calcium concentration. An exception to this general rule is the
presence of severe hypophosphatemia, in which the plasma
phosphate concentration is below 1 mg/dL.
• TREATMENT OF CONCOMITANT VITAMIN D DEFICIENCY ?
the Third International Workshop on Asymptomatic Primary
Hyperparathyroidism recommends measuring 25OHD in all patients
with PHPT and repleting those with low levels (defined as ≤20 ng/mL
[50 nmol/L]) prior to making any management decisions .
• we suggest cautiously repleting vitamin D in patients with underlying
hyperparathyroidism since worsening hypercalcemia and
hypercalciuria have been reported in this setting .
"...treating illnesses is why we became doctors,
treating patients is what makes most doctors
miserable.“ Dr.House saying .