Case presentation of primary hyperparathyroidism

HAIFA ALSHWIKH

Case presentation• 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 -FHH -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 screening.

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 psychic groans

Classic presentaion of PHPT divided to .“osteitis fibrosa cystica < 5 % in USA and nephrolithiasis <15-20%.

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 one patient

• Nephrolithiasis 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 hypercalciuria.

- increase in filtered calcium due to hypercalcemia, -high serum calcitriol concentration (PTH stimulation of renal

hydroxylation of 25-hydroxyvitamin D )

Clinical manifestations of hypercalcemiaRenal Polyuria ,Polydipsia ,Nephrolithiasis ,Nephrocalcinosis ,Distal renal tubular

acidosis , Nephrogenic diabetes insipidus ,Acute and chronic renal insufficiency

Gastrointestinal Anorexia, nausea, vomiting Bowel hypomotility and constipation Pancreatitis

Peptic ulcer disease

Musculoskeletal Muscle weakness ,Bone pain ,Osteopenia/osteoporosis

Neurologic Decreased concentration ,Confusion , Fatigue ,Stupor, coma

Cardiovascular 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 densitometry

• 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 patient's hypercalcemia.

• 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

D/D:

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 Urine Cr]

• 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 possibilities

• 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 duration)

• 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 parathyroidectomy.

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 ???

NO 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

MIBI SPECT images of parathyroid adenoma

• 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 .

ADVANTAGES: - US is highly sensitive in experienced handsinexpensive, 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 hyperparathyroidism.

DISADVANTAGES :

-operator-dependent, -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 parenchyma.

(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

dimension

• 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 ?surgery

• 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/dlAge= 44 yrsT score= -3.2

Patient undewent parathyroidectomy of Rt upper and lower glands .

• 2 procedure choices for parathroidectomy :

• Bilateral parathyroid exploration• Focused parathyroid exploration

Bilateral parathyroid exploration :cure rates (95 to 99 percent).

Indications :

-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 glands.

-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 exploration.

• 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 cervical exploration.

Advantages : The smaller incisions and less extensive dissection lead to

reduced postoperative pain and a lower incidence of hypocalcemia from ischemia of other glands.

Indications: -imaging suggesting unilateral pathology. -no suggestion of concomitant, thyroid disease requiring

surgical intervention. -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 6 mg/dl.

• What are the Complication of parathyroidectomy ? :

-Hematoma-Postoperative hypocalcemia ( transient , hungrey bone syndrome )-Permanent hypoparathyroidism -Wound infection-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 bone syndrome.

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.-Both.-Malabsorption.-Permanent hypoparathyroidism (injuried glands )( low PTH ).

What are the Criteria for diagnosis of hungrey bone syndrome ?

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.4-Older age.

Preoperative serum calcium and PTH levels did not provide additional predictive information.

Presentation of hungrey bone syndrome :

-Hypocalcemia . -Hypophosphatemia : 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 ? Preoperative preparation

-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 hyperkalemia.

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 .

THE END

"...treating illnesses is why we became doctors, treating patients is what makes most doctors miserable.“ Dr.House saying .