Hyperparathyroidism &

TreatmentBabak Larian MD, FACS

Clinical Chief of Head & Neck Surgery,

Cedars-Sinai Medical Center

Objectives

• Parathyroid gland physiology

• Biochemical and molecular basis of disease

• Spectrum of primary hyperparathyroidism

• Indications for treatment

• Medical and surgical treatment

PHPT

• Most common endocrine disorder

• 1/800 people

• 1/250 women over the age 60

• 1:1 M:F under age 40, 1:4 over age 60

• 100,000 new cases diagnosed annually

• Most are undiagnosed or misdiagnosed

Hyperparathyroidism

IncidenceDifferent Incidence in

different ethnic groups

based on a 15 year CA

Kaiser database.

US EMR survey 0.86%

Canadian Multicenter

Osteoporosis Study:

- 1.4% Hypercalcemic

PHPT

- 3.3% Normocalcemic

PHPT

Ethnic

Group

Incidence in

Women per

100,000

Incidence in

Men per

100,000

African

Americans 92 46

Caucasians 81 29

Asian

Americans 52 28

Latinos 49 17

Yeh, MW, J. Clin. Endocrinologist. Metab. 2013; 98. 1122-

29.

Hyperparathyroidism

Prior to 1970 most

common presentation

symptomatic disease.

After 1970 (multichannel

analyzer) most patients in

the US and Europe are

asymptomatic.

In countries where

screening biochemistries

are routine, asymptomatic

diseases is most common. Bilezikian, J. P. Nat. Rev. Dis. Primers 2016;10.1038

Symptoms

Overt symptoms of

PHPT are generally but

not unanimously

considered to be:

• Fragility fractures

• Mental status

change

• Peptic ulcer disease

• Kidney stones

Types of Pathology

• 85% Single Adenoma

(Monoclonal)

• 10% Multiple

Adenoma (Monoclonal)

• 5% Hyperplasia

affecting all glands

(Polyclonal)

• <1% Parathyroid

Cancer

Single Adenoma Multiple Adenoma

Hyperplasia Parathyroid Cancer

Parathyroid Embryology

Occurs at 6 weeks

gestation

Can lead to variability

of position

3% have 3 glands

3-20% have 5 or more

glands

Parathyromatosis

Ectopic Parathyroids

Characteristics

• PHPT develops over a period of years.

• Calcium elevation usually plateaus with parathyroid

adenomas, even though PTH levels continue to elevate.

• Calcium level does not correlate the size of parathyroid

adenoma.

• The size & weight of abnormal parathyroid gland(s) is directly

proportional to PTH level & inversely proportional to Vitamin D

levels.

• Degree and severity of symptoms do not always correlate

with Ca levels.

Characteristics

• Bone mass density loss occurs with all forms HPT, even in

Normocalcemic HPT.

• BMD usually presents after 8+ years of disease process.

• 25 (OH) Vitamin D levels are low (< 30 ng/ml) in 82% patients

with PHPT.

• 1,25 (OH) Vitamin D levels are normal or high.

• Meeting NIH surgical criteria does not predict progression of

disease.

Parathyroid

Axis

Marx SJ. N Engl J Med 2000;343:1863-1875.

Calcium Sensing

Receptor (CASR)

Strewler, G. J. JAMA 2005;293:1772-1779

Regulation of PTH Synthesis &

Secretion

Normal or elevated

calcium:

• Inhibits Adenylate

cyclase pathway

• Stablizes PTH

Vesicles

Khundmiri S. Comprehensive Physiology 2016;6:561-601.

Regulation of PTH Synthesis &

Secretion

Low Calcium:

• Acute - immediate

release of PTH

vesicles

• Chronic - Increase

PTH gene expression

thus synthesis

Vitamin D & PTH

Vitamin D attaches

to a DNA elements:

• Suppress PTH mRNA

production

• p21 protein - decrease

cell proliferation

The size of adenomas

inversely proportional to

Vitamin D status

PTH

Khundmiri S. Comprehensive Physiology 2016;6:561-601.

• Made in endoplasmic

reticulum

• Pre & Prosequences

are cleaved in the

Golgi apparatus

• 1-84 segment make

up the intact PTH

• 1-34 are active part

• Made in endoplasmic

reticulum

• Pre & Prosequences

are cleaved in the

Golgi apparatus

• 1-84 segment make

up the intact PTH

• 1-34 are active part

• Made in endoplasmic

reticulum

• Pre & Prosequences

are cleaved in the

Golgi apparatus

• 1-84 segment make

up the intact PTH

• 1-34 are active part

PTH & PTHReceptor

Khundmiri S. Comprehensive Physiology 2016;6:561-601.

Kidney

• Decreased expression of Na-PO4 cotransporter.

• Increase Ca reabsorption via Ca channels

• Activate 1 alpha hydroxylase - Thus activate Vitamin D

Bone

• Stimulates Osteoblasts (only if PTH secretion is pulsatile)

• Osteoclasts maturation - Increased bone resorption

Adrenal Gland

• Increase Aldosterone production -

causing an elevation in BP

PTH & PTHReceptor

Khundmiri S. Comprehensive Physiology 2016;6:561-601.

• PTH1 Receptor - Bone & Kidney

• PTH2 Receptor - High levels in

Limbic system & hypothalamus,

pancreatic islet cells, cartilage,

heart muscle

• After PTH binds to receptor - the

two are internalized

• Some are recycled

• Most are degraded in

lysosomes

• Receptors are down regulated

with high PTH exposure

Vitamin D25(OH) Vit D3 has a long

1/2 life (2-3 weeks).

Preferred for testing.

Vitamin D

• High bolus

ingestion is rapidly

cleared by fat &

muscle and not

released into

circulation.

• Smaller daily

doses 1000-2000

IU are preferred

PHPT Mechanism

Set Point Alteration

Bilezikian, J. P. Nat. Rev. Dis. Primers 2016;10.1038

HPT Effects

Molecular

Genetics

Two mechanisms

1. Loss of

homeostatic

control of PTH

production &

secretion.

2. Increased cell

proliferation

Molecular

GeneticsCASR

1. Mutation causing

decreased

sensitivity to Ca

2. Decreased

expression

3. Alteration in

proteins involved in

the signaling

pathway

Molecular

GeneticsProliferation via:

• Proto-oncogenes

& Tumor-

suppressor

• Cell cycle

promoters

• Apoptosis

inactivation

Molecular

Genetics

Peri centromeric

inversion at

Chromosome 11

placing the PTH gene

promoter upstream

from Cyclin D1.

Germline Mutations

Spectrum of Primary

HyperparathyroidismKey to diagnosis is a

non-suppressive

relationship between

calcium & PTH

Degree of symptoms does

not depend on Ca levels

All forms may present with

low Vitamin D

Normocalcemic PHPT -

a certain percentage go

on to develop

Hypercalcemia.

Presentation Calcium PTH

Classic PHPT High High

Normocalcemic

PHPT

Normal or

High NormalHigh

Normohormonal

PHPTHigh

Normal or

High Normal

Biochemically

Normal PHPTNormal Normal

PHPT - Symptomatic46 year-old male presents with a several week

history of fatigue, headache and polyuria. He has had a history of nephrolithiasis. On exam lethargic and dehydrated.

• Calcium 12.3 mg/dL (8.8-10.2)

• iPTH 230 pg/mL (15-65)

• Cr 3.3 mg/dL (0.7-1.3)

• 24 hr urine calcium 465 mg (<400)

51 year-old post menopausal female complains of fatigue, memory loss, increased anxiety and aches. States "I feel old". Has not been able to work in 2 years.

• Calcium 10.4 mg/dL (8.8-10.2)

• iPTH 75 pg/mL (15-65)

• 25 (OH) Vitamin D 35 ng/ml (>30)

• 1,25 (OH) Vitamin D 80 ng/ml (15-75)

• 24 hr urine calcium 200 mg (<400)

• Femoral Neck T-score (-2.0)

PHPT - Asymptomatic

2008 guidelines for surgery in asymptomatic

primary hyperparathyroidism

Factor Cutoff Comment

Serum

calcium

>1.0 mg/dL above normal Arbitrary

BMD T-score <-2.5 at any site Defines osteoporosis

Age <50 Arbitrary, Presumed to be

predictive of disease

progression

Fragility

fracture

Any with impact being

disproportionate to

fracture

Increased risk of subsequent

fracture independent of BMD

24 hr urine

calcium

Not included anymore Hypercalicuria is only one risk

factor for kidney stones

Surgery in 59

9 Sx (nephrolithiasis)

50 ASx

116 Patients - Columbia U.

99 symptomatic (Sx) 85%

17 asymptomatic (ASx) 15%

No Surgery 57

8 Sx (nephrolithiasis) - 100% dz

progress

49 ASx -

20 w/ surgical criteria - 35% dz progress

29 w/o surgical criteria - 38% dz

progress100% Normalized Ca/PTH

100% Improved bone

density

~ 10% increase at 15 years

Stable Dz 31

31 ASx

13 w/ surgical criteria - 18 w/o

59% had decreased bone density (10%+)

Patient Choice

Dz Progression 22

8 Sx (nephrolithiasis)

18 ASx - 7 w/ surgical criteria

11 w/o surgical criteria

Ca 10.8

PTH

144

Ca 10.5

PTH

116

11 Died of cardiovascular causesCa 10.5

PTH

161

20 chose surgery (Improved BMD/Ca/PTH)

Rubin MR. JCEM 2008:9

Should asymptomatic patients be monitored

or referred for surgery?

Rubin MR et al,.JCEM 2008;9:3462-70.

• Rubin et al: (15yr data) BMD declines

after 9 yrs. Calcium rises showed a

plateau

• Decline seen in cortical bone (femur &

radius) per DEXA

• Recent Data shows DEXA not accurate

in assessing cancelous bone (Spine)

• Meeting surgical criteria did not predict

biochemical disease progression

Surgical outcomes in patients with

asymptomatic PHPT

• Cohort studies show that

asymptomatic patients have a higher

risk of fractures compared to controls

• Studies on fracture risk for observed

PHPT vs controls are lacking

• However, a prospective study shows a

50% reduction in hip fractures over a

20 year period postoperatively

Rubin MR et al,.JCEM 2008;9:3462-70. Years of Follow-Up

58 year-old female suffering from a low impact wrist fracture, HTN, depression, constipation and aches.

• Calcium 9.8 mg/dL (8.8-10.2)

• iPTH 92 pg/mL (15-65)

• 25 (OH) Vitamin D 32 ng/ml (>30)

• 24 hr urine calcium 190 mg (<400)

• Radius T-score (-2.8)

Normocalcemic PHPT

• Formally recognized as a disease entity in the Third International

Workshop on Management of Asymptomatic PHPT (2008)

• Secondary causes of elevated PTH must be excluded:

A. Vitamin D deficiency - to be confident in Dx it's advisable to

maintain 25 (OH) Vit D levels above 30 ng/ml

B. Reduced Creatinine Clearance - PTH rises with GFR lower then 60

ml/min

C. Medications - HCTZ & Lithium can cause elevated PTH.

Abnormality persisting several months after medication withdrawal.

D. Malabsorption syndromes - Gluten enteropathy: can be

asymptomatic, with low normal calcium, low Vit D,

hypocalciuria

Normocalcemic PHPT

Two subsets:

• 18-40% progress to

become hypercalcemic

(Biphasic group)

• Majority continue to

remain Normocalcemic

with persistently elevated

PTH.

Normocalcemi

c PHPT

Normal Lab Values• Based on a bell curve a population that is otherwise

healthy

• The middle 95% is considered a normal lab value

• 2.5% at either

end are normal

and healthy

Two subsets:

• Clinical presentation is

similar to PHPT

• BMD loss prevalent

• Post-operative Ca levels

lower

• Post-operative PTH in

the normal range and

follows a suppressive

pattern

Normocalcemi

c PHPT

64 year-old female complains of fatigue, memory loss, increased anxiety and aches. States "I feel old".

• Calcium 10.9 mg/dL (8.8-10.2)

• iPTH 52 pg/mL (15-65)

• 25 (OH) Vitamin D 25 ng/ml (>30)

• 24 hr urine calcium 200 mg (<400)

• Femoral Neck T-score (-2.8, 10% decline in 2 years)

Normohormonal PHPT

Wallace et al studied all PHPT between 2005-2010

• 46/843 (5.5%) had Normohormonal PHPT

• Clinical presentation: 74% incidental finding on routine lab

• 70% had at least one symptom

• 50% had abnormal bone density

• 17% Nephrolithiasis

• 37% reported at least 1 neuropsychiatric symptom

Normohormonal PHPT

Wallace LB. J Surg 2011;150 (6) 1102-12.

Normohormonal PHPT

Wallace LB. J Surg 2011;150 (6) 1102-12.

Cleveland ClinicGroup I

PTH always <40

2 Pt's (PTH 5 & 15)

Group II

PTH between

(10-60)

Group I

PTH Intermittently

>60

Incidental Dx During

Thyroid Work Up43% 32% 0

Pre-operative Localization 60% 74% 90%

• Patients underwent

exhaustive work up early

in the study

• Average delay in surgery

6.5 months

• 74% single adenoma

• 26% multi gland disease

• Post operatively

normalized Ca & lowered

PTH

Normohormonal PHPT

Wallace LB. J Surg 2011;150 (6) 1102-12.

Possibility of Higher Sensitivity to PTH

Guidelines for Surgery in

Asymptomatic PHPT

hyperparathyroidism

Work-up of

Asypmtomatic

PHPT

Guidelines have

shifted from

finding a reason

to treat to finding

a reason not to

treat!

Guidelines for Surgery in

Asymptomatic PHPT (4th International

Workshop 2013)Cardiovascular

• Hypercalcemia helps propagate vascular calcification

• High PTH is associated with 1. Increased left

ventricular mass 2. Carotid stiffness 3. Aortic

plaque area

• Parathyroidectomy however did not improve any of

these parameters

• Recommendation is against cardiac work up to

determine if parathyroidectomy should be done.

Guidelines for Surgery in

Asymptomatic PHPT (4th International

Workshop 2013)

Neuropsychiatric and Cognitive

• Literature review clearly indicates an association

between neuorpsychiatric & cognitive symptoms and

PHPT

• In their opinion the data regarding improvement of

these symptoms after surgery are inconsistent.

Psychiatric & Cognitive Functioning

Roman et al, at Yale University 2004-2008

• 212 English speaking patients enrolled (comorbidites were

accounted for). 102 patients completed the study.

• Underwent a battery of tests pre-op, 1, 3 & 6 months post op. 1. Beck Depression Inventory (BDI)

2. Spielberg State-Trait Anxiety Inventory (STAI)

3. Brief Symptom Inventory (BSI-18) - Global psych distress

4. Rey Auditory Verbal Learning Test - Recall test

5. Groton Maze Learning Test - Spatial memory

• All patients showed improvement in all the test even if they

had tested in the normal range pre-op.

• Greater PTH level change correlated more with improvement

on testing.

Surgical Considerations

• 85% Single Adenoma

(Monoclonal)

• 10% Multiple

Adenoma (Monoclonal)

• 5% Hyperplasia

affecting all glands

(Polyclonal)

• <1% Parathyroid

Cancer

Single Adenoma Multiple Adenoma

Hyperplasia Parathyroid Cancer

Impact of PTH Level on Surgical

Treatment

Kandil &

Tufano at

Johns Hopkins:

447

consecutive

patients (2002-

2006)

PTH < 150 PTH > 150

Calcium 11.0 11.4

Alkaline

Phosphatase87 104

Vitamin D 23 16

Abnormal

parathyroid gland

weight

415 mg 910 mg

Sestamibi

Localization68.9% 83.7%

Post op Ca/PTH at

6 months9.6/39 9.5/46

Impact of PTH Level on Surgical

Treatment

Clark &

Pellitteri at

Geisinger:

284

consecutive

patients (2005-

2007)

PTH < 100 PTH > 100

Calcium 10.9 11.1

PTH 74 134

Vitamin D 30 25

Multi-Gland

Disease20% 9%

Sestamibi/CT

Localization54% 62%

Post op Ca/PTH at

6 months8.8/41 8.9/57

Incidence of MGD

Glenn et al. Medical College of Wisconsin (1993-2013)

MGD was associated with:

• Age > 60

• Higher BMI > 30

• History of Lithium therapy

• Lower 24 hour urine calcium excretion

• Higher Alkaline Phosphatase

• Smaller size of first excised gland

Localization

Studies

Ultrasound

4D CT ScanSestamibi/SPECT

Localization Studies

How do u decide?

Sensitivity Radiation

Ultrasound 59-89% 0

Sestamibi/Spe

ct54-89% 7.8 mSv

4D CT Scan 65-88% 10.4 mSv

Localization StudiesUltrasound

• Good accuracy when done by expert ultrasonagrapher,

endocrinologist or surgeon.

• Less reliable for ectopic lesions & superior pole lesions

• Can be misleading in patients with thyroiditis

adenopathy.

• Should be the first line study for all patients.

• Very important for surgeons to perform their own US. It

serves as a GPS and they have a practical

understanding of the neck anatomy.

Localization StudiesSestamibi/SPECT

• Operator dependent

• Imaging center must be efficient and proficient

• Study results are only accurate if the first scan is

done immediately after injection

• Since tracer uptake is based on negative polarity

of mitochondria (due to respiratory cycles in

mitochondria) the more active glands (higher

PTH) the more likely it is that the scan will be

positive.

• More useful when PTH >150 pg/mL

Localization Studies

4D CT Scan

• Probably the most accurate and surgically helpful

study.

• It can potentially see normal parathyroids and

overcall MGD.

• Best suited for US negative, PTH less then 150.

• Scan of choice in re-operative cases.

• Highest dose of radiation so less favored in

younger patients.

Evolution of Surgical

Approach

Single Adenoma

Multiple Adenoma

Hyperplasia

The high incidence of MGD (15%) is

the complicating factor in surgical

approach.

• Until 1990's - Bilateral exploration

and 4 gland identification and biopsy.

Evolution of Surgical

Approach

Single Adenoma

Multiple Adenoma

Hyperplasia

• 1990's - Combination of pre-op

localization with US & Sestamibi as

well intra-op Gamma probe.

• Tracer uptake is very good in large

very active gland and poor in smaller

less active gland (PTH < 100).

• A certain percentage of hyperplastic

glands have a poor affinity for the

tracer.

Evolution of Surgical

Approach

Single Adenoma

Multiple Adenoma

• 2000's - Combination of pre-op

localization studies US,

Sestamibi/SPECT & 4D CT scan as well

intra-op rapid PTH testing.

• Half-life of PTH 3.5-4 minutes. 50% rule

by Goerge Irvin III, MD.

• IoPTH is very accurate in most cases.

Less accurate in MGD with low starting

PTH.

• Also limited in double adenomas or MGD

where the set point for each gland is far

apart. Multiple Adenoma

10.6

12.2

11.9

12.2

12.2 9.2

Evolution of Surgical

Approach

Asymmetric Hyperplasia

Spectrum of Hyperplasia

• 4 gland symmetric hyperplasia

• 4 gland asymmetric hyperplasia

• Adenoma on a background of

hyperplasia

Adenoma on a background of Hyperplasia

10.4

12.2

Hyperplasia

10.4

Minimally Invasive

Parathyroidectomy• In Pre-op localized adenoma, can limit surgery and

confirm success and perform focused unilateral surgery.

• Under loco-regional anesthesia awake or with sedation.

• No hospitalization necessary

• Post op Ca/Vit D

replacement

• Recurrence rate

3%

Medical Management

• Adequate hydration

• Calcium intake should not be restricted

• Vitamin D levels above 20-30 ng/ml

• Calcimimetics

• Bisphosphonates

Cinacalcet

• Increase the sensitivity of the calcium-sensing

receptor

• Lowers PTH secretion, gene transcription, cell

proliferation

• Lowers serum calcium

• Adverse effects are minor and uncommon: N/V, Diarrhea

& Headaches

• No significant effect on Bone Density

Cinacalcet• FDA approved for:

1. parathyroid carcinoma

2. secondary hyperparathyroidism of ESRD

3. PHPT who are unable undergo surgery

Aledronate

• Alendronate decreases bone turnover and increases BMD at the lumbar spine and proximal femur in primary hyperparathyroidism

• Increased BMD comparable to eucalcemic populations and to the response from surgery in hyperparathyroidism

• No long-term effect on serum & urine calcium levels or PTH

• Fracture outcomes not evaluated

Aledronate

Khan et al. JCEM 89:3319–3325, 2004

Spine Total hip

Femoral neck Radius

Femoral neck Radius

Summary• PHPT is a common disorder

• The whole spectrum PHPT must be taken into

account when assessing a patient

• Progression of disease is independent of severity of

disease at time of presentation

• Majority of patients with PHPT will have progressive

BMD loss

• Vitamin D replacement is crucial

• Treating physicians must understand the nuances of

disease well to treat effectively (medically &

surgically)