Disorders of Calcium and Parathyroid Gland Aidar R. Gosmanov, M.D., Ph.D. Associate Professor of Medicine Division of Endocrinology, Diabetes, and Metabolism University of Tennessee HSC [email protected]

  Recommended Supplemental Reading: Pathophysiology of Disease. An Introduction to Clinical Medicine, 6th edition by Stephen  J.  McPhee,  Gary  D.  Hammer: –  Chapter 17

Objectives 1. Differentiate pathophysiology and clinical presentation of primary, secondary and tertiary hyperparathyroidism. 2. Formulate approach in initial work up of calcium disorders. 3. Describe clinical presentation and develop initial approach in management of patients with hypocalcemia and hypercalcemia 4. Explain pathophysiology, clinical presentation, biochemical findings and therapeutic approaches in patients with Multiple Endocrine Neoplasia syndromes.

Outline 1. Calcium -Hypercalcemia -Hypocalcemia 2. Parathyroid hormone -Primary, secondary, and tertiary hyperparathyroidism 3. MEN 1, 2a, 2b

Mineral  Metabolism   Key  players  

•  Cellular  level   –  –  –  –  – 

Calcium   Phosphorous   PTH   Vitamin  D   FGF23  

•  Tissue  Level   –  –  –  –  – 

Parathyroid  glands   Gut   Kidney   Bone   Liver  

Minor  players   •  Cellular  level   –  Calcitonin   –  Magnesium   –  Acid-­‐base  state  

•  Tissue  Level   –  Skin  

Calcium distribution Total body calcium ~ 1 kg –  99% in bone (hydroxyapatite) –  1% extracellular and soft tissues –  0.1% intracellular

Serum calcium –  40% protein bound –  10% complexed (citrate or phosphate ions) –  50% ionized – free calcium that is bioavailable CLINICALLY WE MEASURE THE TOTAL SERUM CALCIUM

Calcium Balance 1000 mg/day

Soft Tissues 300 mg/day (30%) (Duodenum) Extracellular Fluid

500 mg/day

500 mg/day

150 mg/day

Bone 1000,000 mg (1.0 kg)

Stool 850 mg/day 150 mg/day Net 1000 mg/day out Mundy and Guise. 1999.

Low Calcium Stimulates release

25(OH)D 1α-OHase + 1,25(OH)2D

Increase  calcium   mobilizaLon  from  bone  

Increase  calcium   reabsorpLon  from  DCT  

Increase  calcium   absorpLon  from  intesLnes  

Parathyroid  hormone  also   •  activates 1α-hydroxylase 25(OH)2D3

1,25(OH)2D3

•  stimulates reabsorption of Ca (distal nephron) •  inactivates phosphate transporter (PCT) Calcium reabsorption

êtype II Na*Pi

transporter

Inhibits phosphate reabsorption

PTH:    

84  aa   pepLde  

13

Calcium-­‐sensing  receptor  senses   Ca++  level   CaSR found in: -parathyroid -kidney -C cells thyroid -bone

CaSR is a member of the GPCR family

PARATHYROID CELL

Stimulating the calcium sensing receptor results in an Intra-cellular cascade to reduce PTH secretion

Stewart, NEJM editorial 2004

Work up of hypercalcemia (Differential Diagnosis) 1.  History and Physical 2.  Check albumin and total calcium x 2 3.  Check a PTH

PTH dependent

PTH independent

− Hyperparathyroidism (primary/tertiary) − Familial hypocalciuric hypercalcemia − Medication-induced (Lithium or HCTZ-mediated)

-Tumor induced (PTHrP or bone metastases) -Granulomatous diseases (TB), sarcoidosis, lymphoma ↑ 1,25 vit.D -Multiple myeloma -Hyperthyroidism/adrenal failure -Immobilization -Medication-induced: (vitamin D toxicity, vitamin A, milk-alkali)

Primary Hyperparathyroidism

Primary  Hyperparathyroidism     -­‐80-­‐85%  adenoma   -­‐15%  hyperplasia  (MEN1,   MEN2A,  HPT-­‐Jaw  Tumor   Syndrome,  familial  HPT)   -­‐W>H), sex (F>M) Etiology unknown abdominal

psychic

serendipity stones moans groans bones

Yeh, M. et al., J Clin Endocrinol Metab, March 2013, 98(3):1122–9

Primary  HPT  -­‐  Pathogenesis    

Symptoms in Primary Hyperparathyroidism •  •  •  •  •  •  • 

Fatigue/weakness Musculoskeletal pain Polydipsia/Polyuria Constipation Anorexia/nausea/Dyspepsia Pruritus Depression/Memory loss

•  • 

•  •  •  • 

Renal failure/Kidney stones Osteoporosis/Fracture Pancreatitis Hypertension

Symptoms  are  non-­‐specific   Majority  of  paLents  are  asymptomaLc  

Primary  HPT  –  Work  up   •  Biochemical: •  •  •  • 

calcium, Albumin (ionized calcium), PTH, 25-OH vitamin D, 24-hour urine calcium (to differentiate from FHH)

•  Imaging: •  •  • 

Thyroid US 99Tc-sestamibi scan DXA

Localization studies

Management  of  Primary  HPT:   Parathyroidectomy   2009 guidelines for parathyroid surgery in asymptomatic PHPT (one criteria suffices for parathyroidectomy)

Management  of  Primary  HPT   ConservaLve  management  

•  Adequate  hydraLon   •  Use  of  bisphosphonates  in  paLents  with   osteoporosis   •  Maintenance  of  vitamin  D  status  (20-­‐30  ng/mL)   •  Cinacalcet  has  been  approved  by  FDA  for  those   who  do  not  qualify  for  surgery  and  have   moderate  hypercalcemia  (Ca  >12.5  mg/dL)   •  Annual  follow  up:  Ca/PTH,  renal  funcLon,  DXA    

Familial Hypocalciuric Hypercalcemia 1.  Inactivating mutation of CaSR, 100% penetrance 2.  Mildly ↑ serum Ca, high-normal/mildly ↑ PTH, hypocalciuria 3.  Asymptomatic 4.  Work up: Serum Ca, PTH, 24-hr urine calcium (800 units/day) showed ~20% reduction in risk of fractures –  – 

Benefits of vitamin D replacement for prevention of cancer, diabetes mellitus, infections, hypertension are controversial; J-shape association between mortality and vitamin D levels

Hypocalcemia

   Hypocalcemia:    Clinical  signs     -­‐agita3on   -­‐hyperreflexia   -­‐convulsions   -­‐hypertension   -­‐long  QT  

   

Hypocalcemia:  DifferenLal  Diagnosis   Hypoparathyroidsm (low PTH) – Primary process as low PTH decreases Calcium Post-thyroidectomy Idiopathic – antibodies to PTH Autoimmune Parathyroid agenesis – e.g. DiGeorge syndrome Hypomagnesaemia, hypermagnesemia, hyperphosphatemia

Hyperparathyrodism (high PTH) – Secondary process or when PTH increases due to low calcium from other reasons Renal Failure Vitamin D deficiency Vitamin D or PTH resistance syndromes

Miscellaneous Causes of Hypocalcemia Acute pancreatitis – free fatty acids chelate calcium Massive transfusion – infusion of citrate will complex with calcium leading to decreased ionized calcium Tumor Lysis Syndrome or rhabdomyolysis – Phosphate release binds to ionized calcium Severe sepsis- Cytokines mediated? Medications – phosphate, bisphosphonates Hungry bone syndrome

Work up of hypocalcemia 1.  History and Physical 2.  Check albumin and total calcium x 2 3.  Check PTH

PTH is low

PTH is high

Hypoparathyroidism Magnesium deficiency Phosphate excess

Severe vitamin D deficiency Renal failure Vitamin D resistance or PTH resistance

Pseudohypoparathyroidism •  The  idiopathic  inherited  forms  of  PTH   resistance   •  PaLents  have  elevated  PTH  (1000s),   hypocalcaemia,  hyperphosphatemia   and/or  specific  morphological  features   including  short  stature,  rounded  face,   foreshortened  4th  and  other   metacarpals,  obesity  (Albright`s   Hereditary  Osteodystrophy-­‐  AHO)   •  Molecular  defect  -­‐  inability  of  PTH   sLmulate  intracellular  signaling  events   (cAMP  pathway)  due  to  mutaLon  in   Gsα  subunit  or  elements  downstream   to  cAMP  signaling   •  Variability  in  AHO  and  PTH  renal   resistance,  the  condiLon  is   subclassified  

PseudohypoparathyroidismClassification  

PHP  1a

Urinary cAMP

Urinary PO4

after PTH

after PTH

↓

↓

AHO

Other hormonal resistance. Comments

Yes

YES.  ↓mentaLon,  ↓  olfacLon   ↓  TSH,  glucagon,  LH/FSH

PHP  1b

↓

↓

No

NO.  Renal  resistance  to  PTH

PHP  1c

↓

↓

Yes

YES.  Gsα  acLvity  normal,  defect   in  cAMP  pathway

Pseudo-­‐

normal

normal

Yes

Coexist  in  PHP  1a  kindreds

PHP PHP  2

NO.  Paternal  mutant  gene.  

normal

↓

No

NO.  ?  triggered  by  vit.  D   deficiency,  ?  acquired

Hypocalcaemia - Treatment •  Acute Hypocalcemic Crisis: –  Always correct Magnesium if low –  Calcium Gluconate (93 mg elemental Ca++/10 ml) •  1 - 2 ampules over ~10 – 20 minutes •  0.5-2.0 mg/kg/hr of elemental Calcium IV •  Long-term Management: –  Oral Calcium salts (up to 3 grams of elemental Ca/day) –  Vitamin D •  Ergocalciferol/Cholecalciferol (act in 10-14 days) - effective only if PTH is present •  Calcitriol - 0.5-1.0 mcg/day –  Hydrochlorothiazide – increases reabsorption of Calcium in the distal tubule

MEN Syndromes

MEN – Multiple Endocrine Neoplasia A syndrome in which 2 or more endocrine tumors occur in a single patient 1. Autosomal dominant (e.g., DNA deletion) -germline or sporadic mutations (2nd hit hypothesis)

2. Different penetrance (varying phenotype) 3. Benign and malignant 4. Functionally active and inactive

MEN1- Summary Affected

Presentation/

Signs/

Screening

Therapy

gene

penetrance

Symptoms

MENIN

Prevalence up to

Kidney stones,

-Calcium, PTH

1. Definitive:

11q12-13

20/100,000; 2nd-3rd

hyperCaemia,

-gastrin

resection of

decade

recurrent peptic

-insulin,glucose tumor(s) (e.g., 3

1.Parathyroid (Primary

ulcers, fasting

-prolactin

and ½

HPT) – 80-95%

hypoglycemia,

-IGF-1

parathyroidectomy

2.Pancreas (insulinoma,

hypogonadism,

-ACTH, cortisol

+/- thymectomy)

gastrinoma, VIPoma) –

galactorrhea,

2. Symptomatic:

50%

weight gain,

proton pump

3. Pituitary (prolactinoma, diarrhea

inhibitors,

Cushing`s disease,

octreotide

acromegaly) - 25%

Timeline  of  the  MEN1  Phenotype   •  Hypercalcemia  due  to  10   HPT  manifests  by  age  40   (19-­‐40)   •  Pituitary  tumors   diagnosed  on  average  at   age  38  (12-­‐83)   •  PancreaLc  tumors:   –  Insulinoma  at  age  25   –  Gastrinoma  at  age  35   Marx S, Spiegel AM, Skarulis MC, et al. Ann Intern Med. 1998;129:484-494

Parathyroid Surgery and Gastrin in Patients with PHPT and Gastrinoma •  Parathyroidectomy improves hypercalcemia and decreases gastrin

Jensen RT. J Intern Med. 1998;243:477-488

MEN2 - Summary Affected

Presentation/

Signs/

gene

penetrance

Symptoms

Screening

Therapy 1. Definitive: total

RET

1/30,000, any age, more in

Thyroid nodule,

-Calcitonin, CEA

10q11.2

adults, 80% of all MEN2

hypertension,

-plasma and urine thyroidectomy with

Mutation at

1. Medullary thyroid

spells, diaphoresis,

metanephrines

lymph node

hypercalcemia,

-Calcium, PTH

dissection,

-Chromogranin A

adrenalectomy,

codon Cys634 carcinoma – almost 100% 2. Pheochromocytoma – 40%

MEN2A

3. Primary HPT – 25%

parathyroidectomy 2. Symptomatic: therapy of HTN

RET

1/30,000, early onset, 5% of

Thyroid nodule, skin -Calcitonin, CEA

10q11.2

all MEN2

neuromas,

Mutation at

1.Medullary thyroid carcinoma Hirschsprung`s

codon Met634 (more malignant) – 100%

  MEN2AB  

disease,

1. Definitive: total

-plasma and urine thyroidectomy with metanephrines

lymph node

-Chromogranin A

dissection,

2. Mucosal neuromas – 100% hypertension,

adrenalectomy

3. Marfanoid habitus – 50%

2. Symptomatic:

4. Pheochromocytoma – 50%

spells, diaphoresis,

therapy of HTN

Some Clinical features of MEN2B •  Mucosal neuromas •  marfanoid habitus

Screening Strategies   •  Biochemical   –  In  index  paLent,   complete  screening  by   tesLng  funcLon  of  other   endocrine  glands  of  MEN   –  In  first  degree  relaLves,   iniLate  screening  to   idenLfy  hyperfuncLon  of   an  endocrine  gland(s)   known  to  be  part  of   MEN    

•  GeneHc   –  In  index  paLent,  screen  for   most  prevalent  geneLc   mutaLon  for  this  type  of   MEN  (provide  geneLc   counseling)   –  In  first  degree  relaLves,   consider  geneLc  screening   once  the  mutaLon  was   confirmed  in  the  index   paLent.  Children  are  the   most  vulnerable  group    

 

The End