The Parathyroid Glands, Function and Dysfunction + Glands/Tumours Pathology

In your body where is calcium?

99% in the bone 0.9% in SR and ER 0.1% ECF (2.2-2.6 mmol/l) - ECF --> bound, free, complexed types

What are some causes of secondary hyperparathyroidism?

Causes: Chronic renal failure, vit D deficiency or synthesis (Vit D needed for efficient mobilization of Ca from bones) - eg CRF leads to decreased GFR: - reduced phosphate excretion --> retained phosphate has stimulatory effect on PTH secretion (via lowering of ionized calcium) - reduced 1, 25 - OH Vit D3 from decreased synthesis due to reduced renal function and from hyperphosphatemia (1, 25 OH vit D3 normally has suppressive effect on PTH transcription) - CRF results in elevated levels of PTH and reduced 1, 25 OH vit D3 with impaired Ca2+ absorption from the GI tract

What does ionized calcium do (function)?

Hormonal secretion Blood clotting Muscle contraction Neuromuscular junction Neurotransmitter release Signal transduction

What is the important concentration actively for calcium influence?

Ionized calcium.

What are renal signs and symptoms?

Stones Polyuria, polydipsia Metabolic acidosis (due to kidneys inability to produce bicarbonate) Concentrating defects Nephrocalcinosis

What is the age related penetrance of MEN1?

The age-related penetrance has been calculated as: - 7% at 10 years - 52% at 20 years - 98% at 40 years - 100% at 60 years.

What are systemic symptoms and signs of primary hyperparathyroidism?

Weakness Easy fatigue Weight loss Anemia Anorexia Pruritus Ectopic calcifications

What is the concentration of calcium in the cytosol?

Within the cytosol free calcium concentration is quite low without stimulation

What are GI signs and symptoms?

Peptic ulcer disease Pancreatitis Constipation Nausea Vomiting

Features of gastrinoma (summary)

- 40-50 years - Zollinger-Ellison syndrome --> multiple peptic ulcers related to acid hypersecretion - >50% malignant - metastases to lymph nodes and liver - 30% of cases are found in the pancreas and the majority are in the duodenum - some cases are associated with MEN1

Quick summary: Hypoparathyroidism causes?

- Lower PTH - Hypocalcemia - Hyperphosphataemia - Increased muscular tone - Tetany - May develop cataracts - may have psychological changes and convulsions

What is hypoparathyroidism?

- Tetany (laryngeal muscle spasm - respiratory obstruction) *concern Causes: - Autoimmune destruction of parathyroid - Surgical complications (thyroid, parathyroid, laryngeal) -Magnesium depletion - Post 131-I therapy for Graves or thyroid cancer -Genetic forms (DiGeorge 22q deletion, X-linked Hypoparathyroidism, mutations in pre-proPTH gene)

Insulinomas result in Whipple's triad. What is this?

- attacks of fainting, dizziness, and sweating on fasting - low blood sugar during attack - symptoms disappear when glucose is given (Wikipedia) The diagnosis of insulinoma is suspected in a patient with symptomatic fasting hypoglycemia. The conditions of Whipple's triad need to be met for the diagnosis of "true hypoglycemia" to be made: 1) symptoms and signs of hypoglycemia, 2) concomitant plasma glucose level of 45 mg/dL (2.5 mmol/L) or less, and 3) reversibility of symptoms with administration of glucose.

What is hypocalcemia?

- hypoparathyroidism - PTH resistance (pseudohypoparathyroidism) - magnesium depletion (due to diarrhea, malabsorption, alcoholism, loop diuretics) - vitamin D deficiency or resistance (liver disease, renal failure, defect in Vit D receptor) - failure of homeostasis (drug-induced, bone metastases, pancreatitis -formation of calcium salts)

What are the actions of Parathyroid Hormone?

- increase bone resorption - mobilize calcium - increase phosphate excretion (proximal tubule/NaPi) - increase calcium reabsorption (distal renal tubule/can be saturated in hyperparathyroidism with resulting increase in urinary calcium levels b/c there are limits and you can't reabsorb all of it) - increase formation of 1,25-OH Vitamin D3 in proximal tubules (increase calcium absorption in intestine) (Vit D3 also reduces PTH transcription - binding to Vit D3 response element on PTH gene) Measured clinically in conditions of: - hyper and hypocalcaemia - Renal failure (osteodystrophy)

What is parathyroid hyperplasia?

- may be primary or secondary - enlargement of all glands but necessarily synchronous or equal - diffuse or nodular

What is the connection of PTH and osteoblasts?

- osteoblasts produce RANK-L (osteoclast activating factor) - osteoblasts also secrete M-CSF (involved in osteoclast recruitment and maturation) Glucocorticoids have this same affect (cortisol)

Describe the features of pancreatic neuroendocrine tumours

- rare in clinical practice - account for 1-2% of pancreatic tumours - M:F 1-1 - Happens between 30-60 yrs - 15-25% may be associated with multiple endocrine neoplasia type 1 (MEN-1) Functional tumours are 60-85% - insulin secreting - 70% - Gastrin secreting - VIP, glucagon and others rare Nonfunctional tumours (15-40%) - may present with signs of malignancy

What are you likely to get in MEN1? How is the HPT in MEN 1?

1/30,000 people (mutations in MEN1 gene) Features: - hyperparathyroidism (95%) - gastrinoma (45%) - pituitary tumour (25%) - facial angiofibroma (85%) - collagenoma (70%) HPT in MEN 1 - early onset - multiple glands affected - post-op hypoparathyroidism more common (more extensive surgery happens with these guys) - successful subtotal parathyroidectomy followed by recurrent HPT in 10 years in 50% of cases

What is the normal overall calcium concentration usually supposed to be in the ECF?

2.5 mM

What is a gastrinoma?

A gastrinoma is a tumor in the pancreas or duodenum that secretes excess of gastrin leading to ulceration in the duodenum, stomach and the small intestine. There is hypersecretion of the HCl acid into the duodenum, which causes the ulcers. Excessive HCl acid production also causes hyperperistalsis, and inhibits the activity of lipase, causing severe diarrhea. It is frequently the source of the gastrin in Zollinger-Ellison syndrome. It is usually found in the duodenum, although it may arise in the stomach or pancreas. Those occurring in the pancreas have a greater potential for malignancy. Most gastrinomas are found in the gastrinoma triangle; this is bound by the junction of cystic and common bile ducts, junction of the second and third parts of the duodenum, and the junction of the neck and body of the pancreas.

What are the features of parathyroid adenoma?

A parathyroid adenoma is a benign tumor of the parathyroid gland. It generally causes hyperparathyroidism - peak incidence 40-60 years - F:M 2-3:1 ratio - vary in size - can vary in gross and histological appearance

Describe calcium metabolism

Activated VITD3 helps Calcium be absorbed from the small intestine - pulls phosphate in as well Prolactin has an influence on calcium absorption in the gut as well as it has receptors in the GI which can also upregulate calcium

What occurs to calcium when we are under acute alkalosis?

Acute alkalosis increases calcium binding to protein and decreases ionized calcium - so hyperventilating for example causes less calcium to be free and therefore less calcium we can actually use

What are the features of a parathyroid carcinoma?

Affects males and females the same - neck mass more commonly palpable than with adenoma - often difficult to remove - mutations in the HRPT2 tumour suppressor gene in the majority of cases No definitive histological feature - capsular invasion - vascular invasion - adherence to surrounding structures - broad fibrous bands

Table of WHO classification of pancreatic neuroendocrine tumours

All tumours are regarded as potentially malignant

What is an insulinoma?

An insulinoma is a tumor of the pancreas that is derived from beta cells and secretes insulin. It is a rare form of a neuroendocrine tumor. Most insulinomas are benign in that they grow exclusively at their origin within the pancreas, but a minority metastasize. Insulinomas are one of the functional PanNET group ("functional" because it increases production of insulin; "PanNET" as an abbreviation of pancreatic neuroendocrine tumor) Affects M > F - 40-60 years - most are benign

What happens if you have an insulinoma? How do we treat it?

Beta cells secrete insulin in response to increases in blood glucose. The resulting increase in insulin acts to lower blood glucose back to normal levels at which point further secretion of insulin is stopped. In contrast, the secretion of insulin by insulinomas is not properly regulated by glucose and the tumors will continue to secrete insulin causing glucose levels to fall further than normal. As a result, patients present symptoms of low blood glucose (hypoglycemia), which are improved by eating. The diagnosis of an insulinoma is usually made biochemically with low blood glucose, elevated insulin, proinsulin and C-peptide levels and confirmed by localizing the tumor with medical imaging or angiography. The definitive treatment is surgery.

What is Calcitonin?

Calcitonin is a 32 amino acid peptide hormone - secreted by the parafollicular or C cells of the thyroid gland - released in response to increased plasma [calcium] - Calcitonin acts oppositely to PTH via bone osteoclasts to reduce bone resorption - lesser role in daily overall balance. (Gastrin increases calcitonin secretion - calcium uptake into bone after meals) - marker medullary Ca of thyroid

What happens in the kidney related to calcium? What effects does PTH/Calcitonin have here?

Calcium can go to the kidney via passive filtration. PTH and calcitonin have opposite effects. PTH will increase the reabsorption of calcium back into the ECF and calcitonin wants to block that and let us excrete it out in the urine.

What is pseudohypoparathyroidism?

Decreased end-organ responsiveness (increased PTH)

What are neuropsychiatric and neuromuscular signs and symptoms of hyperparathyroidism?

Depression Poor concentration Memory deficits Peripheral sensory neuropathy Motor neuropathy Proximal and generalized muscle weakness

The normal pancreas contains?

Exocrine tissue - proteolytic enzymes - RNAses - Lipases Islets of Langerhans - insulin - glucagon - somatostatin - pancreatic polypeptide

What does primary hyperparathyroidism present with?

F > M are affected Presents with: - general tiredness and muscle weakness - historically often presented with renal calculi - some developed osteotis fibrosa cystica, a severe bone disease - other complications include duodenal ulceration and acute pancreatitis - metastatic calcification may cause nephrocalcinosis and renal failure, and may affect the soft tissues, heart and other organs

What does the free and bound calcium ratio depend on?

Free and bound calcium ratio depends on acid-base status and corrected for albumin levels - 47% bound to albumin and other globulins - 47% free (ionized) - 6% complexed (citrate, phosphate, bicarbonate)

Gastrinomas cause?

Gastrinoma causes the following symptoms: - Hypergastrinemia - Ulcers of the duodenum, stomach, and small intestine. - Severe diarrhea. - Generalized cancer symptoms.

How can we diagnose parathyroid adenoma?

Hyperparathyroidism is confirmed by blood tests such as calcium and PTH levels. A specific test for parathyroid adenoma is sestamibi parathyroid scintigraphy, the sestamibi scan. This nuclear imaging technique reveals the presence and location of pathological parathyroid tissue Tc99m-sestamibi is absorbed faster by a hyperfunctioning parathyroid gland than by a normal parathyroid gland. This is dependent on several histologic features within the abnormal parathyroid gland itself. Sestamibi imaging is correlated with the number and activity of the mitochondria within the parathyroid cells, such that oxyphil cell parathyroid adenomas have a very high avidity for sestamibi, while chief cell parathyroid adenomas have almost no imaging quality at all with sestambi.

Explain why acute respiratory alkalosis causes neural excitability?

If we become alkalotic we are increasing the binding of calcium to proteins therefore reducing free ionized calcium. If this lowers enough we can develop hypocalcemia. This is the primary cause of tetany. Low ionized calcium levels in the extracellular fluid increase the permeability of neuronal membranes to sodium ion, causing a progressive depolarization, which increases the possibility of action potentials. This occurs because calcium ions interact with the exterior surface of sodium channels in the plasma membrane of nerve cells. When calcium ions are absent the voltage level required to open voltage gated sodium channels is significantly altered (less excitation is required). If the plasma Ca2+ decreases to less than 50% of the normal value of 9.4 mg/dl, action potentials may be spontaneously generated, causing contraction of peripheral skeletal muscles. Hypocalcemia is not a term for tetany but is rather a cause of tetany.

Why is PTH essential for life?

If you remove them you get excitability and tetany - if you have muscle spasms but it is happening in your respiratory muscles then you can go into respiratory failure and die - excitability is related to hypocalcemia - hypercalcemia actually ends up in depression

Describe parathyroid hormone itself

It is an 84 amino acid residue - has a short half-life in circulating blood (about 10 minutes or so) --> acts quickly The secretory granules are chief cells and PTH is metabolized in the liver by Kupffer cells and it is essential for life

What are 2 familial endocrine disorders that affect the parathyroid?

MEN 1: parathyroid/pancreas/pituitary MEN IIA: medullary Ca Thyroid/Pheochromocytoma/Parathyroid

What is MEN2 syndromes?

MEN 2A - Medullary thyroid carcinoma (MTC) - Phaeochromocytoma - 20-50% - Parathyroid hyperplasia - 5-20% MEN 2B - MTC - Phaeochromocytoma - 50% - Mucocutaneous neuromas - Marfanoid appearance

What are the features of MEN-IIA?

MEN-IIA Features: - MTC(95%) - Pheochromocytoma(50%) - HPT(20%) - RET mutation (98%) - 1 in 30,000-50,000 people - Usually single adenoma but can be multi-gland hyperplasia

What is metabolic acidosis?

Metabolic acidosis is a condition that occurs when the body produces excessive quantities of acid or when the kidneys are not removing enough acid from the body. If unchecked, metabolic acidosis leads to acidemia, i.e., blood pH is low (less than 7.35) due to increased production of hydrogen ions by the body or the inability of the body to form bicarbonate (HCO3−) in the kidney.

What are the genetics for MEN2?

Mutations in RET proto-oncogene - localised to chromosome 10q11.2 - consists of 20 exons and encodes a receptor tyrosine kinase - ligand binding induces dimerization and activation - hot spot mutations so screening programme possible MEN2A - 85% mutation at codon 634 - extracellular domain - spontaneous dimerization without ligand binding MEN2B - >95% mutation at codon 918 - intracellular domain, spontaneous activation without dimerization

What are ocular and cardiac signs and symptoms of hyperparathyroidism?

Ocular - band keratopathy Cardiac - shortened QT interval. hypertension

How does calcium inhibit PTH release?

On the Parathyroid cell there are specific calcium receptors and if calcium levels are high it would bind to the calcium receptors and this would have a negative effect on the release of PTH. These are G-protein coupled receptors that activate phospholipase C and inhibits synthesis and release of PTH from secretory granules

What are skeletal and Rheumatologic signs and symptoms?

Osteopenia Pathologic fractures Brown tumours of bone Bone pain Gout Pseudogout Chondrocalcinosis Osteitis Fibrosa Cystica

What does Osteoprotegerin do? (OPG)

Osteoprotegerin is a decoy receptor for the receptor activator of nuclear factor kappa B ligand (RANKL). By binding RANKL, OPG prevents RANK-mediated nuclear factor kappa B (NF-κB) activation which is a central and rapid acting transcription factor for immune-related genes, and a key regulator of inflammation, innate immunity, and cell survival and differentiation. Osteoprotegerin levels are influenced by voltage-dependent calcium channels. OPG can reduce the production of osteoclasts by inhibiting the differentiation of osteoclast precursors (osteoclasts are related to monocytes/macrophages and are derived from granulocyte/macrophage-forming colony units (CFU-GM)) into osteoclasts and also regulates the resorption of osteoclasts in vitro and in vivo. OPG binding to RANKL on osteoblast/stromal cells, blocks the RANKL-RANK interaction between osteoblast/stromal cells and osteoclast precursors. This has the effect of inhibiting the differentiation of the osteoclast precursor into a mature osteoclast.

How is Ca2+ controlled via hormones?

PTH 1, 25-dihydroxy Vitamin D3 (Vitamin D3) - 25 hydroxylation occurs in the liver - 1 hydroxylation occurs in the kidney (mainly proximal tubule) Calcitonin (less important physiologically in fine control of calcium) --> knew this b/c with total thyroidectomy the calcium levels did not fluctuate as much --> calcitonin is secreted from C cells from the thyroid

In terms of your actual bones what hormones do what to them to regulate calcium concentration in the ECF?

PTH, Calcitriol, Cortisol all stimulate bone resorption and increase the Calcium concentration in the ECF - does this via the relationship of RANKL Osteoprotegerin Calcitonin decreases the calcium concentration and stimulates bone growth

What is hyperparathyroidism?

Primary hyperparathyroidism: - hypercalcemia/hypophosphatemia and increase alkaline phosphatase from osteoblasts - single adenoma approx 80%, 15% hyperplastic glands, 3% multiple adenomas, <2% carcinoma Secondary hyperparathyroidism (compensation for hypocalcemia): - hyperplastic glands - malfunction of another organ system (malignancy, PTHrP) - usually renal failure (Vit D deficiency) Tertiary hyperparathyroidism: - similar to secondary but PTH production is now autonomous

Quick summary: What is Hyperparathyroidism classified as?

Primary: when excessive secretion of parathyroid is autonomous Secondary: when the gland secretes parathyroid hormone in response to increased physiological stimulation - chronic renal failure - vitamin D deficiency - Calcium deficiency - Malabsorption Tertiary: when autonomous hypersecretion of hormone develops on a background of secondary hyperparathyroidism

What is RANKL?

RANKL is a member of the tumor necrosis factor (TNF) cytokine family, it binds to RANK on cells of the myeloid lineage and functions as a key factor for osteoclast differentiation and activation. - basically ups OC activity therefore increases bone resorption

Quick review: What is alkalosis? What is it's mechanism?

Respiratory alkalosis is a medical condition in which increased respiration elevates the blood pH beyond the normal range (7.35-7.45) with a concurrent reduction in arterial levels of carbon dioxide. The mechanism of respiratory alkalosis generally occurs when some stimulus makes a person hyperventilate. The increased breathing produces increased alveolar respiration, expelling CO2 from the circulation. This alters the dynamic chemical equilibrium of carbon dioxide in the circulatory system. Circulating hydrogen ions and bicarbonate are shifted through the carbonic acid (H2CO3) intermediate to make more CO2 via the enzyme carbonic anhydrase according to the following reaction: This causes decreased circulating hydrogen ion concentration, and increased pH (alkalosis)

What does the mutations in HRPT2 tumour suppressor gene lead to in nuclear staining?

Results in reduced or absent nuclear staining

Acute respiratory alkalosis can cause?

Seizures Respiratory failure - both due to neural excitability

With the Vit D deficiency in secondary hyperparathyroidism what happens?

Since you are unable to fully activate Vit D you will get less calcium absorption in the gut which leads to lower levels of calcium. This will lead to activation of PTH but since the body is having trouble absorbing calcium in the 1st place it will seek calcium elsewhere which will be in the bones and you can get osteofibrosis cystica or osteoporosis.

What are the genetics involved in MEN1?

The gene involved is MEN1 on chromosome 11q13 - encodes a 610 amino acid protein named menin --> ubiquitously expressed with wide-ranging functions in the regulation of cell proliferation and in DNA damage-dependent cell cycle arrest or DNA damage repair - a mutation is predicted to give rise to a truncated menin protein, presumably with loss of function - mutations scattered throughout the whole of the coding region with no obvious hotspots so difficult to set up a routine genetic screening programme

Describe the anatomy of the parathyroid glands

They are 4 nodules on the posterior side of the thyroid gland. The main blood supply is from the inferior thyroid artery Amount of fat in the parathyroid gland increases with age

What happens to patients who develop acute respiratory alkalosis?

They have increased neural excitability and are prone to seizures due to low ionized calcium in the extracellular fluid which results in increased permeability to sodium ions - calcium stabilises sodium channels

What are the 2 types of PTH receptors and what do they activate?

Type 1 is a PTH/PTHrP - this is for the bone/kidney - cAMP and coupled to IP3/DAG Type 2 PTH - brain/pancreas/testis/placenta and not involved in mineral balance PTHrP - malignancy/many tissues/breast - Ca content of milk

The binding of calcium to albumin is dependent on what?

pH dependent