PTH Calcitonin and Vitamin Department of Biological Sciences

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PTH Calcitonin and Vitamin Department of Biological Sciences Powered By Docstoc
					     Functional Anatomy of the Thyroid and
              Parathyroid Glands

 The thyroid gland is located in the neck, in close
   approximation to the first part of the trachea.
  In humans, the thyroid gland has a "butterfly"
shape, with two lateral lobes that are connected by
       a narrow section called the isthmus.

Most animals, however, have two separate glands
         on either side of the trachea.
  Thyroid glands are brownish-red in color.
Close examination of a thyroid gland will reveal one or more small,
 light-colored nodules on or protruding from its surface - these are
        parathyroid glands (meaning "beside the thyroid").
The image shows a canine thyroid gland and one attached parathyroid
                               gland.
Occasionally, a person is born with one or more of the parathyroid
 glands embedded in the thyroid, the thymus, or elsewhere in the
chest. In most such cases, however, the glands function normally.
        Though their names are similar,
the thyroid and parathyroid glands are entirely
               separate glands,
each producing distinct hormones with specific
                  functions.
         Parathyroid hormone (PTH)

   PTH is the most important endocrine
    regulator of calcium and phosphorus
     concentration in extracellular fluid.
 This hormone is secreted from cells of the
parathyroid glands and finds its major target
          cells in bone and kidney.
      Another hormone,
parathyroid hormone-related
 protein, binds to the same
  receptor as parathyroid
  hormone and has major
   effects on development.
           Parathyroid hormone

Like most other protein hormones, PTH is
     synthesized as a preprohormone.

 After intracellular processing, the mature
 hormone is packaged within the Golgi into
secretory vesicles, the secreted into blood by
                 exocytosis.
             PTH is secreted as a
           linear protein of 84 aa.
Although the 4 parathyroid glands are quite
                  small-
      have a very rich blood supply.

                IMPORTANT-
they are required to monitor the calcium level
         in the blood 24 hours a day.
 As the blood filters through the parathyroid
  glands, they detect the amount of calcium
  present in the blood and react by making
  more or less parathyroid hormone (PTH).
              IMPORTANT-
they are required to monitor the calcium
    level in the blood 24 hours a day.

 When the calcium level in the blood is
  too low, the cells of the parathyroids
      sense it and make more PTH
 Once PTH is released into the blood, it
   circulates to act in a # of places to
 increase the amount of calcium in the
                  blood.
 When the calcium level in the blood is
  too high, the cells of the parathyroids
    make less PTH (or stop making it
  altogether), thereby allowing calcium
             levels to decrease.
     This feed-back mechanism runs
constantly, thereby maintaining calcium
 (and PTH) in a very narrow "normal"
                   range.
   In a normal person with normal
       parathyroid glands, their
parathyroid glands will turn on and
  off dozens of times per day...in an
attempt to keep the calcium level in
 the normal range so our brain and
      muscles function properly.
Physiologic Effects of Parathyroid Hormone

 Function for PTH is straightforward:
    if calcium ion concentrations in
  extracellular fluid fall below normal,
   bring them back within the normal
                  range.

In conjunction with increasing calcium
   concentration, the concentration of
    phosphate ion in blood is reduced.
       Parathyroid Hormone Receptors

PTH and its cousin parathyroid hormone-related
   protein (PTHrP) are critical controllers of
       calcium and phosphorus balance.

The receptors for these two hormones are of high
     interest to drug companies, because such
   understanding may facilitate development of
     antagonists for treatment of a number of
  important diseases, including osteoporosis and
   hypercalcemia associated with some types of
                       cancer.
             Parathyroid Hormone Receptors

Type 1 PTH receptor:
    PTH and amino-
  terminal peptides of
                          Type 2 PTH receptor: Binds
        PTHrP.
                               PTH, but has very low
 G protein-coupled
                             affinity for PTHrP. Only
        receptor
                           expressed in a few tissues- its
                             structure and physiologic
                               significance are poorly
                           characterized. Like the type 1
                              receptor, it is coupled to
                            adenylyl cyclase and ligand
                              binding induces a rise in
                           intracellular concentration of
                                     cyclic AMP.
Physiologic Effects of Parathyroid Hormone

Parathyroid hormone accomplishes its job by stimulating at least
                        three processes:

         Mobilization of calcium from bone

Although the mechanisms remain obscure, a well-
  documented effect of parathyroid hormone is to
   stimulate osteoclasts to reabsorb bone mineral,
           liberating calcium into blood.
Physiologic Effects of Parathyroid Hormone

Enhancing absorption of calcium from the small
  intestine: Facilitating calcium absorption from
 the small intestine would clearly serve to elevate
               blood levels of calcium.
 PTH stimulates this process, but indirectly by
    stimulating production of the active form of
    vitamin D in the kidney. Vitamin D induces
      synthesis of a calcium-binding protein in
 intestinal epithelial cells that facilitates efficient
         absorption of calcium into blood.
Physiologic Effects of Parathyroid Hormone

 Parathyroid hormone accomplishes its job by stimulating at least
                         three processes:

Suppression of calcium loss in urine: In addition to
   stimulating fluxes of calcium into blood from
      bone and intestine, PTH puts a brake on
   excretion of calcium in urine, thus conserving
     calcium in blood. This effect is mediated by
    stimulating tubular reabsorption of calcium.
      Another effect of PTH on the kidney is to
      stimulate loss of phosphate ions in urine.
        Control of Parathyroid Hormone Secretion

 PTH is released in response to low extracellular
          concentrations of free calcium.

Changes in blood phosphate concentration can be
  associated with changes in PTH secretion, but
     this appears to be an indirect effect and
 phosphate per se is not a significant regulator of
                  this hormone.
   Control of Parathyroid Hormone
                Secretion

When calcium concentrations fall below
    the normal range, there is a steep
    increase in secretion of PTH. Low
    levels of the hormone are secreted
   even when blood calcium levels are
  high. The figure depicts PTH release
       from cells cultured in vitro in
  differing concentrations of calcium.
    The parathyroid cell monitors
         extracellular free calcium
       concentration via an integral
  membrane protein that functions as
        a calcium-sensing receptor.
             Extracellular Calcium-Sensing Receptor

Maintaining tight control over the concentration of calcium in blood
                and extracellular fluid is a critical task.
    It stands to reason that a calcium sensor would evolve as a
    component of the system responsible for calcium homeostasis.
   Considering its involvement in modulating so many physiologic
   processes, calcium itself can be thought of as a type of hormone,
                 and the calcium sensor as its receptor.

 The DNA sequence encoding the extracellular calcium sensor was
    originally isolated from bovine parathyroid gland. Since then,
   corresponding sequences have been isolated from a broad range
    of species, enabling serious study of this intriguing membrane
                                protein.
The calcium-sensing receptor is a member of the G protein-coupled
   receptor family. Like other family members, it contains 7TMDs
  and is present in PM. The large (~600 amino acids) extracellular
   domain is known to be critical to interactions with extracellular
  calcium. The receptor also has a rather large (~200 amino acids)
   cytosolic tail. -intracellular domain has kinase phosphorylation
                                   sites.
The calcium sensor is expressed in a broad range of
    cells, including parathyroid cells and C cells in
   the thyroid gland, indicating its involvement in
       controlling the synthesis and secretion of
         parathyroid hormone and calcitonin.

  Functional studies and investigation of animals
   with mutations in the calcium sensor gene have
     confirmed that the calcium sensor directly
      affects secretion of these two hormones.
                        Calcitonin

     Calcitonin is a hormone involved in calcium and
                   phosphorus metabolism.
 In mammals, the major source of calcitonin is from the
    parafollicular or C cells in the thyroid gland, but it is
      also synthesized in a wide variety of other tissues.

     Calcitonin is a 32 aa peptide cleaved from a larger
                          prohormone.
It contains a single disulfide bond, which causes the amino
            terminus to assume the shape of a ring.
                  Calcitonin

Calcitonin is a hormone involved in calcium and
              phosphorus metabolism.

Alternative splicing of the calcitonin pre-mRNA
   can yield a mRNA encoding calcitonin gene-
 related peptide; that peptide appears to function
     in the nervous and vascular systems. The
calcitonin receptor has been cloned and shown to
  be a member of the 7TMD, G protein-coupled
                  receptor family.
                        Calcitonin

               Physiologic Effects of Calcitonin

 A large and diverse set of effects has been attributed to
      calcitonin, but in many cases, these were seen in
   response to pharmacologic doses of the hormone, and
            their physiologic relevance is suspect.

It is clear however, that calcitonin plays a role in calcium
                and phosphorus metabolism.
                            Calcitonin

                  Physiologic Effects of Calcitonin

calcitonin has the ability to decrease blood calcium levels at least in
           part by effects on two well-studied target organs:

  Bone: Calcitonin suppresses resorption of bone by inhibiting the
  activity of osteoclasts, a cell type that "digests" bone matrix,
  releasing calcium and phosphorus into blood.

  Kidney: Calcium and phosphorus are prevented from being lost
  in urine by reabsorption in the kidney tubules. Calcitonin
  inhibits tubular reabsorption of these two ions, leading to
  increased rates of their loss in urine.
                      Calcitonin

   There are species differences in the importance of
    calcitonin as a factor affecting calcium homeostasis.
In fish, rodents and some domestic animals, calcitonin
        appears to play a significant role in calcium
                         homeostasis.
    In humans, calcitonin has at best a minor role in
      regulating blood concentrations of calcium. One
 interesting piece of evidence to support this statement is
    that humans with chronically increased (medullary
   thyroid cancer) or decreased (surgical removal of the
   thyroid gland) levels of calcitonin in blood usually do
    not show alterations from normal in serum calcium
                        concentration.
                   Calcitonin
         Control of Calcitonin Secretion

The most prominent factor controlling calcitonin
   secretion is the extracellular concentration of
                  ionized calcium.
Elevated blood calcium levels strongly stimulate
 calcitonin secretion, and secretion is suppressed
 when calcium concentration falls below normal.
 A number of other hormones have been shown to
 stimulate calcitonin release in certain situations,
       and nervous controls have also been
                   demonstrated.
                  Calcitonin

                Disease States

A large number of diseases are associated with
   abnormally increased or decreased levels of
 calcitonin, but pathologic effects of abnormal
   calcitonin secretion per se are not generally
                    recognized.
 Endocrine Control of Calcium and
       Phosphate Homeostasis

 It would be very difficult to name a
    physiologic process that does not
    depend, in one way or another, on
                 calcium.
  critical to maintain blood calcium
  concentrations within a tight normal
                  range.

Deviations above or below the normal
range frequently lead to serious disease.
   Endocrine Control of Calcium and Phosphate Homeostasis

Hypocalcemia refers to low blood calcium concentration.
      Clinical signs of this disorder reflect increased
  neuromuscular excitability and include muscle spasms,
             tetany and cardiac dysfunction.

 Tetany -the involuntary contraction of muscle caused by
    diseases and other conditions that increase the action
                    potential frequency.
    Endocrine Control of Calcium and Phosphate Homeostasis

                                Tetany
                             Mechanism
   When the membrane potential is upset, for instance by low
    levels of ions (such as Ca++) in the blood (hypocalcemia),
                 neurons will depolarize too easily.
   In the case of hypocalcaemia, calcium ions are drawn away
 from their association with the voltage-gated sodium channels
     thus sensitizing them. The upset to membrane potential is
therefore caused by an influx of sodium to the cell, not directly
                        by the hypocalcaemia.
    As a result, too many action potentials are sent to muscles
                            causing spasm.
   Endocrine Control of Calcium and Phosphate Homeostasis

Hypocalcemia refers to low blood calcium concentration.
      Clinical signs of this disorder reflect increased
  neuromuscular excitability and include muscle spasms,
             tetany and cardiac dysfunction.

Hypercalcemia indicates a concentration of blood calcium
     higher than normal. The normal concentration of
  calcium and phosphate in blood and extracellular fluid
    is near the saturation point; elevations can lead to
   diffuse precipitation of calcium phosphate in tissues,
  leading to widespread organ dysfunction and damage.

Preventing hypercalcemia and hypocalcemia is largely the
         result of robust endocrine control systems.
      Body Distribution of Calcium and Phosphate

          3 major pools of calcium in the body:

Intracellular calcium: A large majority of calcium within
        cells is sequestered in mitochondria and ER.

Intracellular free calcium concentrations fluctuate greatly,
      from roughly 100 nM to greater than 1 uM, due to
   release from cellular stores or influx from extracellular
                              fluid.
    These fluctuations are integral to calcium's role in
    intracellular signaling, enzyme activation and muscle
                         contractions.
      Body Distribution of Calcium and Phosphate

          3 major pools of calcium in the body:

 Calcium in blood and extracellular fluid: Roughly half
   of the calcium in blood is bound to proteins. The
concentration of ionized calcium in this compartment is
 normally almost invariant at approximately 1 mM, or
  10,000 times the basal concentration of free calcium
 within cells. Also, the concentration of phosphorus in
    blood is essentially identical to that of calcium.
     Body Distribution of Calcium and Phosphate

        3 major pools of calcium in the body:




 Bone calcium: A vast majority of body
calcium is in bone. Within bone, 99% of the
calcium is tied up in the mineral phase, but
   the remaining 1% is in a pool that can
    rapidly exchange with extracellular
                  calcium.
 Endocrine Control of Calcium and Phosphate Homeostasis


  Fluxes of Calcium and Phosphate
Maintaining constant concentrations of
   calcium in blood requires frequent
  adjustments, which can be described
 as fluxes of calcium between blood and
        other body compartments.
Three organs participate in supplying
 calcium to blood and removing it from
          blood when necessary:
   Endocrine Control of Calcium and Phosphate Homeostasis

 Three organs participate in supplying calcium to blood
       and removing it from blood when necessary:

   The SI is the site where dietary calcium is absorbed.
   Importantly, efficient absorption of calcium in the SI is
    dependent on expression of a calcium-binding protein

Bone serves as a vast reservoir of calcium. Stimulating net
      resorption of bone mineral releases calcium and
  phosphate into blood, and suppressing this effect allows
              calcium to be deposited in bone.
  Endocrine Control of Calcium and Phosphate Homeostasis

             Fluxes of Calcium and Phosphate

The kidney is critically important in calcium
   homeostasis. Under normal blood calcium
     concentrations, almost all of the calcium
         that enters glomerular filtrate is
    reabsorbed from the tubular system back
   into blood, which preserves blood calcium
                       levels.
If tubular reabsorption of calcium decreases,
      calcium is lost by excretion into urine.
               Hormonal Control Systems

Maintaining normal blood calcium and phosphorus
       concentrations is managed through the
                  concerted action of
                  three hormones
 that control fluxes of calcium in and out of blood
                and extracellular fluid:
                   Hormonal Control Systems

   PTH serves to increase blood concentrations of calcium.
  Mechanistically, PTH preserves blood calcium by several major
                             effects:

Stimulates production of the biologically-active form of vitamin D
                         within the kidney.

Facilitates mobilization of calcium and phosphate from bone. To
    prevent detrimental increases in phosphate, PTH also has a
 potent effect on the kidney to eliminate phosphate (phosphaturic
                                effect).
 Maximizes tubular reabsorption of calcium within the kidney.

    This activity results in minimal losses of calcium in urine.
                 Hormonal Control Systems
Vitamin D acts also function to increase blood concentrations
     of calcium. It is generated through the activity of PTH
                         within the kidney.
 Far and away the most important effect of vitamin D is to
   facilitate absorption of calcium from the small intestine. In
      concert with PTH, vitamin D also enhances fluxes of
                       calcium out of bone.

 Calcitonin is a hormone that functions to reduce blood
                      calcium levels.
         Vitamin D (Cholecalciferol, Calcitriol)

Vitamin D is a steroid hormone that has long been known
      for its important role in regulating body levels of
  calcium and phosphorus, and in mineralization of bone.
   More recently, it has become clear that receptors for
  vitamin D are present in a wide variety of cells, and that
     this hormone has biologic effects which extend far
            beyond control of mineral metabolism.
           Structure and Synthesis-Vitamin D

The term vitamin D actually refers to a group
     of steroid molecules. Vitamin D3, also
  known as cholecalciferol is generated in the
      skin of animals when light energy is
                 absorbed by a
  precursor molecule 7-dehydrocholesterol.
              Structure and Synthesis-Vitamin D

Vitamin D is thus not a true vitamin, because individuals
    with adequate exposure to sunlight do not require
                 dietary supplementation.

There are dietary sources of vitamin D, including egg yolk,
               fish oil and a number of plants.

   The plant form of vitamin D is called vitamin D2 or
      ergosterol. However, natural diets typically do not
   contain adequate quantities of vitamin D, and exposure
    to sunlight or consumption of foodstuffs purposefully
   supplemented with vitamin D are necessary to prevent
                        deficiencies.
 Vitamin D, as either D3 or D2, does not have significant biological
                                activity.

 Rather, it must be metabolized within the body to the hormonally-
                              active form.
This transformation occurs in 2 steps, as depicted in the diagram on
                             the next slide

      Within the liver, cholecalciferal is hydroxylated
      to 25-hydroxycholecalciferol by the enzyme 25-
                          hydroxylase.


Within the kidney, 25-vitamin D serves as a substrate for
            1-alpha-hydroxylase, yielding 1,25-
 dihydroxycholecalciferol, the biologically active form of
                         vitamin D.
Each of the forms of vitamin D is hydrophobic and is
    transported in blood bound to carrier proteins.

The major carrier is called, appropriately, vitamin D-
                    binding protein.

The half-life of 25-hydroxycholecalciferol is several
 weeks, while that of 1,25-dihydroxycholecalciferol
                   is only a few hours.
         Control of Vitamin D Synthesis
 Hepatic synthesis of 25-hydroxycholecalciferol
    is only loosely regulated, and blood levels of
      this molecule largely reflect the amount of
     amount of vitamin D produced in the skin or
                       ingested.
In contrast, the activity of 1-alpha-hydroxylase
   in the kidney is tightly regulated and serves
    as the major control point in production of
    the active hormone. The major inducer of 1-
     alpha-hydroxylase is PTH: it is also induced
           by low blood levels of phosphate.
The Vitamin D Receptor and Mechanism of Action
The active form of vitamin D binds to intracellular
    receptors that then function as transcription
        factors to modulate gene expression.
Like steroid hormones and thyroid hormones, the
   vitamin D receptor has hormone-binding and
               DNA-binding domains.

  The vitamin D receptor forms a complex with
   another intracellular receptor, the retinoid-X
   receptor (RXR), and that heterodimer is what
                  binds to DNA.
In most cases studied, the effect is to activate
  transcription, but situations are also known
        in which vitamin D suppresses
                 transcription.

The vitamin D receptor binds several forms
    of cholecalciferol. Its affinity for 1,25-
  dihydroxycholecalciferol is roughly 1000
  times that for 25-hydroxycholecalciferol,
   which explains their relative biological
                   potencies.
     Physiological Effects of Vitamin D

  Vitamin D is well known as a
   hormone involved in mineral
   metabolism and bone growth.
  Its most dramatic effect is to
 facilitate intestinal absorption of
calcium, although it also stimulates
   absorption of phosphate and
          magnesium ions.
         Physiological Effects of Vitamin D


In the absence of vitamin D, dietary calcium
        is not absorbed at all efficiently.
  Vitamin D stimulates the expression of a
         number of proteins involved in
  transporting calcium from the lumen of the
  intestine, across the epithelial cells and into
    blood. The best-studied of these calcium
   transporters is calbindin, an intracellular
     protein that ferries calcium across the
             intestinal epithelial cell.
             Physiological Effects of Vitamin D

   Numerous effects of vitamin D on bone have been
                        demonstrated.
As a transcriptional regulator of bone matrix proteins, it
   induces the expression of osteocalcin and suppresses
                  synthesis of type I collagen.
 In cell culture, vitamin D stimulates differentiation of
   osteoclasts. However, studies of humans and animals
 with vitamin D deficiency or mutations in the vitamin D
   receptor suggest that these effects are perhaps not of
    major physiologic importance, and that the crucial
    effect of vitamin D on bone is to provide the proper
       balance of calcium and phosphorus to support
                        mineralization.
           Physiological Effects of Vitamin D



Vitamin D receptors are present in most if not
        all cells in the body. Additionally,
      experiments using cultured cells have
    demonstrated that vitamin D has potent
   effects on the growth and differentiation of
                many types of cells.
   Hence, vitamin D has physiologic effects
       much broader that a role in mineral
          homeostasis & bone function.
                     Disease States

Vitamin D deficiency: The classical manifestations of
vitamin D deficiency is rickets, which is seen in children
 and results in bony deformaties including bowed long
                          bones.
                          Disease States

Deficiency in adults leads to the disease osteomalacia. Both rickets
      and osteomalacia reflect impaired mineralization of newly
  synthesized bone matrix, and usually result from a combination
  of inadequate exposure to sunlight and decreased dietary intake
                              of vitamin D.
                  Disease States

Vitamin D deficiency or insufficiency occurs in
several other situations, which you might predict
         based on the synthetic pathway

 Genetic defects in the vitamin D receptor: a
    number of different mutations have been
  identified in humans that lead to hereditary
              vitamin D resistance.

Severe liver or kidney disease: this can interfere
with generation of the biologically-active form of
                   vitamin D.
             Disease States



Insufficient exposure to sunlight:

Elderly people that stay inside and
 have poor diets often have at least
       subclinical deficiency.
             Disease States


     Ironically, it appears that
hypovitaminosis D is very common
      in some of the most sunny
countries in the world - the cause of
 this problem is the cultural dictate
that women be heavily veiled when
           outside in public.
               Disease States


Sunscreens, especially those with SPF
ratings greater than 8, effectively block
   synthesis of vitamin D in the skin.
     However, people that use such
  sunscreens usually live in industrial
    countries where many foods are
   supplemented with vitamin D, and
vitamin D deficiency is thereby averted
           by dietary intake.
                  Disease States

  Vitamin D toxicity: Excessive exposure to
  sunlight does not lead to overproduction of
   vitamin D. Vitamin D toxicity is inevitably
      the result of overdosing on vitamin D
           supplements. Don't do this!
Ingestion of milligram quantities of vitamin D
     over periods of weeks of months can be
    severely toxic to humans and animals. In
    fact, baits laced with vitamin D are used
         very effectively as rodenticides.
                Disease States

 Both increased and decreased secretion of
   PTH are recognized as causes of serious
         disease in man and animals.
Excessive secretion of parathyroid hormone
             is seen in two forms:
       Primary hyperparathyroidism
 Is the result of parathyroid gland disease,
     most commonly due to a parathyroid
     tumor (adenoma) which secretes the
     hormone without proper regulation.

Common manifestations of this disorder are
     chronic elevations of blood calcium
   concentration (hypercalcemia), kidney
      stones and decalcification of bone.
  hypercalcemia is what usually signals the doctor that something
            may be wrong with the parathyroid glands.

In 85% of people with this disorder, a benign tumor (adenoma) has
     formed on one of the parathyroid glands, causing it to become
                              overactive.
 In most other cases, the excess hormone comes from two or more
      enlarged parathyroid glands, a condition called hyperplasia.
     Very rarely, hyperparathyroidism is caused by cancer of a
                           parathyroid gland.
 This excess PTH triggers the release of too much calcium into the
   bloodstream. The bones may lose calcium, and too much calcium
    may be absorbed from food. The levels of calcium may increase
   in the urine, causing kidney stones. PTH also acts to lower blood
    phosphorous levels by increasing excretion of phosphorus in the
                                 urine.
Why Are Calcium and Phosphorous So Important?

        Calcium is essential for good health.
   It plays an important role in bone and tooth
   development and in maintaining bone strength.
  It is also important in nerve transmission and
                 muscle contraction.

   Phosphorous is found in every body tissue.
  Combined with calcium, it gives strength and
        rigidity to your bones and teeth.
            What Causes Hyperparathyroidism?

      In most cases doctors don't know the cause.
The vast majority of cases occur in people with no family
                  history of the disorder.
 Only about 3-5 % of cases can be linked to an inherited
                         problem.
Familial endocrine neoplasia type I is one rare inherited
   syndrome that affects the parathyroids as well as the
             pancreas and the pituitary gland.

  Another rare genetic disorder, familial hypocalciuric
    hypercalcemia, is sometimes confused with typical
                  hyperparathyroidism.
     How Common Is Hyperparathyroidism?


  In the U.S., about 100,000 people develop the
  disorder each year. Women outnumber men by 2
          to 1, and risk increases with age.

In women 60 years and older, 2 out of 1,000 will get
              hyperparathyroidism.
      What Are the Symptoms of Hyperparathyroidism?

may have severe symptoms, subtle ones, or none at
                      all.

Increasingly, routine blood tests that screen for a
  wide range of conditions including high calcium
 levels are alerting doctors to people who, though
  symptom-free, have mild forms of the disorder.
       What Are the Symptoms of Hyperparathyroidism?

   When symptoms do appear, they are often mild and
   nonspecific, such as a feeling of weakness and fatigue,
      depression, or aches and pains. With more severe
    disease, a person may have a loss of appetite, nausea,
   vomiting, constipation, confusion or impaired thinking
      and memory, and increased thirst and urination.
      Patients may have thinning of the bones without
            symptoms, but with risk of fractures.

Increased calcium and phosphorous excretion in the urine
           may cause kidney stones. Patients with
    hyperparathyroidism may be more likely to develop
    peptic ulcers, high blood pressure, and pancreatitis.
         How Is Hyperparathyroidism Diagnosed?

Hyperparathyroidism is diagnosed when tests show
    that blood levels of calcium as well as PTH are
                        too high.
Other diseases can cause high blood calcium levels,
   but only in hyperparathyroidism is the elevated
         calcium the result of too much PTH.
 A blood test that accurately measures the amount
        of PTH has simplified the diagnosis of
                 hyperparathyroidism.
        How Is Hyperparathyroidism Diagnosed?

Once the diagnosis is established, other tests may
         be done to assess complications.

  Because high PTH levels can cause bones to
   weaken from calcium loss, a measurement of
 bone density may be done to assess bone loss and
   the risk of fractures. Abdominal radiographs
  may reveal the presence of kidney stones and a
       24-hour urine collection may provide
  information on kidney damage and the risk of
                  stone formation.
          How Is Hyperparathyroidism Treated?

  Surgery to remove the enlarged gland(s) is the only
 treatment for the disorder and cures it in 95 % of cases.

However, some patients who have mild disease may not
   need immediate treatment, according to a panel of
 experts convened by the National Institutes of Health in
                         1990.

Patients who are symptom-free, whose blood calcium is
 only slightly elevated, and whose kidneys and bones are
   normal, may wish to talk to their doctor about long-
                     term monitoring.
              How Is Hyperparathyroidism Treated?

In the panel's recommendation, monitoring would consist of clinical
       evaluation and measurement of calcium levels and kidney
   function every 6 months, annual abdominal x-ray, and bone mass
                    measurement after 1 to 2 years.

  If the disease shows no signs of worsening after 1 to 3 years, the
               interval between exams may be lengthened.

  If the patient and doctor choose long-term followup, the patient
       should try to drink lots of water, and get plenty of exercise.
      Immobilization and gastrointestinal illness with vomiting or
    diarrhea can cause calcium levels to rise, and if these conditions
   develop, patients with hyperparathyroidism should seek medical
                                 attention.
   Are There Any Complications Associated With Parathyroid
                           Surgery?

Surgery for hyperparathyroidism is highly successful with
    a low complication rate when performed by surgeons
                 experienced with this condition.
About 1% of patients undergoing surgery have damage to
   the nerves controlling the vocal cords, which can affect
                             speech.
1-5% of patients develop chronic low calcium levels, which
   may require treatment with calcium and/or vitamin D.
  The complication rate is slightly higher for hyperplasia
    than it is for adenoma since more extensive surgery is
                            needed.
    Are Parathyroid Imaging Tests Needed Before Surgery?
                          NOPE

 The NIH panel recommended against the use of
  expensive imaging tests to locate benign tumors
                before initial surgery.
Research shows that such tests do not improve the
    success rate of surgery, which is about 95 %
     when performed by experienced surgeons.
 Localization tests are useful in patients having a
    second operation for recurrent or persistent
                hyperparathyroidism.
                   Secondary hyperparathyroidism
is the situation where disease outside of the parathyroid gland leads
              to excessive secretion of parathyroid hormone.
  A common cause of this disorder is kidney disease - if the kidneys
      are unable to reabsorb calcium, blood calcium levels will fall,
        stimulating continual secretion of parathyroid hormone to
                 maintain normal calcium levels in blood.

 Secondary hyperparathyroidism can also result from inadequate
     nutrition - for example, diets that are deficient in calcium or
   vitamin D, or which contain excessive phosphorus (e.g. all meat
                         diets for carnivores).

       A prominent effect of secondary hyperparathyroidism is
       decalcification of bone, leading to pathologic fractures or
                            "rubber bones".
    There is no doubt that chronic secretion or
        continuous infusion of PTH leads to
    decalcification of bone and loss of bone mass.

However, in certain situations, treatment with PTH
  can actually stimulate an increase in bone mass
   and bone strength. This seemingly paradoxical
  effect occurs when the hormone is administered
  in pulses (e.g. by once daily injection), and such
  treatment appears to be an effective therapy for
            diseases such as osteoporosis.
   Inadequate production of parathyroid hormone –

   hypoparathyroidism - typically results in decreased
  concentrations of calcium and increased concentrations
                  of phosphorus in blood.

Common causes of this disorder include surgical removal
   of the parathyroid glands and disease processes that
         lead to destruction of parathyroid glands.
 The resulting hypocalcemia often leads to tetany and
     convulsions, and can be acutely life-threatening.
 Treatment focuses on restoring normal blood calcium
    concentrations by calcium infusions, oral calcium
            supplements and vitamin D therapy.
         Parathyroid Hormone-Related Protein
    Parathyroid hormone-related protein
    (PTHrP) is actually a family of protein
     hormones produced by most if not all
              tissues in the body.
  A segment of PTHrP is closely related to
    PTH, hence its name, but these peptides
   have a much broader spectrum of effects.
PTH and some of the PTHrP peptides bind to
  the same receptor, but PTHrP peptides also
        bind to several other receptors.
              Parathyroid Hormone-Related Protein
                              .

PTHRP was discovered as a protein secreted by certain tumors that
   caused hypercalcemia (elevated blood calcium levels) in affected
                                 patients.
 It was soon shown that the uncontrolled secretion of PTHRP by
       many tumor cells induces hypercalcemia by stimulating
   resorption of calcium from bone and suppressing calcium loss in
       urine, similar to what is seen with hyperparathyroidism.
   However, it quickly become apparent that PTHRP had many
                      activities not seen with PTH.
          Hormone Structures, Receptors and Sources
PTHrP is encoded by a single gene that is highly conserved among
     species. It should probably be described as a polyhormone,
       because a family of peptide hormones are generated by
  alternative splicing of the primary transcript and through use of
    alternative post-translational cleavage sites. To make matters
       even more complex, some cells appear to use alternative
   translational initiation codons to produce forms of the protein
  that are targeted either for secretion or nuclear localization. The
  figure below shows one of the characterized processing patterns
   of the PTHrP preprohormone, in this case yielding 3 bioactive
                               peptides.
          Parathyroid Hormone-Related Protein
  The diverse activities of PTHrP result not only from
 processing of the precursor into multiple hormones, but
   from use of multiple receptors. It is clear that amino-
 terminal peptides of PTHrP share a receptor with PTH,
  but they also bind to a type of receptor in some tissues
                    that does not bind PTH.
 Moreover, it is almost certain that the midregion and
     osteostatin peptides bind other, unique receptors.
In addition to the secreted forms, there is considerable
    evidence that a form of PTHrP is generated in some
     cells that is not secreted and, via nuclear targeting
     sequences, is translocated to the nucleus, where it
                    affects nuclear function.
         Parathyroid Hormone-Related Protein

  Moreover, it is almost certain that the midregion and
     osteostatin peptides bind other, unique receptors.
 In addition to the secreted forms, there is considerable
    evidence that a form of PTHrP is generated in some
     cells that is not secreted and, via nuclear targeting
     sequences, is translocated to the nucleus, where it
                    affects nuclear function.

The consequences of this "intracrine" mode of action are
    not yet well characterized, but may modulate such
      important activities as programmed cell death.
          Parathyroid Hormone-Related Protein

PTHrP is secreted from a large and diverse set of cells, and
            during both fetal and postnatal life.
 Among tissues known to secrete this hormone are several
    types of epithelium, mesenchyme, vascular smooth
            muscle and central nervous system.

   Although PTHrP is found in serum, a majority of its
       activity appears to reflect paracrine signaling.
   Physiologic Effects of Parathyroid Hormone-
                     Related Protein
  One thing to recognize about PTHrP is that its
     name is inadequate to describe its activities.
Like PTH, some of the effects of PTHrP result from
    its effects on transepithelial fluxes of calcium,
   but many of its actions have nothing to do with
                  calcium homeostasis.
     Most prominently, PTHrP peptides exert
       significant control over the proliferation,
     differentiation and death of many cell types.
    They also play a major role in development of
               several tissues and organs.
  Physiologic Effects of Parathyroid Hormone-Related
                            Protein
                              .
  Much of our understanding of the biologic effects of
   PTHrP comes from experiments with transgenic mice.
Mice with targeted deletions in the PTHrP gene (knockout
   mice), mice that overexpress PTHrP in specific tissues
    (transgenic mice), and crosses between knockout and
   transgenic mice have been critical in delineating many
                   effects of this hormone.
    Humans with mutations in the PTHrP gene or the
       parathyroid receptor have also played a role in
        confirming the activity of PTHrP. Some of the
      physiologic effects of PTHrP garnered from these
           studies are indicated on next few slides
 Physiologic Effects of Parathyroid Hormone-Related
                          Protein

Cartilage and Bone Development: Mice null for PTHrP
 gene die at birth, if not earlier. A developmental defect
  in proliferation and differentiation of cartilage. These
      and other types of studies indicate that PTHrP
     stimulates the proliferation of chondrocytes and
 suppresses their terminal differentiation. These effects
   of PTHrP appear due to interaction of the PTH-like
              peptide with the PTH receptor.
  Physiologic Effects of Parathyroid Hormone-Related
                           Protein
                            .
 Mammary Development and Lactation: The mammary glands of
  female mice with homozygous inactivation of the PTHrP gene fail
     to develop, except for the earliest stages. Development of the
    mammary gland depends upon a complex interaction between
      epithelial and mesenchymal cells that apparently requires
     PTHrP. In normal animals, mammary epithelial cells secrete
   large amounts of PTHrP, which suggests a role of this hormone
     in adapting maternal metabolism to the calcium demands of
                                lactation.

Placental Transfer of Calcium: The "midregion" peptide of PTHrP
    (see above) has been shown to control the normal maternal-to-
    fetal pumping of calcium across the placenta. In the absence of
             fetal PTHrP, this gradient is not established.
   Physiologic Effects of Parathyroid Hormone-Related
                            Protein
Smooth Muscle Functioning: PTHrP is secreted from smooth muscle
   usually in response to stretching. It acts to relax smooth muscle,
   thereby serving, among other things, as a vasodilating hormone.
   Transgenic mice that express PTHrP in vascular smooth muscle
        manifest hypotension. PTHrP may also have effects on
        contraction of muscle in the bladder, uterus and heart.
  Physiologic Effects of Parathyroid Hormone-Related
                           Protein

Other Effects: PTHrP is highly expressed in skin. Transgenic mice
  that overexpress PTHrP in skin show alopecia, and treatment of
 mice with a PTHrP antagonist leads to increased numbers of hair
   follicles and a shaggy appearance. Another interesting defect in
     PTHrP-null mice is that teeth develop normally, they fail to
        erupt. Finally, both PTHrP and its receptors are widely
  expressed in the CNS, and appear to influence neuronal survival
       by several mechanisms. It should be clear from the above
  examples that PTHrP hormones have profound effects on a large
      number of physiologic processes. Ongoing research on this
  polyhormone is certain to reveal additional effects in this already
                            complex system.