ENDO REPRO REVIEW

PRINCIPLES OF

ENDOCRINOLOGY

Modes of Action

Hypothalamus

• 2 general types of neurons constitute the endocrine hypothalamus:

• Magnocellular neurons: axons terminate in the posterior pituitary

• Releases Oxytocin and AVP

• Parvicellular neurons: axons terminate in the median eminence.

• Releases: Corticotropin-releasing hormone, Growth hormone–releasing hormone,

Thyrotropin-releasing hormone, Dopamine, Luteinizing hormone–releasing

hormone, and Somatostatin that control anterior pituitary function

Hypothalamic

Hormone

Anterior Pituitary

Hormone

Action Feedback

TRH TSH Stimulates release of T3 and T4

in the thyroid

T3 and T4, SRIF

GHRH GH Stimulate growth, lipolysis, amino

acid uptake in the muscle, IGF

production in the liver

IGF-1, SRIF

GNRH LH and FSH Women: Estrogen production,

ovulation

Men: testosterone,

spermatogenesis.

Estradiol, Testosterone,

Inhibin, Progesterone

Dopamine Inhibits PRL Tonic inhibition of prolactin (milk

production and secretion

N/A

SRIF Inhibits TSH and GH Sets basal GH secretory tone N/A

CRH ACTH Maintain metabolic homeostasis Cortisol

**AVP and Oxytocin are produced by the hypothalamus and released in the posterior pituitary

Positive Feedback

• Most endocrine loops are controlled by negative feedback, but rarely

release of a hormone will set off a cascade of effects that increase

release.

• E.g.

• Oxytocin and birth contractions

• Estrogen and LH surge at ovulation

Negative Feedback

• Long-loop feedback: Uses the hormone produced by the final target

gland to either stimulate (positive) or inhibit (negative) the secretion of

the tropic hormone by acting directly on the pituitary cell or

hypothalamus.

• Short-loop feedback: Modulation of hypothalmic releasing hormone

by the pituitary hormone.

• Ultrashort loop: Some releasing hormones modulate own release.

Testing of the Endocrine Axes:

• If you think that a hormone level is inappropriately HIGH:

• Check the levels are when it is supposed to be low

• Try to suppress it

• If you think that a hormone level is inappropriately LOW:

• Check the levels are when it is supposed to be high

• Try to stimulate it

Categories of Hormones

• Amino acid derived hormones:• Synthesis: Start off as larger precursors (prohormones or preprohormones) and

undergo proteolytic cleavages

• Storage: Large amounts can be stored in secretory granules; which allows the hormone to be released rapidly in response to a stimulus

• Action: Very fast, bind to receptors on plasma membranes of target cell and activate second messenger systems (including cAMP/PKA, Ca2+ dependent protein kinases, protein kinase C, and tyrosine kinases

• Recycling: After receptor-mediated endocytosis, are degraded by lysosomalproteases on the target tissues

• Cholesterol-derived hormones:• Synthesis: Derived from cholesterol ester in tissues

• Storage: Not stored in large amounts like peptide hormones; so slower response• Usually travel with a carrier protein in the blood

• Action: Slower (Half life= hours to days)• Genomic effect: Enters the cell through passive diffusion; captured and bound by receptor

proteins; complex dimerizes and binds to chromatin on specific DNA sequences.

• Recycling: Inactivated in the liver by oxidation, conjugation to sugars, and secreted into the bile

Sensitivity is the hormone concentration

that produces 50% of the maximal

response on that receptor.

It can be changed by changing the affinity

of the receptors for the hormone.

Hormone Resistance

HORMONE ASSAYS

TSH Test Algorithm

• The starting point in thyroid testing is measurement of the

serum concentration of thyroid stimulating hormone

(TSH).

• T4 and T3 inhibit TSH release

• High TSH Primary Hypothyroidism or Secondary Hyperthyroidism

• Low TSH Primary Hyperthyroidism or Secondary hypothyroidism

• Reflex testing: TSH measurement followed by (“reflex”)

measurement of free T4 only if the TSH concentration is outside

decision limits.

• Free T4 is used rather than total T4 measurement because the circulating

concentrations of thyroid-binding globulin (TBG) increase in several common

clinical scenarios (notably in pregnancy and with use of oral contraceptives)

TSH Immunometric Sandwich Assays

• An antibody against human TSH is attached to a solid support (such

as the walls of a test tube) and used to “capture” TSH molecules in a

sample of plasma or serum from the patient.

• A second antibody, which recognizes a different region of the TSH

molecule, is modified to contain a “label” or “tag”, such as a

radioactive atom.

• The second antibody binds to the captured TSH.

• Excess unbound second antibody is removed (washed away), and

thus the amount of “label” or “tag” that remains attached (via the

sandwich) to the solid support is proportional to the concentration of

TSH that is in the sample.

Calcium Test

• Investigation of parathyroid abnormalities begins with measurement of the concentration of calcium in plasma.

• Calcium is almost always measured spectrophotometrically by dye-binding assays. The tests are analytical accurate and they are widely used in developed countries.

• Hyperparathyroidism is routinely diagnosed before it is symptomatic

• The serum/plasma concentrations of calcium are held in a very narrow range within an individual Calcium is one of only a few common tests for which the analytical variation Is larger than the biological variation

• Albumin levels will effect calcium measurements and should be accounted for. Add 0.8 for every 1.0 decrease in Albumin.

• Free calcium can be measured by use of an ion-specific electrode

• Shifts of water into and out of the vascular space affects measurements.

PTH Test

• In patients with hypercalcemia of unknown etiology, the first

laboratory test is usually measurement of PTH in serum or

plasma to distinguish parathyroid from non-parathyroid

etiologies of the hypercalcemia.

• Primary hyperparathyroidism is the most common pathological cause of

hypercalcemia in ambulatory patients.

• If the hypercalcemia is caused by non-parathyroid conditions (such as cancer), the

PTH concentration will low because high calcium concentrations suppress the

secretion of PTH by the parathyroid gland.

• The reference interval (“normal range”) for PTH depends upon the

assay used to measure PTH.

• Also uses an immunometric sandwich assay

• Analytically sensitive and precise and avoid interference from the C-terminal

fragments that accumulate in renal failure.

Testosterone Test

• Immunoassay can be used in males

• Routine assays (immunoassays) are not adequate to measure

testosterone in women, children and hypogonadal males.

• Mass spectrometric assays are available for use in these settings and must be

specified by the ordering physician

• Men are often misdiagnosed a testosterone deficient because

samples were drawn in the afternoon. Collect samples in the morning.

HAMA Intereference

• Immunoassays are subject to interference from antibodies the

patient makes themselves (heterophilic antibodies).

• Human anti-mouse antibodies cause problems in many immunoassays

• Heterophilic antibodies that the patient makes bind to the capture

antibody and to the detection antibody making a sandwich. This leads

to false positives or false negatives.

• False positive if HAMA binds to both “capture AB” and “detection AB” and then get

detected.

• False negative if HAMA only binds to “detection AB” and gets washed away without

being detected.

• HAMAs aren’t filtered by kidneys → use urine hCG (instead of serum

hCG because there is no risk of HAMAs interfering with result)

Use urine hCG if there is any doubt about

the serum hCG.

Hemoglobin A1C

• Hemoglobin A1c is formed by the slow, non-enzymatic reaction of glucose with hemoglobin.• A1c concentrations thus reflect the average concentration of glucose in blood during

the life span of the red blood cells in the sample.

• A1c concentrations are most highly correlated with the average blood glucose concentration during the 2 months before the sample was obtained.

• A1c concentrations have been shown to reflect the adequacy of control of blood sugar in people with diabetes and to predict the rate of development of complications of diabetes such as retinopathy.

• A1c is usually measured (in whole blood) by either (1) high-performance ion-exchange liquid chromatography or (2) immunoassay.

• Misleading when lifespan of RBCs is altered or hemoglobin is not predominantly hemoglobin A Bleeding or Sickle Cell

For people without diabetes, the normal

range for the hemoglobin A1c test is

between 4% and 5.6%.

Hemoglobin A1c levels between 5.7%

and 6.4% indicate increased risk of

diabetes

Levels of 6.5% or higher indicate

diabetes.

Urine Albumin Testing

• Rate of excretion of albumin in the urine (albumin excretion rate, AER) is a continuous risk marker for cardiovascular events in patients with Diabetes.• The risk of cardiovascular events increases beginning at AERs far below the

concentrations detected by standard urine “dipsticks”.

• Measurement of these important low concentrations requires use of immunoassay techniques.

• Urine albumin excretion is usually best estimated by use of the albumin:creatinine ratio (ACR) in an untimed sample of urine.

• Unless proteinuria is already evident by standard dipstick, annual testing of albuminuria begin in pubertal or postpubertal individuals five years after diagnosis of type 1 diabetes and at the time of diagnosis of type 2 diabetes, regardless of treatment.

• The currently available “microalbumin” dipstick tests do not appear to be a suitable substitute for albumin and creatinine assays performed in an accredited laboratory.

Test Difference beyond normal variation

Calcium 5%

Free Thyroxine 15%

Glucose, fasting 15%

Hemoglobin A1C 7-20%

PTH 50-75%

TSH 60%

Urine Albumin 40%

Vitamin D Varies Seasonally

ELISA Methods• Direct ELISA:

• Antigens are immobilized and enzyme-conjugated primary antibodies are used to detect or quantify antigen concentration. PROS: minimum procedure; avoids cross-reactivity from secondary antibody.

• CONS: requires labeling of all primary antibodies - high cost; not every antibody is suitable for labeling.

• Indirect ELISA:• Primary antibodies are not labeled, but detected instead with enzyme-conjugated secondary antibodies that recognize the

primary antibodies.

• PROS: secondary antibodies are capable of signal amplification; many available secondary antibodies can be used for different assays; unlabeled primary antibodies retain maximum immunoreactivity.

• CONS: cross-reactivity may occur.

• Sandwich ELISA:• The antigen to be measured is bound between a layer of capture antibodies and a layer of detection antibodies. The two

antibodies must be very critically chosen to prevent cross-reactivity or competition of binding sites.

• PROS: sensitive, high specificity, antigen does not need to be purified prior to use.

• CONS: antigens must contain at least two antibody binding sites.

• Competitive ELISA:• The antigen of interest from the sample and purified immobilized antigen compete for binding to the capture antibody. A

decrease in signal when compared to assay wells with purified antigen alone indicates the presence of antigens in the sample.

• PROS: crude or impure samples may be used, high reproducibility.

• CONS: lower overall sensitivity and specificity.

Western Blot

• Detects Ab in serum/sample and Ag in patient sample

• Uses gel electrophoresis to separate proteins in a sample, usually on basis of molecular wt. • 1) Separated proteins are then transferred to a stable membrane where they’re

probed for reactivity w/ known Ab

• 2) Membrane may contain known samples which are probed by pt’s serum/sample

• Enzyme-conjugated 2ndary Ab reacts w/ substrate to form either colored precipitate (chromogenic) on membrane or light output (luminescence) that can be recorded on X-ray film

• Cons• Time consuming

• Radioactivity may be necessary

• Can look at multiple proteins at one time (HIV)

Immunofluorescence

• Characterization of protein expression in living cells

• Detection of Ag-Ab rxns in IFM is accomplished through labeled secondary Ab

(Ab is conjugated to a fluorescent molecule that will emit light when stim by a

certain wavelength of energy)

• Pros

• Rapid

• High sensitivity due to fluorescent detection

• Staining patterns are useful to choose 2nd level diagnostic tests

• Cons

• Specificity relies upon capture method-cellular antigens can be unreliable

• Cost associated w/ fluorescence microscopy equipment

PANCREATIC ISLETS

The pancreas contains two types of

glands: (1) exocrine glands, which secrete

digestive enzymes and HCO 3 − into the

intestinal lumen and (2) endocrine glands,

called the islets of Langerhans .

Insulin

• Insulin is made only in the β cells of the pancreatic islet.

• It is encoded by a single gene on the short arm of chromosome 11.

• Most of the insulin (∼60%) that is secreted into the portal blood is

removed in a first pass through the liver

• The change in the concentration of plasma glucose that occurs in

response to feeding or fasting is the main determinant of insulin

secretion.

Insulin Response in Normal Subjects

• Normal Subject receiving oral glucose:

• Modest increase in plasma [glucose] provoke marked increases in insulin and C-

peptide secretion and raises the plasma [insulin]

• Conversely, a decline in plasma [glucose] markedly lowers plasma [insulin]

• When the glucose is given intravenously rather than orally—but in a manner that

exactly reproduces the time course of plasma [glucose] in response to oral glucose

in the green curve—the time course of plasma [insulin] is lower and slower.

• The difference between the insulin responses in the solid and dashed red lines is

the result of the incretin effect of oral glucose ingestion.

• Normal subject receiving IV glucose

• If the glucose challenge is given intravenously, then the plasma [glucose] rises

much more rapidly than it does with an oral glucose load.

• Sensing a rapid rise in [glucose], the β cells first secrete some of their stores of

presynthesized insulin.

• Following this acute phase, the cells secrete both presynthesized and newly

manufactured insulin in the chronic phase, which lasts as long as the glucose

challenge.

Insulin Response in DM

• In a patient with type 1 diabetes, the same glucose load as that in A

causes plasma [glucose] to rise to a higher level and to remain there

longer.

• The reason is that plasma [insulin] rises very little in response to the

glucose challenge, so the tissues fail to dispose of the glucose load

as rapidly as normal.

• The diagnosis of diabetes is made if the plasma glucose is higher

than 200 mg/dL at the second hour.

Insulin Synthesis

• Transcription of the insulin gene product results in production of mRNA that encodes preproinsulin .

• Preproinsulin is cleaved to form proinsulin which consists of domains B, C, and A.

• Proteases cleave the proinsulinmolecule at two spots and thus excise the 31–amino acid C peptide.

• The resulting insulin molecule has two peptide chains, designated the A and B chains , that are joined by two disulfide linkages

C peptide has no established biological

action. However, because it is secreted in

a 1 : 1 molar ratio with insulin, it is a useful

marker for insulin secretion.

Insulin

Secretion• Glucose Cell Entry

• Glucose Metabolism

• Increased ATP

• Inhibits K+ Channel

• Depolarization

• Activates Ca2+ Channel

• Ca2+ influx and release

• Exocytosis of insulin

β -Adrenergic stimulation augments islet

insulin secretion, whereas α -adrenergic

stimulation inhibits it.

Parasympathetic stimulation through the

vagus nerve, which releases

acetylcholine, causes an increase in

insulin release.

Insulin Receptor

Insulin Binding• Once insulin is secreted into the portal blood, it first travels to the liver, where

more than half is bound and removed from the circulation.

• The insulin that escapes the liver is available to stimulate insulin-sensitive processes in other tissues.

• At each target tissue, the first action of insulin is to bind to a specific receptor tyrosine kinase on the plasma membrane, a heterotetramer, with two identical α chains and two identical β chains.

• The insulin receptor can phosphorylate both itself and other intracellular substrates at tyrosine residues.

• The targets of tyrosine phosphorylation include a family of cytosolic proteins known as insulin-receptor substrates (IRS - 1, IRS-2, IRS-3, and IRS-4) as well as Src homology C terminus ( SHC )

• The IRS proteins are docking proteins to which various downstream effector proteins bind and thus become activated.

Three Downstream Pathways

• 1. PI3K• PI3K phosphorylates a membrane lipid phosphatidylinositol 4,5-

bisphosphate (PIP 2 ) to form PIP 3

• Leads to major changes in glucose and protein metabolism.

• 2. Ras• Phosphorylated SHC and activated GRB2 trigger the Ras signaling

pathway, leading through MEK and MAP kinases.

• Leads to increased gene expression and growth

• 3. SH2 Containing Proteins• The third signaling pathway begins with the binding of SH2-containing

proteins—other than PI3K and GRB2, already discussed—to specific phosphotyrosine groups on either the insulin receptor or IRS proteins. This binding activates the SH2-containing protein.

• Leads to lipogenesis.

In a physiologically normal individual, the

glucose response to insulin is maximal

when only ∼5% of the receptors are

occupied; that is, the target cells have

many “spare” receptors for insulin.

Receptor Expression

• The number of insulin receptors present on a target cell is determined

by the balance among three factors:

• (1) Receptor synthesis

• (2) Endocytosis of receptors and recycling of receptors back to the cell surface

• (3) Endocytosis followed by degradation of receptors.

• Cells chronically exposed to high concentrations of insulin have fewer

receptors than do those exposed to lower concentrations.

• This is seen particularly with the GLUT4 receptor in muscles and

adipocytes of subjects with insulin resistance and Type II DM

GLUT-1, -5, and -2 are insulin-

independent.

GLUT-1: RBCs, brain, cornea

GLUT-5: Spermatocytes, GI tract

GLUT-2: B islet cells, liver, kidney, SI

Effect of Insulin on Hepatocytes• Increase Glycogen Synthesis

• Enhances transcription of glucokinase

• Diminishes activity of G6Pase

• Activates glycogen synthase

• Inhibits glycogen phosphorylase

• Increase Glycolysis and carbohydrate oxidation• Increases activity of glucokinase, phosphofructokinase, and pyruvate kinase

• Promotes glucose metabolism through the hexose monophosphate shunt

• Stimulates pyruvate dehydrogenase

• Inhibits the activity of PEPCK, FBPase and G6Pase

• Synthesis and storage of fats• Increases the activity of acetyl CoA carboxylase and fatty acid synthase

• Increases synthesis of apoproteins packaged with VLDL

• Increased levels of malonyl CoA inhibit CAT I

• Inhibition of fat oxidation shunts fatty acids to esterification as triglycerides and storage as VLDL or lipid droplets.

• Promotes protein synthesis and inhibits protein breakdown

In muscle, insulin promotes the uptake of

glucose and its storage as glycogen.

Effect of Insulin on Muscle Cells

• Glucose Uptake• Insulin promotes glucose uptake by recruiting GLUT4 transporters to the

plasma membrane.

• Glycogen Synthesis• Insulin promotes glycogen synthesis from glucose by enhancing the

transcription of hexokinase ( 1) and by activating glycogen synthase ( 2).

• Glycolysis• Insulin promotes glycolysis and carbohydrate oxidation by increasing the

activity of hexokinase ( 1), phosphofructokinase ( 3), and pyruvate dehydrogenase ( 4).

• Little or no gluconeogenesis occurs in muscle.

• Protein Synthesis• Insulin promotes protein synthesis ( 5) and inhibits protein breakdown ( 6).

The insulin-induced increase in glucose

utilization permits the muscle to diminish

fat utilization and store fatty acid as

triglycerides.

The stored triglycerides and glycogen are

major sources of energy that muscle can

use later when called on to exercise or

generate heat.

Effect of Insulin on Adipocytes

• Glucose Uptake• Insulin promotes glucose uptake by recruiting GLUT4 transporters to the plasma

membrane.

• Glycolysis• Insulin promotes glycolysis, leading to the formation of α-glycerol phosphate. Insulin

also promotes the conversion of pyruvate to fatty acids by stimulating pyruvate dehydrogenase ( 1) and acetyl CoA carboxylase ( 2).

• Formation of Triglycerides• Insulin promotes the esterification of α-glycerol phosphate with fatty acids to form

triglycerides, which the adipocyte stores in fat droplets.

• Insulin inhibits hormone-sensitive triglyceride lipase ( 3), which would otherwise break the triglycerides down into glycerol and fatty acids.

• Synthesis of LPL• Insulin promotes the synthesis of LPL in the adipocyte. The adipocyte then exports

this enzyme to the endothelial cell, where it breaks down the triglycerides contained in chylomicrons and VLDL, thus yielding fatty acids. These fatty acids then enter the adipocyte for esterification and storage in fat droplets as triglycerides.

Ingestion of protein and blood glucose

stimulate release of glucagon.

Glucagon's principal target tissue is the

liver.

Glucagon

• Glucagon is a 31–amino acid peptide synthesized by α cells in the islets of Langerhans.

• In humans, the glucagon gene is located on chromosome 2

• Although amino acids are the major secretagogues, the concentrations of amino acids required to provoke secretion of glucagon in vitro are higher than those generated in vivo suggesting that other neural or humoralfactors amplify the response in vivo, analogous to the effects of incretinon insulin secretion.

• Whereas glucose and several amino acids both stimulate insulin secretion by β cells, only amino acids stimulate glucagon secretion by α cells

• Glucose, somatostatin and insulin inhibit glucagon secretion.

Effect of Glucagon on the Liver

• Glucagon generally antagonizes the effects of insulin in the liver.

• Glucagon binds to a Gα s-coupled receptor, thereby activating the adenylyl cyclase/cAMP/PKA cascade

• Glyogenolysis• Glucagon promotes net glycogen breakdown. Glucagon inhibits glycogen synthesis by reducing

the activity of glucokinase ( 1) and glycogen synthase ( 2). However, glucagon promotes glycogen breakdown by activating glycogen phosphorylase ( 3) and G6Pase ( 4).

• Gluconeogenesis• Glucagon promotes net gluconeogenesis. The hormone inhibits glycolysis and carbohydrate

oxidation by reducing the activity glucokinase ( 1), phosphofructokinase ( 5), and pyruvate kinase ( 6). Glucagon also stimulates gluconeogenesis by increasing the transcription of PEPCK ( 9), FBPase ( 10), and G6Pase ( 4).

• Oxidation of Fats• Glucagon promotes the oxidation of fats. The hormone inhibits the activity of acetyl CoA

carboxylase ( 11). Glucagon indirectly stimulates fat oxidation because the decreased levels of malonyl CoA relieve the inhibition of malonyl CoA on CAT ( 13).

During fasting, the decline in insulin and

the increase in glucagon promote

ketogenesis; this process is of vital

importance to the CNS, which can use

keto acids but not fatty acids as fuel.

Somatostatin

• Somatostatin inhibits the secretion of multiple hormones, including

growth hormone, insulin, glucagon, gastrin, vasoactive intestinal

peptide (VIP), and thyroid-stimulating hormone.

• This property has led to therapeutic use of a long-acting somatostatin

analogue (octreotide) in some difficult-to-treat endocrine tumors,

including those that produce growth hormone (acromegaly), insulin

(insulinoma), serotonin (carcinoid)

• Recall that blood flows from the center of each islet—which is where

the bulk of the β cells are—to the periphery of the islet—which is

where the δ cells tend to be located. This spatial arrangement

minimizes the effect of somatostatin on the islet from which it is

secreted.

Hypoglycemia and Hyperglycemia

• Hypoglycemia• Early manifestations include palpitations, tachycardia, diaphoresis,

anxiety, hyperventilation, shakiness, weakness, hunger, and nausea.

• For prolonged or severe hypoglycemia, manifestations include confusion, unusual behavior, hallucinations, seizures, hypothermia, focal neurologic deficits, and coma.

• Hyperglycemia• Early manifestations include weakness, polyuria, polydipsia, altered

vision, weight loss, and mild dehydration.

• For prolonged or severe hyperglycemia (accompanied by metabolic acidosis or diabetic ketoacidosis), manifestations include Kussmaulhyperventilation (deep, rapid breathing), stupor, coma, hypotension, and cardiac arrhythmias.

Type I DM• IDDM is caused by an immune-mediated selective destruction of the β cells of the

pancreas.

• Insulin deficiency is severe, and glucose and ketone production by the liver occur at a rate that greatly exceeds the rate at which they are being used.

• Increased glucose and ketones provide an immense solute load to the kidney that causes osmotic diuresis.

• The keto acids that are produced are moderately strong organic acids (pK < 4.0), and their increased production causes severe metabolic acidosis.

• If these patients are not treated with insulin, the acidosis and dehydration lead to death from diabetic ketoacidosis .

• Treatment: Insulin• Chronic consequences of diabetes: blood vessel injury that can lead to blindness, kidney failure,

and accelerated atherosclerosis.

Type II DM• In type 2 diabetes, the cause of hyperglycemia is more complex.

• β Cells not only are present but also are frequently hyperplastic (at least early in the course of the disease)

• β cells do not respond normally to increases in plasma glucose by increasing insulin secretion.

• Patients with type 2 diabetes become resistant to the action of insulin.

• Metabolism of glucose in response to insulin and the secretion of insulin are abnormal in type 2 diabetes.

• The insulin resistance seen in individuals with type 2 diabetes appears to bring with it an increase in the prevalence of hypertension, obesity, and a specific dyslipidemia characterized by elevated triglycerides and a low high-density cholesterol.

• Because each component of this syndrome has adverse effects on blood vessels, these individuals are at particularly increased risk for early atherosclerosis.

Sulfonylurea Drugs

• The sulfonylureas enhance insulin secretion by β cells by binding to

the SUR subunits of K ATP channels, thereby decreasing the

likelihood that these channels will be open.

• This action enhances glucose-stimulated insulin secretion. By

increasing insulin secretion and decreasing blood glucose, the

sulfonylureas decrease the insulin resistance that is seen in these

patients.

• Unlike insulin, which must be injected, sulfonylureas can be taken

orally and are therefore preferred by many patients.

GLOBAL OVERVIEW OF

DIABETES

Metabolic Syndrome

• Type II Diabetes

• Hypercholesterolemia

• Hypertension

Diagnostic Testing

Test Normal Prediabetes Diabetes

A1C 4.5-5.7% 5.7-6.4% >6.5%

Fasting Plasma Glucose 70-99 mg/dL 100-125 mg/dL >126 mg/dL

2hr Plasma Glucose <140 mg/dL 140-199 mg/dL >200 mg/dL

Random Plasma Glucose >200 mg/dL

Pre-diabetes is associated with increased

CV risk.

Diabetes Epidemiology

• Type 1• Prevalence: By far the rarer of the two

• 0.47% of the US population has type 1 diabetes.

• Relatively weak genetic predisposition

• Associated with HLA DR3 and 4

• High insulin sensitivity

• Ketoacidosis is common

• Look for autoimmune disease

• Type 2• Prevalence: More common.

• 8.4% of the US population has type 2 diabetes.

• Relatively strong genetic predisposition, polygenic

• Ketoacidosis is rare

• Low insulin sensitivity, Insulin resistance

• Higher prevalence of systemic symptoms upon presentation

29.1 million people in the US have

diabetes. 5% of these have Type I.

Type I Diabetes Progression

Acute Diabetes Complications

Diabetic Ketoacidosis

Non-Ketotic Hyperosmolar Coma

Alcoholic Ketoacidosis

Lactic Acidosis

Hypoglycemia

Necrotizing Infections

Always give insulin for diabetic

ketoacidosis.

Chronic Diabetes Complications

• Microvascular• Retinopathy

• Leading cause of blindness in adults

• Mild, Moderate and Severe NPDR

• PDR

• Neuropathy• Most frequent cause of non-traumatic amputations

• Sensorimotor

• Autonomic

• GI neuropathy

• Genitourinary neuropathy

• Nephropathy• Leading cause of end stage renal failure

• Macrovascular• Coronary artery disease

• Peripheral vascular disease

• Cerebrovascular disease

• Sixth leading cause of death due to cardiovascular effects resulting in atherosclerosis, coronary artery disease, and stroke

Neurons and cells in eye can take up

sugar without insulin leading to

chronic complications.

Macrovascular Risk Factors

1. Testing should be considered in all adults who are overweight

(BMI ≥25 kg/m2*) and who have one or more additional risk factors:

Criteria for Testing

• Physical inactivity

• First-degree relative with diabetes

• High-risk race/ethnicity

• Women who delivered a baby weighing

>9 lb or were diagnosed with GDM

• Hypertension (≥140/90 mmHg or on

therapy for hypertension)

• HDL cholesterol level <35 mg/dL (0.90

mmol/L) and/or a triglyceride level >250

mg/dL (2.82 mmol/L)

• Women with polycystic ovarian

syndrome (PCOS)

• A1C ≥5.7%, IGT, or IFG on previous

testing

• Other clinical conditions associated with

insulin resistance (e.g., severe obesity,

acanthosis nigricans)

• History of CVD

Recommendations for Glycemic, Blood

Pressure and Lipid Control

A1C <7.0%*

Blood pressure <140/80 mmHg†

Lipids: LDL cholesterol

<100 mg/dL (<2.6 mmol/L)‡

Statin therapy for those with history of MI or age >40+ or other risk factors

Goals should be individualized based upon the patient.

Treatment

• CV

• Statins, sometimes other lipid agents, and good BP control are the

mainstay of CV risk reduction along with anti-platelet drugs for

appropriate patients.

• Glycemic control may or may not have a long term benefit on CV

health.

• Microvascular Complications

• Glycemic control is critical for prevention of microvascular

complications.

87

Defining Diabetic Dyslipidemia

Small, dense LDL particles

• LDL cholesterol levels same as patients without diabetes

• LDL particles more atherogenic

HDL cholesterol levels

Triglycerides

• VLDL-TG

DIABETES

PHARMACOLOGY

All Type I Diabetics should be treated with

insulin, due to the risk of progression to

diabetic ketoacidosis and death.

Insulin Resistance

• In pharmacological terms insulin resistance simply means that the

dose response curves for insulin in its target tissues are shifted to the

right.

• Thus, insulin is able to stimulate glucose uptake in insulin-resistant

tissues, but higher than normal concentrations of the hormone are

required.

Therapeutic overview

• Type 1 Diabetes Mellitus• Insulin

• Insulin plus thiazolidinedione (when insulin resistance is severe)

• Diet

• Exercise

• Type 2 Diabetes Mellitus• Diet and weight reduction

• Exercise

• Biguanides (eg.,Metformin)

• Oral hypoglycemic agent (sulfonylurea and meglitinide)

• Thiazolidinedione

• Amylin (eg. Pramlintide)

• Exendin-4 (eg. Exenatide)

• DPP-4 inhibitors (eg. Sitagliptin)

• α-glucosidase inhibitor (in combination with one of the above)

• Na-glucose cotransporter 2 (SGLT2) inhibitors

• Combination of metformin plus thiazolidinedione or sulfonylurea

• Insulin

A major problem in treating diabetes

mellitus is that control of blood glucose

cannot be achieved with a fixed

concentration of insulin.

General Strategy

• The general strategy is to inject a short-acting insulin preparation to

produce a peak in insulin that coincides with the rise in blood glucose

that follows a meal.

• An extended-action preparation is used to establish a baseline

concentration to prevent hyperglycemia between meals and during

the overnight period.

• Administering insulin with variable-rate infusion pumps provides a

more flexible means to control circulating insulin.

• There is evidence that tighter control of the blood glucose concentration is

possible with these devices, although hypoglycemic episodes are also more

frequent.

FACTORS AFFECTING INSULIN SECRETION

STIMULATE

NUTRIENTS

Glucose

Amino acids

Fatty acids

Ketone bodies

HORMONES

Secretin

Glucagon

Pancreozymin

Gastrin

Vasoactive intestinal peptide

Gastric inhibitory polypeptide

DRUGS

-Adrenergic agonists

Cholinergic agonists

Sulfonylureas and meglitinides

INHIBIT

Somatostatin

-Adrenergic agonists

Insulin Preparations

• Rapid Acting

• Lispro Insulin

• Aspart Insulin

• Short Acting

• Regular Insulin

• Intermediate Acting

• NPH

• Long Acting

• Glarginine

• Detemir

• Inhalable insulin

NPH cannot mix with long acting and

rapid acting insulin

NPH can mix with regular insulin

Pla

sm

a i

nsu

lin

levels

0 2 4 6 8 10 12 14 16 18 20 22 24

Regular (6–10 hours)

NPH (12–20 hours)

Detemir (12–20 hours)

Hours

Glargine (20-26 hours)

Aspart, Lispro, Glulisine (4–6 hours)

Insulin Side Effects

• Hypoglycemia Insulin Coma

• Be sure to distinguish insulin coma from diabetic coma!!!

• Temporary Visual Disturbances

• Local Fat Accumulation

• Allergic Reactions

Oral hypoglycemic agents refer to a

category of drugs that decrease blood

glucose levels by promoting release of

insulin from pancreatic β cells.

There are two classes: sulfonylureas and

meglitinides.

Sulfonylureas

• Drug Class• 1st gen: Tolbutamide, tolazamide, acetohexamide, and chlorpropamide

• 2nd gen: Glyburide, glipizide and glimepirmide

• MOA: • Sulfonylureas promote insulin release by binding to SUR1, a subunit of an

inwardly rectifying ATP-sensitive K+ channel. Binding inhibits channel conductance Partial depolarization Calcium release Insulin exocytosis

• Increase in insulin sensitivity over time

• Indications• Control of Type II DM (not for Type I)

• Side Effects• Hypoglycemia

• Weight Gain

• GI disturbance

• Allergic/dermatological problems

• Disulfiram reaction with alcohol

Second generation sulfonylureas are

effective at 10-100x lower concentration in

comparison to the 1st generation.

Meglitinides

• Repaglinide

• Netaglinide

• MOA• Meglitinides inhibit K+ conductance by KIR6.2. Although the

meglitinides bind a site distinct from that occupied by sulfonylureas, the end result is the same—membrane depolarization and insulin release.

• More rapid onsets and shorter durations of action than sulfonylureas.

• Indications: • Control of Type II Diabetes

• Side Effects:• Hypoglycemia

• Weight Gain

• GI disturbance

• Allergic/dermatological problems

• Drug interactions with Cytochrome p450

Antihyperglycemic agents refer to a

category of drugs that are capable of

lowering elevated levels of blood glucose,

but which have relatively little potential to

produce hypoglycemia.

Biguanides

• Metformin

• MOA:

• Inhibits hepatic glucose output, enhances insulin uptake in muscles

and fat, and inhibits glucose absorption from gut.

• Decreases blood glucose in Type II Diabetes and reduces long

term complications

• Does not cause weight gain

• Side Effects

• GI disturbance

• Lactic acidosis (In patients with renal dysfunction)

Thiazolidinediones

• Rosiglitazone, Pioglitazone

• MOA:

• The thiazolidinedione receptor is the ligand-activated transcription

factor, PPAR-γ. Binding of thiazolidinediones activates PPAR-γ,

thereby increasing the expression of mRNAs encoding enzymes

and proteins required for optimal insulin sensitivity.

• Increased insulin sensitivity in muscle, liver, and adipose tissue.

• Show synergy with sulfonylureas

• Side Effects:

• Weight Gain

• Fluid Retention

DDP-4 Inhibitors

• Sitagliptin

• MOA:

• Inhibit DPP-4 activity, which is the main enzyme for metabolizing

incretin such as GLP-1 and GIP. The major function of incretin is to

stimulate insulin synthesis and release and to suppress glucagon

secretion.

• Slows down incretin metabolism, to increase insulin

synthesis/release, and to decrease glucagon levels.

• Side Effects:

• Upper respiratory tract infection

• Sore throat

• Running nose

• Diarrhea

α-Glucosidase Inhibitors

• Acarbose and miglitol

• MOA:• Inhibit α-glucosidases, which are enzymes in the gastrointestinal tract

involved in the degradation of complex carbohydrates.

• By preventing the generation of monosaccharides, which are more readily absorbed than complex carbohydrates, the inhibitors blunt the rise in blood glucose concentrations after a meal.

• Delay glucose absorption and are without effect on fasting blood glucose.

• Most often used in combination with another antihyperglycemicagent or with an oral hypoglycemic agent.

• Side Effects:• Malabsorption Syndrome

• GI Upset

• Contraindications• IBD, colonic ulceration, partial intestinal obstruction

Combination Therapy

DIABETES MANAGEMENT

Type I vs. Type II Diabetes

Type I

• Type I

• Histology:

• B cell number in islets is decreased

• Islet leukocytic infiltrate

• Clinical Findings

• Rapid onset

• Polyuria, polydipsia, polyphagia, weight loss

• Ketoacidosis: hyperglycemia, coma

• Lactic acidosis from shock

• Treatment

• Insulin

Type II Diabetes• Histology

• Variable B cell numbers in islets

• Fibrotic ß-islet cells contain amyloid

• Clinical Findings• Insidious onset

• Recurrent blurry vision

• Recurrent infections

• Nephropathy, retinopathy, neuropathy, CAD

• Reactive hypoglycemia

• Increased risk for Alzheimer’s

• Hyperosmolar nonketotic coma

• Lactic acidosis

• Rarely see ketoacidosis

• Treatment• Weight loss

• Exercise

• Oral hypoglycemic agents

• May require insulin

• Sulfonylurea, which stimulate pancreatic insulin secretion

• Biguanide drugs (metformin)

Complications are most often seen in

Type II Diabetes at diagnosis but both

Type I and Type II have similar risk of

progression to complications

Treatment

• Treatment approaches • Patients glucose should be monitored either through self monitoring or A1C

• Medical Nutritional Therapy (MNT) is recommended for all people with T1, T2 and pre diabetes

• Type 1• Split dose insulin mixtures:

• Intensive insulin therapy: three injections = regular insulin + NPH (am); regular insulin (pm); NPH (bedtime)

• Long-acting insulin maintains basal level + insulin lispro covers each meal

• Insulin pump to allow continuous infusion throughout day

• Type 2• First try weight control, healthy eating, and increased physical activity

• Metformin is the preferred initial treatment.

• If insufficient control is attained, consider sulfonylurea, thiazolidinedione, DPP-4 inhibitor, GLP-1 receptor agonist, insulin

Type 1 DM you are going to likely start on

.5 units/ kg/ day, Type 2 DM you are likely

going to start on 1 unit/kg/day, and may

have to increase from there depending on

the level on insulin resistance.

Should screen annually for renal

ophthalmology and cardiovascular side

effects

Diabetic Ketoacidosis

• Clinical presentation• Air hunger (dyspnea)

• Kussmaul respirations (rapid/deep breathing)

• Acetone breath (fruity odor)

• Nausea/vomiting/ abdominal pain

• psychosis/ delirium

• dehydration

• Coma

• Laboratory findings• Hyperglycemia (300-600 mg/dL)

• Blood ketone levels

• Dilutional hyponatremia

• Hyperkalemia

• Volume depletion

• Osmotic diuresis

• Increased anion gap metabolic acidosis

Cardiovascular disease is the major

cause of morbidity and mortality in

Diabetes.

Lipid Profiles

• Chylomicron - synthesized in intestinal epithelium• Transports diet-derived TG in blood (“FEEDING” state)

• Apolipoprotein B48

• VLDL - synthesized in liver• Transports liver-synthesized TG in the blood

• This is what will increase in hypertriglyceridemia

• LDL - derived from intermediate density lipoprotein (IDL) by action of capillary lipoprotein lipase (CPL)• Transports cholesterol in blood

• IDL derived from VLDL via CPL

• This is what increases in hypercholesterolemia

• HDL - synthesized by liver and small intestine• Removes cholesterol from peripheral tissue (transports to liver), source of

apolipoproteins for other lipid particles

OBESITY

Obesity

BMI is not a perfect measure: very

muscular individuals will have a high BMI.

Waist Circumference

• Excess abdominal fat,

assessed by measurement

of waist circumference or

waist-to-hip ratio, is

independently associated

with higher risk for diabetes

mellitus and cardiovascular

disease.

• Measurement of the waist

circumference is a surrogate

for visceral adipose tissue

and should be performed in

the horizontal plane above

the iliac crest.

Obese patients only need a 5% decrease

in weight to have an impact on

complications and medical outcomes.

Complications

Complications

• Metabolic syndrome• Increased waist circumference >102 cm in men

• Low HDL cholesterol <40 mg/dL in men

• Hypertryglyceridemia >150 mg/dL

• Hypertension >140 sys or >85 dias

• Impaired fasting glucose or diabetes >100 mg/dL

• Diabetes Mellitus type 2

• Arthritis

• Obstructive sleep apnea

• Cardiovascular disease

• Hypertension

• Non-alcoholic steatohepatitis

• Cancer

Obesity as a disease

• In 2013, the American Medical Association voted to classify obesity as

a disease. This is still hotly debated.

• Pros

• Increased fat deposition in obesity affects every organ system within the body and is

associated with many bad things

• Cons

• By medicalizing obesity, pharmacotherapy and bariatric surgery become the

mainstays of treatment rather than appropriate lifestyle changes.

Obesity is the 2nd leading cause of

preventable death

Successful Weight Management

• National weight registry has found the following behaviors

to be consistently associated with successful weight

maintenance:

• Low fat diet

• Eating breakfast every day

• Regular weights

• Close monitoring of caloric intake

• Daily exercise

• Long-term relationship with a care provider

Lifestyle Management

• Obesity care involves attention to three essential elements of lifestyle:

dietary habits, physical activity, and behavior modification.

• Because obesity is fundamentally a disease of energy imbalance, all

patients must learn how and when energy is consumed (diet), how

and when energy is expended (physical activity), and how to

incorporate this information into their daily lives (behavior therapy).

• Lifestyle management has been shown to result in a modest (typically

3–5 kg) weight loss compared with no treatment or usual care.

The National Heart, Lung, and Blood

Institute (NHLBI) guidelines recommend

initiating treatment with a calorie deficit of

500–1000 kcal/d compared with the

patient's habitual diet. This reduction is

consistent with a goal of losing

approximately 1–2 lb per week.

Basal Metabolic Rate goes down after

weight loss, making it more difficult to

keep the weight off!

Weight Loss Drugs• Currently, there are three FDA approved drug therapies for long-term weightloss

• All of them are associated with moderate (5-10% of body weight) weight loss.

• Orlistat (tetrahydrolipostatin)

• MOA: Blocks pancreatic lipase and prevents absorption of lipids

• SE: Steatorrhea, reduced levels of lipid-soluble vitamins (ADEK), rare liver toxicity

• Phentermine/topirimate extended release

• MOA: Unknown, possible hypothalamic centers for satiety

• SE: Cleft lip/palate, metabolic acidosis, suicidal behavior

• Lorcaserin

• MOA: Lorcaserin is believed to activate serotonin 5-HT2C receptors, which stimulate pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus, leading to increased alpha-melanocortin stimulating hormone release at melanocortin-4 receptors and resulting in satiety and decreased food intake.

• SE: Dry mouth, constipation, serotonin syndrome/neuroleptic malignant syndrome

Bariatric Surgery

• Bariatric therapy/Surgery: Usually reserved for patients with severe

obesity (BMI>40) or BMI>35 with obesity related complications .

• Must demonstrate a willingness to make lifestyle changes and

undergo psychological evaluation.

• Not all insurance companies cover it, but the recent trend is towards

better coverage as data has shown a positive effect on obesity related

complications such as diabetes.

Classification of Bariatric Operations

I. Malabsorptivea) Jejunoileal bypass (JI Bypass)

II. Restrictivea) Vertical Banded Gastroplasty (VBG)b) Gastric Banding (Lap Band)c) Sleeve Gastrectomy

III. Combinationa) Roux-en-Y Gastric Bypass (RNYGBP)b) Biliopancreatic Diversion (BPD)c) Duodenal Switch

Gastric Bypass

Roux en Y Gastric Bypass

Sleeve Gastrectomy

Lap Gastric Band

Biliopancreatic Diversion

Risks

• Weight regain

• Risk for bleeding and infection.

• Risk for leak, band slip, anastamotic stenosis, small bowel obstruction, fistula, ulcers, blood clots in the lungs or legs, stretching of the pouch or esophagus, recurring vomiting and abdominal pain, inflammation of the gallbladder, and failure to lose weight.

• Abdominal hernias are the most common complications

• Patients are at an increased risk for nutritional deficiencies.

• 10-20% of patients who have weight loss operations require follow-up operations to correct complications.

• In the first year after surgery, frequent visits are scheduled to assess for weight, nutritional status, activity level, and evidence of complications.

Small bowel obstruction presents

differently in gastric bypass patients. Pain

is the most common presentation. Fluid

filled stomach can be seen on CT.

Malabsorptive Complications

• Protein calorie malnutrition

• Severe diarrhea

• Vitamin deficiencies

• Calcium malabsorption

• Oxalate stones

• Osteoporosis

• Bacterial overgrowth

• Iron deficiency anemia

• Death

Post Op Labs

Operative Mortality

(< 30 days)

Biliopancreatic diversion 1.1%

Gastric bypass* 0.3%

Purely restrictive procedures 0.1%

*Gastric Bypass has same risk as appendectomy

PITUITARY ANATOMY,

HISTOLOGY AND

PATHOLOGY

Development: Origins

• The pituitary gland is entirely ectodermal in origin but is composed of

2 functionally distinct structures that differ in embryologic

development and anatomy: the adenohypophysis (anterior pituitary)

and the neurohypophysis (posterior pituitary).

• The adenohypophysis develops from Rathke’s pouch, which is an

upward invagination of oral ectoderm from the roof of the stomodeum

(Oropharynx)

• The neurohypophysis develops from the infundibulum, which is a

downward extension of neural ectoderm from the floor of the

diencephalon.

Development: Progression

• The transition from Rathke’s pouch to the adenohypophysis involves

the formation of the pars distalis from the rapidly proliferating anterior

wall, the pars intermedia from the less active posterior wall, and the

pars tuberalis from an upward outgrowth of the anterior wall.

• The neurohypophysis develops from the differentiation of neural

ectoderm into the pars nervosa, the infundibular stem, and the

median eminence. The infundibular stem is surrounded by the pars

tuberalis.

The Developed Pituitary

• The fully developed pituitary gland weighs approximately 0.5 g.

• The adenohypophysis constitutes roughly 80% of the pituitary and

manufactures an array of peptide hormones.

• The release of these pituitary hormones is mediated by hypothalamic

neurohormones (parvocellular) that are secreted from the median eminence and

that reach the adenohypophysis via a portal venous system.

• The neurohypophysis is not glandular and does not synthesize hormones.

Instead, it is a site where axons (magnocellular) project from neuronal cell

bodies in the supraoptic and paraventricular nuclei of the hypothalamus.

• These hypothalamic cell bodies produce hormones that undergo axonal transport

through the pituitary stalk and into terminal axons within the neurohypophysis.

• The hormones are then stored and released directly into the systemic vasculature.

Adenohypophysis

• The pars distalis forms the majority of the adenohypophysis and

resembles a typical endocrine gland. Cords and clusters of cuboidal

secretory cells within the pars distalis contain hormones stored in

cytoplasmic granules that are released via exocytosis and taken up

by nearby sinusoidal capillaries. Histochemical staining of these

granules with pH-dependent dyes allows categorization of the cells

into acidophils, basophils, or chromophobes.

• The pars tuberalis is a thin, highly vascularized component of the

adenohypophysis that surrounds the infundibular stem. The principal

secretory cell type within this tissue is the gonadotrope, which

contains FSH and LH.

Neurohypophysis

• The pars nervosa of the neurohypophysis contains unmyelinated

axons that project from neuronal cell bodies in the hypothalamus.

• ADH and oxytocin are synthesized in the supraoptic and

paraventricular nuclei respectively of the hypothalamus and stored in

the axon terminals of these neurons.

• Pituicytes are specialized glial cells that support the axons and are

positively stained by GFAP .

• A network of capillaries surrounds the axon terminals and facilitates

the uptake of released hormones into the vasculature.

Microscopic Anatomy

• In general, acidophilic cells contain polypeptide hormones, basophilic cells contain glycoprotein hormones, and chromophobes have minimal to no hormone content.

• Acidophilic Cells: Somatotropes and Lactotropes• The most common cell type is the acidophilic somatotrope, which is

concentrated in the lateral regions of the adenohypophysis and secretes growth hormone (GH).

• Lactotropes are also acidophilic but are more scattered throughout the adenohypophysis and secrete prolactin (PRL).

• Basophilic Cells: Corticotropes, Thyrotropes, and Gonadotropes• Corticotropes are the most common

• Thyrotropes are among the least prevalent secretory cells of the pars distalis

Synthesis of Peptide Hormones

• 1. Preprohormone synthesis occurs in the endoplasmic reticulum and

is directed by a specific mRNA.

• 2. Signal peptides are cleaved producing a prohormone which is

transported to Golgi apparatus.

• 3. Additional peptide sequences are cleaved in the Golgi apparatus to

form the hormone which is packaged into secretory granules for

release.

Glycoproteins

• TSH, LH, and FSH

• Biosynthesis• Synthesis of TSH is stimulated by TRH and inhibited by Somatostatin, T3 and

T4 (IP3 mechanism)

• GnRH binds to its receptor on gonadotropes and initiates a signaling cascade that results in release of FSH and LH (IP3 mechanism)

• Structure: • Each has an α and β subunits, the α subunits are identical and the β subunits

are unique.

• Secretory Patterns:• TSH: pulsatile in response to TRH

• FSH and LH: pulsatile in response to GnRH

• Actions: • TSH: increases synthesis and secretion of T3 and T4 by follicular cells via

adenylate cyclase- cAMP mechanism, enhancing Thyroid Peroxidase action.

• Male: FSH acts on Sertoli cells to maintain spermatogenesis and LH acts on Leydig cells to stimulate testosterone synthesis

• Female: FSH and LH cause steroidogenesis in the ovarian follicle, follicular development, ovulation and luteinization

POMC Derivatives

• ACTH, MSH, β-lipotropin, β-endorphin

• Biosynthesis:• Secreted from corticotropes in the adenohypophysis in response to

hypothalamic CRH (cAMP increased POMC)

• POMC is cleaved by endopeptides to form ACTH

• Cortisol inhibits secretion of CRH and ACTH

• Structure:• Peptide

• Secretory Patterns:• Pulsatile, stimulated by CRH which is released in diurnal patterns

• Highest at 8am and 4pm, lowest at midnight

• Actions• ACTH: Increases steroid hormone synthesis in all zones of the adrenal cortex

and upregulates its own receptor to increase sensitivity

• MSH: Skin pigmentation

• β-endorphin: Endogenous opiate

• β-lipotropin: Stimulate production of melanin

Growth Hormone

• Biosynthesis• Synthesized in the somatotrophs of the anterior pituitary

• Structure• 191-amino acid straight-chain polypeptide with 2 internal disulfide bridges.

• Secretory Patterns• Secreted in a pulsatile pattern stimulated by GHRH.

• Secretion is increased by sleep, stress, puberty, exercise and hypoglycemia.

• Secretion is inhibited by somatostatin/somatemedins, obesity, hyperglycemia and pregnancy

• Actions• GH causes production of IGF in the liver

• Direct Actions

• Decreased glucose uptake, increased lipolysis, increased protein synthesis

• Indirect Actions (IGF)

• Increased protein synthesis and linear growth in chondrocytes

• Increased lean body mass and organ size

Prolactin

• Biosynthesis:• Synthesized in lactotropes of the anterior pituitary

• Structure• Structurally homologous with GH

• 198-amino acid straight-chain polypeptide with 3 disulfide bridges.

• Secretion• Tonically inhibited by dopamine secreted by the hypothalamus

• Interruption of this inhibition secretion

• Inhibits secretion of GnRH

• TRH increases secretion

• Estrogen, pregnancy, breast feeding, sleep and stress also enhance release.

• Somatostatin, Dopamine agonists, and Prolactin inhibit release

• Action• Major hormone responsible for lactogenesis

• Stimulates milk production, breast development

• Inhibits ovulation, inhibits spermatogenesis via GnRH inhibition

ADH

• Biosynthesis:• Originates in supraoptic nucleus of hypothalamus

• Stored as large precursor prohormone protein, endopeptidases cleave to form the bioactive hormone (ADH)

• Structure: • Peptide with 9 AA (homologous to oxytocin)

• Secretory patterns:• Stimuli: Increased plasma osmolality (tighter control), Low effective circulating

volume (blood loss, dehydration, etc)• Changes in osmolality are sensed by l osmoreceptors in the anterior ventral hypothalamus

• Changes in volume are sensed by arterial baroreceptors and atrial/renal stretch receptors

• Other stimuli: Nicotine, pain, stress, nausea

• Inhibitory: Ethanol, alpha agonists, ANP

• Actions:• Increased water reabsorption in kidney via aquaporin channels (DCT and CD)

• Maintains the interstitial medullary gradient through reabsorption of urea

• Constricts blood vessels to maintain BP

• May influence release of ACTH from anterior pituitary in stress

Oxytocin

• Biosynthesis:• Originates in paraventricular nuclei of hypothalamus

• Large precursor prohormone proteins (stored) → cleaved to active hormone

• Structure: • Peptide with 9 AA and disulfide bridge (homologous to ADH)

• Secretory patterns:• Sensory neurons in the uterus and nipple signal hypothalamus to increase

release of oxytocin

• Plasma levels of oxytocin increase as labor proceeds

• Peaks during cervical dilation and vaginal distension

• Actions:• Initiation of labor: dilation of the cervix in pregnancy results in oxytocin release

• Contraction of the uterine smooth muscle facilitates parturition

• Synthetic oxytocin can be administered for artificial induction of labor

• Milk Ejection• Oxytocin released upon nipple stimulation in postnatal period acts on myoepithelial

cells surrounding lactiferous ducts of the mammary glands → lactation

• Males: Enhances the transport of sperm & refilling of duct system

Pituitary Adenoma

• Benign neuroendocrine tumors derived from the adenohypophysis• Clinically functioning or nonfunctioning depending on endocrine syndrome

• Predominantly affect females

• Variety of histological patterns including diffuse, papillary, and trabecular

• Composed mostly of one cell: acidophilic, basophilic or chromophobe

• Grow expansively and do not have an acinar architecture

• Classified according to the hormone content (IHC analysis)

• Have significant morbidity and mortality

• Rarely progresses to pituitary carcinoma

• Radiological Classification• Microadenomas : Tumors <1cm in diameter

• Macroadenomas: Tumors >1cm in diameter• Macroadenomas show increased tendency toward suprasellar extension, gross

invasion, and recurrence

• Giant adenomas: Tumors > 4 cm may rarely occur

• The Hardy Classification is used in practice

Genetics

• Pituitary adenomas arise mostly in a sporadic manner and only a

minority of adenomas is part of hereditary or familial syndromes.

• Hereditary conditions associated with development of pituitary

adenomas include:

• 1. Multiple Endocrine Neoplasia Type 1 (MEN-1) : mutations of MEN-1 gene

• 2. Carney Complex: mutations of the tumor suppressor gene PRKAR1A

• 3. McCune-Albright syndrome: activating mutation of the gsp oncogene.

Clinically Functioning Adenomas• ACTH-secreting adenomas Cushing’s disease

• PRL-secreting adenomas Hyperprolactinemia

• GH-secreting adenomas Acromegaly/Gigantism

• GH/PRL-secreting adenomas Acromegaly & Hyperprolactinemia

• TSH-secreting adenomas Hyper/Hypothyroidism

Clinically Non-Functioning Adenomas

• Gonadotropins-secreting adenomas Hypogonadism (tumor-mass effect)

• Null-cell adenomas tumor mass-effect symptoms

• Silent adenomas tumor mass-effect symptoms

Clinical Classifications

MRI is the best method for the visualizing

hypothalamic-pituitary anatomy. Once a

pituitary adenoma is found, it is necessary

to determine the type of adenoma

(secretory vs. nonsecretory), pituitary

function, and whether there is any visual

field defect.

Sequelae of Macroadenomas

• Tumor Mass Effect

• Headache

• Bitemporal hemianopsia

• Disruption of hypophyseal blood supply

• Hypopituitarism except for prolactin (upregulation)

Left Right

Left

Homonymous

hemianopsia

Bitemporal

heteronymous

hemianopsia

Total right eye

blindness/

anopsia

Right nasal

hemianopsia

3

1

2

4

Diagnosis of Pituitary Adenoma

Histopathological analysis – H&E and Reticulin

Immunohistochemical analysis – Abs against pituitary

hormones ( ACTH, GH, PRL, βLH, βFSH, βTSH, α-

subunit of glycoproteins)

Electron microscopy (rarely)

Hypopituitarism

• Adrenal insufficiency• Fatigue, weight loss, hypoglycemia, low grade fever, hyponatremia

• Hypopigmentation (due to loss of MSH from anterior pituitary)

• Hypothyroidism• Weakness, leg cramps, low BMR, bradycardia

• Dry skin, cold intolerance (hypothermia)

• Loss of pubic/axillary hair

• GH deficiency• Decreased exercise tolerance, decreased strength, increase in fat,

decrease in bone density, decreased quality of life

• Hypogonadism• Women: Amenorrhea, vaginal atrophy, hot flashes, osteoporosis

• Men: Infertility, decreased energy, decreased libido

• Diabetes insipidus: VERY RARE ON PRESENTATION• Polydipsia, polyuria

Hypopituitarism occurs with loss of 75% of

the pituitary

The sequential loss of pituitary hormones

secondary to a mass effect is in the

following order: GH, LH, FSH, TSH,

ACTH,and prolactin.

Hypopituitarism vs. 1° Adrenal Insufficiency

• ACTH deficiency does not cause salt wasting, volume contraction,

and hyperkalemia because it does not result in clinically important

deficiency of aldosterone.

• ACTH deficiency does not result in hyperpigmentation.

• Both forms of adrenal insufficiency can cause hyponatremia.

• This abnormality is due to inappropriate secretion of antidiuretic hormone

(vasopressin) that is caused by cortisol (not aldosterone) deficiency

The two hormones you need to live are

thyroid hormone and cortisol.

Carniopharyngiomas

• Epidemiology:• Common cause of hypopituitarism

• 1–2% of all intracranial neoplasms

• 10% of the tumors of the sellar region

• Majority arise in childhood and adolescence (5-15 years)

• Second minor peak of incidence in adults (45-60 years)

• Presentation:• Children - Hormone abnormalities, growth retardation, and diabetes insipidus

• Adults - compressive effects including visual defects and hypopituitarism

• Diagnosis:• Calcified, solid and/or cystic lesions, with a complex lobular appearance.

• Adamantinomatous craniopharyngiomas and Papillary craniopharyngiomas

• Treatment• Surgery

Papillary Craniopharyngeoma

Sheehan Syndrome

• Cause of hypopituitarism

• Most common in developing world

• During pregnancy, there is a high demand for hormone and pituitary

doubles in size without increasing its blood supply.

• When a woman undergoes birth and loses a great deal of blood, the

pituitary can undergo infarction.

• Poor lactation, loss of pubic hair are important signs

Pituitary Apoplexy

• Etiology

• Sudden hemorrhage into the pituitary gland is called pituitary apoplexy.

• Hemorrhage often occurs into a pituitary adenoma.

• Presentation

• In its most dramatic presentation, apoplexy causes the sudden onset

of excruciating headache, diplopia due to pressure on the oculomotor

nerves, and hypopituitarism.

• All pituitary hormonal deficiencies can occur, but the sudden onset of

ACTH and cortisol deficiency can cause life-threatening hypotension.

• Treatment

• May regress spontaneously

• Emergency Surgery may be needed

• High dose glucocorticoids

Diagnosis of Hypopituitarism

• Corticotropin (ACTH) secretion: Measure serum cortisol at 8 to 9 AM on two or more occasions • <3 mcg/dL Cortisol deficiency and >15 mcg/dL Cortisol sufficiency

• Intermediate Metyrapone test (attempt to stimulate ACTH secretion)

• (TSH) secretion: Measure total T4 and T3 uptake or free T4. • Diagnosis is confirmed by low/normal TSH in the presence of low T4

• Gonadotropin secretion:• Gonadotropin deficiency is diagnosed in the presence of low or normal LH and

FSH levels in postmenopausal women, in reproductive-aged women with amenorrhea, or in men with low testosterone levels (<200 ng/dL)

• Growth hormone secretion:• GH deficiency is best evaluated by dynamic testing, including the insulin

tolerance test or GH-releasing hormone (RH)/arginine test (attempt to stimulate release)

Principles of Hormonal Testing

• If you think the hormone level is LOW:

• Measure it when it should be at its highest, or try to induce its

secretion

• If you think the hormone level is HIGH:

• Measure it when it should be at its lowest, or try to suppress its

secretion

Management of Hypopituitarism

• Lack of ACTH primarily causes cortisol deficiency. Treatment consists of the administration of hydrocortisone or other glucocorticoid in an amount and timing to mimic the normal pattern of cortisol secretion.

• TSH deficiency, which results in thyroxine (T4) deficiency, is treated with Levothyroxine. Keep T4 level in upper range and T3 at normal.

• In men with gonadotropin deficiency, testosterone replacement is indicated. Testosterone may be replaced by intramuscular injection, transdermal patch, or a gel.

• In women with gonadotropin deficiency, treatment depends upon the patient's goals. • Estradiol and progestin replacements Treats osteopenia

• Gonadotropin or pulsatile GnRH therapy Ovulation induction and fertility

Evaluate the ACTH before initiating

levothyroxine replacement, because

therapy in those with underlying adrenal

insufficiency can result in an

adrenocortical crisis secondary to an

increase in metabolic demand.

Posterior Pituitary Disorders• Diabetes Insipidus: ADH deficiency

• Central: no/reduced production of ADH, responsive to desmopressin

• Nephrogenic: resistance / lack of response to ADH, no response to desmopressin

• Presentation• Polydipsia, polyuria, hypernatremia, high serum osmolality, low urine osmolality, low urine SG

• Diagnosis: • Water deprivation test: no increase in urine osmolality

• Give desmopressin to distinguish the types of diabetes insipidus

• SIADH: Excess ADH• Excessive resorption of free water → hyponatremia

• Etiology:• Ectopic ADH production (small cell carcinoma), drug effect, infection, trauma, CNS disorder, pulmonary

infection

• Presentation• Cerebral edema and neurological dysfunction due to hyponatremia, low serum osmolality

• Diagnosis:• Hyponatremia

• Low serum osmolality (< 280 mOsm/kg)

• Low BUN

• Urine Osmolality > 100 mOsm/L

• Elevated urinary sodium level

Pituitary adenomas rarely present with

diabetes insipidus.

Management of Hyponatremia

• Hypovolemic → Isotonic saline

• Hypervolemic → Salt and fluid restriction, loop diuretics

• Normovolemic and asymptomatic → Free water restriction

• Overtly symptomatic hyponatremia → Hypertonic saline (3%)

• Do not exceed 1-2 mEq/hr

• Psychogenic polydipsia → Psychiatric and Pharmacologic RX

• Medications

• Demeclocycline - vasopressin antagonism

• Aquaretics - vasopressin receptor antagonists

• Lithium

Management of Hypernatremia

• Correct serum sodium at rate of 1-2 mEq/L/hr

• Replace 50% of calculated water deficit over first 12-24 hrs

• Replace remaining deficit over next 24 hrs

• Perform measurements of serum and urine electrolytes every 1-2 hrs

• Perform serial neuro exams and decrease rate of correction

• If chronic hypernatremia with no/mild sxs - correct at rate below 0.5

mEq/L/hr and a total of 8-10 mEq/L/hr

• If a volume deficit and hypernatremia are present → intravascular

volume restored with isotonic saline prior to free water admin

Hyperprolactinemia

• Etiology:• Prolactinomas are the most common type of pituitary adenoma

• Most common in women, peak incidence during childbearing years.

• Presentation:• Women of reproductive age present with amenorrhea, decreased libido, and

galactorrhea

• Prolactin inhibits GnRH which suppresses LH and FSH amenorrhea

• Men and postmenopausal women usually come to medical attention because of mass effect, such as headaches and visual field defects

• Diagnosis• Serum prolactin level above 100 μg/L Prolactinoma

• Rule out pregnancy, drugs, hypothyroidism, RF, cirrhosis, spinal cord lesions

• Treatment• Dopamine agonists (Bromocriptine and Cabergolin) decrease adenoma size,

restore normal prolactin level and reverse visual field defects

• Visual field defects associated with prolactinomas are not a neurosurgical emergency

• Surgery

Macroadenomas, particularly those with

suprasellar extension, and head trauma

may cause hyperprolactinemia unrelated

to prolactinoma due to stalk effect.

Acromegaly

• Etiology• The most common cause of acromegaly is a somatotroph (growth hormone-

secreting) adenoma of the anterior pituitary (99%)

• Effects due to high GH and IGF-1 or mass effect

• Presentation• Onset is insidious, and progression is usually slow

• Large tongue, deep voice, swollen hands/ feet, acral enlargement, coarse facial features, insulin resistance, HTN, CHF, arrhythmias, cardiomegaly, sleep apnea

• Cardiac Failure is the most common cause of death

• Risks• Increased risk of malignancy (premalignant adenomatous colon polyps and colon

cancer)

• Diagnosis• Elevated serum IGF-1

• Failure to suppress serum GH following oral glucose tolerance test

• Treatment• Surgery

• Medical: Octreotide, bromocriptine, pegvisomont

• Radiotherapy

Causes of Cushing’s Syndrome

• CS is a constellation of symptoms associated with prolonged exposure to abnormally high levels of free plasma glucocorticoids, secondary to multiple potential causes.

• Exogenous glucocorticoid intake is the most common cause of CS

• ACTH-Dependent Cushing’s Syndrome• Cushing’s disease (67%) – usually microadenomas

• Ectopic ACTH secretion (12%)

• Ectopic CRH secretion (<1%)

• ACTH-Independent Cushing’s Syndrome• Adrenal adenoma (10%)

• Adrenal carcinoma (8%)

• Micro- and macronodular adrenal hyperplasia (1%)

Cushing’s Disease

• Etiology: • MCC: ACTH secreting pituitary microadenoma

• Effects due to elevated ACTH and cortisol

• Clinical Presentation• Hypertension, weight gain, unexplained osteoporosis, proximal myopathy,

moon facies, wide purplish striae (>1 cm), immunosuppression, hyperglycemia, amennorhea, spontaneous bruising, depression

• Diagnosis• Screen by 24h urine free cortisol

• Dexamethasone suppression test

• Increased cortisol after low dose (no feedback)

• Midnight salivary cortisol

• ACTH/ 8AM cortisol to check for ACTH independent potential cause

• Treatment

• Surgical removal of tumor

• Inoperable or refractory cases: Radiotherapy or Ketoconazole

TSH Hypersecretion

• Etiology:• TSH-producing tumor - Less than 1% of all pituitary tumors

• Mean age at presentation = 40 years; slight female predominance

• Presentation• Hyperthyroidism & goiter → initial complaints

• Weight loss, heat intolerance, fatigue, heart racing, frequent loose stools, tremors, tachycardia,

• Followed by mass-effect manifestations

• Diagnosis• Most important biochemical feature = elevated T3 and T4 with elevated or

inappropriately normal TSH level

• May see MRI evidence of tumor later in disease course

• Treatment• Surgery is primary approach; radiation utilized for residual tumor;

• Somatostatin analogs (Octreotide) are effective to control excess TSH

• Beta blockers for uncontrolled HTN; anti-thyroid meds can be used for short periods before surgery

Gonadotropin Excess

• Etiology:• Gonadotrophin-producing tumor – 80-90% of clinically nonfunctioning tumors

• Presentation:• Often detected incidentally via MRI, gradual visual deficit arising from optic

chiasm compression, headache and hypopituitarism due to mass effect.

• Diagnosis• FSH, LH, and alpha-subunit concentrations may be low, normal or elevated

• Often not associated with specific endocrine symptoms

• Look for other hormonal abnormalities

• ICH staining and monomorphic cell population on biopsy

• Treatment• Transphenoidal surgery

• Radiotherapy

• Dopamine agonists have minimal efficacy

Evaluation of Pituitary Hormone Excess

• Prolactinoma: • Elevated PRL Pituitary MRI

• Somatotrope Adenoma: • Elevated IGF-1 and Elevated GH after OGTT Pituitary MRI

• Corticotrope Adenoma:• For Cushings:

• Elevated midnight salivary cortisol and Abnormal LDDST/CRH

• Normal/High ACTH Pituitary MRI and HHDST/CRH

• Low ACTH Adrenal CT

• Thyrotrope Adenoma• Elevated T3 and T4 with Normal/High TSH

• Gonadotrope Adenoma• FSH and LH may be high in functional tumors or low due to mass effect in

nonfunctional tumors

Sellar and Suprasellar Tumors

• 1. Tumors of the anterior pituitary: • Pituitary adenoma

• Pituitary carcinoma

• 2. Tumors of the posterior pituitary: • Pituicytoma

• Granular cell tumor

• Gangliocytoma

• 3. Tumors of non-pituitary origin: • Craniopharyngioma

• Meningioma

• Chordoma

• Langerhans cell histiocytosis

• Metastases

Pituitary Carcinoma

• Clinical features:• Less than 1% of all pituitary neoplasms.

• Characterized by craniospinal dissemination or systemic metastases.

• The majority are clinically functioning tumors

• Most common: PRL-secreting

• The initial course is often indistinguishable from benign pituitary adenoma

• An extended clinical course, often exhibiting multiple local recurrences, is then followed by metastatic dissemination.

• Histopathology and immunohistochemistry• Diagnosis dependent upon the demonstration of metastatic spread.

• Hypercellularity, nuclear and cellular pleomorphism, increased mitotic activity, necrosis, and dural/osseous invasion are commonly present but are not diagnostic of carcinoma.

• Pituitary carcinomas are immunopositive for neuroendocrine markers including synaptophysin and chromogranin A.

Pituicytoma

• Epidemiology:• Subtype low grade astrocytoma in the posterior pituitary

• Rare tumors seen in adults with male predominance

• Presentation:• Mass effect and Diabetes Insipidus

• Morphology and Histology:• Gross: Pituicytomas are grossly soft, tan lesions indistinguishable from

pituitary adenomas.

• Histology: Tumors are composed of elongate, piloid cells arranged in fascicles, in a pattern that resembles pilocytic astrocytoma.

• Tumors lack biphasic pattern and characteristic Rosenthal fibers and eosinophilic granular bodies seen in astrocytoma.

• Immunohistochemistry –• Pituicytomas do not show any immunoreactivity for neuroendocrine

markers including chromogranin or for pituitary hormones.

• The tumor cells are typically immunoreactive for glial markers including GFAP, vimentin and S-100 protein.

Tumors and Lesions of the Sellar Region

• Pituitary Adenoma 74 %

• Rathke’s cleft cyst (RCC) 5 %

• Craniopharyngioma 4 %

• Cysts other than RCC 2 %

• Pituitary Apoplexy 2 %

• Metastases 1 %

• Inflammatory lesions 1 %

• Miscellaneous 1 %

Primary intracranial tumors:

Gliomas > Meningiomas > Pituitary Adenomas

Treatment for Pituitary Tumors

• Surgery• 85% of pts with microadenomas achieve normal IGF-1 levels post-resection;

however success rate not nearly as good for macroadenomas

• Invasion into surrounding tissues often prevents a curative outcome

• Conventional Radiation therapy• GH levels fall by 50% in first 1-2 years and continue to decrease slowly

• Medical therapy often needed to bridge latency period until radiotherapy becomes effective

• Gamma knife • Advantage over conventional is largely limited to need for only a single dose

procedure; only good for small tumors

• Dopamine agonists • Dopamine stimulates GH release in normal individuals but paradoxically inhibits it in

subjects with GH secreting adenomas

• RARELY effective

• They are the DOC for prolactinomas.

• GH antagonists (Pegvisomant) • Blocks GH from activating GH receptors -- inhibits GH action (effective in GH

producing tumors)

About 10-20% of patients following

transsphenoidal surgery have syndrome

of inappropriate antidiuretic hormone

secretion which leads to polydipsia and

hyponatremia.

Patients with cortisol deficiency cannot

excrete a water load and therefore they

may present with similar symptoms.

Hormone Metabolic Effects

• Corticosteroids• Protein catabolism Muscle Wasting

• Lipolysis and Free FA Fat redistribution to central areas

• Hepatic Gluconeogenesis Diabetes

• Hepatic Glycogenolgysis Diabetes

• Decreased uptake of glucose in muscle Diabetes

• Growth Hormone• Protein anabolism Increased muscle and organ mass

• Lipolysis and FA oxidation

• Thyroid Hormone• Hepatic Gluconeogenesis (insulin response prevents hyperglycemia)

• Hepatic Glycogenolysis

• Protein catabolism Muscle wasting

• Lipolysis Weight loss

• Futile cycles of catabolism and anabolism comsume O2 and energy

Four hormones protect the body from

hypoglycemia: Glucagon, Epinephrine,

Growth Hormone and Cortisol

GROWTH DISORDERS

Growth Hormone and IGF

• Growth hormone (GH) stimulates IGF-1 production in the liver (for endocrine distribution) and various tissues (to act as a paracrine factor).

• GH travels to the liver bound to GH Binding Protein, then binds to the GH Receptor STAT5b transcription factor causes the release of IGF-I, IGF Binding Protein-3, and Acid Labile Subunit.

• These travel in a complex to tissue.

• Growth hormone (GH) can also stimulate IGF-I production in the tissues (to act as a paracrine factor).• IGF-I production in prechondrocytes stimulates clonal expansion of

early chondrocytes linear growth at the epiphyses

Factors Affecting Release

• Factors that Promote GH Secretion• GHRH

• Androgens

• Cortisol

• Hypoglycemia

• Thyroid hormones

• Arginine

• L-dopa

• Glucagon

• Factors that Inhibit GH Secretion• IGF-I (negative feedback)

• Somatostatin (from hypothalamus)

Dual Effector Model of Growth

Thyroid Hormone and Growth

• Effects:

• Increases GH release

• Potentiates local GH-stimulated IGF-1 production

• Increases response to IGF-1 in chondrocytes

• Increases other hormones that stimulate growth that act in paracrine

fashion: epidermal growth factor, nerve growth factor, erythropoietin

• Hypothyroidism: common cause of poor growth, Cretinism

• TH: Brain maturation, Basal metabolic rate, Bone Growth, Beta

adrenergic effects

Sex Hormones and Growth

• Testosterone:

• Stimulates chondrocyte proliferation, differentiation

• Increases local IGF-1 synthesis, IGF-Receptor expression

• Estrogen:

• Stimulates growth plate maturation

• Speeds fusion of epiphyses (ie closing of growth plates)

• Also increases mineralization of bone

Glucocorticoids and Growth

• Effects:

• Have a direct, inhibitory effect on growth plate

• Inhibit chondrocyte proliferation and hypertrophy

• Inhibit cartilage matrix synthesis

• Molecular mediators not known

• Basis of short stature in Cushings

• Bone age continues to progress despite growth suppression, so

growth potential is reduced

• Unlike GH deficiency, where bone age progression is “paused”

Epidermal growth factor, nerve growth

factor, platelet-derived growth factor, and

angiogenic and antiangiogenic factors are

stimulated by TH and cause bone growth.

Linear Growth Failure

• Linear growth failure: Refers to height that shows a non-linear

pattern

• Curve may be within the normal range but show low growth velocity, or

decreasing of the slope.

• A curve below the 5% may be “okay” (non-pathological) if the slope is constant

(steady growth) and above the 3%

• Failure-to-thrive: Refers to poor weight gain (bottom curve

decreasing slope) that usually precedes linear growth failure since,

during childhood, growth requires adequate nutrition.

Linear growth

failure

Poor weight gain

“Failure to thrive”

Constitutional Delay of Growth

• Constitutional delay of growth: • Physiologic delay of growth or a “late bloomer.”

• Delay of bone age can be seen, with the bones looking like a younger child’s bones, and having preserved growth potential.

• The growth pattern follows the bone age, not the chronological age.

• They often start puberty later, which gives them extra time to grow before hitting the pubertal growth spurt, and a chance at reaching a normal stature.

• Boys grow to bone age of 18 yrs

• Girls grow to bone age of 15 years

• Growth potential = height + time to epiphyseal fusion

• Not Pathologic: • Normal growth velocity, but may result in shorter final stature.

• Diagnosis of exclusion- must rule out other, pathological, causes (poor nutrition, chronic diseases, hormonal, etc.)

Never forget that bad measurements can

be a factor in changes in growth velocity.

Predicting Adult Height

• (Fathers Height + Mothers Height)/2

• Add 2.5” for a boy

• Subtract 2.5” for a girl

Poor weight gain precedes linear growth

failure. Poor nutrition poor growth.

Chronic Disease and Growth

• Mechanisms of growth failure with chronic disease:

• Cytokine effects at growth plate

• Crohn’s, Celiac Disease, Intestinal Parasites

• Suppression of growth factor production

• Poor nutrition (i appetite, i absorption)

• Cancer: chemotherapy effects

• In the developing world, chronic inflammation may be combined with

poor nutrition, which both impair linear growth.

Hormone Abnormalities: GH

• Accelerated growth• Growth hormone excess

• Caused by pituitary adenoma secreting GH

• Leads to gigantism

• Insufficient growth• Growth hormone deficiency

• Causes

• Pituitary development• Optic nerve hypoplasia

• Gene defects

• Brain injury/trauma

• Idiopathic/autoimmune

• GH Receptor, IGF-1 Receptor and STAT5b Mutations all present with similar growth pattern

• Presentation• Poor linear growth; weight gain often not affected.

Test IGF-1 (sensitive) and IGF- BP3

(specific) when assessing GH-IGF-1 axis.

GH release is pulsatile and not reliable as

an indicator

Hypothyroidism presents with a very

similar growth curve to GH deficiency.

Assess clinical history for signs and

symptoms of hypothyroidism.

Cushing’s Syndrome and Growth

• Overweight + growth failure

• Glucocorticoids have a direct

inhibitory effect on the growth plate

• Endogenous Cushing’s syndrome is

rare in childhood; consider:

• ACTH-secreting pituitary adenoma

• Adrenal adenoma

• Exogenous Cushing’s syndrome is

more common in childhood:• Glucocorticoid therapy for asthma or IBD

• Also causes decreased bone

mineral density

• 1st test: 24 hour urine cortisol

X

Obesity is common but

obesity + early growth

failure is not.

Early Puberty

• Sex hormones → Growth spurt

and bone fusion

• Early release of sex hormones

leads to early puberty

• Final height is lower because the

child had less time to grow before

fusion of growth plates.

Puberty: Growth spurt

and growth cessation

Genetics and Insufficient Growth• Turner’s syndrome

• Cause• Genetic abnormality caused by a single 23rd X Chromosome (45 XO phenotypic females)

• Reduced dosage of the SHOX gene, Short stature homeobox gene on X

• Presentation:• Wide neck, Square body build with a broad chest. High arched palate, Increased angle at the

elbow, Blunting of the fourth knuckle (i.e., fourth metacarpal)

• Heart disease• Coarctation of the aorta

• Bicuspid aortic valve

• Kidney problems• Horseshoe kidney

• Duplicated collecting system

• Gonadal dysgenesis

• Diagnosis • Karyotype

• Russell-Silver syndrome• Genetic cause of being small for gestational age

• Triangular face

• Clinodactyly

Differential Diagnosis

• Normal linear growth, poor weight gain

• Failure to thrive (can also present with poor linear growth later on)

• Poor linear growth, normal weight gain

• Growth hormone deficiency

• Hypothyroidism

• Poor linear growth, increased weight gain

• Cushing’s syndrome

• Low height, normal to low weight

• Turner’s syndrome

• Small for gestational age

• Russel Silver Syndrome

• Early leveling off of height curve, normal weight curve

• Early puberty (early growth spurt and growth cessation)

Diagnosis

• History and physical• Look for chronic diseases and information about birth

• Take accurate weight/height measurements

• Calculate the midparental height

• Assess bone age (in children older than 5 years)

• Labs:• Inflammatory diseases (Crohn’s, JIA, celiac disease)

• Hormones:

• Growth hormone• IGF-1 is sensitive, not specific for GH deficiency

• IGF-BP3 is specific for GH deficiency

• Hypothyroidism• Measure TSH levels and free T4 levels

• Cushing’s• 24 hour urine free cortisol

• Genetic Testing• Karyotyping

• Genetic testing

Bone age is best assessed after 5 years

of age.

Management

• Recombinant human growth hormone (hGH) • Administered SC on daily basis

• T1/2 ~20-30 min, peak GH at 2-6 h; peak IGF-1 at ~20 h

• Expensive (~$20,000/yr)

• FDA-approved indications:

• GH deficiency

• Genetic syndromes

• Turner Syndrome, SHOX deficiency

• Noonan’s Syndrome

• Prader-Willi Syndrome

• SGA children who remain <3rd %tile at 3 y.o.

• Idiopathic short stature (final predicted height <1.2%tile)

• Adverse Effects:

• Diabetes Mellitus, Antibody resistance requiring increased dosing

• Patients with GH deficiency usually respond quickly

• Patient without GH deficiency usually respond slowly

Management

• Recombinant IGF-1: mecasermin (Increlex)

• Administered SC twice daily

• T1/2 ~2 h

• Expensive (~$30,000/yr)

• Can produce hypoglycemia: requires lower dose initially

• FDA-approved indications:

• GH-receptor deficiency (Laron syndrome)

• IGF-1 deficiency (IGF-1 < 3 std dev below normal, height <3 std dev below normal)

Management: Acromegaly

• Octreotide• Analogue of somatostatin

• Inhibits GH release centrally, inhibits insulin peripherally

• Treatment of acromegally, gigantism from GH adenoma

• Administered SC three times daily

• Bromocriptine: • Dopamine agonist used to inhibit GH release

• Pegvisomant• GH analogue with poly-ethylene glycol moities

• Binds GH receptor dimerization, signaling

• Results in increased GH but decreased IGF-1

• Potential liver toxicity

• Administered SC

Treatment of children with idiopathic short

stature with Human Growth Hormone is

highly controversial.

ANATOMY AND HISTOLOGY

THYROID, PARATHYROID AND

ADRENAL

Classification of Hormones

• Amino Acid Derived• Proteins/Polypeptides:

• Insulin

• Calcitonin

• Parathyroid hormone (PTH)

• Small peptides: • Vasopressin (ADH)

• Biogenic Amines: • Norepinephrine (NE)

• Thyroid Hormone

• Cholesterol Derived• Steroid Hormones:

• Estrogen

• Testosterone

• Glucocorticoids

• Aldosterone

Thyroid

• Thyroid

• In front of the upper trachea enclosed w/in a connective tissue capsule

• One of the largest endocrine organs = ~20g in North American adults

• In pathologies like goiter the thyroid can reach >200g

Thyroid Structure

• The structural unit of the thyroid gland is the follicle that is formed by a sphere of cuboidal epithelial follicular cells surrounding a lumen that is filled with colloid.

• Each follicle is enmeshed in a capillary network.

• Parafollicular cells (C) are located between the follicles.

• The thyroid gland is unique in that it stores large amounts of inactive precursor hormone (thyroglobulin) in the extracellular lumen of the follicles (colloid).

Cells of the Thyroid

Biosynthesis of Thyroid Hormone

• Iodide Trapping: • Follicular cells concentrate iodide from the blood using Na+/I- cotransporter

• Thiocyanate and peroxidase competitively inhibit this transporter

• Oxidation: • Iodide is oxidized to iodine (Thyroid Peroxidase)

• Organification: • Thyroid peroxidase iodinates the newly synthesized thyroglobulin

• Coupling: • MIT and DIT then can dimerize to form MIT-DIT (T3) or DIT-DIT (T4)

• Cleavage: • (TSH) stimulates endocytosis of thyroglobulin and endocytic vesicles fuse w/

lysosomes that cleave thyroglobulin T3/T4 release

• Transport:• Free T4/T3 molecules cross the cell membrane and enter the blood where they

are bound by thyroxine-binding globulin

Most thyroid hormone is released as T4.

T3 is more bioactive than T4.

T3 is also derived from de-iodination of T4

by liver/kidney

TSH

• Stimulates iodine uptake,

thyroglobulin synthesis, and thyroid

peroxidase activity

• Follicular cells will appear either

flattened (large amount of

thyroglobulin stored in the lumen) or

cuboidal (active mobilization of

thyroglobulin)

• High T3 negatively feedbacks on

TSH secretion

Parathyroid

• There are usually four parathyroid glands (two upper and two lower)

embedded in the thyroid connective tissue capsule. This location is a

major concern during radiation therapy for thyroid disease.

• The parathyroid glands are formed by densely packed cords of cells

around a capillary network. They consist of two major cell types:

• 1. Principal or Chief Cell: secrete parathyroid hormone (PTH).

• 2. Oxyphilic cell: unknown function, increase in number with age and may

represent a degenerative form of chief cell.

PTH

• PTH is a peptide hormone that is synthesized as a pro-hormone and rapidly processed to mature PTH (1-84). There is a limited reserve of stored PTH. When released into the blood, PTH is rapidly metabolized into smaller fragments and has a half-life of less than 5 min. The PTH 1-34 fragment has full biological activity.

• PTH functions to maintain blood calcium levels in the normal range of 2.2-2.6 mM (or 9-10.5 mg/dL). PTH acts in collaboration with calcitonin released from parafollicular C cells and vitamin D.

• Calcium-sensing receptors on the cell surface of principal cells detect small changes in extracellular calcium to regulate the secretion of PTH. • Low calcium stimulates, while high calcium inhibits the secretion of PTH.

• PTH activates osteoclasts that function in bone resorption.

• PTH promotes renal calcium resorption and enhances vitamin D synthesis in the kidney proximal tubule.

• Vitamin D stimulates calcium uptake in the small intestine.

Cell Types

Chief Cell

Oxyphilic Cell

Oxyphil cells are thought to be degenerate chief cells

Adrenal Glands• The adrenal (or suprarenal) glands are triangular glands positioned above each kidney and

normally weigh about 4 g. Adrenal tissue can also develop at extra-adrenal sites in the body.

• The adrenals consist of two functionally distinct endocrine glands within a single capsule that are derived from different embryonic tissues.

• The cortex develops from coelomic mesoderm and can be functionally divided into three different regions of cells that synthesize the adrenal steroid hormones.

• The medulla is formed by invasion of the cortex by neural crest cells during development. It consists of cords of cells that secrete catecholamines.

• The adrenal glands are highly vascularized and receive arterial blood:

• 1. Directly from the branches off the aorta

• 2. From the suprarenal branches off the renal arteries

• 3. From branches off the phrenic arteries

• Form a subcapsular plexus that will both feed the sinusoidal network of the cortex (cortical arterioles) and dive straight down to supply the medulla (medullary arterioles).

• Glucocorticoids secreted by the cortex will travel to the medulla first and can regulate catecholamine release.

Hormone Production

• Zona Glomerulosa: mineralocorticoids (namely aldosterone)• Controlled by ACTH, volume status, Angiotensin II, and potassium

• Zona Fasciculata: glucocorticoids (namely cortisol)• Controlled by ACTH

• Zona Reticularis: renal androgens (DHEA)• Controlled by ACTH and cortical androgen stimulating hormone

• The adrenal cortex cells synthesize steroid hormones from cholesterol ester using enzymes found in the smooth endoplasmic reticulum and mitochondria.

• The release of steroid hormones is controlled by the rate of their synthesis.

• Common to all three zones are:• Extensive smooth ERs and a high proportion of mitochondria with amplified inner

membranes

• Lipids droplets containing cholesterol (to be used in steroid hormone formation)

• Accumulated lipofuscin

Adrenal Medulla• The adrenal medulla chromaffin cells synthesize the catecholamines epinephrine

or norepinephrine from the amino acid tyrosine.

• Catecholamine synthesis is regulated at the first enzymatic step, tyrosine hydroxylase. A proton pump (H+-ATPase) drives the accumulation of catecholamines in secretory granules. Large amounts of epinephrine or norepinephrine are stored in an extensive population of secretory granules.

• Other substances are packaged along with the catecholamines, including peptide hormones such as neuropeptide Y, substance P, and enkephalin, and the chromogranins that are involved in packaging of catecholamines.

• The chromaffin cells are modified postganglionic cells that are innervated by pre-ganglionic sympathetic neurons.

• The release of acetylcholine during the alarm (fright, fight or flight) response stimulates the release of catecholamines directly into the blood. They mimic the SNS to increase heart rate and blood flow, and stimulate the release of glucose from the liver.

THYROID IMAGING

Hypothyroidism

• Clinical Presentation:

• Slow BMR, Weight gain, Cognitive slowing, Fatigue, Cold Intolerance, Constipation, Bradycardia, Decreased CO, SOB, Increased vascular resistance, Hypercholesterolemia, Oligomenorrhea, Coarse hair, Puffy face, Cretinism (in infants)

• Causes

• Hashimoto’s Thyroiditis

• Iodide Deficiency

• Iatrogenic Hypothyroidism

• Thyroidectomy

• Radioablation

• Drugs: Lithium, Amiodarine, PTU, Methimazole

• Iodide Excess (Wolf-Chaikoff)

• Secondary (central) hypothyroidism (mass effect)

Hyperthyroidism

• Clinical Presentation• Palpitations, heat intolerance, nervousness, breathlessness, increased

bowel movements, fast heart rate, trembling hands, weight loss, muscle weakness

• Causes• Common

• Graves’ disease / Diffuse toxic hyperplasia

• Toxic multinodular goiter

• Toxic adenoma

• Subacute thyroiditis (De Quervain’s thyroiditis)

• Rare• Levothyroxine Overdose

• Hyperfunctioning thyroid carcinoma

• Struma ovarii: Thyroid tissue w/in ovarian teratoma)

• Trophoblastic disease (Hydatidiform mole and Choriocarcinoma)

• Thyrotrope pituitary adenoma

Gamma Imaging

• Gamma scan: Scintigraphy

• Used to image gamma radiation emitting radioisotopes.

• Procedure

• 1. Radioiodine is given orally

• 2. Uptake in thyroid is measured with a scintillator

• 3. Positive emission of gamma radiation indicates presence of iodine

• 4. In thyroid, the uptake of iodine indicates ongoing and excessive

synthesis of thyroid hormone

I-123

• The best radiotracer

• Tracer specific for thyroid

• Has NO beta radiation

• Has gamma ideal for imaging

• Truly physiologic

• Trapped and organified

• No risk of discordant nodule ambiguity

• Tc-99m has discordant nodule ambiguity

• I-131 has higher radiation exposure

• Tc-99m MIBI is not used in the thyroid

• (Heart, Parathyroid, and breast)

• Tc-99m pertechenate is used in pregnant women

Gamma Imaging Indications

• To relate the general structure of the thyroid gland to its function.

• Graves’ disease vs. toxic nodular goiter

• To determine the degree of function in a palpable nodule

• To locate ectopic thyroid tissue (i.e. lingual) or suspected

“thyroglossal duct cyst”.

• To assist in evaluation of congenital hypothyroidism.

• To evaluate a neck or substernal mass.

• To differentiate thyroiditis (i.e. subacute or silent) and factitious

hyperthyroidism from Graves’ disease and other forms of

hyperthyroidism.

Evaluation of Uptake

• Absence of iodine uptake • Thyroiditis

• Extrathyroidal source of thyroid hormone

• Iodine overload (Wolff-chaikoff effect)

• Levothyroxine treatment

• Renal Failure

• Cancer

• Cyst

• Increased uptake• Autonomous adenoma: focal

• Graves: diffuse

• Iodine deficiency

• TSH administration

• Rebound after stopping anti-thyroid medication

• Recovering subacute thyroiditis

• Trh secreted stimulators (gonadal and chorionic origin)

Interfering Factors

• Methimazole (thionamide) and PTU• Inhibits thyroid peroxidase → less thyroid hormone production → less

iodine uptake

• Thyroxine (T4)• Decreased need for T3/T4 synthesis → decreased iodine uptake

• Amiodarone• Amiodarone can act as thyroxine (T4) and downregulate T4/T3

synthesis

• Amiodarone induced thyrotoxicosis (AIT)• Type I – increased synthesis of thyroid hormone, mimics Graves

• Type II – increased release of T3 and T4 due to a destructive thyroiditis

• High Iodine diet (kelp!)• Wolff-Chaikoff effect

I-131 Therapy

• I-131 iodine: • Oral intake → circulation → actively transported to follicular cells

• Used for diagnosis and treatment of hyperthyroidism

• Emits short path length beta emissions which cause follicular cell damage and can be used for treatment

• Also emits gamma particles which can be used for diagnostic purposes

• Hyperthyroid vs Cancer: Fixed doses can be given for Graves’ disease or can individualize dose based on thyroid size and 24 hr radioiodine uptake. Higher doses for toxic adenoma and toxic multinodular goiter.

• Note on using I-131: Don’t use during a thyroid storm! Killing the cells can release more T3 and T4 and cause more problems. Instead, use a thionamide + non radioactive iodine

“Cold” Nodule

• Cold- tracer decreased compared to normal / rest of gland

• Indicates decreased functioning of that tissue

Differential diagnosis:

1. thyroid adenoma/goiter

2. thyroid carcinoma

3. thyroid cyst

4. others

THYROID ACTION,

REGULATION, PATHOLOGY,

PHARMACOLOGY

Thyroid Hormone Biosynthesis

• Iodide Trapping and Oxidation: • Iodide (I-) is “trapped” in the follicular epithelial cells via a Na+/I- symporter and then

transported into the follicular lumen where it is oxidized into iodine (I2) by TPO.

• Organification• I2 is then “organified” with thyroglobulin to form MIT (single iodine) or DIT (two) by

TPO.

• Coupling• MIT and DIT then can dimerize to form MIT-DIT (T3) or DIT-DIT (T4) with T4

“coupling” predominating.

• Cleavage• When the thyroid is stimulated, T3 and T4 are endocytosed, “cleaved” from

thyroglobulin by TPO

• Transport• T3 and T4 are released into circulation where they are mostly bound to TBG (70-

80%) and albumin/ transthyretin (20%) with minimal amounts free and available to bind to receptors (.03% of T4 and .3% of T3).

• Bioactivation• T3 is more active than T4. Tissues activate T4 to T3 using a 5’-monodeiodinase.

Iodide• Iodide (I-) is a nutritional requirement because it’s needed for thyroid

hormone synthesis. Iodine deficiency is a major cause of hypothyroidism worldwide.

• The current Dietary Reference Intake for non-pregnant, non-lactating adults is 150 μg/day

• Foods rich in iodide include seafood, seaweed, kelp, dairy products, and some vegetables. Iodized salt is another major source of iodide.

• Iodine is absorbed as iodide from the GI tract and is actively trapped by the thyroid gland and oxidized to iodine prior to incorporation into thyroglobulin.

• Most of the body’s iodine is located within in the thyroid.

• Circulating iodide is excreted primarily in the urine.

Wolff-Chaikoff Effect

• High amounts of iodide in the thyroid gland (excessive dietary intake, administration of iodinated contrast materials, or after therapeutic iodine):

• a) Inhibit further iodide uptake

• b) Inhibit iodination of thyroglobulin

• c) Inhibit the cAMP response after TSH receptor agonism

• d) Inhibit thyroidal release of T3 and T4

• e) Reduce gland size

• This autoregulatory phenomenon in response to high iodide concentrations is called the Wolff-Chaikoff effect.

• This effect is short-lived (1-2 weeks); down-regulation of the sodium/iodide symporter normally allows follicular cells to “escape”

TSH

• TSH is a glycoprotein released by the anterior pituitary. It binds its Gs-coupled TSH-receptor on the basolateral membrane of follicular epithelial cells and activates adenylyl cyclase. • Adenylyl cyclase generates cAMP which potentiates each step of thyroid hormone

synthesis.

• TSH receptor stimulation causes:• iodide uptake by follicular cells

• thyroglobulin synthesis

• thyroid peroxidase activity

• thyroid hormone release

• thyroid growth (hypertrophy)

• The main stimulus for TSH secretion is thyrotropin-releasing hormone (TRH) from the hypothalamus

• TSH release from the pituitary is strongly inhibited by T3 and T4 in a classical negative feedback arrangement. Chronic elevation of TSH causes hypertrophy of the thyroid gland

TSH secretion can be inhibited by

somatostatin, dopamine, and

glucocorticoids.

TSH is often inhibited in the setting of

significant illness, injury, infection, and

starvation.

Thyroid Hormone

• Synthesis occurs outside cell

• Very long plasma half life due to protein binding

• T4• All plasma T4 originates from the thyroid

• Some bioactivity.

• 35% of circulating T4 will become T3 and 40% will become rT3 T3

• T3• 20% of circulating T3 originates from the thyroid; the rest results from

peripheral conversion of T4 to T3 by 5’-monodeiodinases (Type I or Type II)

• Most bioactive. T3 is 4-10x more potent than T4.

• Increases BMR, metabolism, cardiac output, growth formation, and bone maturation. In the perinatal period, thyroid hormone is necessary for appropriate CNS development.

• rT3• Type III deiodinase is a 5-monodeiodinase that converts T4 to rT3.

• No bioactivity

TBG

• In the circulation most of T3 and T4 are bound to Thyroxine-binding

globulin (TBG)

• In Hepatic Failure, TBG levels decrease leading to a decrease in

total thyroid hormone levels, but normal levels of free hormone

• In Pregnancy, TBG levels increase, leading to an increase in total

thyroid hormone levels, but normal levels of free hormone.

Deiodinases and Breakdown

• Type I deiodinase is a 5’-monodeiodinase found in many peripheral

tissues, including liver, kidney, and thyroid (but NOT in the pituitary).

Type I deiodinase converts T4 to T3, and its major role appears to be

the maintenance of circulating levels of T3.

• Type II deiodinase is a 5’-monodeiodinase found primarily in the

pituitary, brain, thyroid, muscle, and placenta. Thus, type II deiodinase

regulates intracellular levels of T3 in key tissues such as the brain—

where maintenance of T3 levels is most critical.).

• Type III deiodinase is a widely distributed 5-monodeiodinase that

deactivates both T4 (by converting to rT3) and T3 (by converting to

T2). This enzyme is up-regulated in the brain in states of thyroid

hormone excess (a protective mechanism).

Binding and Transport• The tight binding of thyroid hormones to plasma proteins explains the very long

elimination half-lives of thyroid hormones (~ 7 days for T4, ~ 1 day for T3)

• Thyroxine-binding globulin (most important thyroid binding protein)

• α-globulin produced by the liver

• Has the highest affinity for thyroid hormone

• Each TBG molecule binds only one thyroid hormone molecule but it binds ~ 75% of all T4 and T3 in the plasma

• TBG has higher affinity for T4 than T3

• Thyroxine-binding prealbumin

• Tetramer that can bind two thyroid hormone molecules

• Affinity for thyroid hormone is intermediate

• Approximately 10% of circulating thyroid hormone is bound to TBPA.

• Albumin

• Binds only one thyroid hormone molecule, has low affinity for thyroid hormones

• 15% of circulating thyroid hormone is bound to albumin.

Actions: CNS

• CNS development and function: In the developing brain, thyroid hormone influences myelinization, proliferation of axons, and the growth of cerebral and cerebellar cortices.

• Hypothyroidism can be associated with a number of CNS symptoms including fatigue, lethargy, slowed mentation/speech.

• Conversely, thyroid hormone excess can lead to CNS symptoms such as anxiety, irritability, restlessness, and poor sleep.

• Untreated congenital hypothyroidism can lead to Cretinism• Caused by either maternal hypothyroidism in utero before the fetal thyroid is developed,

thyroid agenesis or infantile iodine deficiency

• Characterized by significant mental retardation, impaired motor development, ↑ weight, and short stature

• 6 P’s of Cretinism: Pot-bellied, Pale, Puffy-faced, Protruding umbilicus, Protuberant tongue, and Poor brain development

Actions: Bone

• Growth promotion and bone development: Thyroid hormones

stimulate growth hormone synthesis; bone ossification and linear

growth; and maturation of epiphysial bone centers.

• In adults, thyroid hormone excess is associated with increased bone

turnover/remodeling and can reduce bone mineral density.

Actions: Heart

• Cardiovascular: Thyroid hormones have inotropic (increased

forcefulness of cardiac contraction) and chronotropic (increased heart

rate) effects on heart.

• Increased Sympathetic NS activity and sensitivity: expression of Beta

1 adrenergic receptors.

• Together these lead to increased cardiac output.

• Thyroid hormone excess is associated with a higher risk of atrial

dysrhythmias (e.g., atrial fibrillation) and various other alterations of

cardiac function.

Actions: Metabolic

• Metabolic: A primary action of thyroid hormone is to increase cellular activity/metabolism. • Increase Na-K Pump activity

• Thyroid hormones enhance uncoupling protein production, which increases fatty acid oxidation with heat generation rather than ATP production.

• Thyroid hormones increase intestinal absorption of glucose; increase entry of glucose into fat and muscle cells; potentiate insulin-stimulated glucose uptake; and regulate hepatic triglyceride and cholesterol metabolism. • Increased hepatic gluconeogenesis

• Futile cycles of lipolysis and lipogenesis, protein catabolism and anabolism

• Overall, thyroid hormones favor depletion of glycogen and fat stores and protein catabolism.

Hypothyroidism

• Primary hypothyroidism reflects a reduced ability of the thyroid to produce adequate amounts of thyroid hormone despite appropriate stimulation by TSH.

• Central hypothyroidism results from insufficient TSH stimulation of the thyroid, as may occur with pituitary and/or hypothalamic disease.

• Overt hypothyroidism: TSH is high and free T4 is low. Such patients often have symptoms related to hypothyroidism.

• Subclinical hypothyroidism: TSH is high, but serum free T4 concentration remains within the reference range. This implies mild hypothyroidism. These patients may have few or no symptoms attributable to hypothyroidism. However, the designation of “subclinical hypothyroidism” is based on biochemical testing only—it does not necessarily imply the absence of symptoms that can occur with hypothyroidism.

Hypothyroidism

• Slow BMR

• Weight gain

• Cognitive slowing

• Fatigue

• Cold Intolerance

• Constipation

• Bradycardia, Decreased CO, SOB

• Increased vascular resistance

• Hypercholesterolemia

• Oligomenorrhea

• Coarse hair

• Cretinism (in infants)

Hashimoto’s Autoimmune Thyroiditis

• Epidemiology:• MCC of primary hypothyroidism in the U.S.

• Autoimmune disease involving cell- and antibody-mediated dysfunction and/or destruction of thyroid tissue.

• Genetic susceptibility:• Family history of autoimmune thyroid disease

• Genetic polymorphisms: HLA-DR5

• Both Turner and Down syndrome as well as Klinefelter’s syndrome

• Over 90% of pts have high anti-thyroglobulin and anti-TPO antibodies

• Presentation:• Presents early as hyperthyroidism with leakage of thyroid hormone from

destroyed hormones until follicle undergo fibrosis and hyperplasia causing hypothyroidism.

• Natural history: progressive cellular damage with fibrosis and thyroid failure.

• Histology• Chronic inflammation with formation of germinal centers

• Hurthle cells

• Risk for B Cell Lymphoma

Iatrogenic Hypthyroidism

• Total thyroidectomy will cause primary hypothyroidism and

hemithyroidectomy, usually accompanied by isthmusectomy, leads to

hypothyroidism in 20-30%

• Radioiodine therapy (I-131) for Graves’ disease can cause

hypothyroidism over months or years

• External radiation of the neck can also cause hypothyroidism, with

the effect being dose-dependent and gradual (ex: adolescent who got

radiation for acne)

• Drugs: Lithium, Methimazole and PTU, Amiodarone

Iodide Deficiency and Excess

• Iodide Deficiency

• Intake <150 mcg/day

• The most common cause of primary hypothyroidism worldwide

• Rare in North America where salt is iodized

• Especially common in some mountainous areas

• Iodide Excess

• Iodine excess can cause primary hypothyroidism by inhibiting iodide

organification and other steps along the thyroid hormone biosynthetic pathway

(i.e., the Wolff-Chaikoff effect).

• Normal subjects quickly “escape” from the Wolff-Chaikoff effect

• But patients with underlying thyroid abnormalities may not.

Secondary Hypoparathyroidism

• Etiology:

• Central (secondary) hypothyroidism: inadequate TSH stimulation

• Most often related to a large pituitary adenoma, which can compress pituitary

thyrotropes and/or interrupt hypothalamic-pituitary blood flow

• Presentation:

• Usually coexists with other pituitary hormone deficiencies but can be isolated

• Other causes

• TRH deficiency with resulting TSH deficiency may result from any disorder

causing damage to the hypothalamus or interrupting hypothalamic-pituitary

portal blood flow

• Rarely related to inactivating mutations of the TSH or TRH genes

Complications

• Hemorrhage

• Compression of jugular vein causing neck congestion

• Primary hypothyroidism

• Toxic nodular goiter:• one or more nodules become TSH-independent

• Hoarseness (compresses laryngeal nerve)

• Dyspnea (compresses trachea)

• Myxedema coma• Represents life-threatening hypothyroidism

• Follows a precipitating event (cold, infection, drugs like sedatives and opiates, trauma, stroke GI bleeding)

• Neurological signs (altered mental status, somnolence, coma) bradycardia, hypoventilation, and hypothermia are most common signs/symptoms

• Mortality of 20-50%

• Treat with Levothyroxine, supportive therapy and glucocorticoids

Diagnosis

• TSH

• High: Primary hypothyroidism

• Low: Central hypoparathyroidism

• Free T3 and T4

• Low

Management

• Levothyroxine

• Starting dose:• 1.6 mcg/kg lean body weight (50-200 mcg) once daily

• lower (25-75 mcg) in subclinical hypothyroidism

• 50 mcg/day in pts over 50

• 25 mcg/day in pts with cardiac problems

• Takes 4-6 weeks to reach steady state

• Repeat thyroid testing at 6 weeks

• Goal: reestablish euthyroidism

• Periodic testing every 6-12 months

• The following conditions may alter the approach to treatment:• 1. Pregnancy

• 2. Advanced Age

• 3. Heart Disease

• 4. Pituitary Disease

Levothyroxine

• Pharmacokinetics/Pharmacodynamics:• Once daily, oral

• ~7 day half life (just like endogenous T4)

• Best absorbed on empty stomach (before breakfast, before bed)

• Indications• Primary, secondary, tertiary hypothyroidism with confirmed thyroid dysfunction

• NOT in pts with hypothyroid sx but normal thyroid function

• TSH >10mIU/L **

• Side effects• Rare; occasional allergy to “inert” components (dyes)

• **Pregnant patients with subclinical hypothyroidism should be routinely treated with levothyroxine.

• Since T4 can hasten cortisol metabolism, administration of levothyroxine to patients with untreated adrenal insufficiency can potentially precipitate adrenal crisis.

Thyrotoxicosis

• Thyrotoxicosis” refers to a state in which circulating thyroid hormone

concentrations are excessive for the body’s needs.

• “Hyperthyroidism” specifically refers to thyrotoxicosis related to

excessive synthesis and secretion of thyroid hormone by thyroid

tissue.

• Thyrotoxicosis is usually related to one of four primary mechanisms:

• (1) Inappropriate stimulation of the thyroid by trophic factors

• (2) Constitutive activation of thyroid hormone synthesis/secretion leading to

autonomous release of excess thyroid hormone

• (3) Passive release of thyroid hormone following thyroid injury

• (4) Extra-thyroidal sources of excessive thyroid hormone

Hyperthyroidism

• Weight loss

• Heat Intolerance and sweating

• Increased cardiac output

• Arrhythmia

• Tremor, Anxiey, Insomnia

• Staring gaze with lid lag

• Diarrhea with malabsorption

• Oligomenorrhea

• Bone resorption with hypercalcemia

• Decreased muscle mass and weakness

Graves Disease

• Epidemiology:• MCC hyperthyroidism overall

• Autoimmune antibodies against TSH receptor stimulate thyroid hormone synthesis/release and thyroid gland growth

• Presentation:• Hyperthyroidism

• Goiter

• Exopthalmos and pretibial myxedema• Due to GAGs released upon antibody stimulation

• Histology and Morphology:• Histology: Follicular hyperplasia, reduced follicular colloid, and patchy

lymphocytic infiltration.

• Scalloping of the colloid can be seen.

• Gross: Diffusely enlarged with no palpable nodules

• Labs• Increased free T3 and T4

• Low TSH

• Hypocholesterolemia, and Hyperglycemia

Multinodular Goiter

• Etiology:

• Enlarged thyroid gland with multiple nodules

• Toxic goiter: Nodules release T3 and T4 w/out TSH stimulation

• Autonomy derived from activating somatic mutations of TSH receptor genes

and/or activating mutations of the Gsa protein gene.

• Prevalence increases with age and in the presence of iodine deficiency.

• Presentation

• Toxic nodules and multinodular goiters usually grow very slowly (over years

and decades), so these symptoms almost always have an insidious onset.

• Hyperthyroidism is generally slowly progressive.

• Patients may develop obstructive symptoms related to the size and position of

the goiter and/or nodule(s). Such symptoms can include neck fullness, a sense

of choking, dysphagia, dyspnea, and cough.

• Labs

• High T3, T4, low TSH

Thyroiditis will cause a transient

thyrotoxicosis.

Thyroiditis

• Subacute thyroiditis (DeQuervain’s) is a viral or post-viral inflammatory phenomenon, usually characterized by constitutional symptoms (fever, malaise), an exquisitely tender thyroid, and mild, diffuse thyroid enlargement.

• Painless thyroiditis accounts for 5-10% of thyrotoxicosis and is felt to reflect a robust autoimmune insult to the thyroid. A typical presentation is symptoms of mild hyperthyroidism for less than two months, with no thyroid pain/tenderness and little or no thyroid enlargement.

• Postpartum thyroiditis is basically painless thyroiditis that occurs within a year of parturition. This may be related to a postpartum rebound of immune activity. Compared to painless thyroiditis, women with postpartum thyroiditis are more likely to have high serum antithyroid antibodies and more likely to develop permanent hypothyroidism

Indications for biochemical testing include

symptoms/signs consistent with

thyrotoxicosis, the presence of potential

complications of long-term

hyperthyroidism (e.g., atrial fibrillation,

osteoporosis), and nodular thyroid

disease.

Diagnosis

• Primary hyperthyroidism: low TSH with normal to high free T4/T3

• Central hyperthyroidism: normal to high TSH with high free T4/ T3

• Thyroid hormone resistance: high TSH with high free T4/T3

• TSH is the most sensitive single test for thyrotoxicosis.

Radioiodine Scintigraphy

• These radioisotopes are trapped by thyroid follicular cells (and organified into thyroglobulin in the case of 123I) and will emit gamma (γ) rays that can be detected by a gamma scintillation counter.

• A normal or high radioiodine uptake in the setting of thyrotoxicosis indicates ongoing and excessive synthesis of thyroid hormone. • Graves’ disease

• Toxic multinodular goiter

• Toxic (solitary) adenoma.

• Absence (or near absence) of radioiodine uptake in the setting of thyrotoxicosis usually indicates thyroiditis (inflammation and damage of thyroid tissue with release of preformed hormone)

I123 Radioiodide Scans

Thyroid ultrasound is indicated in nodular

disease.

Diagnostic Algorithm

• Get a TSH level, then T4• if TSH is High, Measure T4

• Low T4 → Primary hypothyroidism

• High T4 → TSH-secreting adenoma

• if TSH is Normal, Measure T4• High → Partial thyroid hormone resistance

• if TSH is Low, Measure T4• Low T4 → Secondary hypothyroidism

• High T4 → Primary hyperthyroidism

• High T4 with low iodine uptake and low thyroglobulin Exogenous ingestion

• Other Tests• Anti-TSHR antibody levels → Graves’

• Serum thyroglobulin levels

• Scintillography

• Ultrasound with thyroid nodules

Management Overview• Thionamides

• Indications• Control before definitive therapy

• Pregnancy

• Contraindications• High Transaminases

• Adverse reactions

• Radioablation• Indications

• Definitive Therapy

• Contraindications• Pregnancy or lactation

• Thyroid Cancer

• Grave’s Opthalmopathy

• Low Iodine Uptake

• Surgery• Indications

• Definitive therapy

• Large goiter, compressive sx

• Thyroid cancer

• Contraindications• Comorbidities

• Previous neck surgery/RXR

Management: I131 vs I123

• I-123:• Primary use is for visualization through gamma scintillography

• Planar images are obtained 3-24 hrs after ingestion and the uptake is reported as an estimated 24-hour radioiodine uptake (normal uptake is 5-30%)

• Half-life: 13 hours

• Radiation burden to the thyroid is far less than I-131

• No therapeutic value (gamma ray radiation is not effective for therapy)

• I-131:• Primary use is for treatment of Graves’ disease and thyroid cancer

• 90% of radioactive emission are beta rays which cause cell death

• Can reduce size of goiter in Graves’ disease, toxic adenomas, and “hot nodules” in a nodular goiter

• Half-life: 8 days

• Dosing:

• Higher doses for Toxic Adenoma or Multinodular Goiter than Grave’s Disease

Radioablation

• MOA: • Causes acute thyroid follicular cell damage by emission of short path length (1-

2mm) beta-emissions.

• Indications• Indicated if a one year course of beta blockers and thionamides does not work

• Contraindications• Pregnancy and breastfeeding

• Moderate to severe active disease

• May actually worsen Graves’ ophthalmopathy

• Coexisting thyroid cancer or reasonable suspicion of thyroid cancer

• Desire for pregnancy w/in 4-6 mos

• Advantages• Reduces size of goiter

• Disadvantages• May worsen Graves’ ophthalmopathy by inducing hypothyroidism

• Cannot/should not be used w/ thionamides

• May take months (6-18 weeks) to induce hypothyroidism

Glucocorticoids may prevent worsening of

Grave’s Opthalmopathy with use of

radioablation.

Management: Medical

• Beta Blockers• Relieve beta adrenergic symptoms of hyperthyroidism

• Thionamides• Inhibit thyroid peroxidase (can affect scintigraphy)

• Preferred for Grave’s Disease due to chance of remission

• Methimazole• Methimazole is preferable to PTU because of its more rapid reduction of

thyroid hormone concentrations, lower likelihood of adverse effects

• Pancreatitis, aplastic anemia, vasculitis

• PTU• Preferred in pregnancy and thyroid storm (can inhibit T4 T3)

• Agranulocytosis, hepatic necrosis

• Assess thyroid at 4-8 weeks and then every 3 months

• Adverse effects• Rash, arthralgias, arthritis, GI, fever, NSAIDs for painful thyroiditis

Surgery

Hemithyroidectomy is indicated for

unilateral toxic adenoma.

For all other causes a total/near-total

thyroidectomy is recommended.

Reliable hypothyroidism.

Indications for Surgery

• Local compressive symptoms (upper airway obstruction)

• Very large goiters (≥ 80 grams)

• Low radioiodine uptake in a patient needing definitive therapy

• Documented thyroid cancer (nodules likely to be thyroid cancer)

• Coexisting hyperparathyroidism requiring surgery

• Need for rapid and definitive reversal of hyperthyroidism.

• Surgery could be the only viable option for (a) patients failing both

thionamides and radioiodine and (b) pregnant women with both

marked fully hyperthyroidism and thionamide intolerance.

• Contraindications: Comorbidities, previous neck surgery or radiation,

pregnancy, no access to skilled surgeon.

Thyroid Storm

• Severe life-threatening thyrotoxicosis

• Occurs after an acute event in patients with hyperthyroidism precipitates decompensation

• Death from arrhythmia, heart failure, and hyperthermia are common.

• Manifestations:• Cardiovascular—marked tachycardia, atrial fibrillation, congestive heart failure

• CNS—agitation, delirium, psychosis, stupor, coma

• GI system—vomiting, diarrhea, jaundice, hepatic failure

• Marked hyperpyrexia (high-fever) also common (~104-106° F)

• Treatment: • ICU support

• Thionamides at high doses (PTU favored)

• Non-radioactive iodine

• High dose corticosteroids reduce T4 to T3 conversion and address any potential concomitant adrenal insufficiency

• Beta-blockers

THYROID NODULES

Thyroid Congenital Anomalies

• Most congenital abnormalities develop secondary to migration problems during embryogenesis.

• Thyroid tissue may remain along the path of the migrating thyroid.

• Lingual thyroid: When it is left at the base of the tongue, it is called.

• Thyroglossal duct cyst: Glandular tissue left between the tongue and thyroid gland can often become cystic.• These lesions often present when they become acutely infected.

• Cysts may be lined by a columnar or even squamous epithelium.

• Surrounding fibrosis and inflammation may focally contain thyroid follicles.

• Congenital hypothyroidism: Rarely, there is complete absence of the thyroid gland. This occurs more frequently in parts of the world where iodine deficiency is common. • Untreated developmental abnormalities and severe mental retardation.

• Other causes of congenital hypothyroidism include enzyme deficiencies and defects of the TSH receptor.

Thyroid Hyperplasia• Hyperplasia is defined as the non-neoplastic, non-inflammatory enlargement of

the thyroid gland. Although “goiter” simply means “neck mass”, it is most commonly used for patients with noticeable thyroid enlargement secondary to hyperplasia.

• Hyperplasia can result in markedly enlarged thyroid glands and may appear either diffuse or nodular.

• Histologically, it is characterized by enlarged follicles that vary greatly in size with abundant intermixed fibrosis, calcification and hemorrhage.

• The disease is much more common in parts of the world where people have a low dietary intake of iodine and is more common in women.

• Most commonly results from compensatory hypertrophy due to iodine deficiency• Patients often still euthyroid!

• Present due to mass

• Female to male; 8 to 1

The most common reason for a single

thyroid nodule is hyperplasia

Papillary Carcinoma

• Epidemiology:• The most common malignancy of the thyroid gland. Excellent Prognosis!

• More common in women and may present at any age.

• Risk factors include previous irradiation, thyroiditis, hyperplasia, iodine excess and genetic mutations (FAP, Cowden).

• Somatic mutations- MAP KINASE activation (RET/PTC translocation, BRAF, RAS)

• Presentation• Papillary carcinoma may present as a single thyroid mass but can be multifocal

and may even present with lymph node metastases.

• Even with lymph node metastases, patients rarely die from this disease.

• Histology and Morphology:• Grossly, a white, firm and gritty mass can be identified.

• Histologically, numerous branching papillae with fibrovascular cores and follicle formation.

• The tumor is not defined by its architecture

• Papillary carcinoma is instead defined by nuclear features• Nuclear enlargement, overlap, central clearing (orphan Annie eyes), nuclear

pseudoinclusions, and grooves all considered diagnostic features.

Follicular Adenoma

• Epidemiology

• Benign neoplasm with follicular architecture

• Most common neoplasm of the thyroid

• Women: Men; 7:1

• Presentation

• Presents as solitary mass in 4th to 5th decade

• Histology and Morphology

• Grossly:

• Lesions are usually single and well-defined, surrounded by a capsule.

• They have a fleshy appearance and are usually less than 5 cm in size.

• Microscopically:

• Neoplasms are composed of uniformly sized microfollicles

• Vascular invasion and extra-capsular extension should not be seen.

Follicular Carcinoma

• Epidemiology:

• Uncommon, <15% of thyroid malignancy

• Follicular patterned carcinoma without papillary formations or

nuclear features of papillary carcinoma

• Minimally invasive or widely invasive

• Minimally Invasive- 3% develop metastases

• Focal angio-invasion or capsular penetration

• Widely Invasive – 50% develop metastases

• Tumor spreads hematogenously (bone and lung) and do not usually

involve the lymph nodes

• Nuclear features of papillary carcinoma should not be present!

Anaplastic Carcinoma

• Epidemiology:

• <10% of thyroid cancer

• Develop in pre-existing papillary or follicular carcinoma in older

individuals

• Large, invade adjacent vital structures.

• Universally fatal (6 mo)

• Histology:

• Tumors are, by definition, anaplastic.

• Composed of sheets of very large, markedly atypical cells and may

be hard to identify as epithelial in nature.

Medullary Carcinoma

• Epidemiology• 5% of thyroid carcinoma

• Arises from C-cells

• 80% sporadic, 20% familial (MEN 2A and B, RET mutation)

• Presentation• Familial (AD) presents at a younger age and is associated with C-cell

hyperplasia

• 50% 5 year survival

• Can have both lymph node and hematogenous spread

• Diagnosis:• Secrete calcitonin (can be measured as a serum level).

• Histology and Morphology:• Grossly, superior thyroid, multicentric. grey/white and somewhat circumscribed.

• Histologically, the tumors may show a variable appearance (endocrine).

• Amyloid can often be identified.

• Tumor cells often have “nested” appearance. Spindled, fried egg.

Lymphoma

• Lymphomas represent less than 2% of thyroid malignancies.

• They may arise in a background of chronic thyroiditis.

• The prognosis for these lesions is similar to that for lymphoma

diagnosed elsewhere except that some low-grade malignancies

restricted to the thyroid may be cured by simple excision.

Indications for FNA*

• All palpable nodules (by nature >1-1.5 cm)

• Some incidental nodules (ultrasound features, especially size)

• All PET-positive nodules

*This is excluding “HOT” nodules

Suspicious Ultrasound Features

• Hypoechoic features

• Microcalcifications

• Irregular / lobulated margins

• Intra-nodular vascularity

• Nodal metastases or extrathyroidal spread

The Bethesda System for Reporting Thyroid Cytopathology:

Implied Risk of Malignancy and Recommended Clinical Management

Diagnostic Category Risk of

Malignancy (%)

Usual Management

Nondiagnostic or

Unsatisfactory

Repeat FNA with

ultrasound guidance

Benign 0-3% Clinical follow-up

Atypia of Undetermined

Significance or Follicular

Lesion of Undetermined

Significance

~ 5-15% Repeat FNA

Follicular Neoplasm or

Suspicious for a Follicular

Neoplasm

15-30% Surgical lobectomy

Suspicious for Malignancy 60-75% Near-total thyroidectomy

or surgical lobectomy

Malignant 97-99% Near-total thyroidectomy

Fish et al, Endocrinol Metab Clin N Am 2008; 37:

401

High risk

Courtesy of Dr. D. Lambert

Intermediate risk

Low risk

Very low risk

Benign

In the presence of two or more thyroid

nodules >1 cm, those with a suspicious

sonographic appearance should be

aspirated preferentially.

If none are suspicious, aspirate the largest

nodule.

ADRENAL

The Adrenal Cortex

• Zona Glomerulosa

• Depends on ACTH for the first step in steroid biosynthesis

(cholesterol to pregnenolone) but otherwise controlled by the renin-

angiotensin-aldosterone system

• Secretes mineralocorticoids (aldosterone, DOC)

• Zona Fasciculata

• Regulated by the hypothalamic-pituitary axis (CRH/ACTH)

• Secretes glucocorticoids (cortisol)

• Zona Reticularis

• Regulated by the hypothalamic-pituitary axis (CRH/ACTH)

• Secrete sex hormones (DHEA, androstenedione)

Zona Glomerulosa

Zona Fasciculata

Zona Reticularis

Normal Adrenal Cortex

• Zona Glomerulosa• Thin, subcapsular

• Amphophilic cytoplasm

• Secretes aldosterone, responsive to angiotensin and potassium

• Zona Fasiculata• Broad band, lipid filled

• “Clear cell” appearance

• Secrete glucocorticoids, responsive to ACTH

• Zona Reticularis• Deep, “compact cells”

• Granular eosinophilic cytoplasm

• Secrete sex steroids, responsive to ACTH

Zona Glomerulosa

• Aldosterone

• Regulation of salt and water balance

• Stimulated by renin, angiotensin II, and potassium levels

• 11-Deoxycorticosterone and Corticosterone are weak mineralocorticoids

11Beta-HSD II transforms cortisol to

cortisone preventing stimulation of the

mineralocorticoid receptors.

Licorice will inhibit this enzyme

Zona Fasciculata

• Cortisol

• Regulation by CRH/ACTH

• ACTH’s second messenger: cAMP

• ACTH and cortisol are secreted in a diurnal rhythm• Highest levels beginning shortly before

arising in the morning

• Lowest levels near midnight

• Cortisol circulates bound to protein (<5% free)

Zona Reticularis

• DHEA-s

• Potency approx. 10% that of testosterone

• Whether there is specific hormonal control of z.r. is unknown

• Adrenarche: onset of adrenal androgen production at age 6-8

• Probably responsible for pubarche (appearance of pubic hair)

Actions of Cortisol

• Metabolism• Protect body from hypoglycemia

• Stimulate hepatic gluconeogenesis

• Increases activity of PEPCK and glucose-6-phosphatase

• Enhanced responsiveness to cAMP

• Inhibit peripheral glucose utilization

• Decrease insulin sensitivity of adipose tissue

• Enhance lipolysis and proteolysis

• Increase in circulating free fatty acids and amino acids

Actions of cortisol• Immune System

• Inhibit phospholipase A2, anti-inflammatory • Inhibit production of IL-2 and proliferation of T lymphoctyes• Inhibit release of histamine and serotonin from Mast Cells and platelets

• Vascular• Upregulates alpha-1 receptors on arterioles, increasing sensitivity to

catecholamines

• CNS• Can induce euphoria

• Bone• Inhibits formation of type I collagen• Inhibits formation and function of osteoblasts• Inhibits intestinal calcium absorption/ Antagonizes vitamin D action• Increases bone resorption

• Neccesary to excrete free water load

Hyposecretion of Glucocorticoids

• Decreased cortisol, aldosterone and androgens

• Increased ACTH

• Hypoglycemia

• Weight loss, weakness, nausea, vomiting

• Hyperpigmentation

• Decreased pubic and axillary hair

• ECF volume contraction, hyperkalemia and metabolic acidosis

Hypersecretion of Glucocorticoids

• Increased cortisol and androgen levels

• Decreased ACTH

• Hyperglycemia

• Increased protein catabolism and muscle wasting

• Central obesity

• Moon face, supraclavicular fat, buffalo hump

• Poor wound healing

• Virilization of women

• Hypertension

• Osteoporosis

• Dark colored Striae

Mineralocorticoids

• Hypersecretion

• Hypertension (DIASTOLIC)

• Hypokalemia

• Metabolic Alkalosis

• Decreased Renin secretion

• Conn’s Disease LVH and Renal Disase

• Hyposecretion

• Hyponatremia

• Hyperkalemia

• Hypotension/Dehydration

• High Creatinine, BUN, and Renin

Congenital Adrenal Hyperplasia

• 21β-Hydroxylase Deficiency• Decreased cortisol and aldosterone

• Increased ACTH

• Increased adrenal androgens

• Hyperplasia of zona fasciulata and reticularis

• Virilization in women

• Acceleration of linear growth

• 17α-Hydroxylase deficiency• Decreased androgen and glucocorticoid levels

• Increased mineralocorticoid levels

• Increased ACTH

• Lack of pubic and axillary hair

• Hypoglycemia

• Metabolic alkalosis, hypokalemia, hypertension

Adrenal Insufficiency• Primary (Addison’s disease)

• High ACTH and low cortisol, low aldosterone

• Idiopathic/autoimmune 65%

• Tuberculosis 20%

• Others 15%• Adrenal hemorrhage

• Metastatic disease

• Congenital Adrenal Hyperplasia

• Congenital Adrenal Hypoplasia

• Fungal infections

• Amyloidosis

• Sarcoidosis

• Secondary• Low ACTH and low cortisol, Aldosterone is NOT affected

• HPA axis suppression from chronic glucocorticoid administration

• Hypothalamic or Pituitary Lesions• Neoplasm

• Infection

• Sarcoidosis

• Trauma

Cushing’s Syndrome

• ACTH Dependent• Cushing’s Disease: Pituitary adenoma

• Ectopic ACTH

• Bronchial, Pancreatic or Thymic carcinoid

• Small cell lung CA

• Medullary Carcinoma Thyroid

• Pheochromocytoma

• Ectopic CRG

• Bronchial carcinoid

• ACTH Independent• Adrenal adenoma

• Adrenal Carcinoma

• Nodular adrenal disease

Diagnosis and Treatment

• Addison’s Disease

• Diagnosis

• 8 AM cortisol

• Insulin or Arginine Stimulation

• Treatment

• High doses of hydrocortisone

• Fluid and electrolyte management

• Cushing’s Syndrome

• Diagnosis

• Midnight salivary cortisol

• 24 hour urine cortisol

• OGTT or Metapyrone test

Catecholamine Excess

• Pheochromocytoma

• Catecholamine producing tumors of the chromaffin cells in the adrenal medulla

• Associated with MEN2A and SB

• Symptoms:

• Pressure (increased BP)

• pain (headache)

• perspiration

• palpitations (tachycardia)

• Pallor

• Anxiety

• Nausea

• Weakness/fatigue

• Weight loss

• Flushing

• Diagnosis: Plasma and urine metanephrines

Treatment of Pheochromocytoma:

1. Alpha adrenergic blockade

2. Beta adrenergic blockade

3. Surgery

The two most common imaging

modalities for the adrenal gland are CT

and MRIOthers

- Ultrasound

- Arteriography

- Venography

- Venous sampling

- Percutaneous biopsy

- Radionuclide imaging, PET scan

Indications for Adrenal Imaging

• Characterization of incidentally detected lesion

• Unexplained adrenal hormone hyperfunction

• Suspected metastatic disease

• Most likely from lungs

• Trauma, follow up

Adrenal Lesions

• Hyperplasia

• Mass

• Adrenal Incidentalomas

• Adenoma

• Adrenal cyst

• Myelolipoma

• Metastases

• Adrenocortical Tumors

• Adenoma

• Carcinoma

• Adrenal Medullary Tumors

• Neuroblastoma

• Pheochromocytoma

• Others

• Calcification

• Hemorrhage

Approach

• 1. Look for fat in the lesion Myelolipoma

Approach

• 2. Assess Housefield Units

• If the number is less than 10 Hounsfield unit (HU)

• Lipid rich adenoma Benign

• If the number is more than 10 HU

• Dedicated adrenal lesion CT/MRI protocol

-2HU

Approach

• 3. Assess Washout

• (Immediate post contrast – delayed post contrast)/ (Immediate post

contrast – Non-contrast) * 100 = Washout Percent

• >60% Benign

Thin walled

Water density

Adrenal Cyst

•Hemorrhage,

trauma

•TB/Histoplasmosis

•Carcinoma

•Neuroblastoma

•Ganglioneuroma

Adrenal Calcification

Case 4- Pheochromocytoma

T2W fat suppressed MRI image

Right adrenal lesion-

•Light bulb bright

•Salt and pepper appearance

•Intense enhancement post

contrast administration

MEN

MEN Familial Disorders

• MEN 1: Loss of function mutation in MEN 1 gene (Menin)• Parathyroid adenoma

• Enteropancreatic neoplasm: gastrinoma, insulinoma

• Pituitary tumor

• Most are BENIGN

• MEN 2A: Activating mutation in RET proto-oncogene• Medullary thyroid cancer

• Pheochromocytoma

• Parathyroid adenoma

• Significant morbidity and mortality

• MEN2B: Activating mutation in RET proto-oncogene• Medullary thyroid cancer

• Pheochromocytoma

• Ganglioneuromatosis

• Marfanoid Habitus

• Significant morbidity and mortality

PGA Syndromes

• Causes

• Autoimmune

• Infectious

• Tuberculosis

• HIV-associated

• Malignancy- metastatic disease

• Lung

• Breast

• Bleeding

• Heparin/coumadin

• Waterhouse–Friderichsen (Neisseria meningitidis)

PGA Type 1

• Chronic mucocutaneous candidiasis

• Hypoparathyroidism

• Adrenocortical failure: Addison’s Disease

• AKA: autoimmune polyendocrinopathy candidiasis-ectodermal

dystrophy (APECED) syndrome

• Primarily a disease of children

• Relatively rare

• Attributed to mutations in the autoimmune regulator (AIRE) gene

PGA Type 2

• Autoimmune Addison’s disease and either

• Autoimmune thyroid disease (Schmidt’s syndrome)

• Type 1 diabetes

• Other autoimmune conditions:

• Hypogonadism

• Hypoparathyroidism

• Pernicious anemia

• Vitiligo

• Autoimmune hepatitis

• Myasthenia gravis

PGA Type 3

• Autoimmune thyroid disease and something other than

hypoparathyroidism or adrenal disease

• Other autoimmune conditions:

• Type 1 diabetes

• Chronic autoimmune gastritis

• Pernicious anemia

• Vitiligo

• Alopecia

• Myasthenia gravis

• Hypogonadism

• Autoimmune arthritis