Disorders of the Adrenal Medulla

What are some complications of untreated pheochromocytoma

Hypertensive retinopathy (retinal hemorrhages or papilledema) Nephropathy Myocardial infarction resulting from either catecholamine-induced myocarditis and/or dilated cardiomyopathy or coronary artery vasospasm and cardiovascular collapse (sometimes fatal) Pulmonary edema, secondary either to left-sided heart failure or noncardiogenic causes Stroke from cerebral infarction, intracranial hemorrhage, or embolism from mural thrombi in dilated cardiomyopathy Ileus, obstipation, and abdominal discomfort resulting from a large adrenal mass Maternal morbidity and fetal demise in pregnancy Increased blood sugar levels, even diabetes mellitus Increased blood lactate concentrations Weight loss (or, in children, lack of weight gain) from an increase in metabolic rate Mild basal body temperature elevation, heat intolerance, flushing, or sweating Marked anxiety, visual disturbances, paresthesias, or seizures and psychosis or confusion during paroxysms Paraneoplastic syndromes: hypercalcemia (excessive production of PTH-related peptide [PTHrP] or PTH itself in MEN-2a); or Cushing syndrome (ectopic production of ACTH)

Major catecholamine produced by chromaffin cells of adrenal medulla -VMA, major urine metabolite

Epinephrine

Which method is most often used to measure fractionated catecholamines (epinephrine, noreponephrine, and dopamine)?

Measurement by HPLC with electrochemical detection

Which assay using 24-hour urine is considered the best single screening test for pheochromocytoma?

Metanephrines

Episodic hyperadrenergic symptoms (5 Ps)

Pressure (Increased BP) Pain (headache) Perspiration Palpitation (tachycardia) Pallor

Carcinoid Syndrome(unrelated to adrenal medulla)

Related to overproduction of products derived from amino acid tryptophan from tumor cells which stain with silver (Ag) salts: argentaffin cells

Fill in The Blank ________results in the enhanced secretion of catecholamines from the adrenal medulla and the secretion of cortisol from the adrenal cortex.

Stress

Serotonin and melatonin are derived from what amino acid?

Tryptophan

What is the NORepinephrine metabolite found in Urine?

Urinary VMA "Kanye's daughter's name is NORth"

Fill in The Blank Catecholamine production by the adrenal medulla is assessed by measuring the levels of catecholamines, metanephrines, and _____ in the urine.

VMA

Fill in The Blank As part of the stress response, the _________ _________ secretes epinephrine and norepinephrine into the blood in concert with activation of the sympathetic nervous system.

adrenal medulla

What does the Adrenal medulla secrete?

catecholamines (epinephrine, norepinephrine, dopamine)

What transferase catalyzes the methylation of norepinephrine to epinephrine?

phenylethanolamine N-methyltransferase (PNMT).

A tumor of the adrenal medulla that secretes catecholamines

pheochromocytoma

Fill in the Blank: A 39-year-old woman comes to the office complaining of episodic anxiety, headache, and palpitations. Without dieting, she has lost 15 pounds over the past 6 months. Physical examination is normal except for a blood pressure of 200/100 mm Hg and a resting pulse rate of 110 bpm. Chart review shows that prior blood pressures have always been normal, including one 6 months ago. A ___________________ diagnosis is entertained.

pheochromocytoma

What is the Most common tumor of adrenal medulla in Adults?

pheochromocytoma

dopamine aka

somatostatin

What amino acid is serotonin derived from?

tryptophan

Fill in The Blank Epinephrine and norepinephrine are made from the amino acid _______________ via a series of enzymatically controlled reactions

tyrosine

Dopamine

-is prominent in midbrain neurons -is released from the hypothalamus and inhibits prolactin secretion; in this context it is called prolactin-inhibiting factor (PIF) or somatostatin -is metabolized by MAO and COMT ---D1 receptors activate adenylate cyclase via a Gs protein ---D2 receptors inhibit adenylate cyclase via a Gi protein ---Parkinson disease involves degeneration of dopaminonergic neurons that use D2 receptors ---Schizophrenia involves increased levels of D2 receptors

Epinephrine

-is synthesized from norepinephrine by the action of phenylethanolamine-N-methyltransferase (PNMT) in the adrenal medulla - a methyl group is trasnferred to norepinephrine from S-adenosylmethionine (SAM)

Norepinephrine

-is the primary transmitter released from postganglionic sympathetic neurons -is synthesized in the nerve terminal and released into the synapse to bind with Alpha or Beta receptors on the postsynaptic membrane -is removed from the synapse by reuptake or is metabolized in the presynaptic terminal by monamine oxidase (MAO) and catechol-O-methyltransferase (COMT) -Metabolites are: ----3,4-Dihydroxymandelic acid (DOMA) ----Normetanephrine (NMN) ----3-Methoxy-4-hydroxyphenylglycol (MOPEG) ----3-MEthoxy-4-hydroxymandelic acid or vanillylmandelic acid (VMA)

Identify three hormones produced by the adrenal medulla:

1) Epinephrine, 2) Norepinephrine 3) Dopamine

What genetic mutations are found in patients with pheochromocytoma?

10 known susceptibility genes are associated with familial pheochromocytoma and/or paraganglioma. Examples include: — Neurofibromatosis type 1 (Recklinghausen disease): NF1 gene mutations — Von Hippel-Lindau syndrome: VHL tumor suppressor gene mutation — Multiple endocrine neoplasia type 2 (MEN-2): missense point mutations in the RET proto-oncogene 10-20% of sporadic cases and most familial cases of familial pheochromocytoma and/or paraganglioma carry germline mutations in VHL, RET, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, or MAX. Somatic mutations in VHL and RET occur in 10-15% of tumors

What 24hr urine test is used to diagnose carcinoid sydrome?

5-HIAA

Which metabolite is most often increased in carcinoid tumors of the intestine?

5-Hydroxyindoleacetic acid (5-HIAA)

Serotonin (5-HT)

5-Hydroxytryptamine

The release of epinephrine from the chromaffin granules of the adrenal medulla into the bloodstream in response to neural stimulation is mediated by which of the following? (A) Acetylcholine (B) γ-Aminobutyric acid (GABA) (C) Cortisol (D) Dopamine (E) Serotonin

A

The screen for adrenal cortical hypERfunction with the greatest sensitivity and specificity is: A) 24hr urine free cortisol B) plasma cortisol C) urinary 17-hydroxycorticosteroids D) plasma corticosterone

A

Histology and immunohistochemistry of pheochromocytoma.

A. hematoxylin & eosin, B. chromogranin, C. synaptophysin, C and B stain chief cells D: S-100 stains sustentacular cells. E, F. Immunohistochemistry with SDHB antibody: positive staining (granular cytoplasmic staining) indicates intact SDHB (E), whereas negative staining (endothelial cells positive as internal control) (F) indicates structurally changed or absent SDHB due to a germline mutation in the SDHB gene, which was confirmed by molecular genetic analysis of a blood sample. (Parts A-D and F were provided courtesy of Dr Helena Leijon, Helsinki. Part E was provided courtesy of Dr. Kurt Werner Schmid, Essen.)

Degeneration of dopaminergic neurons has been implicated in: A) Schizophrenia B) Parkinson disease C) myasthenia gravis C) curare poisoning

B

Which statement regarding the measurement of urinary catecholamines is true? A) an increased excretion of total urinary catecholamines is specific for pheochromocytoma B) 24-hour urinary catecholamine assay avoids pulse variations associated with measurement of plasma catecholamines C) Total urinary catecholamine measurement provides greater specificity than measurement of urinary free catecholamines D) Total urinary catecholamines are not affected by exercise

B) 24-hour urinary catecholamine assay avoids pulse variations associated with measurement of plasma catecholamines Measurement of total urinary catecholamines is NOT a specific test for pheochromocytoma. Urine levels may be increased by exercise and in muscular diseases. Catecholamines in urine may also be derived from dietary sources rather than endogenous production. Most catecholamines are excreted as the glucoronide, and the urinary free catecholamines increase only when there is increased secretion. Measurement of free hormone in urine is equal in clinical sensitivity and specificity to measurement of metanephrines. 24hr urine is the sample of choice because plasma levels are subject to pulse variation and affected by the patient's psychological and metabolic condition at the time of sampling.

Which of the following neuroendocrine responses contributes to meeting the enhanced energy demands during exercise? A)Glucagon stimulation of hepatic glycogen synthesis B) Epinephrine stimulation of hepatic glycogenolysis C) Norepinephrine-induced stimulation of insulin release D) Cortisol inhibition of gluconeogenesis

B) Epinephrine stimulation of hepatic glycogenolysis Explanation: The enhanced energy demands during exercise are met by neuroendocrine stimulation of glycogenolysis and sympathetic inhibition of insulin release. Glucagon stimulates gluconeogenesis (not glycogen synthesis), and cortisol facilitates (does not inhibit) gluconeogenesis.

Urinary HVA is most often assayed to detect: A) Pheochromocytoma B) Neuroblastoma C) Adrenal medullary carcinoma D) Psychiatric disorders such as manic depression

B) Neuroblastoma HVA is the major metabolite of dopa, and urinary HVA is elevated in more than 75% of neuroblastoma patients. Neuroblastomas also usually produce VMA from norepinephrine. Thus HVA and VMA are assayed together and this increases the sensitvity of detection to around 90%.

Which of the following statements applies to both measurement of VMA and metanephrines in urine?

Both can be measured by specific HPLC and MS assays

Which of the following is an inhibitory neurotransmitter in the central nervous system (CNS)? A) Norepinephrine B) Glutamate C) Gamma-aminobutyric acid (GABA) D) Serotonin E) Histamine

C) Gamma-aminobutyric acid (GABA) GABA is an inhibitory neurotransmitter. Norepinephrine, glutamate, serotonin, and histamine are excitatory neurotransmitters.

Which of the following regarding the catecholamines is true? A) They are derived from tryptophan B) They are produced by the zona glomerulosa of the adrenal cortex C) Plasma levels show both diurnal and pulsed variation D) They are excreted in urine primarily as free catecholamines

C) Plasma levels show both diurnal and pulsed variation Catecholamines---epinephrine, norepinephrine, and dopamine---are produced from the amino acid tyrosine by the chromaffin cells of the adrenal medulla. Plasma and urinary catecholamines are measured in order to diagnose pheochromocytoma. Symptoms include hypertension, headache, sweating, and other endocrine involvement. Plasma catecholamines are oxidized rapidly to metanephrines and VMA; only about 2% is excreted as free catecholamines. The zona glomerulosa is the outermost portion of the adrenal cortex, where aldosterone is mainly produced.

Individuals with Parkinson's disease have dopamine deficiency in the substantia nigra of the central nervous system. Which of the following would compromise the best strategy for therapy? A) Feedback inhibition of dopamine oxidation B) Competitive inhibition of biosynthesis from histidine C) Provision of metabolites in the tyrosine pathway D) Stimulation of monamine oxidase E) Provision of metabolites in the alanine pathway

C) Provision of metabolites in the tyrosine pathway Dopamine is produced from L-DOPA (3,4-dihydroxy-L-phenylalanine), which in turn is made from tyrosine. Therapy with the L-DOPA precursor increases dopamine concentrations and improves the rigidity and immobility that occur in Parkinson disease. Stimulation of monamine oxidase (incorrect answer a) or inhibition of dopamine oxidation (incorrect answer a) would not increase dopamine; incorrect answers b and c involve pathways unrelated to dopamine metabolism. Dopamine is degraded in the synaptic cleft by monamine oxidases A and B (MAO-A and MAO-B), producing 3,4-dihydroxyphenylacetaldehyde (DOPAC). DOPC is in turn broken down to homovanillic acid, which can be measured in spinal fluid to assess dopamine metabolism. Inhibitors of MAO-A and MAO-B have some use in treating Parkinson disease. The metabolism of histidine or alanine is not related to that of dopamine, but phenyalanine is a precursor of tyrosine and L-DOPA (small molecules like L-DOPA can cross the blood brain barrier).

A 15-year-old boy presents to the endocrinologist with multiple mucocutaneous neuromas and a marfanoid habitus (tall with long extremities). His older brother has had a thyroidectomy for medullary carcinoma of the thyroid and later has been diagnosed with bilateral tumors of the adrenal medulla. It is likely that further investigation in both brothers will demonstrate an abnormality in which of the following genes or gene-products? A) Bcr-abl B) N-myc C) Ret D) Amylin E) Insulin-associated peptide

C) Ret Ret codes for a transmembrane receptor tyrosine kinase that is mutated in the MENIIa and MENIIb sydnromes, as well as in sporadic cases of medullary carcinoma of the thyroid. Bcr-abl fusion results from the chromosomal translocation of chronic myelogenous leukemia (CML) N-myc is amplified in neuroblastoma Amylin derived from islet amyloid polypeptide accumulates in the pancreatic islets in type 2 diabetics

An 11-year-old girl presents to your office because of a family history of medullary carcinoma of the thyroid. Physical examination is normal. Which of the following tests would you perform? A) Urine vainillylmandelic acid (VMA) level B) Serum insulini level C) Serum gastrin level D) Serum glucagon level E) Serum somatostatin level

C) Serum gastrin level Medullary carcinoma occur in families as part of syndormed call multiple endocrine neoplasia (MEN) type 2A and type 2B. MEN2A consists of multicentric medullary thyroid cancer, pheochromocytomas, or adrenal medullary hyperplasia, and hyperparathyroidism MEN2B consists of medullary cancer, pheochromocytoma, and mucosal neuromas, gangliomas, and a Marfan-like habitus. These patients may develop medullary carcinoma at a very young age, and any patient with MEN2B should be assumed to have medullary cancer until proven otherwise. Patients are followed carefully for pheochromocytoma with urine VMA For hyperparathyroidism with serum calcium and for medullary carcinoma with serum calcitonin. however, as some patients have a normal basal calcitonin, a pentagastrin or provocative calcium infusion test should be performed in these high risk patients. Patients though to have MEN1 sydnrome (pituitary, parathryoid, and pancreatic tumors) or Zollinger-Ellison syndrome should be assayed for serum gastrin, insulin, glucagon, and somatostatin. These assays may prove inappropriately high in MEN 1 sydnrome due to pancreatic islet cell tumors.

Which statement about sample collection for catecholamines and metabolites is true? A) Blood for catecholamines is collected in the usual manner following a 12-hour fast B) Twent-four-hour urine for vanillylmandelic acid, catecholamines, or metanephrines is collected in 1 mL of boric acid C) Twenty-four-hour urine creatinine should be measured with vanillylymandelic acid, homovanillic acid, or metanephrines D) There is no need to discontinue medications if a 24-hour urine collection is used

C) Twenty-four-hour urine creatinine should be measured with vanillylymandelic acid, homovanillic acid, or metanephrines Stress, exercise, and upright position induce catecholamine elevation, and therefore, patients must be resting supine for at least 30 minutes prior to blood collection. The preferred method of collection is catheterization, so that the anxiety of venipuncture is not a factor. A 4-hour fast is also recommended. Many drugs contain epinephrine, which may falsely elevate catecholamine measurements. In addition many drugs inhibit monoamine oxidase, which is needed to convert metanephrines to VMA. Therefore, medications should be removed prior to testing whenever possible. Twenty-four-hour urine samples for catecholamines are usually preserved with 10mL of 6N HCl because some degradation occurs during storage when pH is greater than 3. Renal clearance affects excretion of catecholamine metabolites; it is preferable to report VMA, HVA, and metanephrines in ug/mg creatinine. The urinary creatinine measurement should be at least 0.8g/day to validate the completeness of the 24-hour urine sample.

Which assay using 24-hour urine is considered the BEST single screening test for pheochromocytoma? A) Total urinary catecholamines B) VMA C) Homovanillic acid (HVA) D) Metanephrines

D) Metanephrines Catecholamines are metabolized to metanephrines and VMA. Urinary catecholamines are increased by exercise and dietary ingestion. Measurement of a 24-hour urinary metanephrine is about 95% sensitive for pheochromocytoma, and is the best single test. Specificity and sensitivity approach 100% when both VMA and metanephrines are measured.

The urinary excretion product measured as an indicator of epinephrine production is: a) dopamine b) dihydroxyphenylalanine (DOPA) c) homovanillic acid d) vanillylmandelic acid (VMA)

D) vanillylmandelic acid (VMA) Vanillylmandelic acid (VMA) is the major metabolite of both epinephrine and norepinephrine. VMA is measured in a 24 hour urine. Homovanillic acid is a metabolite of dopamine DOPA is a precursor to dopamine, made from tyroside Dopamine is an intermediate in the production of norepinephrine and epinephrine [Arneson 2007, p396; Bishop 2018, p451]

A 26-year-old woman has episodic hypertension with headache, diaphoresis, and palpitation. Which of the following diagnostic procedures would be most useful in evaluating the possibility that a pheochromocytoma might be the cause of these findings? A) Serum C-peptide B) Serum calcitonin C) Serum hemoglobin A1c (glycosylated hemoglobin) D) Urinary aldosterone E) Urinary vanillylmandelic acid

E) Urinary vanillylmandelic acid Urinary vanillylmandelic acid(VMA), a norepinephrine metabolite, is markedly elevated in pheochromoctyoma. Serum C-peptide is elevated in insuloma. Serum calcitonin is sometimes used to screen for medullary carcinoma of the thyroid. Serum HbA1c is an indicator of long-term blood glucose control in diabetes mellitus. Urine aldosterone is elevated in aldosteronism, both primary and secondary

carcinoid tumors

NOT related to adrenal medulla overproduce the neurotransmitter serotonin, with the accumulation of the primary metabolite 5-hydroxyindole acetic acid (5-HIAA) -when these tumors metastasize to the liver, they cause carcinoid syndrome, which is characterized by diarrhea, flushing, wheezing, and cardiac valve damage

What is the most common tumor of the adrenal medulla in children?

Neuroblastoma

Which catecholamines are secreted by the human adrenal medulla? Of these, which is the major product?

The adrenal medulla secretes: epinephrine, norepinephrine, and dopamine Most (80%) of the catecholamine output of the adrenal medulla is epinephrine

After extensive testing, a 60-year-old man is found to have a pheochromocytoma that secretes mainly epinephrine. Which of the following signs would be expected in this patient? a) Decreased heart rate b) Decreased arterial blood pressure c) Decreased excretion rate of 3-methoxy-4-hydroxymandelic acid (VMA) d) Cold, clammy skin

d) Cold, clammy skin Increased circulating levels of epinephrine from the adrenal medullary tumor stimulate both alpha-adrenergic and beta-adrenergic receptors. Thus, heart rate and contractilitity are increased and, as a result, cardiac output is increased. Total peripheral resistance (TPR) is increased because of arteriolar vasoconstriction, which leads to decreased blood flow to the cutaneous circulation and causes cold, clammy skin. Together the increases in cardiac output and TPR increase arterial blood pressure 3-Methoxy-4-mandelic acid (VMA) is a metabolite of both norepinephrine and epinephrine; increased VMA excretion occurs in pheochromocytomas

HVA is a breakdown product of

dopamine

For the past 5 years, a 48-year-old man has had episodic "attacks" of headache, palpitations, anxiety, and profuse sweating, the latter often drenching his bed sheets. His pulse is 160/minute and the average of three blood pressure readings is 180/120 mm Hg. A CT of the adrenal glands reveals a mass lesion in the right adrenal. Which of the following laboratory tests would be most useful in finding the cause of the hypertension? a) Complete urinalysis b) Serum electrolytes c) Urine for free cortisol, 24 hours d) Urine for 17-ketosteroids, 24 hours e) Urine for metanephrines, 24 hours

e) Urine for metanephrines, 24 hours (urine for metanephrines, 24 hours) This patient has hypertension due to a pheochromocytoma, which is a benign tumor originating in the adrenal medulla. He demonstrates the classic triad of headache, palpitations, and excessive perspiration. Hypertension is characterized as sustained, sustained with paroxysms (most common), or paroxysmal only. A 24-hour urine test for metanephrines (most sensitive test) and vanillylmandelic acid are most often used as screening tests.

Fill in The Blank 3-Methoxy-4-mandelic acid (VMA) is a metabolite of both _______________ and ___________________ ; increased VMA excretion occurs in pheochromocytomas

epinephrine norepinephrine

Catecholamines

hormones secreted by the adrenal medulla that affect the sympathetic nervous system in stress response Epinephrine Norepinephrine Dopamine

Fill in The Blank Catecholamines are metabolized to __________________ and ________.

metanephrines VMA

Neuroblastoma

most common tumor of the adrenal medulla in children Labs: Elevated HVA (breakdown product of dopamine) Pathophysiology: Overexpression of N-myc oncogene associated with rapid tumor progression

Adrenal Medulla Disorders

• Disorders of the adrenal medulla are divided into catecholamine excess and catecholamine deficiency • Catecholamine excess results as a consequence of adrenal medullary chromaffin cell tumors; the most important tumor clinically is pheochromocytoma