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THYROID

Hypothalamic-Pituitary-Thyroid Axis Regulation

T3 and T4 Metabolism

Thyroxine Metabolism• T4 produced only in thyroid

• T3 is produced by deiodination of T4 (80%)/Thyroid (20%)

• Enzymes made in multiple tissues:• Type I – PTU sensitive

• Liver, kidney, thyroid

• rT3>T4>T3

• Type II – PTU insensitive

• Muscle, brain, pituitary, skin and placenta

• T4>rT3

• T3 most biologically active but degraded quickly

• rT3 degraded even faster than T3 (but is biologically inactive)

• T4 and T3 are protein bound• FREE molecules are the players

Laboratory Testing Options

• TSH

• T3

• T4

• Free T4

• Anti-thyroglobin

• Anti-thyroid peroxidase

• Also have more esoteric testing that is sent out• Takes a long time

• More expensive

Thyroid Function Laboratory Testing

Laboratory Testing

• First Test Always!!!!!• TSH

• If elevated TSH:• Hypothyroid state

• Clinical TSH > 10

• Subclinical TSH 5-10

• If decreased TSH:• Hyperthyroid state

• Endogenous Graves’ disease, multinodular goiter, thyroid producing neoplasm

• Exogenous Taking oral thyroxine

Laboratory Testing

• If normal TSH:• EuthyroidMaybe, maybe not

• Important to keep in mind whether there is an appropriate response versus an impaired response!!!!!!

• Free T4

• Elevated despite normal TSH hyperthyroid state

• Depressed despite normal TSH hypothyroid state

• TRH stimulation test• Used to help determine whether pituitary-associated hyperthyroidism

• Normal: Following TRH injection TSH rise

Radioiodine Uptake Testing

• Increased uptake: • Solitary

• Toxic adenoma

• Diffuse• Graves’ disease

• Decreased uptake:• Thyroiditis

Fine Needle Aspiration

• Biopsy superficial masses to determine their significance.

• Cytology: The appearance of the cells themselves and the context of the background help determine a diagnosis.

• Pros: On-site evaluation, quick, no need for surgery, you get to visit with your friendly pathologist

• Cons: Cannot definitively diagnose follicular lesions, cannot always get diagnostic material

FNA Procedure

Entities that can be diagnosed by FNA

• Non-neoplastic• Acute thyroiditis• Subacute thyroiditis• Hashimoto’s thyroiditis• Reidel’s thyroiditis• Graves’ disease• Amyloid goiter

• Neoplastic• Follicular carcinoma• Hurthle cell carcinoma• Papillary thyroid carcinoma• Poorly differentiated carcinoma• Undifferentiated carcinoma• Medullary thyroid carcinoma• Metastatic neoplasms• Lymphoma

Screening

Disease

Neoplastic

Benign

Cyst Nodule Adenoma Hurthle cell

Malignant

Papillary

Tall cellFollicular variant

Etc

Follicular Anaplastic

Non-neoplastic

Inflammatory Autoimmune Goiter

Disease

Thyrotoxicosis Hypothyroid Euthyroid

Graves’ Disease

• Hypermetabolic state• Decreased TSH

• Increased T4, T3

• Overactivity of the SYMPATHETIC nervous system

• Symptoms• General: Inability to gain weight, sweating, ex ophthalamos

• Skin: Dry skin

• CV: Palpitations, tachycardia, cardiomegaly, arrhythmia

• CNS: Anxiety, tremor, insomnia, emotional lability

• GI: Hypermotility, diarrhea

• Musculoskeletal: Osteopenia/porosis, loss of muscle tone

Graves’ Disease

Graves’ Disease

• Diffuse hyperplasia and hypertrophy of epithelial cells• Looks papillary

• NO fibrovascular cores

• Scalloped colloid

• Inflammatory infiltrate –lymphocytes, plasma cells

Normal Thyroid

Graves’ Disease

Multinodular Goiter

• Asymmetric enlargement of the thyroid• Can involve one or all aspects of the gland

• Can reach >2000g

• Can degenerate and form scar, calcifications, and hemorrhage

• Microscopic: • Colloid-rich follicles lined by flattened, inactive epithelium with follicular

hyperplasia

Multinodular Goiter

Benign Thyroid Nodule

Sheets of follicular cells with NO overlapping, round nuclear borders, possible nucleoli

Thyroid Storm

• Abrupt onset of hyperthyroidism

• DANGEROUS!• Arrhythmia leading to death

• Sx:• Febrile

• Tachycardia

Disease

Thyrotoxicosis Hypothyroid Euthyroid

Thyroiditis

• Disease of the thyroid that includes inflammation

• Two typical presentations• Painful

• Infectious thyroiditis

• Subacute granulomatous thyroiditis

• Thyroid dysfunction• Hashimoto’s thyroiditis

• Subacute lymphocytic thyroiditis

• Fibrous (Reidel) thyroiditis

Hashimoto’s Thyroiditis

• Common cause of hypothyroidism in US

• Women 10-20:1

• Benign

• Inflammatory!!!! Autoimmune destruction!• Anti-Thyroglobulin

• Anti-thyroperoxidase

• Description: Extensive lymphoctyic infiltrate with plasma cells. Well developed germinal centers. Breakdown of thyroid colloid. Hurthlecell change.

Hashimoto Thyroiditis

Hashimoto’s Thyroiditis FNA

Hurthle cells with abundant eosinophilic cytoplasm

Lymphocytes

Subacute Granulomatous Thyroiditis

• AKA: De Quervain thyroiditis

• Etiology: viral illness

• Painful thyroid

• Transient condition but will be hyperthyroid• ↓ TSH, ↑ T3 , ↑ T4

• Description: Look for neutrophils and microabscesses destroying the follicles early in the disease course. Later, see multinucleated giant cells, histiocytes, lymphocytes, and plasma cells.

Subacute Granulomatous Thyroiditis

What’s at the solid arrows?

What is within the dashed circles?

What are the dashed arrows pointing to?

What do the boxes enclose?

Subacute Lymphocytic Thyroiditis

• Painless

• Sx:• Mild hyperthyroidism

• Diffuse thyroid enlargement

• Description: hyperplastic germinal centers within the thryoid parenchyma and patchy disruption of colloid follicles. Hurthle cell metaplasia, fibrosis NOT prominent.

Thyroid Follicular Neoplasms

BenignMalignant

Criteria to distinguish benign versus malignant thyroid FOLLICULAR neoplasms:

1)Capsular invasion2)Lymphovascular invasion3)Metastasis

Follicular Adenoma

• Typically solitary, well-encapsulated nodule

• Can see hemorrhage, fibrosis, calcifications, cystic change

• Microscopically: Uniform appearing cells that contain colloid. Looks different from the normal thyroid (more densely crowded, but still bland). Mitotic figures are rare.• NO lymphovascular or capsular invasion

Follicular Adenoma

Follicular Carcinoma

• Similar to Adenoma BUT:• Capsular invasion +/- lymphovascular invasion

• Pleomorphic nuclei

• Mitoses

Follicular Carcinoma

Papillary Thyroid Carcinoma

• Most common thyroid carcinoma (85%)

• Younger women

• Metastasis common

• Microscopic: • Papillary architecture – look for fibrovascular cores

• Psammoma bodies – laminated calcified structures

• Cytology – EXTREMELY important• Nuclear inclusions

• Nuclear grooves

• Powdery chromatin

• Overlapping cells

Papillary Thyroid Carcinoma

PTC

Nuclear grooves

Fine chromatin

Inclusion

Medullary Carcinoma

• Arise from C cells• Identified by calcitonin

• Sporadic • Solitary nodule

• MEN2A or MEN2B syndrome• Bilateral, multinodular

• Microscopic: polygonal to spindle-shaped cells, form nests or trabeculae, amyloid deposits

Medullary Carcinoma

Medullary Carcinoma

Left: Spindled, bland appearing hypercellularsmear.

Below: spindled cells with amorphous amyloid deposits.

ENDOCRINE PANCREAS

Endocrine Pancreas Function

• Hormones• Insulin

• Glucagon

• Incretins

• Somatostatin

Insulin

• Pre-proinsulin insulin + C-peptide • [C-peptide] in serum is much higher than insulin

• Insulin has high hepatic clearance

Insulin

• Hyperinsulinemia• Cirrhotic

• High insulin and High C-peptide

• Exogenous• High insulin and Low/Absent C-peptide

• Neoplasm• Insulinoma

• High insulin and High C-peptide

• Profound hypoglycemia

Endocrine Pancreas

ALPHA CELLS BETA CELLS

Diabetes

• Diabetes Type 1• Insulin DEPENDENT

• DKA

• Lifelong

• Autoimmune

• Destruction of Beta islet cells

• Diabetes Type 2• Insulin Resistance

• Hyperosmolar

• Can be prevented

• Multifactorial• Genetics

• Environmental

Diabetes Continued

• Gestational Diabetes• Pregnant women

• Leads to increased risk of Type 2 diabetes later on (within 5-10 yrs)

• Requires very close follow-up during the course of the pregnancy

• Very strict glucose control throughout pregnancy

Ketone Bodies

• Products of fatty acid degradation:• Acetone

• Beta-hydroxybutyrate (BH)

• Acetoacetic acid (AA)

• BH:AA in serum• Normal: 1:1

• DKA: ↑ ↑BH:AA

• Urine test strips are frequently used to ID ketosis:• Test strips DO NOT test for BH

• AA and acetone levels increase during therapy

• Do not use strips to monitor treatment of DKA

• Follow electrolytes and BH assays for treatment!• BH assays can be enzymatic, colorimetric, etc.

Hypoglycemia

• Glucose levels < 55 mg/dL (healthy person)

• Two types:• Neurogenic

• Tremulousness, diaphoresis, anxiety, palpitations

• Neuroglycopenic• Dizziness, tingling, blurred vision, alterations of mentation

• Severe, prolonged hypoglycemia can lead to BRAIN DEATH!

Hypoglycemia

Glucagon• Produced by Alpha cells

• Stimulates glucose production• Important for glycogenolysis, gluconeogenesis and ketogenesis

• Diabetes:• Gradual decrease in alpha cells occurs in Type I

• Glucagon deficiency

• Increasing glycemic fluctuations

• Difficulty recovering from hypoglycemia

• Glucagonoma• Presents with: necrotizing migratory erythematous rash, stomatitis, glossitis, weight

loss, anemia and mild DM

• Increased levels in cirrhosis, pancreatitis, Cushing’s syndrome, acromegaly, and renal insufficiency

Somatostatin

• Made in DELTA cells• 5-10% of islet cells

• Inhibits:• Pituitary

• GH and thyrotropin

• Gastrointestinal• Gastrin, secretin, VIP

• Pancreatic hormones• Insulin

• Glucagon

• Non-endocrine function• Gastric acid secretion

• Gastric emptying

• Pancreatic enzyme release

Pathology of Diabetes

Every Organ System can be Affected!

Diabetes Pathophysiology

Diabetes Effects on Pancreatic Islet Cells

Type I Type II

Inflammatory infiltrate composed of lymphocytes: INSULITIS

Hyalinization with deposition of AMYLOID

Diabetic Complications

Vasculature• Atherosclerosis

• Peripheral vascular disease

• Erectile dysfunction

• Why?

Kidney• Thickening of basement

membrane

• Kimmelstiel-Wilson nodules

Glomerulus

Arteriole

Kimmelstiel-Wilson Nodule

Neuroendocrine Neoplasms of the Pancreas

• 1 - 2% of all pancreatic neoplasms

• Occur at any age but are rare in childhood (usually age 40-60), no sex predilection

• Approximately 10% are associated with a syndrome and will occur at a younger age • multiple endocrine neoplasia type 1 syndrome (60% of patients have

pancreatic neuroendocrine tumors and 80% have pancreatic microadenomatosis/hyperplasia)

• neurofibromatosis 1 syndrome (1% of patients have pancreatic neuroendocrine tumors)

• von Hippel-Lindau syndrome (16% of patients have pancreatic neuroendocrine tumors)

• tuberous sclerosis complex (rare)

Neuroendocrine Neoplasms of the Pancreas

• Nonfunctional tumors are encountered incidentally and are usually larger at time of diagnosis

• Local obstruction/mass effect, if located in the pancreatic head

• Other clinical features of MEN1, VHL, NF1 or TSC if have syndrome

• Clinical hormonal syndromes in functioning tumors

• Elevated serum chromogranin A in 60-80%

• Solid or solid cystic lesion within any part of the pancreas on radiology

• Surgical resection is the predominant treatment with resolution of both mass effect symptoms and symptoms associated with hormone secretion. Chemotherapy has a limited role unless high grade or extensive disease

Neuroendocrine Neoplasms of the Pancreas

• Insulinoma• Most common functioning pancreatic neuroendocrine tumor

• Insulin secretion

• Hypoglycemic syndrome

• Solitary tumor < 2 cm

• 5 - 10% of insulinomas are associated with MEN1 and are usually multiple

• Benign in 90%

Neuroendocrine Neoplasms of the Pancreas

• Gastrinoma: • Second most common functioning pancreatic neuroendocrine tumor

• Gastrin secretion

• Zollinger-Ellison syndrome (peptic ulcers, gastroesophageal reflux, diarrhea)

• "Gastrinoma triangle" (common bile duct, duodenum, pancreatic head)

• Duodenum affected more than pancreas

• 20 - 30% of gastrinomas are associated with MEN1

• Malignant in 80%

Neuroendocrine Neoplasms of the Pancreas

• Glucagonoma• 4Ds: diabetes, dermatitis (necrolytic migratory erythema), deep vein

thrombosis, depression

• Solitary, large

• Tail > head

• > 50% have metastasis at presentation

• VIPoma• Verner-Morrison syndrome: watery diarrhea, hypokalemia,

achlorhydria/hypochlorhydria

• Solitary, large

• Tail > head

Neuroendocrine Neoplasms of the Pancreas

• Somatostatinoma• Diabetes mellitus, diarrhea or steatorrhea, anemia, malabsorption,

cholelithiasis

• Very rare

• Solitary, large

• > 50% have metastasis at presentation

• Ectopic hormone producing neuroendocrine tumor• ACTH (Cushing syndrome), serotonin, growth hormone

• Usually malignant

• Solitary, large

Neuroendocrine Neoplasms of the Pancreas

Neuroendocrine Neoplasms of the Pancreas

• Firm, commonly well circumscribed, homogeneous

• Tumors may have a cystic component

• Color varies according to the degree of vascularity and amount of stroma and ranges from white to pink to tan to brown; may be yellow if necrosis present

• "Pigmented black pancreatic neuroendocrine tumor" is composed of intracytoplasmic lipfuscin and mimics metastatic melanoma

• "Lipid rich" pancreatic neuroendocrine tumor mimics adrenal cortical neoplasia

• Features of malignancy: invasion of fibroadipose tissue (as satellite nodules), invasion of adjacent organs, invasion of large vessels

Neuroendocrine Neoplasms of the Pancreas

• Well differentiated neuroendocrine tumors• Organoid architecture: solid nests, trabeculae, gyri, cords, festoons, ribbons,

glandular, acinar, cribriform • Small to medium cells with eosinophilic to amphophilic and finely granular

cytoplasm; nuclei are uniform, central, round/oval, with "salt and pepper" (finely stippled) chromatin; no/inconspicuous cytoplasm

• Rich vascular network • Amyloid deposition in insulinomas• Psammoma bodies in somatostatinomas• Hyaline globules

• Poorly differentiated neuroendocrine carcinomas• Sheets or nests of atypical cells with pleomorphic, hyperchromatic nuclei and

abundant mitotic figures • "Salt and pepper" chromatin is lost • Necrosis often present • May be small cell (molding nuclei, scant cytoplasm) or large cell (abundant

amphophilic cytoplasm; may also have visible nucleoli)

Neuroendocrine Neoplasms of the Pancreas

Neuroendocrine Neoplasms of the Pancreas

• Cytology description• Small / medium sized cells

• Amphophilic, finely granular cytoplasm (neurosecretory capability)

• Round / oval, uniform, centrally located nuclei without prominent nucleoli

• May be plasmacytoid

Neuroendocrine Neoplasms of the Pancreas

Neuroendocrine Neoplasms of the Pancreas

Neuroendocrine Neoplasms of the Pancreas

Neuroendocrine Neoplasms of the Pancreas

Neuroendocrine Neoplasms of the Pancreas

Neuroendocrine Neoplasms of the Pancreas

Neuroendocrine Neoplasms of the Pancreas

Neuroendocrine Neoplasms of the Pancreas

Endocrine Syndromes

THE END

• Questions, Comments:• Lisa.Lopez@BSWHealth.org

• 254-724-3690