Pathoma Endocrine Pathology Flashcards
What are the two most common types of pituitary adenomas? How does this relate to most common presentation?
- Prolactinomas
- Gonadal (non-functional)
Most common presentation is reproductive dysfunction
Prolactin -> GnRH inhibition
Gonadal -> nonfunctional tumor impinges and causes hypopituitarism
What are some causes of hyperprolactinemia which are not prolactinoma?
- Estrogens - i.e. pregnancy or birth control pills -> number one cause of lactotroph hyperplasia
- Primary hypothyroidism - Increased TRH levels stimulate PRL
- D2 antagonist antipsychotics, cocaine use
How can pituitary stalk disease be related to prolactin levels?
Compressing lesions (i.e. macroadenoma, sarcoidosis) of the hypothalamus and pituitary stalk may occur and cause decreased dopamine levels -> less tonic inhibition of lactotrophs
-> note that compression can also cause Diabetes Insipidus
What are the symptoms of acromegaly?
Think acral (distal extremities) + megaly (large)
Prognathism - enlarged chin Acral growth - large hands / feet Visceromegaly - increased organ size Hypermetabolism -> diabetes, HTN Hyperhidrosis - increased sweating Arthritic complaints -> joint swelling
What are the common causes of death in acromegaly / what important conditions are they at greater risk for?
Congestive heart failure -> most common cause of death
Patients also have increased relative risk of colon and breast cancer
-> IGF-1 has a permissive effect in tumorigenesis
How is diagnosis of acromegaly made?
- Increased serum IGF-1 levels -> represents the integration of growth hormone levels
- Glucose suppression test -> if IGF-1 is inconclusive, glucose can be given. A positive test is failure to suppress GH levels by administration of glucose.
- > since GH normally increased glucose levels / causes insulin resistance
Give three medical treatments for the treatment of acromegaly (resection of the pituitary GH adenoma should be obvious as first-line).
- Octreotide (GHIH/somatostatin analog)
- Pegvisomant (GH receptor antagonist)
- Cabergoline (dopamine agonists have some efficacy in treatment of this condition, mechanism unknown, possibly due to somatotrophs / lactotrophs having the same precursor)
What screening test is commonly used for Cushing’s syndrome? How does it work?
Overnight dexamethasone suppression test
-> 1 mg of dexamethasone is taken at 10pm. Plasma cortisol is drawn next morning at 8am. If cortisol is suppressed to <5 micrograms/dL, Cushing’s syndrome is very unlikely
What are other screening tests other than the dexamethasone suppression test which can be used for Cushing’s syndrome?
- 24 hour urine cortisol - will be elevated
- Midnight salivary cortisol level -> cortisol should be lowest at this time. If increased there is likely an issue (cortisol is lowest at 8am and highest at midnight).
If 2 screening tests are normal, Cushing’s syndrome is unlikely.
Give two drugs which are used in the treatment of Cushing’s syndrome.
- Ketoconazole - inhibits 17,20 desmolase, the first step of steroid synthesis. Think of the tin man opening the witch’s area with the key where she is using her book to make make male/female hormones and moon facies
- Mifepristone - potent antiprogesterone + potent glucocorticoid receptor antagonist -> remember the medpharm coursepack, it’s real homie.
What are some causes of hypopituitarism?
- Congenital
- CNS irradiation
- Mass effect
- Empty sella syndrome
- Ischemia (pituitary apoplexy)
Occurs when >75% of pituitary tissue is lost
What hormones are most likely to be affected by CNS irradiation?
More peripherally located cell types in the gland -> GH / PRL, rather than centrally located ACTH / TSH (more essential for life)
What is pituitary apoplexy and what patients are most susceptible?
Sudden hemorrhage into the pituitary gland. Usually occurs in patients with the presence of an existing pituitary adenoma requiring extra oxygenation -> hemorrhagic infarction.
What are the symptoms of pituitary apoplexy?
- Sudden onset severe headache
- Visual disturbance -> bitemporal hemianopia
- Diplopia due to CN3 palsy
- Features of hypopituitarism -> i.e. emergent cortisol insufficiency leading to hypotension
It is a medical emergency.
What is Sheehan syndrome and what causes it? What type of infarct is it?
ISCHEMIC (not hemorrhagic) infarct of pituitary following postpartum bleeding -> hypotension leads to infarction of pituitary gland which was increased in size during pregnancy (to secrete more prolactin)
What are the presenting symptoms of Sheehan syndrome?
Failure to lactate -> loss of prolactin secretion
Absent menstruation / loss of pubic hair -> failure of LH / FSH secretion
Cold intolerance -> loss of TSH
What are the possible causes of central DI?
Pituitary tumor (mass affect disrupting posterior pituitary or hypothalamus), autoimmune, trauma, surgery, ischemic encephalopathy, idiopathic
Is a tumor more likely to secrete ACTH + FSH/LH or GH + PRL and why?
More likely to be GH + PRL
-> lactotrophs and somatotrophs have a closer common cell lineage
What is lymphocytic hypophysitis and what causes it?
Autoimmune inflammation of adenohypophysis caused by infiltration of lymphocytes, leading to destruction of anterior pituitary with fibrosis.
Usually occurs in women during late pregnancy or shoftly after delivery
What is empty sella syndrome / how does it occur?
Syndrome where pituitary appears missing +/- loss in pituitary function due to compression by herniation of the subarachnoid space with CSF into the sella (area of bone).
-> Pituitary is normally not surrounded by CSF because the diaphragma sellae is a piece of dura which forms a covering and disallows CSF from leaking in
What is primary vs secondary empty sella syndrome and who does it occur in? How does it present?
Primary - protrusion of a diverticulum of arachnoid membrane into sella. Occurs in middle-aged women, often with obesity and hypertension (same demographic as pseudotumor cerebri) -> presents as headache.
Secondary - pituitary fails to take up entire space of sella which allows CSF to seep in, follows surgical resection, apoplexy, or radiation treatment of sellar tumor
What is one cause of SIADH related to the lungs which is NOT small cell lung cancer?
COPD is associated with SIADH by an unknown mechanism
Also, obviously Legionnaire’s disease can cause it.
How does hyperthyroidism increase BMR and also increase SANS?
BMR - by increasing synthesis of Na+/K+ ATPase to allow cells to depolarize more often / work faster
SANS - upregulate B1 receptor (remember that cortisol is responsible for the alpha1 receptor upregulation)
How does hypothyroidism cause secondary lipoproteinemia? Why is this clinically relevant?
- Low BMR slows LPL activity
- LDL levels increased due to lack of T4 stimulation of SREBP2
Relevant because hyperlipidemia responds very well to T4 replacement therapy -> should be screening for hypothyroidism especially in young females with dyslipidemia
-> hyperthyroidism actually causes HYPOcholesteremia
How does T3/T4 affect blood glucose levels?
Hyperthyroidism - hyperglycemia (increased stress)
What is the pathogenesis of Hashimoto’s thyroiditis? What antibodies are present and are they the cause of disease?
Sensitization of autoreactive CD4+ cells to thyroid antigens, causing activation of immune system.
CD8 T cells -> perforin/granzymes / Fas pathways.
Cytokine-mediated -> macrophage activation via IFNy
Antibody-dependent cell-mediated cytotoxicity via NK cells -> probable minor role of antibodies, more of a marker.
- Antithyroglobulin antibodies
- Anti-thyroperoxidase antibodies (antimicrosomal)
How does the thyroid appear microscopically in Hashimoto’s? What cells are characteristically seen?
Replacement of thyroid parenchyma with a diffuse mononuclear inflammatory infiltrate causing follicular atrophy
- > looks like a lymph node
- > can progress to marginal B cell lymphoma (t(11;18))
Hurthle cell change - characteristic of this disease -> eosinophilic metaplasia of follicular cells, as they have no colloid to hold onto anymore.
What is the pathogenesis of Subacute Granulomatous Thyroiditis and what is it also called?
Also called De Quervain thyroiditis
Pathogenesis: Viral infection -> antigen-induced, CD8 T-cell mediated injury to thyroid follicular cells -> It is a type of infectious thyroiditis, but we put it in its own class because of its unique histology
What is Subacute Lymphocytic Thyroiditis and who tends to get it? What is the pathogenesis?
Also called Painless thyroditis (vs de Quervain), it is an auto-immune mediated lymphocytic infiltrate, so it is more common in women. (Note: all thyroid conditions are more common in women)
However, it is especially common in POSTPARTUM women
-> this is analogous to lymphocytic hypophysitis seen in the pituitary during pregnancy
What does the thyroid look like in subacute lymphocytic thyroiditis and is it painful? What’s the clinical progression?
Thyroid looks mildly enlarged with a lymphocytic infiltrate, however it is subacute and vs de Quervain’s it is NONPAINFUL (autoimmune, non-infectious mediated)
Similar thyroid hormone level presentation as de Quervains: mild early thyrotoxicosis -> hypothyroid -> euthyroid resolution
What can you confuse Riedel thyroiditis with and why? How does it present?
Simulates an invasive neoplasm such as anaplastic carcinoma since it invades surrounding structures with fibrosis (i.e. retroperitoneum). Riedel “fibrosing” thyroiditis -> an autoimmune condition.
Presents as a “hard as wood” / rock hard PAINLESS goiter, some may be hypothyroid. But patients are generally too young to have anaplastic carcinoma and there are no malignant cells on biopsy.
What is the true definition of a goiter?
A goiter is a process by which impaired thyroid hormone synthesis leads to increased TSH secretion and thus thyroid follicular hyperplasia. It does not refer to Hashimoto’s or graves’ which is a “goitrous enlargement” where the thyroid is enlarging due to a pathologic process (i.e. inflammatory infiltrate, or nonstop stimulation of thyroid release)
What is the general underlying mechanism of goiter which causes diffuse -> multinodular?
There is some reason for impaired thyroid hormone synthesis, which leads to increased TSH secretion.
Persistent TSH stimulation causes variable response of thyroid follicular epithelial cells (initially diffuse, becomes nodular). This leads to uneven hyperplasia + areas of involution = nodules. Rupture of follicles / blood vessels causes hemorrhage / fibrosis of the gland, with dystrophic calcification. Surrounding areas are variably active -> multinodular
What are the etiologies of goiter?
- Iodine deficiency - most common in developing world
- Hereditary enzyme defects in thyroid synthesis -> more TSH is needed to stimulate gland -> goiter
- Ingestion of goitrogens -> i.e. brussel sprouts, cabbage, cauliflower
- Idiopathic need for increased TSH to maintain euthyroid.
What is hot nodule vs a cold nodule? Which one is more likely malignant?
Based on the amount of radioactive iodine uptake. Hot = lots of uptake.
Hot nodules as in a goiter or Graves disease (more diffuse) are usually benign.
“Cold” nodules, or low uptake, are usually benign as well, but warrant biopsy (malignant nodules are generally cold). These ones can be malignant.
What is the hormonal thyroid state of most people with goiter?
Goiter -> clinically euthyroid, but have a goiter to maintain that euthyroid state.
Those with “toxic” multinodular goiter will have autonomous nodules and may present with hyperthyroidism
-> toxic = produce T3/T4 independent of TSH
What is a benign neoplasm of the thyroid called, and what does it look like histologically? How can it be differentiated from a carcinoma?
Thyroid adenoma, usually a follicular adenoma with proliferation of thyroid follicles. -> in rare instances they can produce hormone and still be benign, but are generally cold.
These have a well-circumscribed capsule. Differentiated from a follicular carcinoma via lack of invasion through capsule or vasculature.
What two types of thyroid carcinoma are associated with RET mutations. Which one is associated with an MEN, and what cell is it derived from?
- Papillary carcinoma - associatied with RET fusion protein
- Medullary carcinoma of thyroid (Parafollicular / C cell derivation) - associated with RET mutation, in MEN2A and MEN2B syndromes.
What are the three types of thyroid carcinoma derived from follicular cells, which one is most common, and what mutations are associated with them?
- Papillary carcinoma - most common, associated with RET mutation
- Follicular carcinoma - associated with RAS mutations. Similar to follicular adenoma.
- Anaplastic carcinoma - no mutation in particular
What is the primary risk factor for papillary carcinoma of the thyroid and who tends to get it?
Risk factor: Exposure to ionizing radiation in childhood (i.e. lymphoma, acne treatment, nuclear radiation)
Tends to be seen in younger females
What is the histologic appearance of papillary carcinoma and how is the diagnosis definitively made?
Typically a papillary growth structure, with psammoma bodies (since a papillary carcinoma).
Diagnosis definitively made based on nuclear features of the cancer, even in the absence of papillary growth pattern:
“Orphan Annie Eyes” - Empty-appearing nuclei with chromatin on the edge, and intranuclear grooves with a ground-glass appearance of the nucleus.
Papi and Moma adopted Little Orphan Annie
What is the risk factor for follicular carcinoma of the thyroid and how must diagnosis be made?
Increased prevalence in areas of endemic iodine DEFICIENCY.
Diagnosis is made via biopsy with detection of invasion through the capsule or into the vasculature! Need to biopsy the entire sample to tell
-> this is the reason why fine needle aspiration for a follicular adenoma is insufficient to rule out cancer.
What is the pattern of spread of follicular carcinoma of the thyroid carcinoma and its prognosis?
Despite being a carcinoma, this is one of the few carcinomas which spreads hematogenously to lungs / bone. Remember this because it infiltrates VASCULAR structures (seen in lab). Other examples of carcinomas which do this are RCC, HCC, and choriocarcinoma.
Prognosis is actually pretty good, depending on tumor stage.
Other than salt and pepper chromatin, what else can be seen histologically on examination of a medullary thyroid carcinoma?
Amyloidosis -> due to accumulated AE amyloid derived from calcitonin.
Remember that it can occur bilaterally in MEN2 syndromes, and the tumor marker is calcitonin
Give two causes of dyshormonogenetic goiter and what syndrome they can cause in a person?
Cause congenital hypothyroidism - Cretinism, due to inability to properly produce thyroid hormone. This is just one cause of the condition.
- Genetic defect in thyroperoxidase - most common
- Pendred syndrome - mutation in Cl-/I- anion exchanger
What are two common places for myxedema to occur in hypothyroidism? Why does this occur?
Larynx - giving them a deepening of the voice
Tongue - macroglossia
Occurs due to deposition of GAGs
Where does papillary thyroid carcinoma spread to and what is the prognosis?
Generally spreads to cervical lymph nodes regionally, the prognosis is very good even despite this.
What mutations are associated with familial primary hyperparathyroidism (including parathyroid adenomas)?
- MEN1 - autosomal dominant -> parathyroid adenoma
- RET - MEN2A -> parathyroid hyperplasia by constitutive activation of tyrosine kinase
- CaSR - loss of function mutation -> hypercalcemic hypocalciuria
What is PTHrP and what cancers secrete it?
An unmeasured analog to PTH which was expressed in developing bone, placenta, and fetus
Secreted by: sQuamous cell cancers of lung, head, and neck;
Renal and bladder
Breast and ovarian
Think Q (near P) + urinary + BRCA
What type of receptor is the PTH receptor and why is this clinically relevant?
It is a GalphaS receptor
-> increased urinary cAMP can be measured whenever PTH levels are high and the signalling pathway is working properly
What are primary, secondary, and tertiary hyper-PTH usually caused by? (not all of these will be associated with elevated serum calcium levels)
Primary - Usually parathyroid adenoma or hyperplasia, less commonly parathyroidism carcinoma.
Secondary - due to hypocalcemia, i.e. renal failure
Tertiary - autonomous hyperparathyroidism from renal disease (nodule becomes autonomous from longstanding secondary)
What drug works as a CaSR receptor agonist and what is it used to treat? Side effect?
Cinacalcet -> used to treat primary or secondary hyperparathyroidism, makes the body think there is enough calcium (activates CaSR) and it can stop producing PTH.
Side effect is hypocalcemia.
What are the causes of primary hyperparathyroidism and what will the glands look like in the two most common cases?
Parathyroid adenoma - 80% of cases. Single enlarged nodule / one gland enlarged gland, with other three atrophied due to lack of activity -> MEN1
Parathyroid hyperplasia - all four glands are enlarged -> 20% of cases -> RET
Parathyroid carcinoma
What are the “signs” associated with hypocalcemia?
Trousseau’s sign - PAINFUL (avoid test) carpal SPASM when BP cuff is inflated above systolic pressure for three minutes
Chvostek’s sign - twitching of facial muscles when nerve is tapped at parotid gland (tapping Cheek) -> positive in 10% of normal
What are causes of vitamin D deficiency and hence hypocalcemia?
- Decreased ingestion (malnutrition) or of sunlight
- Deficiency of 25-D3 production due to severe liver disease
- Anticonvulsant use (CYP inducers) -> breakdown vitamin D
- Deficiency of 1alpha hydroxylase activity - advanced renal failure, hypoparathyroidism
What is vitamin D dependent vs resistant rickets?
Vitamin D dependent - 1alpha hydroxylase deficiency
Vitamin D resistant - vitamin D receptor abnormality
What are causes of hypoparathyroidism?
- Surgical - most common, after total thyroidectomy
- Autoimmune
- Idiopathic / genetic -> activating mutation of CaSR, or DiGeorge (lack of pouch 3/4)
- Infiltration of gland -> iron overload, malignancy
- Severe Hypomagnesemia - Mg+2 needed to stop tonic activation of CaSR on chief cells
- Pseudohypoparathyroidism
What is the cause of pseudohypoparathyroidism type 1A and what is the name of the phenotype?
Autosomal DOMINANT defect in Gs protein alpha-subunit -> end-organ resistance to PTH.
Defect must be inherited by MOTHER due to imprinting
Phenotype: Albright hereditary osteodystrophy
What is the phenotype of Albright hereditary osteodystrophy (AHO) and what clinical sign is described?
Short stature, and short 4th / 5th metacarpals leading to absence of prominent MCP joint
-> knuckle-knuckle-dimple-dimple
What lab values characterize secondary hyperparathyroidism and what are some causes?
Low serum calcium with high PTH
- Chronic Kidney Disease - most common
- Vitamin D deficiency
- Malabsorption of calcium
- PTH resistance - pseudohypoparathyroidism type 1A
How do you differentiate between pseudohypoparathyroidism and other conditions with increased PTH but low calcium?
- Plasma phosphate levels will be elevated (vs vitamin D deficiency and malabsorption)
- Urine cAMP will be low (vs kidney failure)
- > indicates receptor is not signaling properly
What produces FGF23 and what are its actions?
FGF23 - produced by osteocytes
Actions:
1. Increased phosphate excretion (inhibited proximal reabsorption)
2. Inhibition of 1-alpha-hydroxyalse
(Basically anti-vitamin D -> can cause rickets and osteomalacia)
How is FGF23 degraded and why is this clinically relevant? What is the inheritance pattern?
PHEX protein, inherited via X-chromosome.
Dominant mutation that causes resistance of FGF23 to degration -> increased phosphate wasting -> X-linked hypophosphatemic rickets
What are the symptoms of hypophosphatemia?
Severe muscle weakness due to decreased ATP synthesis -> may cause paralysis and rhabdomyolysis
Hemolysis -> RBCs require ATP to maintain membrane integrity
Bone pain and osteomalacia (hypophosphatemic rickets)
What is the mechanism of hypophosphatemia in refeeding syndrome and insulin therapy in DKA?
Both lead to increased glucose uptake and initial phosphorylation of sugars -> phosphate depletion
How can alkalosis cause hypophosphatemia?
Alkalosis activates PFK-1, causing increased phosphorylation of glucose
- > most common cause of hypophosphatemia in the hospital
- > think of it as the body trying to produce lactate in order to restore acid-base status
Does hyperparathyroidism cause osteoporosis or osteopenia? What’s the difference?
Osteopenia -> cortical thinning which is more prominent than in the medullary cavity. Especially subperiosteal thinning. Related to increased osteoclast activity with an attempted osteoblast rescue.
Osteoporosis happens more in spongy bone, typically a slow wasting away not due to massively increased osteoclast activity
What is the end stage of hyperparathyroidism called and why?
Osteitis fibrosa cystica
Osteitis -> osteoclasts dissect through bone, causing fractures and bone pain. “-itis” because osteoclasts derived from monocytes.
Fibrosa -> marrow fibrosis and secondary reactive woven bone formation by osteoblasts (derived from osteoprogenitor cells, same precursor as fibroblasts)
Cystic -> formation of brown tumors
What are brown tumors?
The cystic lesions found in osteitis fibrosa cystica
- > areas of hemorrhage, hemosiderin-laden macrophages, granulation tissue, and microfractures
- > osteoclasts have chewed a big gap into the bone
What change is seen pathologically in the pituitary as a result of increased circulating cortisol? Which cells experience it?
“Crooke hyaline change”
- > degenerative change in ACTH-producing cells in anterior pituitary
- > cytoplasmic keratin filament accumulation -> eosinophilic. Looks a bit like Hirano bodies
-> This change will occur in all cells not secreting any ACTH (atrophic), i.e. the entire pituitary in primary adrenal hyperplasia, or the non-pathologic areas of the pituitary in Cushing’s disease.
What is the most common cause of primary hyperaldosteronism?
Bilateral idiopathic hyperaldosteronism -> diffuse adrenal cortical hyperplasia most prominent at periphery (where zona glomerulosa is)
What is Conn syndrome specifically?
An adrenal adenoma which secretes aldosterone
Would not include aldosterone-producing adrenal carcinoma
Give three causes of bilateral adrenal hemorrhage with secondary infarction and who they tend to happen in?
- Difficult delivery - newborns -> too much blood delivered to adrenals due to peripheral vasoconstriction
- Infants / newborns -> Waterhouse-Friderichsen syndrome, hypotension because their glands are so big compared to their body the sepsis / shock has a larger effect
- Those with hemorrhagic diathesis -> DIC / anticoagulant therapy -> hemorrhage since adrenals are so vascular
What is the most common cause of Addison disease? What will be seen histologically? What syndromes is it a part of?
Autoimmune adrenalitis
- > adrenal glands show a lymphocytic infiltrate and only very few active adrenal cortical cells
- > often part of APS1 and AP2
- > usually idiopathic (most common cause of Addison disease in the Western world)
Who is most susceptible to Addison’s disease by infectious causes? Can cancer cause cause Addison’s?
Usually patients with AIDS in developing countries -> especially associated with TB**, destruction of gland via host inflammatory response
Cancer -> lung carcinoma (all types but squamous) are known to invade adrenal gland and replace its architecture. Remember that the adrenal glands is one of the favorite places for lung cancer to spread to.
What is the 10% rule for pheochromocytoma?
10% are the exceptions: 10% - malignant (have metastasized) 10% - bilateral 10% - in extraadrenal sites 10% - not associated with hypertension 10% - arise in children 10%-25% familial: RET, VHL, NF-1
What are common extra-renal sites where pheochromocytoma arises?
- Organ of Zuckerkandl - paraganglion chromaffin cells involved in fetal control of blood pressure, around the IMA
- Carotid body - paraganglion cells
- Bladder wall - SANS paraganglion cells
What is the most common of tumor of the adrenal medulla in children? How old are they when they present? Is it often familial?
Neuroblastoma, kids are generally <5 years old.
Sporadic is much more common than familial
Where does neuroblastoma develop?
- Adrenal medulla
2. Along sympathetic trunk -> paravertebral, including posterior mediastinum and retroperitoneum.
How does neuroblastoma appear / feel grossly and why is this important clinically?
Feels like an irregular, lobulated mass which can cross midline
Wilms tumor (Nephroblastoma) is in similar age group, but is usually smooth and unilateral
What is the precursor cell type for neuroblastoma and how does this relate to its histologic appearance?
Cell of origin is the neuroblast, the same cell of origin as Chromaffin cells and sympathetic ganglion neurons.
Since it is a neuronal blast cell, it forms Homer-Wright Rosettes (like medullablastoma), along nerve processes (eosinophilic collections of neuropil)
Where does neuroblastoma spread to?
Hematogenous dissemination to rather specific places -> bones and periorbital bone
-> infiltration of periorbital bone leads to raccoon eyes
Can also spread via lymph / hematogenously to go to usual spots, and is very locally invasive
What are two genetic markers which are associatied with poorer prognosis in neuroblastoma?
- N-myc amplification (similar to Burkitt which has c-myc amplification, small cell lung cancer which has l-myc)
- Hypo-diploidy (tumor is so malignant it can survive with fewer chromosomes)
What are the symptoms of hypercalcemia to remember?
- Stones - nephrolithiasis (kidney stones due to hypercalciuria), renal failure (post-renal azotemia)
- Thrones - Polyuria (with volume depletion and dehydration)
- Groans - abdominal discomfort from kidney stones, acute PANCREATITIS, nausea/vom
- Bones - osteitis fibrosa cystica
- Psychiatric overtones: Coma, altered mental status
- Metastatic calcification (of normal tissues, i.e. nephrocalcinosis)
Where in the islets are the beta cells present?
The center of the islets.
Which type of diabetes has a stronger genetic predisposition, and what HLA’s predipose you?
Type 2 diabetes has a stronger genetic predisposition than Type 1
HLA-DR3 and DR4 are associated with Type 1 diabetes though.
Think type 1 and not 2, associated with 3 and 4 “1,2,3,4”
What are the signs and symptoms of DKA?
DKA is Deadly
D - delirium / psychosis (from decreased brain perfusion due to hypovolemia)
K - Kussmaul respirations - deep / rapid breathing
A - abdominal pain, nausea / vomiting
D - Dehydration
Fruity odor can be smelled on breath due to exhaled acetone
What can be seen in the pancreatic islets in Type 1 vs Type 2 diabetes?
Type 1 - T lymphocytic infiltration -> autoimmune destruction
Type 2 - amyloidosis - accumulation of AE amyloid from overproduction of insulin + amylin. Actual protein that accumulates is amylin.
How does sorbitol play a role in the pathogenesis of diabetes? What tissues lack the appropriate enzymes and how does this manifest?
Sorbitol pathway uses aldose reductase to capture glucose in cells, and then sorbital DH to regenerate fructose
LuRKS are tissues with insufficient sorbitol dehydrogenase to get rid of sorbitol if it is at high levels.
Sorbital is an osmotic agent which causes damage.
L = Lens = Cataracts
R = Retina = Retinopathy (affects the pericytes of retinal vessels -> vessel dilation/aneurysm -> hemorrhage -> blindness)
K = Kidneys = Nephropathy (some contribution)
S = Schwann Cells = peripheral neuropathy
What are the consequences of the large vessel non-enzymatic glycation in diabetes? What is the most common cause of death in diabetes?
Atherosclerosis - most important, increases strokes and MIs
Coronary artery disease
Peripheral vascular occlusive disease with gangrene -> common cause of limb amputations
Most common cause of death in diabetes is MI
What is the diagnostic cutoff for HbA1c in diabetes and what is the treatment goal?
> 6.5% is likely diabetes, goal is 7% for control (reflects average blood glucose over 3 months)
How can the diagnosis of diabetes be made via random glucose and fasting glucose?
Random glucose > 200 mg/dL
Fasting glucose > 126 mg/dL after 8 hours of fasting
What is the glucose tolerance test and what is diagnostic for diabetes?
Give the patient 75g of glucose in water
If glucose is >200 mg/dL 2 hours after consumption, patient has diabetes
What is the mechanism by which insulin resistance during pregnancy is thought to arise? Why does this occur?
Human placental lactogen (HPL) is produced, which induces insulin resistance. Insulin resistance allows blood glucose levels to be slightly elevated to let the baby use glucose to develop.
It also stimulates lipolysis, allowing the mother to use ketone bodies for energy.
What are the possible fetal consequences of uncontrolled maternal diabetes?
Fetal anomalies due to hyperglycemia-induced oxidative stress.
- Heart - transposition of the great arteries, ASD / VSD
- CNS - neural tube defects
- Large for gestational age (macrosomia)
- Intrauterine growth retardation (if there is placental insufficiency due to vascular disease)
- Caudal regression syndrome
What is the spectrum of caudal regression syndrome which can happen in diabetes?
- Anal atresia - minimal developmental field defect
- Sirenomelia - “mermaid syndrome” - dysgenesis of entire lower trunk i.e. lower extremity fusion and lack of normal rotation
What are the two pathways through which insulin signals? Which one is impeded vs not in Type 2 diabetes and what does this explain?
- MAPK pathway - cell growth and proliferation pathway - not affected in Type 2 diabetes -> explains why Type 2 diabetes is associated with higher cancer risks
- PI3K signalling - glucose import and glycogen / protein / lipid synthesis pathway - affected in Type 2 diabetes
What antibodies are often positive in Type 1 diabetes?
- Anti-islet cell antibodies
- Anti-insulin antibodies
- Anti-glutamic acid decarboxylase antibodies - anti-GAD, cuz memo sure is sweet!!
When do risk of macrovascular vs microvascular complications onset in diabetes?
Macrovascular - with impaired glucose tolerance, as in prediabetes (reason for increased cardiovascular effects in prediabetes = 5.6%-6.4%)
Microvascular - when glucose levels start rising (postprandial spikes first) -> reason why diabetes brings out microvascular changes
Who gets diabetic ketoacidosis and what tends to precipitate it?
Usually Type 1 diabetics, because type 2 diabetics have some basal endogenous insulin which suppresses lipolysis (no ketone bodies will be generated). Can happen in type 2 diabetics with total beta cell failure.
Precipitated by stress (i.e. infection) -> increased epinephrine stimulates gluconeogenesis further.
What is the mechanism of insulin resistance in Type 2 diabetes?
Decreased number of insulin receptors expressed on the cells - per pathoma
What are the clinical symptoms of somatostatinomas?
- Achlorhydria - due to inhibition of gastrin
2. Cholelithiasis with steatorrhea - due to inhibition of CCK
What is the utility of low vs high dose dexamethasone suppression test in diagnosis of Cushing’s syndromes?
Low dose -> can make definitive diagnosis of Cushing’s syndrome of any time, as cortisol will not be suppressed.
High dose -> cortisol WILL be suppressed in Cushing’s disease (pituitary adenoma) but will NOT be suppressed in ectopic ACTH secretion
How does pheochromocytoma look grossly?
A tan mass which turns dark brown with oxidation of stored catecholamines, often with areas of hemorrhage and necrosis
When are stimulation vs suppression tests used and what drug is used for the stimulation test of the adrenal cortex?
Stimulation - used if hormone deficiency is suspected
Suppression - used if hormone excess is suspected (see if it’s suppressable)
Cosyntropin - ACTH analog which can be used for adrenal stimulation test (especially for Addison’s disease)
What condition may glucagonoma be misdiagnosed with? What will patients present with clinically (outside of skin manifestations)?
May be misdiagnosed as intertriginous dermatitis (like diaper rash for adults) -> skin condition in this case is called “Necrolytic Migratory Erythema”
-lesions coalesce to form large plaques with peripheral blistering / scaling, and central clearing which appears brown or bronze-colored #585
Adults present clinically with new onset diabetes + depression
What is Nelson syndrome?
As background, refractory Cushing’s disease (ACTH-secreting pituitary adenoma) often has to be treated via bilateral adrenalectomy.
Nelson syndrome is when the Cushing’s disease adenoma enlarges and causes increased ACTH secretion (loss of negative feedback).
- > causes hyperpigmentation, bitemporal hemianopsia, and headaches
- > ACTH made from POMC, increased MSH stimulates melanocytes to increase pigmentation
What symptoms are specific to Addison’s disease vs secondary adrenal insufficiency?
- Hyperpigmentation- Overproduction ACTH due to lack of negative feedback from primary issue
- Salt craving and hyperkalemia - Addison’s disease only (primary adrenal insufficiency), as zona glomerulosa will also not be working. In secondary adrenal, zona glomerulosa is intact and functioning normal (does not require ACTH)
What X-linked condition can cause Addison’s disease?
X-linked adrenoleukodystrophy (look for in males, peroxisomal problem of VLCFA buildup)
What is the treatment of primary vs secondary adrenal insufficiency? What will renin levels be in each condition pretreatment (this is really a hint).
Primary - administration of a glucocorticoid + mineralocorticoid. Renin levels high pre-treatment. -> Addison’s disease knocks out the ENTIRE adrenal cortex.
Secondary - administration of a glucocorticoid only (aldosterone okay). Renin levels normal.
What is the metyrapone stimulation test? What is normal / abnormal.
Test blocking the last step of cortisol synthesis -> 11-deoxycortisol to cortisol.
Normal: decreased cortisol and compensatory increase in ACTH + 11-deoxycortisol.
Primary adrenal insufficiency: ACTH is increased but 11-deoxycortisol is still low after test.
Secondary / Tertiary adrenal insufficiency: both ACTH / 11-deoxycortisol remain low after the test.
What is the most common cause of congenital adrenal hyperplasia? What accumulates / what is decreased in it?
21-hydroxylase deficiency, enzyme which catalyzes the conversion of 17-OH-progesterone and progesterone to aldosterone and cortisol precursors.
Accumulates: DHEA / androstenedione (androgens) + 17-OH progesterone
Decreased: Cortisol / aldosterone
-> note that obviously cortisol is decreased in ALL congenital adrenal hyperplasias.
What are the symptoms of classical 21-hydroxylase deficiency?
Presents in infancy:
Lack of aldosterone: Hyponatremia, hyperkalemia
Lack of cortisol: Hypotension (salt-wasting type)
Excess androgen:
Females - clitoral enlargement / ambiguous genitalia = female pseudohermaphroditism
In the classical form of 21-hydroxylase deficiency, is salt-wasting always present? Why or why not?
Not always -> only minimal aldosterone needs to be produced (relative to cortisol) to have normal functioning.
Virilization at birth will always happen in the classical form, however.
What is the second most common cause of CAH, and what accumulates / is underproduced?
11-beta-hydroxylase deficiency
-> similar to metyrapone testing
11-deoxycortisol accumulates -> decreased cortisol synthesis
11-deoxycorticosterone accumulates (precursor to aldosterone), but is actually a mineralocorticoid
Some level of excess androgen is also present due to shunting away from cortisol pathway
What are the clinical features of 11-beta-hydroxylase deficiency? Will renin levels be up or down?
Androgen excess -> similar to 21 hydroxylase deficiency, females have virilization at birth
11-deoxycorticosterone -> actually potentially activates mineralocorticoid receptor -> causes hypertension with hypokalemia, low renin levels.
What accumulates or is decreased in 17a-hydroxylase deficiency? Will aldosterone be increased?
Inability to make 17-OH-progesterones, so all is shunted into mineralocorticoid pathway
Accumulates: 11-deoxycorticosterone, mineralocorticoid. Aldosterone not increased because aldosterone synthase under control of angiotensin II
Decreased: cortisol / androgens
What are the clinical features of 17a-hydroxylase deficiency in males and females?
Increased 11-DOC -> hypertension with hypokalemia
Females: Normal genitalia at birth, but primary amenorrhea (lack of sex hormones for puberty)
Males: Normal testes but undescended, ambiguous external genitalia (lack of androgens, but testes present due to SRY)
What test is run at newborn screening to check for congenital adrenal hyperplasia? How will they be changed in the three major conditions?
Failure to thrive, Na+ wasting, hypotension, hyponatremia, and hyperkalemia
In this cause, lack of aldosterone matters since there isn’t ACTH stimulating 17,20 desmolase since cortisol levels will be normal -> 11-DOC will not accumulate enough to compensate for loss of aldosterone.
