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Unit 7: LGS > Week 2 > Flashcards

Week 2 Flashcards

1
Q

How do we analyze hyperglycemia in the lab? What are the time points at which we measure blood glucose levels and what is the relevance of each?

A
  • Fasting
  • 10-15 minutes after eating
  • 2-3 hrs after eating
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2
Q

Fasting

  • importance
  • when is it taken?
  • results
A
  • gives you patient’s baseline glucose level.
  • after 8-10 hrs of fasting
  • Should be between 80-100mg/dL (5.5 mmol/L)
  • If you are above or below this level, glucose metabolism is impaired for some reason
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3
Q

10-15 minutes after eating (post prandial)

  • why this time
  • measure of
  • normal
A
  • this is how long it takes the glucose to reach the blood -> will immediately be followed by the first phase of insulin release which is stored in secretory vessicles of pancreatic beta cells
  • first phase insulin response
  • Blood glucose goes up to 200 mg/dL
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4
Q

2-3 hrs after eating

  • what does it measure
  • normal
A
  • how well blood glucose comes back down in an attempt to reach homeostasis
  • Actually measuring the second and third phase of insulin release
  • Blood glucose should be brought back down to 140 mg/dL
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5
Q

What symptoms would the patient present with if this was a case of type I diabetes?

  • sxs in both DMI and DMII
  • sxs only in DMI
  • sxs in UA
  • labs
  • How would his symptoms differ for diabetes type II?
A
  • polyuria, polydipsia, and blurred vision (overlap in both type I and type II diabetes because they are associated with hyperglycemia)
  • You may see a history of weight loss, Insulin levels would be low (C-peptide)
  • You would also see ketones in the urine analysis and ketoacidosis in the blood analysis (drop in pH)
  • Free fatty acids would be elevated -> body is in a catabolic state since glucose utilization is impaired due to low insulin (beta cells are decreased).
  • History of increased body weight, Tingling in the hands and feet, Increased appetite, Decreased muscle mass, Won’t see DKA in type II unless there is some kind of acute infection or stressor that really throws off the patient’s homeostasis which is pretty rare.
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6
Q

How to measure C-peptide

A

measure C peptide rather than measuring insulin directly because c peptide has a longer half-life

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7
Q

Type I Diabetes causes

  • genetic
  • drugs/chemicals
  • medical causes
A
  • There are 3 genetic causes: 1. MHC class II and HLA-DRs (type II), 2. VNTR (variable number tandem repeats) of a specific region, 3. VNTR of a specific length
  • Chemotherapeutic drugs, High doses of steroid administration
  • cystic fibrosis and pancreatic CA
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8
Q

MHC class II and HLA-DRs (type II)

  • presentation
  • down stream
  • antigens
A
  • external antigens and cause and autoimmune attack against pancreatic beta cells
  • So, mutations in HLA- II mutations leads to structurally mutated MHCs (specifically mutated MHC class IIs). Mutated MHCs have structural modifications which allow them to present internal antigens rather than external antigens and activate T cells against self… this is what initiates the auto-immune attack against self pancreatic beta cells since they heavily produce these internal antigens
  • insulin, tyrosine phosphatase (which is associated with insulin receptor activity), or GAD.
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9
Q

VNTR (variable number tandem repeats) of a specific region

A

upstream to the promoter region of the insulin gene itself

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10
Q

VNTR of a specific length

A
  • 20-60 nucleotide base pair repeats upstream the promoter are generally found in individuals with type 1
  • VNTRs must be found in both maternal and paternal (homozygous) insulin genes
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11
Q

Cystic Fibrosis

A
  • Hypersecretion by the pancreas can clog/obstruct the exocrine pancreas which can cause pancreatitis and destruction of beta cells, decreasing insulin production.
  • Really severe case of necrotizing pancreatitis which knocks out the vast majority of the pancreatic function in a single hit. But it would have to be very severe… severe enough to knock out 80-90% of the pancreas.
  • This is rare, so chronic causes are more likely. Almost always, it is a chronic process with acute on chronic exacerbations of pancreatitis.
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12
Q

normal mechanism of insulin secretion

A

• Eat a meal, high levels of glucose in blood, gets to pancreatic beta cells by GLUT2 transporters (insulin independent at this point), gets locked by phosphorylation (turns to G6P), glucose kinase enzyme causes oxidative metabolism (glycolysis, TCA, ETC) and creates high amount of ATP production, so ATP:ADP ratio goes up, this is sensed by ATP sensitive K channels in membrane, they now close, locks potassium inside beta cells, leads to depolarization and opening of voltage gated Ca channels, Ca influxes in, Ca helps the insulin and C peptides (stored in equimolar amounts in secretory granules) released out into blood by exocytosis

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13
Q

If person has mutated glucokinase gene, makes glucokinase with much higher Km, what happens?

  • what does higher Km mean?
  • function of glucokinase
  • name of this dx
  • type of mutation
  • when does this present
A

• Higher Km is lower affinity for substrate of glucokinase
• Phosphorylates and holds glucose in only when there’s high levels of glucose in beta cells and also in blood –> Once G6P goes to oxidative metabolism it drives the process of insulin release –> So insulin release would only happen in response to very very high blood glucose levels
• This is called GCK-MODY (Glucokinase Related Maturity Onset Diabetes of the Young)
○ Autosomal dominant mutation
- Patient presents with diabetes in a much earlier age (below 25)

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14
Q

Mutant ATP sensitive K channel, what happens?

  • name? when does it start?
  • specific mutation
A

• Decreased insulin release
• Another genetic form of diabetes: Neonatal diabetes –> Have diabetes right from birth
- Can be treated but not cured
- Potassium channel made up of 8 different transmembrane domains, 4 of them made from 1 gene and the others from a second gene: KCNJ11 (makes 4 domains); ABCC8 (other 4 genes)
- Neonatal diabetes can be associated with mutations in the insulin gene itself

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15
Q

Sulfonylureas alter insulin secretion

  • how does it work
  • when is it used
A

• Binds to a domain of the K channel and closes it

- Used for treatment of Type II diabetes

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16
Q

Type of receptor for insulin

-pathway

A
  • RTK
  • Insulin binds, dimerization, autophosphorylation of the beta components of the receptor, phosphorylates downstream to get activation of those pathways and leads to upregulation of GLUT 4 receptors
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17
Q

Target organ insulin binds to

  • Liver
  • Muscles
  • Adipose
A
  • Decreased gluconeogenesis, Increased glycogen synthesis, Increase lipogenesis
  • Increased glucose uptake, Increased glycogen synthesis, Increased protein synthesis
  • Increased glucose uptake, Increased lipogenesis, Decreased lipolysis
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18
Q

Big picture thing that insulin does?

A

Increasing anabolic process to increase glucose uptake and utilization

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19
Q

Difference between insulin sensitivity vs resistance?

  • sensitivity
  • Resistance
  • At level of liver, what happens?
  • At level of skeletal muscle
  • Adipose tissue
A
  • Receptors are responding to insulin, With high sensitivity need lower amount of insulin for uptake
  • Receptors aren’t responding to insulin
  • Glucose uptake decreases, Glycogen synthesis decreases, Blood glucose levels elevated
  • Decreased glucose uptake, decreased glycogen synthesis
  • Activation of hormone sensitive lipase (HSL), excess triglyceride breakdown, excess free fatty acid circulation
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20
Q

How does DMII develop

- other dx they will most likely have

A
  • doesn’t usually occur in isolation
  • Unless there’s a specific gene variant like in MODY, we’re going to see that there’s a wide array of different predisposing factors
  • unusual for standard case of Type II diabetes to be seen without components of metabolic syndrome
  • metabolic syndrome, HTN, dyslipidemia, and eventually down the line would develop atherosclerotic vascular disease
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21
Q

Central adipose vs peripheral

  • difference in function
  • difference in location and importance
  • how does this cause inflammation
A
  • Central adipose is more lipolytic, it will increase free fatty acid production which will lead to abnormal signaling inside the cells.
  • Central is near the liver -> closer to portal circulation -> fat will enter the portal circulation -> increase in free fatty acids in vessel which are broken down and will lead to accumulation of DAG -> allows for increase in toxic metabolites, and increase in gluconeogenesis and glucose levels
  • Adipocytes release TNF-alpha and proinflammatory cytokines.
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22
Q

adipokines

  • what do they do?
  • effect on glucose?
  • when are they released with obesity?
  • what happens to glucose bc of increased fat?
  • what does this do to insulin
A
  • Leptin, adiponectin
  • Satiety signals; Normally decrease blood glucose levels
  • Adiponectin are reduced in obesity and that contributes to insulin resistance. Leptin levels may also go down and you become leptin resistant. What do leptin and adiponectin do?
  • greater central adipose tissue -> less production of adipokines -> no regulation of blood glucose at level of fat -> cause increase in blood glucose.
  • get insulin resistance bc of always having too much glucose
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23
Q

What happens to glucose, fat, and AA metabolism in Type I DM

  • insulin levels
  • glucagon
  • glucose utilization
  • how do they have energy?
  • liver
  • fat
A
  • Insulin levels will be low
  • Glucagon levels will be high
  • Glucose utilization in cells is low. PFK 2 activates PFK 1 (glycolysis) by insulin, so low insulin means this can’t happen–> low glucose utilization-> low ATP production from glucose -> cell compensates by shifting to beta oxidation (levels high in cells)
  • Protein is catabolizing to support gluconeogenesis bc glucose crisis in cell and cell needs to make more glucose –> Alanine, asparate converts to pyruvate and goes to gluconeogenesis; Ketogenic amino acids form, degrade into Acetyl CoA
  • Liver has a lot of acetyl CoA, with excess it’s going to convert them into ketones and release out into blood -> Ketoacidosis in blood
  • High glucagon affects fat metabolism by lipolysis
    Activates HSL, high amount of release of fat from periphery into blood, can contribute to high lipid levels in blood
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24
Q

Insulin and gluconeogenesis

A
  • Normally insulin de-activates PEP carboxykinase –> With insulin resistance, it can’t be dephosphorylated and cannot be deactivated; it remains active
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25
Q

Insulin and lypolysis

- results in?

A
  • Normally, insulin suppresses HSL and induces more storage of fats in periphery but with DMII HSL can’t be turned down
  • More free FA in blood, more triglycerides in blood, liver takes up lots of fat bc there’s lots of nonesterified free FA in blood –> liver compacts excess fats in form of VLDL–> sends out in blood, so VLDL and LDL levels are all elevated so make person prone to CVD –> So much fat in liver which sits there and leads to non alcoholic fatty liver disease
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26
Q

How to Dx DM

  • acute
  • chronic
A

• C-peptide levels: C-peptide is a marker of your endogenous insulin production, So T1DM will have Low C peptide and T2DM will initially have high, then later low C peptide when your beta population goes down
- Diagnosed with HbA1C: Non-enzymatic glycation of hemoglobin in the RBCs
Stays longer & bc RBCs live for 120 days, high hba1c is indicative of poor management of diabetes

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27
Q

marker for how quickly DMI will progress

A
  • Really low C-peptide level = really low insulin level to start with, means patient will probably have a more severe progression of T1DM
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28
Q

How to manage T1DM

  • how many carbs per serving
  • saturated fat and Na
  • transfat
  • how can you get away with having more carbs?
A
  • reduce overall load of glucose -> comes from carb counting
  • ~15
  • 5% or less
  • 0
  • if most of those carbs are from fiber
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29
Q

What is a one carb serving

  • bread
  • oatmeal
  • pasta/rice
  • starchy veggies
  • dairy
  • fruit
A
  • 1 slice of bread
  • 1/2 cup oats
  • 1/2 bagel
  • 1/3 cup cooked pasta or rice
  • 1/2 cup starchy veggies
  • 1 cup skim milk
  • 1 small piece, 1/2 cup cubed fruit, 1/3-1/2 cup juice
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30
Q

Healthy Plate for Diabetes

  • g of carbs
  • rice
  • non-starchy veggies
  • protein
  • yogurt or skim milk
A
  • 40-45
  • 1/4 the plate–1/2 cup
  • 1/2 plate
  • 1/4 plate
  • 1 cup
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31
Q

Rapid acting insulin

- when to give

A
  • Aspart, lispro, glulisine

- Right before meal

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32
Q

Regular insulin

  • when to give
  • why is this important?
  • other name
A
  • the peak is a little delayed so you have to do that 20-30 min before the meal
  • So again with the carb counting, knowing how many carbs you’re about to eat so you can give yourself the right dose ahead of time
  • Sometimes called insulin R
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33
Q

NPH insulin

  • other name
  • time duration
  • dosage
A
  • insulin N
  • middle
  • twice a day – 1 in morning and other at dinner
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34
Q

Detemir

- how long?

A
  • closer to full day but not all the way
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35
Q

Glargine

- duration?

A
  • 24 hours

- Eventually clears

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36
Q

How to dose insulin for T1DM

  • dose for T2?
  • overdose?
A
  • Rapid acting before meals + long acting to prevent basal hyperglycemia
  • Usually just long acting, dont add short acting until it gets bad
  • will cause hypoglycemia which can lead to death
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37
Q

Potential complications of diabetes mellitus

  • general
  • autoimmune
  • psch
  • metabolic
  • vascular
A
  • poor height/weight gain
  • delayed development
  • autoimmune thyroidits and celiac disease
  • depression and eating disorders
  • DKA
  • nephropathy, HTN, neuropathy, retinopathy
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38
Q

Patho underlying the potential complications

A
  • AGES & RAGES

- ROS & inflammation

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39
Q

What is a biguanides

- exmple

A
  • group of oral type 2 diabetes drugs that work by preventing the production of glucose in the liver , improving the body’s sensitivity towards insulin and reducing the amount of sugar absorbed by the intestines
  • metformin
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40
Q

Sulfonylureas

- examples

A
  • increase insulin secretion by pancreatic beta cells by binding to the potassium membrane channel we were looking at earlier
  • slimepiride, glipizide, and glyburide
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41
Q

Glimepiride vs Gliburide

A
  • Glimepiride = least likely to cause hypoglycemia

- Gliburide = most likely to cause hypoglycemia

42
Q

If blood sugar still uncontrolled

  • incretins
  • SGLT-2 inhibitors
  • Thiazolidinediones
A
  • hormones produced in small intestine during a meal that enter vasculature and trigger insulin release by pancreatic beta cells
  • inhibit renal reabsorption of glucose, encouraging excretion of glucose via urine; expensive; potential risk of UTI
  • increase insulin sensitivity by activating peroxisome proliferator-activated receptor gamma, a nuclear receptor with beneficial effects for factors involved in glucose and lipid metabolism; expensive; higher rate of CHF exacerbation
43
Q

Diet for DMII

  • fiber
  • Fat
  • Magnesium
A
  • lowers glycemis index/load
  • monosat and poly unsat omega 3
  • leafy greens, pumpkin seeds, nuts, whole grain, beans, dark chocolate
44
Q

Food for DMII

  • pulses
  • nuts
  • whole grain
  • seed
  • veggie
  • OH
  • caffeine
A
  • lentils, chickpeas, and beans
  • almonds, soybeans, walnuts
  • oats
  • chia
  • onion
  • red wine
    tea/coffee
45
Q

Exercise for DMII

A
  • aerobic and resistance

- improved insulin sensitivity

46
Q

Lifestyle approaches

  • smoking
  • mind body
A
  • smoking impairs insulin sensitivity and predisposes to met syndrome
  • cognitive behaioral therapy provides insight into habits that affects thoughts/actions ; biofeedback reduces plasma cortisol, peripheral vasoconstriction, and other SNS; sleep hygeine alters insulin signaling in adipocytes to improve insulin sensitivity, increase leptin and decrease ghrelin
47
Q

Botanicals for DMII

  • Ivy gourd
  • Marine Collagen peptides
  • cinnamon
  • milk thistle
  • fenugreek
  • gynostemma pentaphyllum
  • alpha-lipoic acid
  • magnesium
  • chromium
  • acetyl-L-carnitine
  • benfotiamine
  • vitamin K 2
A
  • insulinomimetic effects on lipoprotein lipase, G6Pase
  • lower A1C, LDL, FFA, and CRP
  • activates insulin receptor kinase, increase glucose uptake, autophosphorylate insulin receptor
  • decrease A1C and improve lipids
  • increase insulin secretion and inhibits glucosidase activity (increases satiety, gastric emptying, insulin receptor function)
  • decrease A1C
  • potent lipophilic antioxidant , reduces DPN and IR
  • critical for phosphorylation of insulin receptor
  • appears to reduce tissue lipid content
  • reduces DPN
  • synthetic analogue of thiamine, reduces DPN
  • helps reduce vascular calcification via SM/ endo repair -> may stimulate beta cell proliferation and enhance insulin sensitivity
48
Q

Bariatric Surgery for DMII

A
  • leads to complete resolution of diabetes in 78% cases

- long term consideration would be nutrient malabsorption

49
Q

Hypothalamo-Piuitary-Thyroid Axis

A
  • Hypothalamus -> Paraventricular nucleus-> TRH -> Ant. Pituitary -> TSH -> Thyroid -> T3 and T4
50
Q

T3

A
  • Some is produced but not as much as T4
  • Biologically active form
  • Deiodination from T4 to T3 occurs predominantly in liver, kidney, some in thyroid, and in peripheral tissue (muscles, adipose, neurons)–Regulates metabolic rate
51
Q

T4

A
  • Predominate hormone released

- Inactive form

52
Q

Requirements for production of T3/T4; raw materials needed:

A

Iodide and Thyroglobulin

53
Q

Iodide

  • where do you get it?
  • Any other function besides making T3 and T4: No
  • storage
A
  • diet -> sea food/salt, come veggies and meat
  • No
  • all iodide taken in accumulates in thyroid gland and is used to make T3/T4
54
Q

Thyroglobulin

  • what is it
  • where is it
  • what produces it
  • what is it made of
A

○ Almost like an enzyme going to take iodine from follicular cells to apical side to the colloid where it will be stored and used to make T3/4
○ intracellular
○ Glycoprotein produced by follicle cells
- Rich in tyrosine, provide tyrosine for formation of T3/T4

55
Q

What are T3/T4?

A

One AA with iodine residues stuck to it -> modified amino acid

56
Q

How do T3/T4 work?

- how do they act? why?

A
  • Act like steroids because they bind to nuclear receptors instead of membrane bound receptors
  • They go directly through plasma membrane and enter into cell, do NOT need tg bind to membrane bound receptor to get into cell
57
Q

MOA of TRH:

  • kind of receptor and intracellular signaling
  • what does it do?
A
  • TRH binds to cell membrane of thryotropes and activates G alpha q 11 -> activates intracellular phospholipase c -> increase IP3 and DAG-> increase in Ca -> release of TSH
  • Phospholipase C also helps in production of TSH
58
Q

MOA of TSH:

  • what does it do?
  • how many paths?
  • pathway
  • function of cAMP
  • function of PLC
A
  • TSH regulates the hormonal synthesis, growth of the gland, hypertrophy, hyperplasia
    ○ It requires a little more support so it activates 2 pathways
  • TSH binds to TSH receptors on thyrocytes and follicular cells -> G alpha S protein coupled receptor -> AC -> cAMP -> PKA-> production and synthesis of T3-T4
    ○ Functions cAMP: Thyroid hormone synthesis (T3/T4), Production of iodide symporters, Also produce TPO
  • Will also work through PLC -> Ca -> support some functions – Synthesis of hydrogen peroxide -> required for thyroid hormone biosynthesis -> important in iodination
59
Q

50 yr old male w/ complaints of fatigue, lethargy, intolerance to cold and constipation. Pt is on low Na diet bc of hypertension. Adopted. Lives predominately on veggie diet and does not eat meat, fish, seafood. PE with nodule on anterior portion of neck.

  • Predict Lab values
  • why?
  • cause
  • reasoning for mass
  • Are most people from goiter hypo, hyper, or eu thyroid?
  • What causes goiter
  • what does TSH do to thyroid?
  • salt
A
  • High TSH, Low T3/T4
  • Because your brain is trying to tell your thyroid to make more T3/T4
  • Iodine deficiency
  • Over stimulation of thyroid by excess TSH causing hypertrophy of the gland
  • Euthyroid –> the gland hypertrophies so much that it can compensate for lack of iodine
  • Too much TSH -> Therefore if patient has goiter it is deficiency of T3/T4 NOT TSH
  • TSH causes thyroid follicular cells to proliferate and produce T3/T4, the second of which it cannot do.
  • humans add iodine in salt
60
Q

What is difference between diffuse and nodular goiter

- difference from toxic goiter

A
  • they both have same disease process but a diffuse goiter becomes nodular with chronicity and cycles of involution and hyperplasia
  • When an autonomous nodule in a goiter acquired mutations and in this case the patient will be hyperthyroid
61
Q

Pt with hx of autoimmune dx, has fatigue, mental slugishness, feelings of apathy, cold intolerance, weight gain. PE shows cool and pale, thyroid diffusely enlarged, no apparent masses.

  • Importance of Sjogrens Syndrome
  • most likely dx
  • cause; how?
  • labs
  • tx
  • how do the cells die?
  • histo changes
  • herthel cells
A
  • if you have one autoimmune dx then you are more at risj for another autoimmune dx
  • hashimotos
  • Anti TPO or thyroglobulin antibodies; Lack of self tolerance to thyroid antigens
  • TSH, T3/4, anti0thyroid antibody panel
  • levothyroxine
  • Mostly mediated through CD-8 attack; another way is for CD-4 to activate antibodies and macrophages
  • lymphocytic infiltrates with germinal centers, herthel cells, benign thyroid cells that are chewed up
  • epithelial cells with eosinophilic and granular cytoplasm -> stuffed full of mitochondria -> mean that there is degenerative change
62
Q

mechanism of iodide uptake by the thyroid follicular cells

  • how does it get into cell
  • MOA of the symporters
  • what happens after it enters cell…and then?
  • malfunction of pendrin or the Na/I transporter
  • classification
  • presentation
  • what happens to I after pendrin
  • Importance of H2O2
  • next step
A
  • Sodium/iodide symporter on the basolateral surface of the thyroid follicular cells –> taking in Iodide (I-)
  • 2 Na+ coming in (down the concentration gradient) for every 1 iodide ion coming in from the blood into the cell
  • Uses Pendrin (the transporter at the apical surface of the thyroid follicular cells) is a Cl/iodide channel and helps transport/efflux iodide into the colloid present in the center of the follicle
  • it is oxidized w/in the colloid
  • Mutations in the gene producing the symporter or mutations in the gene producing pendrin –> can make them defective –> decreased iodide uptake or release into the follicular lumen affecting the synthesis of T3/T4 leading to low T3/4 production
  • primary hypothyroidism, and it is genetic so congenital forms of hypothyroidism
  • very early age; TSH would be high in these pts
  • Once the iodide gets released into the colloid (lumen) by pendrin I- becomes I+ (via oxidation) we need the enzyme thyroid peroxidase (TPO) for this.
  • H2O2 is the activator of TPO; Produced by reduction of O2 and NADPH will act as a hydrogen donor
  • Once it is oxidized, next step can happen.. which is added to the tyrosine residues and this is called: organification
63
Q

Organification

  • what is it?
  • how does it happen?
  • different forms
  • enzyme needed
  • how are T3 and T4 made
  • T3
A
  • Attachment of oxidized iodine to the tyrosine molecules in the thyroglobulin
  • Iodine will attach to the tyrosine ring in Carbons 3 & 5
  • 1 iodine attached to Carbon 3 –> MIT
  • If 2 iodine molecules attached to 3 & 5 of the tyrosine ring –> DIT
  • TPO and H2O2
  • attachment MITs & DITs together to form T3 and T4
  • T3 will contain 1 MIT and 1 DIT conjugated together by TPO and H2O2.
  • T4: 2 DITs conjugated together by TPO and H2O2
64
Q

How does T4 turn into T3

A

peripherally deiodinated to T3

65
Q

Secretion of T3/T4

  • release
  • thyroglobulin residues
A
  • TSH (regulates everything the thyroid does) stimulation of thyroid follicular cells will induce the secretion of T3/4 into the blood
  • When it is stored in the colloid, it is stored as still bound to thyroglobulin. When the thyroid gland is stimulated by TSH, release occurs..
  • T3/4 attached to the remnant thyroglobulin gets endocytosed back into the follicular cells, the vesicles/endosomes fuse w/ lysosomes w/in the cell and the enzymes help to separate the rest of the thyroglobulin from the T3/4, the conjugated molecules and release happens by exocytosis or it gets transported out into the blood
  • It gets recycled. Goes back to the colloid again and reused. If there are remnant iodine residues those get recycled as well for reorganification
66
Q

Serum levels of T3/T4

  • what is higher in serum
  • what happens next
  • proteins
A
  • T4 less amount of T3
  • Binds to 2 certain binding proteins ( TBG (thyroxine-binding globulin) to prevent it from undergoing proteolytic degradation and removal from the blood
  • transthyretin, albumin (can help in the transport)
67
Q

TBG

  • production
  • what happens in pregnancy
A
  • Liver
  • Estrogen & hCG in pregnancy help increase TBG production from the liver so then you will have low free T4 –> high production of TSH –> increased T3/4 production from the thyroid gland
68
Q

Deiodination of T3/4

  • where does it happen
  • Which iodine is lost?
  • makes?
  • how?
A
  • peripheral tissue
  • Iodine on carbon 5 of the outer ring
  • This will convert it to T3 (Biologically active form, induces cellular effects)
  • It is done by D I and D II –> D I expressed in the liver, kidney, and thyroid ; D II will be present in all other peripheral tissues which include cardiac & skeletal muscle, neurons, adipose, placenta (to some extent)
69
Q

What is reverse T3?

  • how does it happen
  • importance
A
  • The inner ring at carbon 5 is deiodinated
  • It is less active so it might have some activity but very low so reverse T3 production is also very low in the peripheral cells.
70
Q

Metabolization and excretion of T3 and reverse T3

A

Further lose iodine by D III to form T2 and T2 is the totally inactive form which will get excreted

71
Q

MOA of the thyroid hormones

  • what does it bind; how?
  • what about when unbound
  • where is the receptor?
  • corepressor
  • what happens to it when receptor is bound
A
  • Bind to nuclear receptor; It is lipophilic so it can get into the cell (some transporter proteins which can help transport T3/4 into the cells) –> once in the cell can get into the nucleus and bind to the nuclear receptor
  • When the nuclear receptor is unbound to its ligand (T3) it is inactive and prevents transcription of the target gene.
  • So the receptor is already bound to response element w/in the regulatory element of its target gene -> when it is not bound to the ligand, it is bound to other proteins that form the repression complex
  • makes its effect of repression more prominent so it stops transcription of the target gene
  • the corepressor is released and that leads to turning on transcription of the target gene
72
Q

Congenital Hypothyroidism

  • derivation of the word cretinism
  • causes of congenital hypothyroidism?
  • Signs and Symptoms
  • features
  • how to fix
  • pure
A
  • means incapable of sinning -> because people were mentally incapable
  • Maternal iodine deficiency or inborn errors of metabolism that can cause this
  • Decreased stature, Large tongue, mental retardation - this occurs due to impaired development of the CNS
  • prominent forehead, prominent bone structure, umbilical hernia
  • can’t
  • comes about in-utero; the baby is deprived of thyroid hormone or the function of thyroid hormone in-utero while they’re developing
73
Q

Myxedema

  • mild
  • signs and symptoms
A
  • adult-type
  • In very young infants who are deprived of iodine or who have hypothyroidism, you can see findings that are transitional between adult-type myxedema and cretinism
  • Myxedema is basically the manifestations of hypothyroidism when it develops later in life
74
Q

Explain symptoms of hypothyroid

  • low BMR
  • fats
  • glucose
  • energy
  • protein
  • cholesterol
  • heart rate
  • intolerance to cold
A
  • Under normal conditions, thyroid hormones maintain your basal metabolic rate by maintaining the catabolic and anabolic cycles -> between the anabolic and catabolic cycles is lost and the scale becomes heavier toward anabolism
  • If you compare the rate of lipolysis vs lipogenesis or fatty acid synthesis vs fatty acid oxidation, the expression of the rate limiting enzymes of both cycles are lower because you have low levels of T3 and T4 -> rate of lipid synthesis is relatively higher than oxidation -> weight gain
  • Gluconeogenesis glycogenolysis goes down , Blood glucose level will be down
  • Availability of glucose for peripheral cells might be slightly compromised and therefore there will be low energy production –> contributes to fatigue and low energy
  • Protein synthesis and proteolysis rates are down, but protein synthesis levels are higher in a hypothyroid individual compared to proteolysis
  • Serum cholesterol levels are elevated because the cells are using fatty acid oxidation less, so LDL absorption by the peripheral cells is less –> LDL accumulation driving up your cholesterol levels
  • Low heart rate -> because beta adrenergic receptor expression becomes low due to the low thyroid levels
  • ATP production in the cells are low bc with high amounts of ATP production, some of the excess ATP is converted into heat Also T4 and T3 that upregulate the expression of thermogenin (an uncoupler) -> Uncouplers help in heat production by uncoupling the oxidative phosphorylation from the ETC
75
Q

55 yr old female 6 months of restlessness, nervousness, insomnia, and significnat weight loss, family hx significant for autoimmune dx, PE w/ tachycardia, tremors, warm moist hands, and enlarged thyroid.

  • lab values?
  • dx?
  • why the goiter?
  • histo
  • normal characteristic and patho
  • dermatopathy
  • when else can it be seen
A
  • T3 and T4 are high, TSH is low, autoantibodies are present
  • graves dx -> autoantibodies are thyroid stimulating immunoglobulin
  • Overstimulation of gland by TSI vs the TSH –> As far as the gland is concerned, the TSH receptor is being stimulated so the antibody is mimicking TSH; Your real TSH is depressed, but you still end up with a stimulated gland
  • Cells are crowded together and are big and plump and start to pile up
  • Exophthalmos -> Inflammation of retroorbital space by T cells -> Accumulation of glycosaminoglycans (GAGs) -> Fatty infiltration
  • pretibial myxedema: non-pitting edema caused by accumulation of GAG’s
  • in Hashimoto’s, you can see it during those paradoxical cases where they have those spikes of hyperthyroidism
76
Q

Explanation of Hyperthyroid sxs

  • caused by?
  • catabolism
  • blood glucose
  • heat
  • protein
  • fats
  • heat
  • heart
  • hair
A
  • high levels of T3 and T4
    -The catabolic cycle rates will be higher than the rate of the anabolic cycles, which will cause the symptoms
  • Gluconeogenesis and glycogenolysis will be higher than normal –> contributes to increased blood glucose (increased supply of substrate for the peripheral cells) –> increased energy production
  • Excess energy production can escape as heat and leads to increased body temperature, moist skin, and heat intolerance
  • Proteolysis rates will be higher than protein synthesis
    –> will present with muscle wasting, weak muscle and aches and pains of the muscle; if there’s too much, you might see some myoglobin in the blood
    ○ Lipolysis will be higher than synthesis –> There will be more peripheral fat that goes out into the blood –> more utilization of fat –> loss of body fat –> along with loss of protein contributes to significant rapid weight loss
  • overexpression of thermogenin can also lead to heat intolerance
  • Tachycardia –> due to overexpression of your beta adrenoreceptors
  • Both hyper and hypothyroid patients are associated with having brittle nails and loss of hair. What causes those symptoms? regeneration of cells becomes a little bit of an issue –> regeneration of cells in the hair and nails are affected –> affects the volume of the hair or thickness /brittleness of the nails
77
Q

47 year old pt with headaches, sudden anxiety, racing heart, excessive sweating and constipation. SXS becoming more frequent and severe. Labs show increase in blood glucose, plasma free metanephrines and urinary vanillylmandelic acid.

  • what is the condition
  • diagnosis?
  • origin
  • embryo origin
  • gland affected
  • hormones affected
  • rule of 10%
  • presenting features and lab findings in this patient to the pathophysiology of the disorder
  • how to dx
  • tx
A
  • excessive secretion of catecholamines based on the symptoms and also VMA is a byproduct of epinephrine/norepinephrine after they’re metabolized in the liver.
  • pheochromocytoma: Catecholamine secreting tumor
  • chromaffin cells in adrenal medulla
  • neural crest cells
  • medulla of adrenal gland
  • Norepi, epi & dopamine (the catecholamines
  • 10% are bilateral, 10% are malignant, 10% are extramedullary/adrenal, 10% occur in children, 10% calcification
  • tumor secretes catecholamines that’s because it’s a tumor of the adrenal medulla, the chromaffin cells. -> § Anxiety, racing heart, sweating, elevated levels of blood glucose, constipation; Increase in plasma free metanephrine and urinary VMA because it leads to increase in metabolism and increased secretion of metabolites in the urine
  • Increased level of catecholamines in the blood, and increased catecholamines in urine along with increase metanephrine, VMA and HMA
  • Surgical resection of the tumor. Give alpha before resection to decrease chance of hypertensive crisis from excess catecholamines that will be released during resection. May also give Beta adrenergic blockades from pharmaceuticals
78
Q

Catecholamine sythesis

  • where does starting AA come from
  • pathway
A
  • starting AA is tyrosine (aromatic and nonessential) which is made from phenylalanine
  • tyrosine (Tyrosine Hydroxylase-> L- dihydrophenylalanine (Dopa decarboxylase) -> dopamine (dopamine beta- hydroxylase) -> nor-epi (phenylethanolamine N methyltransferase -> epi
79
Q

How are catecholamines regulated

  • SNS
  • factors that increase stimulation
A
  • Whenever there is a response from SNS you have neurons firing from T5–T8 and they release Ach on the pre-sympathetic neurons into the nicotinic receptors on the chromaffin cells which then leads to the production of norepi/epi from chromaffin cells which are released into the circulation through rapid influx of Na-> depolarization-> opening of voltage gated Ca channels-> Ca influx leads to exocytosis of vesicles on the synaptic side.
  • Any stressful condition like trauma, pain, anxiety, hypovolemia, hypoglycemia, hyperthermia, etc; SNS stim-> sympathetic ganglion-> NE/E rel-> axon targets at point of release
80
Q

Map concept of metabolism and how they are excreted

  • Dopamine
  • nor epi
  • epi
A
  • can be turned into Nor epi (dopamine beta hydroxylase) or turned into homovanollic acid by monoamine oxidase
  • can be made from dopamine; then use phenylethanolamine N methyltransferase to be turned into epi OR catechol O methyl transferase turns it into normetanephrine and then to vanillylmandelic acid to be excreted
  • Epi uses COMT to be turned into metanephrine uses MAO to vanillymandelic acid e
81
Q

physiologic actions & effects of catecholamines

A

○ Alpha- vasoconstriction, iris dilation, intestinal sphincter contraction, etc.
- Beta- more vasodilatory, cardioexceleration, increased myocardial contraction, intestinal sphincter relaxation, uterus relaxation, etc.

82
Q

Hypothalamus- pituitary- adrenal axis

  • hypo: which nucleus
  • pituitary
  • what is produced?
  • adrenal
A
  • Ventral medial nucleus secretes CRH; and some from paraventricular
  • CRH acts on the corticotrophes (target cell) in the pituitary (g alpha s)–> downstream signaling molecules increase adenylyl cyclase, leading to increase cAMP, increase in PKA, and PKA phosphorylates downstream enzymes and transcription factors
  • Gene product produced from corticotrophs are POMC -> POMC undergoes post-translational cleavage to make ACTH and different types of MSH and endorphins
  • ACTH is the primary stimulus for the adrenal cortex where it binds GalphaS melanocortin type 2 receptors (MC2R)
83
Q

Types of Cells in the ant. pituitary

A
  • corticotrophs (15-20%)
  • most predominant are somatotrophs and lactotrophs
  • Thyrotrophs and gonadotrophs are about 5% each
84
Q

3 coritcal zones

A
  • zona glomerulosa
  • zona fasiculata
  • zona reticularis
85
Q

Zona glomerulosa

  • where is it
  • hormone produced
  • type of hormone
  • Absence of which enzymes prevent it from making cortisol, adrenal androgens, or anything else but aldosterone?
  • Pathway to make aldosterone
  • why cant they go towards cortisol and sex hormone pathway?
  • main enzyme
A
  • The outermost zone
  • Most predominant hormone produced is aldosterone
  • Mineralocorticoid
  • 17 alpha-hydroxylase
  • Cholesterol (cytoplasm)–>Pregnenolone (in mitochondria)–>progesterone–>11-deoxycorticosterone (DOC)–>aldosterone
  • absence of 17 alpha hydroxylase enzyme also lacks 11 beta-hydroxylase which prevents it from converting 11-DOC to corticosterone and therefore cortisol
  • Aldosterone synthase is the main enzyme that converts 11-DOC to aldosterone
86
Q

Zona fasciculata

  • what size?
  • produces?
  • most predominant
  • least predominant
  • what else?
  • how does cortisol production happen?
  • what is main product?
  • what else can be produced?
A
  • Big layer
  • Glucocorticoids
  • Most predominant hormone secreted is cortisol, Lesser predominant is corticosterone
  • Some adrenal androgens produced here as well
  • Cholesterol –> pregnenolone and progesterone can be converted by 17 alpha-hydroxylase into 17-Hydroxypregnenolone and 17-hydroxyprogesterone, respectively -> Pregnenolone can be hydroxylated into 17-hydroxypregnenolone, or it can be converted into progesterone which is then hydroxylated into 17-hydroxyprogesterone -> 17-hydroxyprogesterone can be converted into 11-deoxycortisol via 21-hydroxylase, and then it is converted into cortisol via 11 beta-hydroxylase
  • You get a higher amount of cortisol produced, and a smaller amount of corticosterone via 11-DOC d/t the presence of 11 beta-hydroxylase
  • Due to these enzymes, pregnenolone has several pathways it can follow
    Zona fasciculate has a small amount of 17,20-lyase as well, so it produces a small amount of androgen precursors
87
Q

Zona reticularis

  • where is it
  • hormone
  • why precursors?
  • main precursors made
  • main pathway
  • other pathway
  • why cant it make aldosterone and cortisol?
A
  • Sits on top of the medulla
  • Most predominant hormone produced is adrenal androgens which are precursors of testosterone and estradiol.
  • Zona reticularis does not have the enzymes to go through process to form testosterone and estradiol, so they leave it at the precursors
  • Predominantly makes DHEA and androstenedione
  • cholesterol -> pregnenolone -> 17 hydroxypregonolone -> DHEA -> androstenedione -> testosterone -> dihydrotestosterone and estradiol
  • Little bit of pregnenolone can form progesterone as well–> 17-hydroxyprogesterone–> produce androstenedione directly
  • 21-hydroxylase not present in this zona which prevents it from making cortisol and aldosterone
88
Q

Stimulation for:

  • aldosterone
  • cortisol
  • adrenal androgens
A
  • Principal stimulus is high potassium levels and angiotensin II but ACTH is not considered primary or principle stimulus, but a little bit maybe
  • ACTH is primary stimulus -> directly related to the axis
  • ACTH; Some ovarian or placental hormones might have an affect on production as well
89
Q

How do we relate cholesterol to adrenal cortical hormones?

A
  • Cholesterol is a precursor to production of these adrenal cortical hormones, which are all steroids
  • Cholesterol is the mother lipid/steroid/sterol to help in production with adrenal cortical steroids
90
Q

How do Leydig cells in the testis, corpus luteum in the ovary, zona glomerulosa or zona fasciculata get cholesterol?

  • when do they need cholesterol
  • which cells make cholesterol
  • why is it important
A
  • They have to have a constant supply of cholesterol
  • All nucleated cells make cholesterol
  • Cholesterol is used for making all steroid hormones, including adrenal steroids, testicular androgens like testosterone, and ovarian estrogen
91
Q

Role of STAR and CYP11A1 in steroid hormone biosynthesis

  • what does STAR stand for?
  • what does STAR do?
  • what is CYP11A1
  • importance of these hormones
  • what happens if these enzymes don’t work
A
  • Steroidogenic acute regulatory protein=STAR
  • Outer mitochondrial protein that helps to transport cholesterol from the cytoplasm into the mito because that is where steroid synthesis begins
  • CYP11A1 is a cytochrome enzyme that acts on the cholesterol and makes into pregnenolone -> makes it much less bulky so now it can get out of mitochondria without much assistance
  • STAR and CYP11A1 are the rate limiting enzymes for steroid hormone biosynthesis
  • no synthesis of steroid hormones will occur
92
Q

consequences if you see 21-hydroxylase deficiencies?

  • Deficiency of which enzyme will only inhibit aldosterone synthesis?
  • Deficiency of which enzyme will inhibit cortisol and aldosterone synthesis?
  • Deficiency of which enzyme will inhibit adrenal androgen synthesis only?
A
  • You can’t make cortisol or aldosterone so the pathway is shunted to producing adrenal androgens
  • Aldosterone synthase deficiency
  • 21-hydroxylase
  • 17,20-lyase
93
Q

If you are deficient in 17 alpha-hydroxylase in your zona reticularis, then….

A

adrenal androgen synthesis is impaired

94
Q

Congenital adrenal hyperplasia (21-hydroxylase deficiency)

  • sxs
  • Lab findings
  • cortisol details
A
  • Virilization in newborn female- Abnormal genitalia or male-looking genitalia, Clitoromegaly=enlarged clitoris
  • Elevated levels of 17-hydroxyprogesterone, ACTH, androsteedione, DHEA and low level of plasma cortisol
  • decreased plasma cortisol–>Increased ACTH production d/t positive feedback
  • High androstenedione and DHEA d/t pathway being shunted to adrenal androgen production
95
Q

If pt is deficient in 21-hydroxylase, why is aldosterone synthesis not affected (since it requires this enzyme for the conversion of progesterone to 11-DOC)?

  • what about mutation that totally disabled the enzyme
  • difference of mutations and examples
A
  • 21-hydroxylase is made from gene CYP21A2 which can develop different kinds of mutations with different penetrations
  • Some mutations totally disable the enzyme, in which case aldosterone synthesis would also be affected
  • Some mutations have lesser penetration, so lesser effects would be seen
  • Make it unable to bind as much to substrate (Affect the stability), Affect its ability to anchor to the membrane lipids (make the enzyme unstable and it is degraded so you have minimum amt of enzyme production)
  • Therefore, you’d have more prominent effects on aldosterone and cortisol production
96
Q

Congenital adrenal hyperplasia types

A
  • Females: neonatal onset
  • Females: non- classical
  • Males: classical, salt-losing
  • Males: non-classical, non-salt losing form
97
Q

Female: classical form (neonatal onset)

  • sxs
  • cortisol
  • androgens
  • tx
A
  • Ambiguous genitalia (virilization)
  • Low levels of cortisol
  • High levels of adrenal androgens and hydroxyprogesterone
  • Genetic d/o so no cure
98
Q

Female: Non-classical CAH (late onset)

  • problem
  • sxs
A
  • Mutations that leads to slight quantitative deficiency of 21-hydroxylase so much later onset
  • Amenorrhea
  • menstrual/ovarian cycle defects d/t increased androgen precursor production
  • virilization (hirsutism, increased acne)
99
Q

Males: Classical, salt-losing form (neonatal onset)

  • problem
  • sxs
  • tx
A
  • Much more severe mutation in CYP21A2
  • Severe salt wasting characteristics
  • If not treated immediately, it can be life threatening
100
Q

Males: Non-classical, non-salt-losing form (late onset)

  • what happens?
  • sxs
A
  • Very high levels of testosterone so you see effects of testosterone prior to puberty (change of voice, facial hair, etc)
  • Adult short stature d/t premature closure of growth plate
101
Q

Congenital lipoid adrenal hyperplasia

  • mutation
  • what does it cause
  • sxs
A
  • STAR mutation–> Inhibiting transfer of cholesterol from cytoplasm into the mitochondria, so inhibits steroid hormone biosynthesis
  • A lot of cells in adrenal cortex, ovary, testes have lipid accumulation–>death of these cells
  • the male will have sometimes female-like phenotypic features because there is blockage of testosterone production and blockage of adrenal androgen production

Unit 7: LGS (4 decks)

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