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609 Cards in this Set
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Why are patients with diabetes thirsty and urinating frequently?
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Osmotic diuresis from increased glucose/AAs, etc in blood.
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What is elevated in the blood of patients with diabetes?
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Glucose
Free fatty acids Amino acids Lippoproteins |
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Insulin effect on cell
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Binds to alpha subunit of insulin receptor
Beta unit of insulin receptor is activated as a tyrosine kinase Interacts with insulin receptor substrates (IRS) and phosphoinositides Activation of enzymes, transcription of genes, activation of transport systems |
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Insulin structure
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Two peptides connected by a disulfide bridge
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Potential mechanisms of diabetes
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Lack of insulin
Lack of response to insulin Lack of secretion of insulin when its needed |
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Diagnostic definitions of diabetes
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Fasting blood sugar > 125 x 2
Random blood sugar > 200 with symptoms 2 hour/75 gm glucose challenge > 200 |
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Type 1 diabetes define and causes
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Profound lack of insulin because islet cells are destroyed
Commonly autoimmune mechanism, but can also be toxin pancreatic surgery |
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Type 1 diabetes time course
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Autoimmune usually onsets by age 20
Patients go from healthy to severe metabolic derangement in months |
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Type 2 diabetes define
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Dual problem with insulin resistance and insulin secretion
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Type 2 diabetes epidemiology
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Onset usually > 35
although being seeing in kids May be diabetic and undiagnosed for years because of insidious onset 12% of US population meets criteria More common in Native americans> African Americans > Hispanic than white |
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In what races in DM1 most common?
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Northern European Causcasians
Less in southern european, africa Way less in asians |
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Pre-diabetes diagnosis
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Fasting 100-124
2 hour/75 g challenge 140-200 25% risk of developing DM2 in 6-10 years At additional risk with blood glucose raising meds |
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Blood glucose raising meds
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Corticosteroids
prednisone, methlyprednisone, dexamethaone |
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What's a the crux of diabetes?
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Risk of damage to small blood vessels
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Pre-diabetes by impaired glucose tolerance test puts you at risk for?
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Damage to large blood vessels
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Gestational diabetes
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Transient diabetic state that resolves after parturition
Exaggeration of normal loss of insulin sensitivity during pregnancy, and failure to secrete enough insulin to overcome this resistance |
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Risks of gestational diabetes
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33% risk of developing DM2 in next 6 years
Increased risk of eclampsia Increased risk of macrosomia in infant |
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When is insulin secreted?
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In response to eating
Much more when nutrients hit bloodstream Enhanced secretion when GLP-1, GIP are secreted by gut |
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GLP-1
GIP |
incretins
glucogon-like peptide 1 gastrinc insulionogenic peptide Secreted by intestinal cells, increase insulin secretion |
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DPP-4
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Peptidase that breaks down the incretins rapidily in blood stream
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What are the effects of insulin
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Liver: stops gluconeogenesis and promotes glycogen synthesis and storage
Muscle/Fat: increases glucose uptake via increase Glu-4s Activates lippoprotein lipase, increasing fat uptake and storage in liver and adipose cells Increases uptake of free amino acids |
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What's insulin doing in fasting state?
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Levels fall
Allows for breakdown of storage glycogen, fats, protein to be used as energy in muscle and brain Levels of insulin regulated glycogenolysis, gluconeogenesis, and substrate mobilization from stores |
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Counter regulatory hormones
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Glucagon, cortisol, GH, epinephrine
Increase nutrient flow out of storage compartments Act in opposition to insulin Secreted at time of stress |
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When is glucagon secreted?
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Basically at the same time as insulin to smooth changes in metabolic direciton
In response to GLP-1 |
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Adiponectin
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Increases sensitivity to insulin
leptin may also do this indirectly |
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Diabetes, why does blood sugar get high?
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Fasting blood sugar is high because utilization in down and gluconeogenesis is up
Post prandial glucose levels are up because gluconeogenesis is not suppressed by eating and glucose is not taken up peripherally |
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Diabetic ketoacidosis
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Total lack of insulin
Glucagon effects are unopposed Increased glucose production and decreased utilization by liver Increased hormone sensitive lipase activity = more free fatty acids in circulation With low insulin, FFAs are taken up by liver and sent to mitochondria FFAs are metabolized to ketones: acetone and betahydroxybutyrate These are organic acids Glucose is also high because of increased production and decreased utilization in the absence of insulin |
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Liver biochemical changes based on lack of insulin
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Glycogen synthetase is phosphorylated and decreased in activity
Glucose-6-phosphatsase is activiated Phosphofructokinase and pyruvate kinase activity down because of glucagon effect FFAs are sent to mitochondria rather than being made into TAGs |
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Comas of diabetes
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Diabetic ketoacidosis
Type 1, rapidly evolving Hyperosmolar non-ketotic coma Type 2, slowly evolving |
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Hyperosmolar non-ketotic coma
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Similar processes to diabetic ketoacidosis but small amounts of insulin prevent overwhelming ketosis
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Why do diabetic patients frequently urinate/get thirst/get dehydrated?
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Osmotic diuresis
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Differentiating between diabetic ketoacidosis and hyperosmolar comas
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pH of blood: lower in DKA
sugar: lower in DKA (500 vs 2000) rehydration: more profound in hyperosmolar evolution: DKA is faster patient: DM1 is DKA |
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Treatment of diabetic comas
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Rehydration
-lowers osmolality, restores BP, reduces epinephrine secretion Regain metabolic control with insulin - relatively easy in hyperosmolar - DKA -- liver output is quickly controlled, but lipolysis and ketogenesis takes a day of high dose insulin to control |
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Electrolytes and diabetic comas
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Massive diuresis can result in low phosphophate, sodium, K
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DKA and potassium
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Low total potassium from diuresis
Increased plasma K because acidosis brings K out of cells into blood With rehydration, plasma K can drop rapidly and result in cardiac issues |
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Another cause of ketoacidosis
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Alcohol induced
In glycogen-low, malnourished person: tonic low insulin levels allow for high levels of FFAs and liver cannot handle this because of alcohol metabolism |
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What is the effect of falling blood volume in diabetic comas
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Release of counter-regulatory hormones (epi, cortisol, GH)
Make tissues more insulin resistant Body perceives full starvation |
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Natural history of insulin secretion and blood sugar type 1 and type 2 diabetes
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DM1
complete loss of insulin secretion with concomitant rise in blood sugar DM2 increases insulin secretion with normal blood sugar (compensated resistance) eventual rise in blood sugar (uncompensated resistance) eventual fall in insulin (loss of beta cells) |
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DM Type1a vs 1b
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1a is autoimmune
1b is idiopathic |
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Pathogenesis of DM1 generally
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destruction of beta cells of pancreas leads to absence of insulin
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Process of autoimmune DM1
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Insulinitis and anti-islet antibodies
Chronic inflammatory process destroys the islet cells Presentation with clinical diabetes |
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What cells are involved in autoimmune destruction of beta cells?
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Hard to say
Looks like a cellular immunity process is probably going on |
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Insulinitis
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Mononuclear (T cell) infiltration of the islet
CD4s, CD8s, macrophages Observed in islets of newly diagnosed DM1s Specificity of destruction (apoptosis) of cells by Fas expression/Fas ligand? |
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Incidence of DM1 over past half century
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Rising
3-5 fold |
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Age of onset
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peaks at 10-14
can definitely happen later many adult onset DM1s may be misdiagnosed as DM2 -- look for autoantibodies |
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FHx and DM1
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5% risk if 1st degree relative has DM1
Father effect is stronger than mother 30-50% of twins 85% of probands ave no affected relatives |
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MHC and DM1
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DR3 and DR4 have increased risk
DR2 and DQB1*0602 are protective |
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IDDM
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gene on 6p21
in MHC class II locus Accounts for 45% genetic component of DM1 |
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Suseptibility genes for DM1
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Almost all have to do with immune system
IDDM2 - pre-proinsuline -10% of risk -shorter tandem repeats is bad CTLA-4 PTPN22 -- T cell signaling related IL-2 receptor Interferon regulated helicase |
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Virus causes DM1?
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Not proven
Could be late effects of virus on pancreas, causing increase incidence in recent decades Some evidence for Coxsackie B virus |
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Multi-hit theory of DM1 pathogenesis
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Environmental exposure + viral infection + stressful life event --> development of diabetes
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Do viruses really cause DM1?
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Maybe
Could also just be non-specific precipitants of crisis based on already declining beta cells or incipient autoimmune process fuel by interferon, etc |
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Anit-islet antibodies
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Good markers of eventually developing DM1
Not thought to be pathogenically important |
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Evidence of DM1 as an environmental disease?
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Identical twins not 100%
Seasonal incidence (winter high, spring low) Migrating populations tend like new location Histology differences with animal models |
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What virus do we know rarely causes DM1
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Congenital rubella
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Breast feeding and DM1?
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Good for kids to avoid DM1
Exposure to gluten/casein in cows milk drives up rate of anti-islet antibodies |
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Dawn phenomenon
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Hypoglycemia overnight with spontaneous rise in blood sugar in the morning
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Somogyi effect
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Rebound hyperglycemia after hypoglycemiia
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Blood glucose goals in DM1 patients
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Fasting 80-140
2-hour post meal: <180-200 |
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Hemoglobin A1c
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Measures how much hemoglobin has been glycosylated
Non-enzymatic, post translational modification based on exposure to glucose during RBC lifetime Gives idea of last 120 days of glucose control |
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Where do errors in A1C come from?
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Altered RBC lifespan
iron def makes it seem artificially high hemolysis make artificially low Weird hemoglobins Renal failure |
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Hemoglobin A1c targets is DM1
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Adults 6.5-7
Elderly, kids <8 Pregnancy <6 |
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Potential mechanisms of autoimmune beta cell damage
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cytokine activation of Th1s
viral infection/exposure and molecular mimicry viral infection of beta cells viral infection and bystander damage to beta cells because of their intolerance to superoxides, etc |
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Islet antibodies in DM1
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Present 90% of time in new onset
Insulin autoantibodies first Glutamic acid decarboxylast (GAD) is most persistent IA-2 (to tyrosine phosphotase) is short lived but high risk |
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Urine testing in diabetes looks for what
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ketones
useful if sugars are >250, concern for acidosis |
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Fructosamine test in diabetes
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Looks a glycosylation of albumin
avg glucose for 2-4 weeks has to be adjusted for albumin levels |
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1,5 anhydrolglucitol test
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Glucose variation within day
Works by looking for something that competes with glucose for urinary excretion, so if glucose has gone up at all you get more of this |
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Pancreatic transplant as diabetes treatment
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Works well
If you don't reject it or have surgical morbidity Usually done with renal transplant Requires lifelong immunosuppression Need 2 donor pancreases |
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Islet cell transplant
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Easier surgery
Easier to get cells to transplant Does not work as well as full pancreatic for treatment |
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Diabetes type 2 definition
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Metabolic disorder of elevated glucose levels enough to cause microvascular damage despite continued secretion of insulin
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Diabetes type 2 epi
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90-95% of US diabetes
8% of US 15% of US >65 Highest in Hispanic, Black |
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Risk of DM2 and other chronic diseases
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Major unmodifiable risk factor for CAD, peripheral vascular disease
Also increased risk of HTN |
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DM2 and mortality
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Over age of 50, cuts 4-6 years
2-3x RR of death 40% by ischemic heart diseae 10% by stroke |
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DM2 and inheritance
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Polygenetic, but very genetic
100% concordance in identical twins |
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DM2 on physical exam
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80% are obese
40% have HTN Retinopathy and neuropathy may be present |
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DM2 on labs
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fasting glucose >126
Glucosuria Mild proteinuria is common Mild hematuria Moderate hypertriglyceremia (elevated VLDL) Low levels of HDL are common |
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Risk factors for DM2
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Age >40
Obesity Prior gestational diabetes Prior glucose intolerance Family history Also: low socioeconomic status, urban dwelling, high saturated fat diet Ethnicity |
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Natural history of treated DM2
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Weight gain and worsening hyperglycemia over time
40% hypertensive 25% macrovascular complicaiton 10% die w/in 15 years of diagnosis |
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Pre-diabetes prognosis
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30% go on to diabetes in 6 years
With lifestyle modification, only 15% (weight reduction 5%, <30% cal from fat, <10% cal from saturated fat, 30 min exercise/day, 15 gm fiber/1000kcal) |
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Prevalence pre-diabetes in US
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6% of adults
15% of >60 |
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Insulin tolerance test
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Dose of insulin should give glucose <40 in 10-15 minutes if not resistant
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Glucose clamp test
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How much glucose is need to overcome a steady dose of insulin
If you are insulin resistant, not very much |
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Can insulin resistance be measured by a fasting insulin level
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NO
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Factors influencing insulin resistance
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Weight
Age Prediabetes Meds Stress |
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What's the increased risk of CV disease with diabetes?
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2-4x risk of MI/stroke
2-8x risk of CHF Lower leg amputations |
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Symptoms of peripheral vascular disease
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Claudication
Pain when severe |
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Signs of peripheral vascular disease
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Cold limb
Reduced peripheral pulses Venous collapse on elevation Femoral or AA bruits Ischemic foot ulcer |
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What is the first step in macrovascular damage?
What is this caused by? |
Endothelial damage
Hyperglycemia Hyperlipidemia Hypertension Smoking |
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What happens in diabetic nephropathy
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Decreased function
Structural changes-- Basement membrane thickening Increase in extracellular matrix proteins in the glomerulus Compensatory increased flow results in more damage Proteinuria with rising creatinine End stage renal disease |
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Who gets diabetic complications?
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Can't predict
Good control is helpful Nephropathy clusters in families |
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What is predictive of long term survival in DM1?
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Avoiding nephropathy
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Renin-aldosterone system and diabetic nephropathy
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Activation of this system can increase systemic blood pressure and constrict afferent arteriole, resulting in glomerular hypertension
Leading to proteinuria and damage Can also result in structural changes like mesangial overgrowth and ECM deposition |
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Microalbuminuria and frank albuminuria
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Micro --
30 mgs/24hrs Albumin/creatinine ratio >30mg/G Macro/Frank >300 mgs/24 hrs Micro is first sign of nephropathy, macro means advanced. Both highly predictive of eventual renal failure. |
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How does insulin resistance effect the liver?
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Deregulation of liver glucose output
Does not effect liver glucose uptake |
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What is postprandial liver glucose output in normal vs diabetic individuals?
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Postprandial should be low
Its high in diabetes |
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What determines hepatic glucose output?
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substrate availability -- alanine, lactate, glycogen, acetyl CoA
cofactor (NADH) availability hepatic concentrations of gluconeogenic enzymes insulin regulation of gluconeogenic enzymes counter-regulatory hormones |
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Insulin resistance in fat cells
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Impairs uptake, but this is limited anyway
Disregulates the release of free fatty acids by adipose cells |
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Are beta cells every completely lost in DM2?
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No
Those that are left in the end are always going at full capacity so cannot respond to any additional challenge |
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Incretins
in DM2? |
Gut secreted hormones that
enhance insulin secretion decrease glucagon release slow stomach emptying those to be reduced in DM2 |
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Glucose toxicity
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With prolonged hyperglycemia, insulin response decreases
Decreased islet cell production of insulin Decreased insulin secretion response |
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MODY genes
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Maturity onset diabetes of the young
AD inheritance |
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MODY-2
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Glucokinase mutation
Constitutively not sensing glucose |
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Endocrine disorders that cause insulin resistance
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Acromegaly
Cushing's Pheochromcytoma |
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Endocrine disorders that impair insulin secretion
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Glucagonoma
Somastatinoma Hyperaldosteronism |
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Drugs that impair insulin sensitivity
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Cortiocosteriods
Beta blockers |
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Drugs that impair insulin secretion
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pentamide
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Drugs that impair insulin sensitivity and secretion
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cyclophosphamide
FK 506 thiazides |
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Drugs that induce diabetes through nutrient flux
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TPN, niacin
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Gastric bypass and DM2
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Immediate improvement in glucose levels, before weight loss
reduced calories -- so insulin that's made can handle it lower free fatty acids from dietary restriction reduced hepatic glucose output GLP1 levels increase |
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Exercise and insulin tolerance
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chronic exercise increases insulin sensitivity
duration and regularity, not intensity important |
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Biochemical mechanisms of diabetic tissue damage
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Non-enzymatic glycation
Superoxide injury Increased PKC Increased glucosamine pathway Disturbances in polyol pathway |
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What determines severity of diabetic complications?
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How well controlled hyperglycemia is
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Is diabetic tissue damage irreversible?
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Early changes appear reversible
With age, advanced glycation end products because irreversibly deposited in tissue |
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Damage in diabetes is to...
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Microvascular endothelium
Leading to inflammation, vasoconstriction, thrombosis ---> Atherogenesis |
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Major complications of uncontrolled diabetes
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Microangiopathy
Accelerated atherosclerosis Opportunistic infection |
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Diabetic microangiopathy features
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Diffuse basement membrane thickening
Endothelial injury Increased protein leakage Increased and abnormally functioning pericytes Happens in capillaries Results in ischemia eventually Strict control slows progression |
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Major microangiopathy manifestations in diabetes
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Retinopathy
Nephropathy Neuropathy Peripheral microangiopathy |
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Diabetic nerve damage
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microangiopathy of small vessels around nerve results in ischemic damage to nerve
Histologic appearance: Pale thickened basement membrane |
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Diabetic retinopathy
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Small vessel damage:
Microaneurysms Proliferation Occlusion Thickening |
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Diabetic nephropathy
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Glomerulopathy--damage to small vessels in glomerulus
Can be nodular (Kimmelstein-Wilson lesion) or diffuse |
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Diabetes and peripheral ulcers
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Chronic ischemic ulcers because of microvascular changes and enhanced atherosclerosis
More susceptible to infection because worsened immune system Can result in gangrene (relative risk 100:1) |
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Diabetes and the immune system
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Suppresses immune system through a variety of mechanisms
Opportunistic infections like mucormycosis of nasal sinus or candida cystitis |
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Diabetes and pyelonephritis
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More common with diabetes
More severe with diabetes Necrotizing papillitis is more common --involving the pyramids |
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Pathologic changes to pancreatic islets in DM1
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Early -- iseltitis, immune infiltrate
Late -- absent beta cells |
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Pathologic changes in DM2 over time
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Early -- nothing
Mid -- beta cell malfunction Later -- beta cell depletion, amylin accumulations leading to amyloid deposition in tissue |
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Acarbose
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Disaccharide inhibitor
Prolong absorption of starches from intestine Must be able to make insulin still Can lower HA1c about 1%/ glucose 20 SE: flatulence, diarrhea |
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Metformin
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Biguanide
Suppressed hepatic glucose output, activates AMP kinase Increase insulin sensitivity, mechanism? Alone lower glucose about 20/HA1c 1% SE: diarrhea, nausea No weight gain or hypoglycemia |
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Sulfonyureas name some
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Long acting
Chlorpropramide Tolbutamide Glyburide Glipizide Glimiperide Short acting Repaglinide Netaglinide |
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Sulfonyureas mechanism
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Increased insulin secretion (on command for short acting and in response to stimulus for long acting) by beta cells
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Thiazolinolides name some
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rosiglitazone, pioglitazone
troglitazone -- hepatitis -- no longer used |
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Thiazolinolides mechanism, SEs
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Increase insulin sensitivity in peripheral tissues by 30-50%
PPAR binding, mech unknown SE: edema, weight gain |
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Exenatide
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GLP-1 analog
Improves diabetes control and produces modest weight loss injectable |
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Sitagliptin
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Inhibitor of the breakdown of GLP-1, increase duration of action
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Insulin in DM2? dosing?
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Used
Weight gain is a problem Have to use 2-5x doses of DM1 because of resistance |
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Pramlintide
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Analog of amylin
Increases sensitivity to insulin, slows gastric emptying Often given with mealtime insulin but they cannot be mixed |
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What is the leading cause blindness in adults?
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Diabetic complication
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What is the leading cause of end stage renal disease?
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Diabetic complication
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What accounts for the majority of diabetes related deaths?
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Macrovascular disease
CVD is more common, more extensive, and more deadly in pts with diabetes |
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What happens to retinal capillaries in diabetes?
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Endothelial cell and pericyte damage
-aneurysms Basement membrane thickening Increased vascular permeability Capillary drop out Lack of perfusion to retina |
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Proliferative retinopathy
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Ischemia fuels new blood vessel formation in retina
New vessels are weak and hemorrhage easily, worsening visual loss Treat with anti-veg F |
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Macular edema
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Another diabetic eye complication
Leakage into temporal arcade is sight threatening If you see hard exudates, might have macular edema |
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Advanced glycation end products
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Non-enzymatically glycated proteins
Can crosslink proteins Happens over time with hyperglycemia to lots of proteins |
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Alpha dicarbonyls
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Methylglyoxal, 3-deoxyglucosone, glyoxal
glucose derivatives that are far more reactive: Inhibit cell growth Mutagenic Inhibit enzymes Protein cross-link and fragment Produce precursors of AGEs |
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Hyperglycemia and oxidative stress
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Autooxidative glycation and lipoxidation leads peroxides, superoxide free radicals, reactive hydroxls
Reactions enhanced by free metals Hyperglycemia stresses mitochondria into making superoxide |
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Aldose reductase and polyol pathway and diabetes
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Aldose reductase takes toxic aldehydes and coverts to inactive alcohols
It can also take excess glucose and turn it into sorbitol Sorbital (before its turned into fructose) can be damaging, including via osmotic mechanisms |
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Protein kinase C mediated effects in diabetes
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Blood flow abnormalities (eNOS, ET-1)
Angiogenesis (VEGF) Capillary occlusion (TGFB, collagen, fibrinonectin) Vascular occlusion (PAI-1) Pro-inflammatory gene expression (NFKB) Increased NADPH oxidase |
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Proposed unifying mechanism of diabetic pathology
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In euglycemia, mitochondria make ATP
In hyperglycemia, mitochondria make a lot of ROS Inhibition of GAPDH This leads to activation of the AGE, Protein kinase C, polyol, hexoamine pathways |
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Evidence that the proposed molecular mechanisms of diabetic complications are true
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Oxidative stress is higher in fibroblasts of DM1 patients who get nephropathy
Methylglyoxal production is higher in pts with diabetic neuropathy GAPDH activity is decreased in nephropathy progressors Variations in protein kinase C genotype vary risk of diabetic ESRD |
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Central obesity, why does it matter
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Increased insulin resistance
Visceral adipose tissues + metabolic syndrome put at higher risk of CVD, DM2, mortality Visceral adipose + obesity -- dyslipidemia w/ high TAGs and low HDL |
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What does increasing insulin resistance put you at risk for?
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DM2
CVA CHD Cancer HTN |
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Diabetic dyslipidemic profile
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Increased LDL, small dense, LDL, TAGs
Decreased HDL |
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Diabetic neuropathy consequences
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Pain, disability
Lower leg amputation GI symptoms ED CV dysfunction |
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Distal symmetric polyneuropathy
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Damage to small fiber neurons
initially causes allodynia, buring, hyperesthesia, hyperalgesia then loss of pain and temp sensation Large neuron damage deep, gnawing pain loss of vibration, proprioception, cold, reflexes usually in older patients |
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Issues that arise with distal polyneuropathy
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Lack of sensation of foot lesion leads to progressive ulcer and severe infection
Coordination and falls are a problem in large neuron damage Also arthropathy, Charcot's joint |
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Pathogenesis of diabetic neuropathy
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Prolonged hyperglycemia slows nerve conduction via metabolic changes
--less Na/K pump activity and Vascular damage to vasa vasorum and endoneurial arterioles |
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Mononeuropathy
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Sudden infarction of a single nerve
Can recover with time |
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Control and complications
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HA1C predicts retinopathy, nephropathy, neuropathy, microalbuminuria
Risk rapidly elevates over 8 |
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What reduces complications?
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Better glycemic control
Shown in both type 1 and type 2 Effects outlast good control |
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Metformin reduces complications, how?
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Reduces AGE formation
--possibility |
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How to treat diabetic nephropathy
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Proven -- tight blood glucose control, ACE-I/ARB
Important - statins/fibrates for lipid control Others: Aminoguanidines--AGEs Oxidative stress- alpha lipoic acid PKC inhibitors Aldose reductase inhibitors |
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Glycemic control and retinopathy
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Good control prevents and slows progression
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Glycemic control and MI
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Above 6 increases risk of MI
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How hard should low HA1C be pushed?
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Getting down is very important for complication reduction
Recent studies were stopped because 6.5 HA1C group had increased number of deaths ? because of polypharmacy Clearly not as good to do this with lots of drugs than diet/excercise Did not show a significant improvement in CV outcomes |
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Metabolic syndrome diagnosis basics
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diabetes/glucose intolerance/insulin resistance
+ 2 of Low HDL HTN Hyper TAGs Central obesity Microalbuminuria -hyperandrogenism is also noted in women |
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Metabolic syndrome cutoffs
HDL HTN TAGs Waist |
HDL <40 men, <50 women
HTN >130/85 TAGs > 150 Waist >47 men, >40 women |
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Is metabolic syndrome common?
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25-35% of US pop
85% of patients with DM2 >50% of over 60 years old |
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What's bad about having metabolic syndrome?
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Increase risk of cardiovascular mortality
--not clear that the sum is greater than its parts Reported 4 fold increase in pts age 40, 2 fold in avg age 54 |
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What's the difference between subq and visceral fat
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Visceral fat ups CAD rate, insulin resistance
Makes less leptin and adiponectin More FFA turnover More angiotensiongen, PAI-1, Il-6 Drains directly into portal circulation (goes to the liver) |
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What does having increased FFAs in circulation do?
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Insulin resistance
Vascular constriction Increase hepatic production of glucose, TAGs Decreased insulin secretion by pancreas ....central cause of metabolic syndrome? |
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Fat cell dysfunction as pathogenesis of the metabolic syndrome?
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Transgenic mice that express glucocorticoids in adipose cells
Get a metabolic syndrome from perturbing fat cells Lipodystrophy from protease inhibitors for HIV also gives metabolic syndrome and fat redistribution PPAR-gamma mutation syndrome inability to trap FFAs in adipose, partial lipodystrophy, hyperinsulinemia, low adiponectin |
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Lipodystrophy
|
Lose subq fat and gain visceral
|
|
|
Leptin deficiency
|
Lipodystrophy
Metabolic syndrome Treatment with leptin corrects features of metabolic syndrome |
|
|
Metabolic syndrome treatment
|
Improve insulin sensitivity
excercise, metformin, TZDs, weight loss Treat LDL to <100 Treat TAGs (non HDL) <130 Treat HTN <135/85 |
|
|
What is the lipid problem in metabolic syndrome
|
High VLDL (cholesterol + TAG)
Very atherogenic May have normal LDL Non-HDL cholesterol is a good thing to measure |
|
|
Associated with metabolic syndrome
|
Obstructive sleep apnea
PCOS Male hypogonadism |
|
|
BMI definition for overweight and obese
|
Overweight 25-30
Obese I 30-35 Obese II 35-40 Extreme obesity >40 |
|
|
Waist circumference is a risk factor independent of BMI for
|
DM2
HTN CVD Hyperlipidemia |
|
|
Is obesity increasing?
|
Since 1980
Overweight % is stable at 33% Obese has double from 15% to 30% |
|
|
Obesity and level of education?
|
Decreasing obesity with increasing education
|
|
|
Medical complications of obesity
|
All cause mortality increase
CVD, CAD DM2 HTN Gallbladder disease Nonalcoholic steatohepatitis Joint disease Carpal tunnel PCOS Sleep apnea GERD Venous stasis disease VTE Cancer -- colon, rectal, breast, cervical, endometrial, ovarian, billiary tract |
|
|
BMI and mortality
|
Below 20 is bad
Above 25 is bad, but above 30 and 35 is worse |
|
|
Cause of obesity
|
Energy balance off
Too much caloric intake Too little caloric expenditure Both |
|
|
Obesity genetic?
|
80% of children of obese parents are obese
14% of children of normal weight parents are obese Adoptees match biologic not adoptive It takes different calorie intakes to can a unit of weight in different people |
|
|
Environmental factors leading to obesity
|
Sedentary lifestyle
High intake of energy dense, micronutrient poor foods Heavy marketing of fast foods, high intake of sugar sweetened beverages Large portions, eating out, restricting/binging eating patterns |
|
|
What should goals of weight loss be?
|
10% of initial body weight
1-2 lbs/week for 6 months weight maintenance after that goals should be to reduce morbidity 30 min moderate exercise daily Success is maintained 10% weight loss for 1 year (25% success rate) |
|
|
How to treat obesity
|
Lifestyle
Diet, exercise, behavioral changes Drugs Silbutramine at BMI >30 or >27 with symptoms as part of a lifestyle regimen Bariatric surgery Severe obesity where other methods have failed |
|
|
Who succeeds?
|
People who have tried and failed before
People who modify both diet and exercise about half use a program |
|
|
Bariatric surgery options
|
Restrictive vs Malabsorptive
Restrictive--vertical and adjustable banding Malabsorptive- Roux en Y, JI bypass |
|
|
Restrictive bariatric procedures
|
Create smaller pouch for food
Early satiety Normal absorption of nutrients |
|
|
Malabsorptive procedure
|
Skip part of small intestine so nutrients cannot get absorbed
|
|
|
Roux en Y is what type of bariatric surgery?
|
Combo!
Malabsorptive and restrictive |
|
|
Clinical objectives of gastric bypass
|
Decreased caloric intake
Loss of 50% of excess weight in one year Long term maintenance of weight loss |
|
|
Criteria for getting gastric bypass
|
BMI >40 or >35 with morbidity
Attendance at support group 15 lb weight loss prior Upper GI/gallbladder studies Surgical clearance |
|
|
Complications of gastric bypass
|
Dumping syndrome 50%
Cholelithiasis ~40% B12 deficiency ~40$ Iron deficiency ~40% Wound infection - 5% Perioperative death -- 0-1% Anastomotic leaks |
|
|
Does gastric bypass work?
|
For a lot of people
Reduced weight Reduced morbidity Reduced mortality |
|
|
Adipose cell changes with obesity
|
Hyperplasia -- early in life especially can get increased number of cells
Hypertrophy -- later in life just add increased fat stores to already present cells Lose weight by reversing the hypertrophy, cannot reverse the hyperplasia |
|
|
Anabolic neuropeptides
|
NPY made by arcuate nucleus hypothalamus and regulated by leptin
AGRP, competitive at alpha MSH, also made in arcuate Melanin concentrating hormone Orexins |
|
|
Catabolic neuropeptides
|
alpha MSH
CRH CART (cocaine and amphetamine regulated transcript) |
|
|
Why is obesity bad for the heart?
|
Comes along with a lot of athrogenic risks
Need for increased CO for increased tissue mass Total body oxygen consumption increased LVH, elevated LVEDP, CHF |
|
|
Obesity and pulmonary fnc
|
Dyspnea is most frequent complaint
Some restriction of capacity Some hypoventilation Pickwickian Obstructive sleep apnea |
|
|
Posterior pituitary, fnc
|
Does not make hormones
Stores ADH and oxytocin before their release |
|
|
What happens if you lose your posterior pituitary?
|
Nothing
If you also damage your hypothalamus...problems like diabetes insipidus |
|
|
Effects of a mass lesion in the pituitary expanding up?
|
Optic chiasm impingement
bitemporal hemianopsia Stretching of the tentora sella headaches Hypothalamic dysfunction w/ diabetes insipidus, prolactin excess, increased appetite, thermoregulation problems, other |
|
|
Effects of a mass lesion in the pituitary expanding laterally?
|
Cavernous sinus impingement
CN III, IV, VI -- diploplia If it keeps going -- temporal lobe epilepsy |
|
|
Effects of a mass lesions expanding inferiorly?
|
Eroding into sphenoid sinus
Can cause CSF rhinorrhea Pretty bad to connect CSF and nasopharynx -- menigitis |
|
|
Endocrine effects of a pituitary adenoma
|
Hyper or hypofunction
|
|
|
Basic HPA axis
|
Oscillator produces CRH from hypothalamus
CRH stimulates pituitary to make POMC, which is cleaved to ACTH ACTH stimulates all zones of the adrenal Cortisol feeds back at the level of the pituitary and hypothalamus Zona glomerulosa (aldosterone secreting) does not require ACTH |
|
|
Thyroid axis
|
Hypothalamus makes TRH and somatostatin
TRH stimulates pit to make TSH Somatostatin suppresses TSH stimulates thyroid to make T4/T3 T4 is converted to T3 peripherally T3 feeds back to pit and hypo T4 feeds back to pit (and hypo via conversion to T3 in hypoathalamus) |
|
|
Sex hormone axis
|
Hypothalamus makes pulsitile GnRH once desuppressed
Pituitary makes LH and FSH LH -- sex steroids FSH -- germ cell production/maturation LH and FSH feedback at hypo and pit Programmed senescence |
|
|
Growth hormone axis
|
Hypothalamus makes GHRH and somatostatin
GHRH stimulates pit to make GH and somatostatin suppressed GH is primarily targeted at liver, which then makes IGF-1 GH and IGF-1 feeds back to pit and hypo |
|
|
Prolactin regulation
|
Hypothalamus tonically secretes dopamine, suppressing pituitary secretion of prolactin
hypoprolactinemia results from hypothalamic injury |
|
|
TRH and prolactin
|
Extremely high levels of TRH may stimulate the production of prolactin
This might occur in extreme hypothyroidism |
|
|
Glycoprotein hormones
|
FSH
LH TSH bHCG Alpha (same) and beta (unique) peptide chains arising from different genes Must be glycosylated for activity |
|
|
How to test for appropriate ADH ?
|
24 urinary volume
Dehydration test with measure of ADH and urinary osmolality |
|
|
Pituitary apoplexy
|
Acute bleeding into a pituitary adenoma, hemorrhagic infarction
HA, visual disturbance, pan hypopituitarism Neurosurgical emergency, need to replace cortisol before doing any surg |
|
|
Pituitary embryology
|
Anterior pituitary is from invagination of oral ectoderm (Rathke's pouch)
Posterior is an extension of the diencephalon (hypothalmic precursor) |
|
|
What is clinical picture of a somatotroph?
|
Hyperfnc
child -- gigantism adult -- acromegaly Hypofnc child -- growth arrest adult -- weight gain, reduced bone density, |
|
|
What is clinical picture of a lactotroph?
|
Hyperfnc
women -- amennorhea, lactation men -- hypogonadism Hypofnc women -- failure to lactate men -- nothing |
|
|
What is clinical picture of corticotroph?
|
Hypofnc
secondary adrenal insufficiency Hyperfnc Cushing's disease |
|
|
What is a functioning pituitary adenoma going to make?
|
Can't tell grossly
Can be any one thing Often multiple from (TSH, GH, PRL) |
|
|
DDx for isolated hyperprolactinemia
|
Functioning adenoma
Damage to stalk/hypothalamus releasing suppression Meds (dopamingeric antagonists, antidepressants, opiates) Hypothyrodism Neural/chest wall stimulation Renal Failure |
|
|
DDx for pituitary hypofnc
|
Genetic (like Pit-1 or receptor mutation)
Nonfunctioning adenoma Mass lession (met, adjacent tumor) Ischemic lesions (apoplexy, sheehan's) Trauma Radiation Infiltrative disease (sarcoid, TB, hemochromatosis) Compression by carotid artery aneurysm |
|
|
Clomiphene and diagnostic testing
|
Suppresses negative feedback of LH on pit/hypo
Can be give and then LH levels tested |
|
|
GH diagnostic testing
|
Straight levels not usually useful because of pulsitilie nature
Provoke secretion with hypoglycemia (via insulin), arginine, GHRH IGF-1 levels can be tested |
|
|
Visualizing somatotrophs
|
Injection of radiolabeled octreotide (a somatostatin analog)
|
|
|
Diagnostic tests in adrenal problems
|
ACTH levels
Midnight salivary cortisol -- screening Suppression with dexa Cortisol in 24 hour urine |
|
|
What is the difference between dexamethasone suppression testing between pituitary and ectopic origin Cushings?
|
Dexa will partially suppress the pituitary adenoma output
No effect on ectopic |
|
|
Acromegaly pathogenesis
|
Somatic mutations cause hyperfunction of somatotrophic cells in pituitary
Overproduction of GH leads to high levels IGF-1 |
|
|
IGF-1 effects
|
Increased protein synthesis
--organomegaly: cardiomegaly, increased GFR, increased tongue size Insulin resistance -- like DM2 Boney end plate growth -- gigantism, joint problems Sodium retention -- hypertension |
|
|
Treatment of acromegaly
|
Surgery
Radiation Medical Dopamine antagonists (bromocriptine, carbergoline) Octreotide -somatostatin analog |
|
|
Prolactin >200 ng/ml
|
Almost always a prolactinoma
|
|
|
Manifestations of hyperprolactinemia
|
Galactorrhea
Amenorrhea Sexual dysfunction (female reduce libido, male impotence) Infertility Arrested puberty Hypogonadism |
|
|
Mechanism of prolactinoma induced hypogonadism
|
Adenoma may damaged FSH/LH producing cells
High prolactin may inhibit GnRH, make FSH/LH cells less responsive to it |
|
|
Treating prolactinoma
|
Surgery
Radiation Medically with long acting dopamine agonists (bromocriptine, cambergoline) |
|
|
Testing for acromegaly
|
IGF-1 levels
Ability to suppress GH with glucose load |
|
|
Octreotide
|
Somatostain analog
Modified to avoid exopeptidase destruction Longer half life than somatostatin |
|
|
Octreotide treatment of somatotroph adenoma
|
Lowers levels of GH and IGF
Sometimes see mass affect, but not consistent |
|
|
One risk of having elevated GH?
|
Colon cancer
colonic proliferation |
|
|
What is a good bioassay for how high someone's GH is?
|
Skin tags
|
|
|
Who presents later with their prolactinomas?
|
Men
symptoms are more subtle often do not present until having headaches and visual field disturbances from mass lesion |
|
|
Why treat prolactinomas?
|
Infertility
Mass effects Osteoporosis |
|
|
What's the best option of treating a prolactinoma
|
Medical therapy with dopamine agonists is preferred because of recurrence rates after surgery
Surgery can be used for pregnancy because the dompamine agonist are not approved |
|
|
Does medical treatment shrink the tumor in prolactinoma?
|
Reliably yes
|
|
|
Heritable forms of hypopituitarism
|
Prop1 -- lose everything by ACTH
PIT1 -- lose TSH, GH, PRL |
|
|
Fetal growth
|
Extraordinary growth rate
Maternal/placental factors important IGF-II mediated (?) Fetal pituitary independent |
|
|
Infant growth
|
Slows down compared to fetal
Starts to be pituitary/GH/IGF-1 mediated |
|
|
Childhood growth
|
Slows to about 5 cm/year prior to puberty
GH and thyroid hormone sensitive Tracts consistently on percentiles Minimal effects of sex hormones |
|
|
Pubertal growth
|
Rapid rise in growth rate 2/2 sex hormones
These have direct effect on linear growth and increase the production of GH/IGF-1 |
|
|
Timing of puberty and overall height
|
Precocious puberty -- short adult height
Early/late w/in norms -- reach same adult height |
|
|
Bone age
|
Measured on X-ray
Indirect measure of completeness of endochondrial ossification Correlates with growth potential, pubertal progression Mediated by estrogens |
|
|
Predicting height from parental height
|
Boys -- mother + father + 5 inches/2
Girls -- mother + father - 5 inches /2 Kids are typically w/in 3.5 of this |
|
|
Predicting height from skeletal maturity
|
Read bone age
See % of adult height attained Divide current height by that percentage |
|
|
Hormones involved in somatic growth
|
GHRH
GH Somatomedins (IGFs) IGF binding proteins Somatostain Ghrelin Thyroxine Gonadal steriods Glucocorticoids |
|
|
GH effects
|
Liver, mesenchyme -- make IGF-1
Fat - lipolytic -- mobilize fat Counter regulatory -- raises glucose Decreases urinary phosphate, increases urinary Ca Retains K, Na, Cl, Mg ?increased bone density |
|
|
Ghrelin and GH
|
Ligand for growth hormone secretogue receptor
Increases GH secretion directly and through GHRH Suppresses somatostatin effects in pituitary |
|
|
IGF-I receptor?
|
Tyrosine kinase
Activates growth pathways (A lot like insulin) |
|
|
IGFII interacts with which receptors?
|
IGF-1 and ?insulin
|
|
|
IGF binding proteins
|
7 different proteins
Bind circulating IGFs Influence level of free IGFs Appear to have metabolic effects beyond association with IGFs |
|
|
Thyroid hormone and growth
|
Linear growth is very sensitive
Hypothryoidism impairs release of GH, delays bone maturation, limits linear growth Hyperthyroidism accelerates linear growth and bone mauration |
|
|
Bone maturation is due to?
|
Estrogen in both males and females
Aromatized from circulating androgens in males |
|
|
Glucocorticoids and growth
|
Delayed maturation
Slow linear growth |
|
|
GH binding protein is...
|
Part of the GH receptor
|
|
|
GH/GRH deficiency causes
|
Tumor
Radiation Genetic syndromes: defects in GH gene, septo-optic dysplasia, prop-1 mutation |
|
|
GH deficiency symptoms
|
In kids
Decreased linear growth Infant hypoglycemia Increased adiposity (ripply abdominal fat) Decreased bone density Delayed bone age Normal weight (appear cherubic) |
|
|
Making the diagnosis of GH deficiency?
|
Failure of provocative testing
|
|
|
How to treat GH deficiency
|
Give GH
|
|
|
Lauron dwarfism
|
Genetic defect in GH receptor
Treat with IGF-I |
|
|
IGF-I deficiency
|
Some type of resistance to GH
High levels of GH Need to treat with IGF-I |
|
|
Defective IGF-I receptors
|
KO fatal in mice
Partial defects reported in humans |
|
|
Hypogonadism and height
|
Continue to grow and reach a tall height
|
|
|
Eunochoid body habitus
|
Disproportionally long arms and legs
What happens if you don't have a pubertal spurt but just keep growing |
|
|
Estrogen receptor defect in men
|
Tall
Osteoporotic Young bone age |
|
|
GH deficiency symptoms in adults
|
Impaired QOL
decreased energy/drive, poor concentration, low self-esteem, social isolation Body composition changes increased body fat, centeral fat deposition, decreased lean body mass, decreased bone density Reduced exercise capacity CV risk factors |
|
|
Diagnosing and treating GH deficiency in adults
|
Provocative testing with <5 (lower standard than kids)
Treat with low dose GH |
|
|
Mann stain
|
Special anterior pituitary stain
Acidophils -- GH Basophils -- ACTH Chromophobes -- multiple |
|
|
How to stain anterior pituitary to see what cells make what?
|
Use the hormones as markers
|
|
|
Pituitary adenomas growth
|
Can be infiltrative or circumscribed
Clonal, but can be polyhormonal |
|
|
Frequency of different pituitary adenoma types
|
Prolactinoma -- 40%
Null-cell (nonstaining) -- 35% Plurihormonal -- 10% Corticotroph Somatatotroph Gonadotroph Somatomammotroph |
|
|
Microadenoma vs adenoma?
|
Micro <10mm
|
|
|
Common somatic mutation in somatroph adenomas
|
G proteins
GNAS1 -- 40% |
|
|
Craniopharyngioma
|
Benign tumor arising from Rathke's pouch
Sellar and suprasellar in location Oily in appearance Cystic, with ill defined borders |
|
|
Sheehan's syndrome clinical picture
|
Adrenal insufficiency
Pallor (decreased MSH) Hypothyroidism Lactation failure Ovarian failure |
|
|
Pathogenesis of Sheehan's syndrome
|
During delivery pituitary has increased blood flow and is enlarged
With post-partum hemorrhage, hypovolemia, pituitary becomes ischemia and infarcts |
|
|
Microscopic appearance of craniopharyngioma
|
Stratified squamous or columnar epithelium in fibrous stroma
Cystic Calcified |
|
|
3,5,3' triiodothyronine
|
T3
|
|
|
T3 v T4
|
T4 is secreted by thryoid
T3 is mostly made from T4 in periphery T4 is more bound by plasma proteins T3 is more active, more avidly binds to nuclear receptor |
|
|
How does T3 get made?
|
Deiodination of T4
Removal of an outer ring iodine This process is impaired by fasting, some drugs, systemic illness |
|
|
Reverse T3
|
Deiodination of T4
Removal of an inner ring iodine Inactive compound |
|
|
Thyroid hormone receptor
|
Nuclear receptor
Heterodimerizes with RXR Interacts with repressor or stimulator molecules in a T3 dependent fashion |
|
|
Thyroid hormone effects
|
Development of brain, long bones in utero
Lipid synthesis and degradation Protein degradation Oxygen consumption Enhances actions of catecholamines Suppresses TSH gene expression, TSH secretion from pit |
|
|
Thyroid binding
|
Free hormone -- physiologically important, body regulates
99% of thyroid hormone is bound Bound by thyroid binding globulin, albumin, pre-albumin |
|
|
Conditions with increased T4 binding to plasma proteins
|
Pregnancy
Estrogen therapy Acute hepatitis Congenital increase TBG Abnormal albumin molecule |
|
|
Conditions with decreased T4 binding to plasma proteins
|
Corticosteroids
Major illness trauma Androgens Phenytoin Salicylates Nephrotic syndrome |
|
|
Effect of changes in thyroid hormone binding on clinical assays
|
With increased binding, total T4 will be high, but the patient is really euthyroid
With decreased binding, total T4 will be low, but the patient is really euthyroid |
|
|
Labs in hyperthyroidism
|
High free hormone, especially T3
Suppressed TSH |
|
|
Hypothyroidism labs
|
In primary -- high TSH and low T4
In secondary -- "normal" TSH and low T4 May have normal T3 with mild/mod primary hypothyroidism because TSH shifts production towards T3 |
|
|
Euthyroid sick syndrome
|
Low free T3 and T4 with "normal" TSH
Seen in severe systemic illness, trauma, starvation Not clinically hypothyroid, not helped by treatment of hypothyroidism Low T4 is sign of dangerous systemic illness |
|
|
Radioactive iodine uptake scan
|
Used to characterize thyroid lesions
Small dose of oral radioactive iodine Inflammatory processes reduce uptake Autonomous glands increased uptake |
|
|
Thyroid radionuclide scan
|
Gamma camera image after dose of radioactive iodine
Characterizes uptake Diffusely hot-- graves Hot nodule -- autonomous nodule Cold nodule -- might be cancer |
|
|
Why test for thyroglobulin
|
Surveillance for thyroid ca recurrence
Look for high levels with inflammatory process Look for low levels in factitious hyperthryoidism |
|
|
Anti thyroid antibodies
|
Anti-thyroglobulin, anti-thyroid peroxidase --- Hashimoto's
Anti-TSH -- Graves Assess graves during pregnancy |
|
|
Types of hypothyroidism
|
Primary -- failure of the thyroid gland
Secondary - Hypo/pit malfunction leading to low thyroid hormone levels Resistance -- rare, usually mutation in one of the thyroid receptor subtypes -can be mixed hypo/hyper |
|
|
Prevalence of hypothyroidism
|
High
Higher in women, elderly Many is undiagnosed |
|
|
Congenital hypothyroidismn causes
|
Either caused by maternal hypothyroidism or agenesis of fetal thyroid
Fetal thyroid start working about halfway through pregnancy |
|
|
Symptoms of congenital hypothyroidism
|
Atonia
Feeding problems Inactivity Constipation Umbilical hernia Large tongue Mottled skin Dry skin Typical facies Open posterior fontenelle Later -- low IQ and short stature |
|
|
Treatment of congenital hypothyroidism
|
Treat hypothyroidism adequately in mother -- Cretinism is largely irreversible
With thyroid agenesis, treating within three months of birth gives 85% of normal IQ |
|
|
Manifestations of hypothyroidism
|
Developmental delay
Slowing of metabolism less oxygen consumption slower metabolism of exogenous and endogenous substances Reduced expression of B-adrenergic receptors |
|
|
Symptoms of hypothyroidism
|
Dry skin
Fatigue Puffy hands, face Cold intolerance Horseness Constipation Weight gain Tingling of fingers Bradycardia Heavy menses Slow reflex relaxation |
|
|
Consequences of slow clearing of endogenous substances in hypothyroidism
|
High CPK (not an MI)
High LDL (not familial hypercholesteremia) Myxedma from not clearing ECM Carpal tunnel from compression from built up ECM |
|
|
Consequences of slow clearing of exogenous substances in hypothyroidism
|
Drugs need to be dose reduced
If not Anesthesia -- prolonged coma Digitalis -- AV block |
|
|
DDx primary hypothyroidism
|
Iodine deficiency
Hashimotos Congenital -- agenesis, mutations Thyroiditis Previous ablation Drugs --amiodarone, PTU, methimazole, lithium |
|
|
DDx for secondary hypothyroidism
|
Pituitary disease
Hypothalamic disease Genetic defect |
|
|
Treating hypothyroidism
|
Iodine in iodine deficiency
Thyroxine daily for all others In primary treat to TSH In secondary treat to symptoms |
|
|
Why do you often have to go up in thyroxine dose during pregnancy?
|
Increased catabolism
Many deiodinases in placenta Really don't want fetus to be deficient |
|
|
Treating hypothyroidism and hypoadrenalism
|
Must replace adrenals first
Treating thyroid first may precipitate addisonian crisis because thyroid hormone effect turnover rate of cortisol |
|
|
Myxdema coma
|
Hypothyroidism, hypothermia, reduced consciousness, myxdema
Often comes along with another systemic illness Emergency |
|
|
Distinguishing types of hypothyroid
|
Primary -- high TSH, low T4, usually goiter
Secondary-- not high TSH, low T4, no goiter Resistance -- high TSH, high T4, goiter |
|
|
Why is myxedma non-pitting?
|
Hygroscopic nature of hyaluronic acid
|
|
|
Polyglandular failure syndrome
|
Autoimmune destruction of multiple endocrine organs
Hashimotos Pernicious anemia DM2 Vitiligo Adrenal insufficiency |
|
|
Why treat with T4 instead of T3?
|
Longer half life (7 days)
Not as potent |
|
|
Hypothyroidism and CAD?
|
Might not treat thyroid as aggressively to avoid the cardiac stress
|
|
|
Thyroid hormone and the heart
|
Increase HR
Increase efficiency Decreased peripheral resistance and BP |
|
|
Clinical testing for free thyroid hormone
|
Direct assay of T3, T4 (may not work when sick)
Equilibrium dialysis to assess free portion is gold standard, $$ Resin uptake test -- for calculating free hormone index |
|
|
Thyrotoxicosis
|
Tissues exposed and respond to excess of thyroid hormone
|
|
|
Hyperthyroidism
|
Hyperfunction of the thyroid gland with resultant toxicosis
|
|
|
Hyperthyroxinemia
|
Elevated thyroid hormone levels measured in the blood
|
|
|
Most common etiologies of thyrotoxicosis
|
Grave's
Multinodular goiter Toxic adenoma Thyroiditis |
|
|
Grave's disease epi
|
Women 7: Men 1
Occurs at any age but peaks in 30s-40s |
|
|
Genetics and thyroid disease
|
Graves is linked to other autoimmune diseases like Hashimoto's, pernicious anemia by HLA type
Some activating receptor mutations, but these are rare |
|
|
Mechanisms of thyrotoxicosis
|
Hyperthyroidism -- TSH receptor antibody, benign tumor, foci of autonomous function
Release of stored hormone -- thyroiditis Exogenous thyroid -- pills or animal thyroids TSH hypersecretion -- pituitary tumor/pituitary resistance to T4, chorinoic gonadoptrophic tumor Struma ovarii Iodine excess |
|
|
Grave's thyroid exam
|
Homogenously enlarged
Fleshy May hear bruit |
|
|
Triad of Graves
|
Diffuse thyroid hyperplasia--often with thyrotoxicosis
Infiltrative ophthalmopathy Infiltrative dermopathy -- pretibial mxyedema, thryoid acropachy |
|
|
Pathogenesis of Graves disease
|
Defect in immune surveillance
? loss of suppressor T cell fncs Autoreactive antibodies |
|
|
Testing for Graves antibodies
|
Non-clinical -- look for antibodies that cause rise in cAMP in cultured thyroid cells
Clinical -- screen for antibodies that block TSH binding to TSH receptor (TSH-binding inhibitory immunoglobulins), useful in pregnancy when you can't do a radioactive iodine test |
|
|
Thyrotoxicosis mechanism
|
B-adrenergic receptor increase
Increased mitochondrial and microsomal protein synthesis |
|
|
Thyrotoxicosis symptoms
|
Insomnia, irritability, psychosis
Heat intolerance, sweating Weight loss, increased appetite Proximal muscle weakness Fine tremor Palpitations, tachy, afib Lymphadenopathy, lymphocytosis Hepatosplenomegaly Smooth, warm, moist skin Hypomenorrhea Osteoporosis Onycholis Lid retraction and lag Increased stools |
|
|
Graves eye disease
|
Infiltrative disease unrelated to catecholamines and thyroid hormone levels
Lid edema, edema of the conjunctiva, infiltration of the extraoccular muscles |
|
|
How to treat Graves eye disease
|
Usually not necessary
Steroids, decompression in severe cases |
|
|
What is pretibial myxedema
|
Deposition of hyaluronic acid
Course, purple, peau d'orange texture |
|
|
Labs in hyperthyroidism
|
Suppressed TSH
High T4, T3, free T4, free T3, T3 resin uptake |
|
|
T3 toxicosis
|
Elevation of T3 with normal T4
May proceed T4 elevation Symptoms same |
|
|
Thyrotoxicosis with normal T4
|
Check thyroid binding protein levels
T3 toxicosis? |
|
|
Non-thyroid labs in thyrotoxicosis
|
Lymphocytosis
Slight neutropenia Hypercalcemia +/- hyperphosphatemia Diabetes --which may not be apparent when euthyroid |
|
|
Treatment of Graves aims
|
Control thyrotoxicosis
Not treating underlying mechanism, eye symptoms, derm symptoms |
|
|
Treating thyrotoxicosis generally
|
Antithyroid drugs
Beta blockers Ablation with subtotal thyroidectomy or I131 |
|
|
Problem with treating Graves with radioactive iodine thyroid ablation?
|
Makes eyes worse
|
|
|
Medical therapy for thyrotoxicosis
|
thiocarbamides: propylthiouracil (PTU) and methimazole
Inhibit coupling, organification -- production of T4/T3 Take a few weeks to work because they do not effect stored hormone |
|
|
What to do before a thyroidectomy
|
Treat with PTU
and iodide a few days before to reduce vascularity |
|
|
AEs with subtotal thyroidectomy
|
Thyroid storm
Recurrence if too sub Tetany with parathyroid damage Horseness with recurrent larygneal nerve damage |
|
|
SEs of antithyroid meds
|
Rash
Fever Hepatitis Agranulocytosis |
|
|
Beta blockers in thyrotoxicosis
|
Fast relief from some peripheral effects
Propronalol reduces the conversion of T4 to T3 |
|
|
Course of toxic multinodular goiter
|
History of goiter
Develops hyperthyroidism as one area of goiter becomes autonomous |
|
|
Radionuclide scan in toxic MNG
|
Heterogenous enlargement with area of increased uptake
|
|
|
Apathetic hyperthyroidism
|
Only symptoms weight loss, tachy, afib
Condition of the elderly Associated with MNG |
|
|
Treatment of MNG
|
Medical
Ablation |
|
|
Toxic adenoma
|
Functional adenoma
Autonomous Almost never malignant Single hot spot on radionuclide scan Treated with ablation |
|
|
Labs in facticious thyrotoxicosis
|
Low TSH, high T4
Low thyroglobulin Radiolnuclide scan with little to no uptake |
|
|
TSH secreting tumors
|
Pituitary adenomas
Thyroids look like Graves May overproduce alpha subunit, which can be used as a tumor marker |
|
|
Trophoblastic tumors and thyrotoxicosis
|
Two thyroid stimulators in placental tissue:
human placental thyrotropin molar thyrotropin bHCG can also stimulate TSH receptors Seen in molar pregnancies, occassional other trophoblastic tumors |
|
|
Subacute thyroiditis
|
Inflammatory process with leakage of stored hormone causing thyrotoxicosis
Nodularity with tenderness Low radioactive iodine uptake NSAIDs, self limiting |
|
|
Silent thyroiditis
|
Leakage of hormone
No pain Low iodine uptake Usually briefly hypothyroid then resolves |
|
|
Struma ovarii
|
Teratomatous tissue of ovary produces T4
|
|
|
What might precipitate Graves disease
|
Stress
Infection Sex steroids |
|
|
What is deposited in Graves eyes
|
Glycosaminoglycans
|
|
|
Medical option for treating TSH adenomas
|
Octreotide
Shrinks and reduces TSH production |
|
|
When would you do a thyroidectomy rather than I131 ablation?
|
Impingement on airway/swallowing
Pregnancy Children Hope for euthyroid result Ascetics Fear of radiation |
|
|
Goiter
|
Enlarged thyroid
Smooth or nodular (MNG) |
|
|
Simple (non-toxic) goiter pathogenesis
|
High TSH
--from problems in thyroid hormon production Clones of cells with intrinsically high growth rates |
|
|
Simple goiter cuases
|
Inherited defect in thyroid hormone biosynthesis
Iodine deficiency Goitrogens Antithyroid drugs Excess iodine |
|
|
Simple goiter symptoms
|
Euthyroid
Asymptomatic Unless large goiter -- dysphagia, dysphonia, cough, faintness with arms above head (Pemberton's sign) |
|
|
Treatment of simple goiters
|
Often not necessary
If big and growing with a high TSH, can give T4 to suppress TSH Simple MNGs which are longstanding will usually not respond to medication, and if need be, are dealt with surgically |
|
|
Incidentally found thyroid nodule, is it a problem?
|
Probably not, and if it is its probably not a bad cancer
|
|
|
Concerning US features of a thyroid nodule
|
>1 cm
Solid, hypoechoic Microcalcifications Irregular border Internal blood flow detected by Doppler |
|
|
Who to FNA with a thyroid nodule
|
Concerning US features
Cold on radionuclide scan (do if TSH is suppressed) |
|
|
Thyroid malignancy on exam
|
Painless nodule
|
|
|
Thyroid cancers
|
Papillary --
Follicular Anaplastic Medullary |
|
|
Papillary thyroid cancer
|
Well differentiated tumor of the follicular cells of the thyroid
Papillary features histolgically Often metastasizes to neck LNs Rarely to other sites Good prognosis Can rarely become aggressive in pts >45 |
|
|
Follicular thyroid cancer
|
Well differentiated tumor of the follicular cells of the thyroid
Histologically resemble follicles If metastatic, its to distant sites (lung and bone) ---this shortens life expectancy |
|
|
Treatment of well differentiated thyroid cancer
|
Total thyroidectomy and LN dissection if suspicious
Adjuvant treatment with I131 to ablate any thyroid tissue left Post-surgical suppression of TSH with T4 to avoid stimulation/regrowth Thyroglobulin can be used as a tumor marker |
|
|
Anaplastic thyroid carcinoma
|
Aggressive and non responsive to treatment
Usually in >60 Can arise from well-differentiated thyroid cancer OS - months 2/2 compressive symptoms 1% of thyroid malignancies |
|
|
Medullary thyroid cancer
|
Arises from C-cells of thyroid (neural crest cells)
Secrete calcitonin (ACTH, serotonin, prostaglandins, histamine) Not associated with hypocalcemia Not curable once metastatic Majority sporadic but associated with MEN syndromes 3-5% of thyroid malignancies |
|
|
Before you take out a medullary thyroid cancer
|
check to see if they have a pheo
these are in the some of the MEN syndromes too Operating on someone with an undiagnosed pheo is not a good idea |
|
|
Primary lymphoma of the thyroid
|
1-2%
Associated with Hashimotos Usually B cells F>M |
|
|
Most common type of thyroid cancer?
|
Papillary carcinoma
85-90% |
|
|
Microfollicular pattern seen on FNA
|
Consistent with
MNG adenoma follicular carcinoma |
|
|
Diagnosing papillary thyroid carcinoma
|
Done by FNA
Features: Papillary architecture Psamomma bodies UNIQUE nuclear features nuclear pseudoinclusions (typically optically clear nuceli) Nuclear grooves |
|
|
Diagnostic features of a follicular adenoma
|
Capsule
No invasion Typically is microfollicular in pattern |
|
|
Diagnosing follicular carcinoma
|
Need tissue sections cannot be done on FNA
Invasion of either vasculatur or through capsule Typically has microfollicular pattern |
|
|
Adrenal gland, what's in there?
|
Cortex --
cortisol aldo sex steriods Medulla chromaffin cells (pheochromocytes) make epi, norepi |
|
|
Adrenal cortex what are the zones and what do they make?
|
From superficial to deep
Zona glomerulosa --aldo Zona fasiculata --cortisol Zona reticularis -- sex steroids |
|
|
Adrenal adenomas
|
Can look like any of the three layers
Do not usually have a capsule May function |
|
|
What makes you worry that this might be an adrenal carcinoma?
|
Size. Big is bad.
Less than 2.5 cm is not malignant |
|
|
Histologic features of adrenal carcinoma
|
Nuclear pleomorphism and atypia
Necrosis Hemorrhage Nuclear pseudoinclusion |
|
|
Pheochromocytoma
|
Arising from adrenal medulla
Richly vascularized Synaptophysin positive |
|
|
Is this pheochromocytoma malignant?
|
Metastasis are the only way to know for sure
|
|
|
Where does a pheo metastasize?
|
LNs
Liver Lung Bones |
|
|
Symptoms of chronic adrenal insufficiency
|
Cortisol
Anorexia and weight loss Fatigue, lethargy N/V, stomach discomfort Hypotension, hyponatremia Hypoglycemia Impaired stress tolerance Hyperpigmentation Aldosterone Hypotension Hyponatremia Hyperkalemia Adrenal androgens Loss of pubic/axillary hair in women, loss of libido |
|
|
Causes of primary adrenal insufficiency
|
Autoimmune adrenalitis (80% of US cases today)
Adrenal hemorrhage (sepsis, anticoagulants) Tuberculosis/fungal Metastatic cancer Amyloidosis Genetic defects in cortisol synthesis CAH AIDS-related infections (CMV) |
|
|
Causes of secondary adrenal insufficiency
|
Hypopituitarism
Hypothalamic disease Isolated ACTH deficiency -- rare |
|
|
Secondary vs primary adrenal insufficiency
|
Primary -- failure of the adrenals
Secondary -- lack of adrenal function because they are not being stimulated |
|
|
Explain fluid balance in total adrenal insufficiency
|
Cortisol loss --reduced cardiac fnc
-- hypotension Aldosterone loss -- K retention by distal nephron H retention -- mild metabolic acidosis Na loss in urine -- hypovolemia ADH is increased in response to hypotension More water and less salt = hyponatremia May also be hyperkalemic -- increased K and increased water |
|
|
Explain fluid balance in hypocortisol only
|
Cortisol deficiency lower cardiac function, making hypotensive
Increased ADH -- increased water retention Hyponatremia usually with a low normal K |
|
|
Why can Na change with water expansion and K remain within norms?
|
Much smaller range for Na
|
|
|
Cosyntropin
|
ACTH analog
Provocative testing of adrenal gland reserve Lack of response to cosyntropin shows primary adrenal insufficiency |
|
|
What does cosyntropin test show with longstanding secondary adrenal insufficiency?
|
Blunted response
Adrenals have shrunk because they lacked trophic hormone |
|
|
Treatment of acute adrenal insufficiency
|
Saline
Cortisol |
|
|
Treatment of chronic primary adrenal insufficiency
|
Hydrocortisone
Fludricortisone (mineralocorticod) |
|
|
Difference in hormone issues between primary and secondary adrenal insufficiency
|
Aldosterone is fine in secondary
Controlled well enough by the renin system |
|
|
Treatment of chronic secondary adrenal insufficiency
|
Hydrocortisone only
|
|
|
What are the 2 'Structural COMPONENTS' of the 'NERVOUS SYSTEM'?
What are the 2 'FUNCTIONAL COMPONENTS' of the 'NERVOUS SYSTEM'? |
Structural:
1. CENTRAL NERVOUS SYSTEM (CNS) 2. PERIPHERAL NERVOUS SYSTEM (PNS) Functional: 1. AUTONOMIC NERVOUS SYSTEM (ANS) 2. SOMATIC NERVOUS SYSTEM (SKELETAL SYSTEM) |
|
|
Acute adrenal insufficiency causes
|
Stress to a person with chronic adrenal insufficiency
Hemorrhage destruction of adrenals during sepsis (like Waterhouse Fredrikson) |
|
|
Symptoms of secondary adrenal insufficiency
|
Hypocortisol symptoms
Pale (rather than hyperpigmented) Symptoms of hypopituitarism Symptoms of cranial mass lesion |
|
|
Partial adrenal insufficiency
|
Basal cortisol is pretty much okay
Only show symptoms at times of stress |
|
|
How do you do provocative testing for adrenal insufficiency during an adrenal crisis
|
Draw cortisol
Treat with dexamethasone Treat with cosyntropin Draw another cortisol Dexamethasone does not show up on the assay |
|
|
Insulin test with adrenal insufficiency
|
Hypoglycemia should result in cortisol secretion
This can be unpleasant/dangerous for a patient who is adrenally insufficient, but does test the HPA axis |
|
|
Adrenal insufficiency and GI illness
|
Emergency if patient cannot take oral cortisol replacement
Needs hospitalization |
|
|
Cushing's syndrome causes
|
Cushing's disease (excessive ACTH from pituitary based on hypo/pit disease)
Ectopic ACTH -- carcinoid, small cell tumors of the lung, pancreatic islet cell tumors Adrenocortical adenomas or carcinomas Exogenous glucocorticoid consumption |
|
|
Diagnosing Cushing's Syndrome
|
Excessive glucocorticoids
Failure to suppress with exogenous glucocorticoids Lack of normal diurnal variation |
|
|
Symptoms of Cushing's syndrome
|
Central obesity (moon face, buffalo hump)
Muscle weakness Bone pain/fractures Mental disturbances Purpura or easy bruising Thin skin Striae Poor wound healing Diabetes symptoms (sometimes actually diabetes) Hyperpigmentation Glucocorticod symptoms: HTH, peripheral edema, hypokalemia Androgen symptoms Hirsuitism in women, acne, reduced menses, reduced libido Mass symptoms |
|
|
DDx with Cushing's
|
PCOS
Metabolic syndrome Obesity with diabetes |
|
|
Clinical features with highest PPV for Cushings
|
Proximal muscle weakness
Osteoporosis in premenopausal women, men Spontaneous bruising Unexplained hypokalemia |
|
|
Tests for Cushings
|
Is diurnal rhythm intact?
midnight salivary cortisol Are adrenals suppressible? dexamethasone overnight Is there overproduction of cortisol? 24 hour urinary cortisol 2 of 3 buys you Cushing's syndrome |
|
|
Problems with the Cushing's diagnostics
|
Stress messes them up
Can't do a realistic midnight salivary cortisol on a hospitalized patient Dexa suppression may not happen in patients who are stressed, depressed, have increased estrogens, are noncompliant, on phenytoin |
|
|
Finding etiology of Cushings
|
Is ACTH high?
No -- assess adrenals Yes -- Chest/Pit imaging, check for other pit hormones, petrosal sinus sampling |
|
|
Ketoconazole
|
Suppresses cortisol secretion
Medical therapy for Cushings |
|
|
When to worry that Cushing's might be ectopic
|
Older male patient
Short course of symptoms Hyperpigmentation Prominent hypokalemia, alkalosis Weight loss, signs of systemic cancer |
|
|
Petrossal sinus testing in Cushings
|
Gold standard to call Cushing's disease vs syndrome
Catheters in both petrossal sinuses (via the femorals) and peripheral vein Sample after giving CRF With pituitary production, CRF will stimulate ACTH production, with ectopic, pituitary will be too suppressed to respond |
|
|
Treatment of Cushing's
|
Surgically remove the source if possible
Can radiate pituitary, removal adrenals in pit tumor Medical therapy (ketoconazole) second line |
|
|
Osteoporosis and Cushing's
|
Glucocorticoids inhibit osteoblasts
and Calcium absorption from the intestine |
|
|
Conn's syndrome
|
Hyperaldosteronism
80% caused by adrenal adenoma |
|
|
Adrenal and metastatic cancer
|
Common site of metastasis
? local immune suppression 2/2 high glucocorticoid levels Mets usually do not cause hypofunction because of large adrenal reserve |
|
|
Chromaffin cells: where?
|
Adrenal medulla - mostly epinephrine
Paraganglia cells - mostly norepi |
|
|
Adrenal medulla cells
|
Innervated by preganglionic fibers from splanchnic nerves
Can be views as post-ganglionic sympathetic nerves w/o axons Make epi and a little norepi |
|
|
What happens if the adrenal medulla is destroyed
|
Nothing
Do not need to treat |
|
|
Where do pheos arise?
|
Adrenal medulla
organ of Zuckerkandl, urinary bladder Perganglionic -- usually nonfunctional More likely to be malignant if outside of adrenals |
|
|
Neuroblastoma often arise in
|
Adrenals
Tumors of precursors of the sympathetic chain cells Can spontaneously remit Can secrete homovanillic acid and VMA loss of 1p and cmyc amp are bad TRK is good Good prognosis in <1 year old, bad in >1 |
|
|
Hirsutism define
|
Appearance in a female of androgen-dependent appearance of hair in areas it would normally be found in a male
-androgens promote hair growth -also convert vellous hair to course hair Regions determined by 5 alpha reductase distribution on skin surface |
|
|
How much T does it take to get changes in female
|
200 ng/dl
hirsuitism, acne, menstrual disturbances, clitoromegaly 300 increased muscle mass 500 temporal balding voice changes |
|
|
Hirsuitism DDx
|
PCOS (85%)
Idiopathic CAH Neoplasm small ovarian, big adrenal Cushing's Exogenous adrogen use |
|
|
Congenital adrenal hyperplasia
|
Enzyme block in cortisol pathway
High levels of ACTH cause hypertrophy of gland and production of precursors/other adrenal cortex hormones 21OH is necessary for gluco/mineralo but not androgens |
|
|
Most common CAH mutation
|
21 - hydroxylase, aka CYP21
Short arm of chromosome 6, in middle of HLA complex Gene frequently recombines with a nearby intron homologue, easy to pick up junk |
|
|
21-hydroxylase deficiency genetics
|
1: 14,500 live births
1:61 heterozygote highest in Aleuts and Ashkenazi Jews |
|
|
21-hydroxylase deficiency phenotype
|
Determined by best functioning allele
With some function, often pretty normal, with hirsuitism in adolescence Classic Ambiguous genitalia (f) or precocious puberty (m) Salt wasting (esp boys) Accelerated growth, short adult stature Cortisol/aldo deficient |
|
|
Diagnosis of 21 hydroxylase deficiency
|
ACTH stimulation and measurement of 17-OH-progesterone
17-OH is the substrate of 21-OH |
|
|
Treatment of CAH
|
Replace glucocorticoids and mineralocorticoids
Suppress sex steroid effects in utero -- prevent ambiguity as child -- avoid hirsuitism, short stature adult -- hirsuitism, fertility, stature boys -- avoid behavior problems, short staure Try to avoid -- inducing Cushing's, short stature from glucocorticoid excess |
|
|
Who should get prenatal treatment of CAH?
|
Later children after diagnosis of CAH
Mutation in girl Treat until sex can be determined and then mutation status |
|
|
How much hypertension is endocrine?
|
15% of HTN is not essential
Those are divided between renal and endocrine causes |
|
|
Mechanisms of endocrine HTN
|
Either increased volume - renin system
or Increased vasoconstriction - catecholamines, calcium or Increased CO-- thyroid hormone |
|
|
Cushing's syndrome and HTN
|
80% are mildly hypertensive
Etiology unclear Increased mineralocorticoids, increased glucocorticoid activity at mineralo receptor Increased production of angiotensinogen Increased responsiveness to endogenous vasoconstrictors (NE and angiotensin II) Increase CO Usually resolves after disease treatment |
|
|
Acromegaly and HTN
|
20-40%, mild D>S
Etiology unclear, related to GH levels Na retention? Contributes to the mortality of acromegaly |
|
|
HTN in exogenous Cushings?
|
Not usually
Exogenous glucocorticoids do not bind the mineralocorticoid receptor |
|
|
Endocrine causes of HTN
|
Primary hyperparathyroidism
Acromegaly Hyper/hypothyroidism Obesity DM Primary hyperaldosteronism Phenochromocytoma Cushing's Some forms of CAH --but endocrinology effects all cases of HTN |
|
|
Hyperparathyroidism and HTN
|
HTN may be preventing symptom
30-60% mild HTN (rarely severe) Hypercalcemia --vasoconstriction, also associated with high plasma renin activity Renal impairment from nephrocalcinosis Can be associated with pheo (MEN2) |
|
|
Treated hyperparathyroidism and persistent HTN
|
May have permanent renal changes even after parathyroidectomy
|
|
|
Hyperthyroidism and HTN
|
>30% have systolic HTN
Increase CO and HR -usually decreased PVR Plasma renin activity usually raised Resolves with treatment of hyperthryoidism |
|
|
Hypothyroidism and HTN
|
15-30% have mild diastolic HTN
Increased peripheral resistance Usually have low plasma renin activity May persist after treatment Hypothyroid patients can also be normotensive or hypotensive |
|
|
Obesity and HTN
|
Worsens with increased BMI
Central obesity worse Complicated mechanism including insulin resistance and increase Na reabsorption Weight loss often improves |
|
|
Diabetes and HTN
|
DM1: 20% onset often with nephropathy
DM2: 60%, often at time at diagnosis Obesity-mediated (DM2) Insulin resistance leads to endothelial changes (DM2) Nephropathy Na retention from hyperglycemia Hyperglycemia decreases NO release, which increases vasomotor tone |
|
|
Effect of having DM and HTN
|
Accelerates development of micro and macro vascular complications
|
|
|
OCPs and HTN
|
OCPs raise risk of mild HTN
Prolonged HTN in this setting can result in increased CV risk Mechanism ? increased renin system action because of increase in angiotensinogen production Part of recommendation that OCPs be avoided if >35, smoker Early high dose pill were way worse |
|
|
CAH and HTN
|
Not a problem in 21 hydroxylase deficiency because can't make aldo either
Problem in 17 hydroxylase because defect is in cortisol pathway only Problem 11 hydroxylase because while this prevents both aldo and cortisol production the precursor that builds up deoxycorticosterone acts as a mineralocorticoid |
|
|
Pheochromocytoma and HTN
|
50% have paroxysmal HTN
rest have sustained HTN 5-15% are normotensive Catecholamine secreting tumor Some experience orthostatic hypotension |
|
|
Classic triad of pheo symptoms
|
Paroxysmal hypertension (constriction based on alpha receptor activation)
Headaches Tachycardia (beta receptor activation) |
|
|
Pheochromocytoma incidence stats
|
0.1% of HTN patients
25% are familial VHL, RET, NF1, SDHB, SDHD |
|
|
What can you measure to monitor a pheochromocytoma
|
Epi, NE
Urine/plasma metanephrines VMA (breakdown product after COMT action) |
|
|
How to locate a pheochromcytoma
|
Usually not hard in a HTNsive patient because it takes a big pheo to get HTN as they are inefficent
CT MRI MIBG radionuclide scan, adrenergic tissues uptake |
|
|
Treatment of pheochromocytoma
|
Operate if possible
Medically manage (preop or if inoperable) -- alpha blockade, then beta blockade if arrythmias Alpha blockade with oral phenoxybenzamine and IV phentalomine |
|
|
What's it like to do surgery to remove a pheo
|
Scary
Big swings in BP Hypotensive crash when removed Start off needing vasodilators Then need lots of volume And pressors |
|
|
Primary hyperaldosteronism
|
Autonomous or semi-autonomous secretion of aldosterone by adenoma or adrenal hyperplasia
Na retention, potassium wasting, volume overload, mild-severe HTN Mild cases (usually the hyperplasia ones) won't be low K |
|
|
Labs in primary hyperaldosteronism
|
High and non-suppressible aldosterone
sodium loading test Suppressed and non-stimulatable renin 70% hypokalemic Test-- elevated aldo/renin ratio |
|
|
Is primary hyperaldosteronism bilateral hyperplasia or an adenoma
|
CT - false pos are a problem
Serum 18-hydroxycortisone -- elevated in adenoma Response to spironolactone is better in adenoma Lateralized by sampling the adrenal veins for aldo |
|
|
Renin tumor
|
High renin
High aldo HTN Low K |
|
|
Glucocorticoid remediable hyperaldosteronism
|
Mutation that makes aldosterone synthetase gene responsive to ACTH
HTN and low K Suppress ACTH with dexamethasone |
|
|
11 B hydroxysteroid dehydrogenase deficiency
|
Apparent mineralocorticod excess
Can't breakdown cortisol so it activates mineralocorticod receptors HTN, low K, low renin, LOW aldo Treat with dexamethasone or spironolactone |
|
|
Licorice HTN
|
Black licorice contains glycyrrhizic acid
Inhibits 11 b hydroxylase Apparent mineralocorticoid excess |
|
|
Liddle syndrome
|
Genetic mutation causing K wasting and Na absorption in renal tubules
HTN Low renin, low aldo Amiloride is treatment |
|
|
Lab workup for newly diagnosed HTN
|
Aldo/renin ration
Calcium Potassium TSH Creatinine Metanephrines if thinking pheo Appropriate to suspected endocrine syndrome |
|
|
Lisch nodules
|
Hamartomas of the iris
Seen in NF1 |
|
|
Hereditary syndromes involving pheo
|
NF1
-1% of patients have Von Hippel Lindau MEN 2 Succinate dehyrdogenase mutations |
|
|
Von Hippel Lindau disease
|
Inherited neoplasm syndrome
Hemangioblastomas of retina, cerebellum Renal cancer Pheochromocytomas in 15% Inactivating mutation VHL, HIF mediated |
|
|
MEN1
|
Multiple endocrine neoplasia
Loss of tumor suppressor MENIN (MEN1) Paraythyroid adenoma (95%) Pancreatic neuroendocrine tumors (50%) usually gastrinoma (ulcers) |
|
|
MEN2a
|
Multiple endocrine neoplasia 2
Activating mutation in RET (neural growth factor receptor) Medullary thyroid carcinoma high penetrant (90% by 40yrs) prophylactic thyroidectomy recommended Pheochromocytoma 50% Parathyroid hyperplasia 20-30% |
|
|
MEN2b
|
Medullary thyroid carcinoma
Pheochromocytomas Hyperparathyroidism Mucosal neuromas |
|
|
Hirschprung's disease
|
Inactivating mutations of RET
Failure of parasympathetic plexus to form in GI tract Megacolon, megaureter |
|
|
RET mutations in MEN2
|
All change cysteine to something else
Result in constitutive phosphorylation (activity) |
|
|
Zactima
Vandetanib |
RET TKI
in development |
|
|
Succindate dehydrogenase mutations
|
20% get pheos
Often extra-adrenal (paragangliomas) Can be malignant Oncogenesis is mediated by increased HIF-1 |
|
|
Define hypoglycemia
|
Blood glucose low enough to cause neuroglycopenia (<40 mg/dl)
This is always associated with pathology |
|
|
Whipple's triad of hypoglycemia
|
Symptoms
Sugar <60 Relief by eating |
|
|
Symptoms versus falling glucose
|
By 50, symptoms start, cortisol rises
By 40, epinephrine is high, cortisol is high, confusion is present |
|
|
Why can kids get hypoglycemic more easily
|
Brain is bigger in comparison to liver
In fasted state, the brain is using 60% of liver glucose output Basal fasting glucose is almost at max in kids So they can out excercise their livers |
|
|
DDx for hypoglycemia in neonate
|
Genetic disorders of glycogen, FA metabolism, amino acid metabolism, hyperinsulinism
|
|
|
Genetic defects resulting in hyperinsulinism
|
Gain of fnc of islet cell glucokinase
--increased perception of glucose Gain of fnc of glutamate dehydrogenase --perception of protein --hyperinsulin and hyperammonia Loss of fnc of beta cell ATP dependent K channel |
|
|
Transient hyperinsulinemia of neonate
|
Hypoglycemia immediately post birth
Insulin made in response to maternal glucose in babies of poorly controlled diabetics |
|
|
Alcohol and hypoglycemia in kids
|
Alcohol inhibits gluconeogenesis
Kids can get profoundly hypoglycemia because gluconeogenesis is highly utilized in fasting state |
|
|
GH, cortisol deficiencies and glucose
|
Hypoglycemia in kids
|
|
|
Autonomic symptoms of hypoglycemia
|
Tachycardia
Anxiety Sweating |
|
|
Toxin/drug induced hypoglycemia
|
Insulin, sulfonylureas
Ethanol Rat poison (Vacor) Rarely - beta blockers |
|
|
Facticious hyperglycemia
|
Intentional consumption of glucose lowering drugs for secondary gain
Want to look for to avoid invasive work up of hypoglycemia |
|
|
Fasting hyperglycemia, general mechanisms
|
Excessive insulin release
Liver dysfunction Non-insulin related hormones |
|
|
Insulinoma
|
Excess, autonomous insulin-secreting islet cell tumors
10% malignant Can be anywhere in pancreas Small tumors can cause big symptoms |
|
|
Nesidioblastosis
|
Non insulinoma pacreatongenous hyperinsulinism
Islet cell hyperplasia ? diffuse insulinoma postprandial/sometimes fasting hypoglycemia |
|
|
What other hormones disorders can result in fasting hypoglycemia in adults
|
Panhypopituitarism
Andrenal insufficiency -- reduction in hepatic gluconeogenic enzymes Tumor secretion IGF-1 GH loss alone is not enough in adults |
|
|
Real causes of post-meal hypoglycemia
|
Glutamate dehydrogenase deficiency in kids
Following gastric bypass, other abdominal surgery excessive insulin secretion often comes with hypotension Noninsulinoma Pancreatongenous Hyperinsulinemia syndrome Rarely insulinomas only show post-prandial sympts |
|
|
Post-meal syndrome
|
Not true hypoglycemia because neuroglycopenia is not there
Autonomic syndromes experienced after a meal, usually simple carb heavy Usually self-limited Can be disabling, can be treated with acarbose |
|
|
What to assess on hypoglycemia patient
|
At time of hypoglycemia assess
Neuro symptoms Glucose Insulin C-peptide - exogenous Proinsulin - insulinomas make more |
|
|
Facticious sulfonylurea hypoglycemia
|
Tough to catch
C-peptide will be appropriate because this is causes secretion of endogenous insulin Get levels |
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What to worry about with facticious hypoglycemia
|
High rate of suicide
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Treatment of Noninsulinoma Pancreotongenous Hyperinsulinemia syndrome
|
Pacreatectomy -- total or partial
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What can cause hepatic dysfunciton leading to hypoglycemia
|
R CHF
Septic shock Fulminant hepatitis |
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Autoimmune cause of hypoglycemia
|
Activating antibodies to insulin receptor
|
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Localizing insulinoma in pancrease
|
Calcium stimulation arteriogram
Calcium will produce insulin burst if you get it in the artery supplying the insulinoma |
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Islet cell tumors
|
60% non functioning
Function ones: insulinoma, gastrinoma (ectopic), glucagonoma, VIPoma, somatostatinoma, GHRH-oma, CRH-oma |
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When you centrifuge plasma, what floats to the top?
|
Cholesterol, free and esterified
Triglycerides Phosphlipids Apolipoproteins |
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What the different appoliproteins?
|
Chylomicrons
VLDL ILDL LDL HDL |
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Chylomicrons
Composition and assembly |
Assembled in intestine from dietary fats
Lots of triglycerides Not that much phospholipids, proteins, cholesterol |
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VLDL
Composition and assembly |
New lipid synthesis, assembled in the liver
Triglyceride with a little cholesterol center Phospholipids and proteins surrounding |
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LDL
Composition and assembly |
Made in plasma by metabolism of VLDL
ILDL is intermediate Core -- lots of cholesterol and a little triglyceride Surrounded by higher % phospholipids and proteins |
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HDL
Composition and assembly |
Lots of proteins and phospholipids with center of cholesterol
Assembled from tissue lipids in plasma from liver made precursor Reverse transporter |
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What apolipoprotein goes is in what plasma lippoprotein
|
ApoE - VLDL
ApoB-100 -- VLDL and LDL ApoA1 -- HDL |
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Path of dietary fats and cholesterol
|
Absorbed by intestinal epithelium
Packaged into chylomicrons LPL takes triglycerides out of chylomicrons and into adipose Chylomicron remnants deliver dietary cholesterol to liver And destroyed by lysosomes Cholesterol is excreted as bile acids or repackaged as VLDL |
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Path of endogenously made fats/cholesterol
|
Made in liver
Packaged into VLDL and sent into bloodstream LPL takes out TGs and puts them in adipose Turns VLDL into ILDL Hepatic lipase further removes TGs (interaction mediated by ApoE) This creates LDL LDL uptake by peripheral cells, macrophages or liver |
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Cholesterylester transfer protein
|
Transfers TGs and cholesterol between lippoproteins
Like from HDL to LDL |
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Cellular cholesterol homeostasis
|
Intracellular high cholesterol levels
Down regulates transcription of LDL-R Increase activity of ACAT to store cholesterold Inhibits HMG CoA reductase from making more cholesterol |
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HDL life
|
Liver secretes pre-HDL
Cellular free cholesterol egresses through ABCG1 protein into preHDL LCAT converts the cholesterol to cholesterol ester Cholesterol returns to the liver via the SR-B1 or via LDL after transfer by CETP |
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Foam cell
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Macrophage that has taken up oxidized LDL
Beginning of atherosclerosis |
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Why is increasing hepatic LDL receptor important to preventing atherosclerosis
|
Efficient metabolism of LDL
Lower LDL levels means less can be oxidized |
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Familial hypercholesteremia
|
Increased Serum Cholesterol
Defect in LDL-R Heterozygote symptomatic, homozygote worse Increased early CV disease risk Tendon xanthomas |
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Familial defective apo B 100
|
Increased Cholesterol
|
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Deficiency of lipoprotein lipase
|
High TGs
|
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Deficiency if apo CII
|
High TGs
|
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Familial dysbetalipoproteinemia
|
Increases TGs and cholesterol
|
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Tangier's disease
|
Decreased HDL
|
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Diabetes mellitus and lipids
|
High TG, low HDL
|
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Hypothyroidism and lipids
|
High LDL
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Nephrotic syndrome and lipids
|
Mixed hyperlipidemia
High LDL dominating |
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Chronic renal failure and lipids
|
High TGs
|
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Arcus juvenilis
|
White ring around iris
Cholesterol deposits Seen in homozygous familial hypercholesteremia kids |
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PSCK9
|
Enzyme that helps breakdown LDL-R
Gain of function mutation is AD for high LDL |
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Hypercholesteremia through diet
|
Acquired deficiency in LDL-R
Down regulation of LDL-R gene based on high intracellular cholesterol Affect enhanced by saturated fatty acids |
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LDL Receptor, how does it work?
|
On most cells, highest density in liver
Binds LDL via ApoB-100 Can be recycled or degraded with the LDL |
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LDL scavenger receptor
|
On macrophages
Unregulated endocytosis of oxidized LDL |
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What is required for the beginning of an artheronmatous plaque?
|
Endothelial damage
Oxidized LDL |
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ApoB100 mutation
|
Phenocopy of LDL-R mutation
LDL cannot connect with LDL-R Hypercholesteremia |
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Trans - unsaturated fat
|
Acts like saturated fat in terms of higher LDL and lower HDL
Made by chemically hydrogenating unsaturated fats |
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Familial increased ILDL
|
Type III
ApoE mutation leaves ILDL unable to interact with liver to become LDL ILDL accumulates High cholesterol and TG--mixed hyperlipidemia Palmar crease xanthoma, planar (eyelid) xanthoma (xanthelasma) Phenotype worsened by obesity, diabetes, hypothyroidism |
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Hyperchylomicronemia (Type I)
|
Elevated TGs, normal cholesterol
Defect in LPL, apoCII (LPL activator) Eruptive xanthomas, lipemia retinalis Abdominal pain -- acute pancreatitis Cream of tomato soup blood |
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Tangiers disease
|
AR mutation in ABCG1
pre-HDLs cannot be loaded up with cellular cholesterol Cholesterol esters accumulates in tissue Worse if LDL is also high Orange tonsils |
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ABCG1 polymorphisms
|
Can lead to low HDL
Not as strong a phenotype as tangiers |
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Total cholesterol
|
LDL + HDL + VLDL
VLDL = TG/5 |
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|
Non-HDL cholesterol
|
Total - HDL
|
|
|
Documenting hyperlipidemia
Translating to hyperlipoproteinemia |
Hyperlipidemia -- fasting cholesterol, TGs
Hyperlipoproteinemia -- measure HDL, estimate VLDL, LDL |
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|
Tube test
|
Look at centrifuged plasma to see where hypertriglyceremia
Large white band on top -- chylomicrons Homogenous appearing -- LDL Lighter in color with small white bad -- ILDL Homogenous and light colored -- VLDL |
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Workup for new hyperlippoproteinemia
|
Document hyperlipidemia
Translate to hyperlippoproteinemia Tube test for TGs Identify goal values for health Genetic vs aquired |
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What are we treating when we treat hyperlipoproteinemia
|
Increased CV risk
Modifying LDL reduces CAD, specific death, disease burden Any reduction helps Best evidence is for lowering LDL with statin in middle aged men Lowering LDL may not be the whole story for why statins reduce CAD |
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Target for LDL treatment
|
Based on CHD risk
With CHD/equivalent : <100 mg/dl With some risk factors of CHD: <130 Low risk for CHD: <160 |
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Targets for TGs
|
Uncertain
<500 to avoid pancreatitis |
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HDL targets
|
Unclear
>40 men, >50 women |
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|
What to treat with in elevated lipids
|
TGs -- nicotinic acid, fibrates, omega 3s
LDL -- statins then Eze, fibrates, nicotinic acid, bile sequestrants (if TGs <200) |
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|
Statins
|
HMG CoA reductase competitive inhibitors
Reduces intracellular cholesterol Increased LDL-R Increased LDL clearance from blood |
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Bile acid sequestrants
|
Prevent recirculation of bile acids
Reduces hepatic cholesterol Increased LDL-R and HMG CoA reductase activity Statins inhibit this endogenous production, working synergistically |
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Ezetimide
|
Reduces the intestinal absorption of cholesterol
Inhibits intestinal cholesterol transporter (NPC1L1) Increases LDL-R 20% reduction in LDL as single agent Some controversy ?increase ca risk, no data on improved CV |
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Nicotinic Acid
|
High dose reduces LDL by decreasing production of VLDL and raises HDL
SE: flushing, decreased glucose tolerance, GI upset, hyperuricemia |
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Fibrates
|
Complex mechanism effecting VLDL/ILDL metabolism
Bind PPARalpha receptor Drug of choice for Type III, increased ILDL |
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Omega 3 FAs
|
Reduce endogenous production of TGs--->VLDL
Can reduce TGs by 50% Prescription (Lovaza) is better than fish oils Cardioprotective more than lipid lower effects: anti-platlet, anti-arrythmic |
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|
Should we try to raise HDL?
|
Through good lifestyle mod : exercise, weight loss, smoking cessation
Isolated increasing (like a CTEP inhibitor) not proven helpful |
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Exocrine pancreas
|
Acinar cells secreting digestive enzymes
Most of the pancreas |
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|
Endocrine pancreas
|
Islets -- about 1% of pancreas
Alpha cells -- secrete glucagon Beta cells - secrete insulin Delta cells - secrete somatostain |
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Effect of chronic changes in albumin on plasma calcium
|
Effects total calcium, free is maintained
Increased albumin = increased total |
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|
Effect of acute changes in pH on plasma calcium
|
Changes in free calcium
Acid kicks calcium off albumin Increased pH --- decreased free calcium Decreased pH -- increased free calcium |
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|
What gives symptoms in calcium related disorders?
|
Free calcium changes
Severity and rapidity of changes matters |
|
|
Hypocalcemia symptoms
|
With increasingly low calcium
Nothing Fatigue Anxiety/irritability Numbness/paresthesias Muscle cramps Carpopedal spasm Tetany Seizures |
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|
Hypercalcemia symptoms
|
With increasing serum free calcium
None Fatigue Polyuria/polydipsia GI complaints/constipation Neuro Lethargy, confusion, coma, death |
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|
Body's response to falling serum free calcium
|
Increased PTH, which increase 1,25 OH D
PTH: increases Ca and PO4 resorption from bone, Ca resorption from urine and PO4 loss into urine VitD: increase Ca and PO4 from bone and GI tract Net effect: increase serum free calcium without change to phosphate |
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|
Calcium sensor
|
Serpentine G-protein associated receptor in parathyroid gland
Extracellular binding of calcium results in intracellular calcium levels rising Inhibits PTH transcription, secretion, and glandular growth |
|
|
Genetic syndrome of inactivation of calcium sensing receptor results in
|
Hypercalcemia from inappropriate secretion of PTH
|
|
|
Hypercalcemia etiology
|
Hyperparathyroidism
Malignancy Granulomatous process Medications Others: immobilization, hyperthyroidism, adrenal insufficiency |
|
|
Two mechanisms by which malignancy causes hypercalcemia?
|
Local osteolysis
PTHrP |
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|
Composition and location of normal parathyroids
|
Endocrine (chief and oncocytic) and adipose tissue
Should be pericricoid Can also be on lower thyroid, thymus, in mediastinum |
|
|
Parathyroid adenoma
|
80-85% of primary hyperparathyroidism
Clonal neoplasm of endocrine cells of parathyroid sometimes see fat, pleiomorphism, atypia Remove should result in immediate drop by half Other parathyroids will appear smaller than adenoma, and smaller than normal |
|
|
Secondary hyperparathyroidism
|
Hyperplasia in response to low calcium
Increase in size of all glands Renal failure is often ultimate cause |
|
|
Tertiary hyperparathyroidism
|
Autonomously functional adenoma arising in hyperplasia
Rare |
|
|
Complications of hyperparathyroidism
|
Renal stones
Osteitis Fibrosa Cystica -- bone lesions from accelerated resorption of cortical bone |
|
|
Mediators of hypercalcemia from boney metastasis
Cancers |
RANK-L, TGFs, interleukin-1, TNFalpha, MIP
Breast, prostate, lymphoma, multiple myeloma |
|
|
PTHrP tumors
|
Squamous cell cancer of the lung
Renal cell carcinoma Ovarian small cell carcinoma Breast Bladder Endocrine |
|
|
Pathogenesis of granulomatous disease mediated hypercalcemia
|
Vitamin D mediated
Macrophages make 1,25 (OH) D |
|
|
Differentiating between cancer and hyperparathyroidism as cause of hypercalcemia
|
Course is shorter in cancer
Calcium is higher in cancer Patients with cancer are sicker Stones more frequent in hyperparathyroidism Blasts and clasts with hyperpara Just blasts in cancer |
|
|
Indications for surgery in hyperparathyroidism
|
Symptoms
Calcium >11.5 Younger Marker hypercalciuria Renal failure, unexplained Osteoporosis |
|
|
Cancers that do not cause hypercalcemia
|
Prostate, GI adenos, Small cell, thyroid
|
|
|
Differentiating between cancer mechanism of hypercalcemia
|
Bone mets in osteolytic
Low urine calcium in PTHrP High cAMP in urine Low 1,25 OH in PTHrP PTHrP is more common |
|
|
Renal failure effects on mineral homeostasis
|
Low Ca, high PO4, bone loss
|
|
|
Osteopenia define
|
Radiologically -- evidence of bone loss
Clinically -- T = -1 to -2.5 |
|
|
Osteomalacia
|
Pathologic diagnosis
Problem with bone mineralization Bone matrix is okay |
|
|
Osteoporosis define
|
Pathologic -- decrease in bone matrix and mineralization
No mineralization defect Clinical - T<-2.5 |
|
|
Bone cell origins
|
Blasts -- Fibroblastic precursor
Clasts -- Monocytic/macrophage line |
|
|
Bone forming unit
|
Osteoblasts and osteoclasts
Working in sequence to remodel bone |
|
|
Osteoporosis pathologically
|
Cortical and medullary bone become thinner
Medullary bone trabecullae are lost |
|
|
Osteomalacia pathologically
|
More osteoid present because of defect in mineralization
Number of trabeculae preserved |
|
|
Osteomalacia, treatable?
|
Yes
If mineralization defect is correct, normal bone can recover |
|
|
Osteoclast activation
|
Mediated by RANK and RANK-L interaction
RANK is on osteoclasts, RANK-L is on osteoblasts/stroma |
|
|
Osteoprotegerin
|
Soluble protein that blocks the RANK/RANK-L interaction
Reduces the number of activated osteoclasts |
|
|
Factors effected bone density
|
Age, >30 bad
Sex steroids, estrogen (androgens) Calcium intake Genetics Activity level Weight gain Nonsmoking Glucocortiocid, excessive thyroxine, anticonvulsants, anticoagulants Illness |
|
|
Dexa Z score
|
Compares patient to same age/gender norms
Score in standard deviations |
|
|
Dexa T score
|
Patient compared to 30 year old same gender bone density
Determines osteporosis |
|
|
Osteoporosis and fracture threshold
|
Certainly higher risk of fractures in osteoporotic population
Still majority of fractures are in women with more bone, this is a much larger chunk of the population |
|
|
Factors influencing fracture rate
|
Age
old bone of any density is more fragile, more falls H/o fracture T < -1.8 Poor health Poor mobility |
|
|
Osteomalacia pathogenesis
|
Mineralization is a passive process
Need adequate Ca, PO4, proper pH Low 1,25(OH) D is most common cause |
|
|
Chromaffin cells
|
Cell derived from neural crest
Stain brown when exposed to chromium salts 2/2 oxidation of catecholamines |
|
|
Pheochromocytomas rules of tens
|
10% are malignant
10% are bilateral 10% are in children 10% are familial Not paraganglioma pheos are less likely to be functional and more likely to metastasize |
