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SFM5 > Metabolic Pathophys: Diabetes, Inborn Errors > Flashcards

Metabolic Pathophys: Diabetes, Inborn Errors Flashcards

1
Q

hereditary fructose intolerance

A
  • aldolase B defect –> toxic accumulation of fructose-1-phosphate in hepatocytes
  • hypoglycemia
  • convulsions
  • eventual liver failure
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2
Q

essential fructosuria

A
  • fructokinase defect
  • benign
  • incomplete metabolism of fructose in liver –> fructose in urine
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3
Q

galactokinase deficiency

A
  • accumulation of non-phosphorylated galactose / can’t be broken down through typical pathway
  • converted to galactitol
  • galactitol accumulation
  • early bilateral cataracts
    less severe than classic galactosemia as there is no accumulation of 1P-gal
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4
Q

classic galactosemia

A
  • galactose-1p-uridyltransferase (GALT) deficiency
  • autosomal recessive
  • phosphorylated galactose can’t be converted to glucose
  • toxic accumulation of phosphorylated galactose, galactitol, other alternative metabolites in hepatocytes
  • liver disease
  • infantile bilateral cataracts
  • sepsis risk
  • premature ovarian failure
  • neurocognitive defects, speech
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5
Q

ketogenic amino acids

A

leucine
lysine

result in ketones when metabolized

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6
Q

glucogenic amino acids

A

alanine
glutamate
aspartate

can be used for gluconeogenesis

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7
Q

phenylketonuria (PKU)

A
  • phenylalanine hydroxylase (PAH) defect
  • autosomal recessive

mx:

  • Phe not converted to Tyr
  • buildup of Phe, phenyl acetate, and other derivatives

sx:

  • severe neurodevelopmental disease w/ seizures if untreated
  • “musty” odor in urine d/t phenyl acetate
  • pale skin, hair, eyes (relatively) d/t reduced melanin synthesis (from Tyr)

tx:

  • phenylalanine free diet
  • initiate ASAP, newborn screening
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8
Q

hyperammonemia w/o metabolic acidosis

A
  • genetic defects in urea cycle
  • low BUN
  • seizures
  • coma
  • hyperventilation
  • lethargy, irritability
  • vomiting
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9
Q

hyperammonemia w/ metabolic acidosis

A
  • defects in metabolism of specific organic acids, such as methyl malonate
  • seizures
  • coma
  • hyperventilation
  • lethargy, irritability
  • vomiting
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10
Q

hyperammonemia w/ hyperbilirubinemia

A
  • liver failure/cirrhosis
  • diminished LFTs
  • seizures
  • coma
  • hyperventilation
  • lethargy, irritability
  • vomiting
  • jaundice
  • other sx of liver failure
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11
Q

hypOketotic hypOglycemia

A
  • fatty acid oxidation disorders (FAOD), when fasting
  • d/t genetic defects in fat metabolism (beta-oxidation/acyl-dehydrogenases or carnitine shuttlers)
  • when fasting, don’t have enough blood glucose (hence hypOglycemia), but also now can’t break down fatty acids (which would generate ketones and, via 3-C stubs, induce gluconeogenesis)
  • energy defecits
  • organ damage
  • neuro damage
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12
Q

key intermediate in cholesterol synthesis

A

HMG-CoA

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13
Q

M6P tag

A
  • tags lysosomal enzymes at Golgi for shuttling to lysosomes (i.e. proteins that are supposed to function in the lysosome, not things being marked for degradation)
  • important in enzyme-replacement therapy for lysosomal storage diseases - therapeutics must contain M6P tag
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14
Q

GSD type I

A
  • G6PD deficiency
  • glycogen storage disease
  • essentially a liver disease because G6PD only functions in glycogen storage in the liver (not heart or muscle)
  • accumulation of glucose-6-phosphate –> increased production/decreased consumption of lactate, triglycerides, uric acid
  • can’t release glucose from glycogen on fasting (glycogenolysis) AND can’t complete gluconeogenesis –> hypoglycemia
  • severe hypoglycemia on fasting
  • hepatomegaly
  • elevated lactate, triglycerides, and uric acid
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15
Q

GSD type 2

A
  • deficiency in lysosomal degradation of glycogen
  • liver, heart, muscle manifestations
  • death w/in 5 years of life
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16
Q

GSD type 3

A
  • deficiency in glycogen debranching enzyme
  • liver, muscle manifestations
  • mild hypoglycemia (no problem with gluoconeogenesis)
  • overal milder
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17
Q

GSD type 5

A
  • deficiency in muscle-specific form of glycogen phosphorylase
  • muscle-specific manifestations (weakness, wasting)
  • myoglobinuria
  • second-wind phenomenon
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18
Q

X-linked adrenoleukodystrophy

A
  • classic peroxisomal disease
  • mutations in peroxisomal transporter for very long chain fatty acids (VLCFAs)
  • VLCFAs then accumulate in cells because they can’t be degraded in mitochondria
  • progressive loss of myelin
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19
Q

refeeding syndrome

A

deficiency of:

  • phosphate
  • magnesium
  • potassium (hypO-K)
  • vitamin B1

d/t prolonged starvation followed by refeeding

  • phosphate, Mg++, K+, and B1 all reached equilibrium during starvation
  • suddenly making a bunch of new cells –> deficiency.
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20
Q

c peptide

A

cleaved from insulin precursor (1:1)

indirect measurement of blood glucose

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21
Q

random and fasting glucose in diabetes

A

Fasting:
>126
<100 is normal
100-125 is prediabetic

Random:
> 200 if symptomatic (polyuria, polydipsia, polyphagia, weight loss)

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22
Q

oral glucose tolerance test (OGGT) in diabetes

A

glucose >200 2 hours after glucose challenge

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23
Q

HgbA1c in diabetes

A

> 6.5

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24
Q

MODY

A

autosomal dominant defect in insulin production or function
several possible gene mutations, generally single defect in a given patient
generally presents in non obese patients <25 y/o

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25
Q

exocrine pancreatic disorders

A

include pancreatitis, trauma, pancreatectomy, CF, hemochromocytosis
damage pancreas –> diabetes

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26
Q

somatostatinoma

A

decreased insulin secretion –> diabetes

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27
Q

drugs associated with insulin deficient diabetes

A

beta cell toxicity:

  • alcohol
  • pentamidine
  • cyclosporine

beta cell autoimmunity:

  • IFN-alpha
  • anti-PD-1
  • anti-CTLA-4

beta cell dysfunction:

  • thiazide diuretics
  • diaxozide
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28
Q

drugs associated with insulin resistant diabetes

A
  • gluococorticoids
  • progesterone
  • atypical antipsychotics
  • ARV protease inhibitors
  • tacromilus
29
Q

infections associated with insulin deficient diabetes

A
  • congenital rubella

- CMV

30
Q

gestational diabetes

A
  • 2nd to 3rd tri
  • IR d/t hormones, weight gain
  • inadequate compensatory insulin secretion
  • high risk for future non-G diabetes
31
Q

stages of T1DM

A

1

  • autoimmunity
  • multiple antibodies
  • normoglycemia

2

  • autoimmunity
  • prediabetes on testing/progressive dysglycemia

3

  • symptomatic
  • hyperglycemia
  • progressive loss of measurable C-peptide
32
Q

antibodies associated with T1DM

A

GAD
ICA
IAA
ZnT8

33
Q

preventative medication T2DM

A

metformin if <60, obese, and very high risk

34
Q

emergent complications of diabetes

A

hypERglycemia :
- DKA
- hypER-osmolar state
hypOglycemia

35
Q

absolute insulin deficiency

A

no insulin at all

–> DKA

36
Q

hypERglycemic hypERosmotic state (HHS)

A

osmotic diuresis –> excessive water/lyte loss

  • -> dehydration –> hypERosmolarity
  • -> impaired renal function
  • hypERglycemic emergency
  • absent or minimal ketogenesis
  • relative rather than absolute insulin deficiency
    • glycogenolysis

sx:

  • dehydration
  • AMS
  • polys
  • ± weight loss
37
Q

diabetic ketoacidosis (DKA)

A

absolute insulin deficiency –> lipolysis, ketogenesis –> depleted alkali reserve –> *metabolic acidosis

lipolysis –> increased free fatty acids to liver –> *hyperlipidemia

hyperglycemia –> *HHS –> impaired renal function

sx:

  • nausea, vomiting
  • abdominal pain
  • fruity breath
  • Kussmaul respirations (rapid and deep)
  • polys
  • ± weight loss
  • dehydration
38
Q

precipitants of hypERglycemic crisis

A
  • infection
  • insulin omission
  • CVA/MI
  • alcohol or drug abuse
  • meds (steroids, antipsychotics, SGLT2i)
  • previously undiagnosed diabetes

excessive stress –> increase in counter regulatory hormones (cortisol, catecholamines, glucagon) –> gluconeogenesis

PLUS

absolute or relative insulin deficiency/insufficient compensatory insulin secretion

39
Q

classes of hypOglycemia

A

1: glucose 54-70
2: <54
“severe:” requires help

40
Q

tx hypOglycemia

A

if able: “rapid” carbs (no fat, which would slow absorption)

  • 15-30 g
  • 15 g = 4 lifesavers, 4 glucose tabs, 4 oz juice, 8 oz skim milk
  • note chocolate and ice cream have too much fat to be as effective

else, IV dextrose ± glucagon

41
Q

hypOglycemia sx

A
  • sweating
  • shakiness
  • anxiety
  • palpitations
  • AMS
or asymptomatic (hypoglycemic unawareness)
- most common in patients w/ frequent hypOglycemia
42
Q

most common cause of hypOglycemia

A

mismatch meds to food/exercise

- too much med to not enough food or too much exercise

43
Q

long term complications of diabetes

A

microvascular:

  • retinopathy
  • nephropathy
  • neuropathy

macrovascular:

  • CVD
  • pulmonary artery disease (PAD)
44
Q

diabetic retinopathy pathogenesis

A

hyperglycemia –>

  • accumulation of sorbitol in retinal cells
  • accumulation of AGEs in extracellular fluid (advanced glycosylation end products)
    • impaired auto regulation of retinal blood flow
  • -> capillary leakage –> macular edema, distortion
  • -> capillary dropout and retinal ischemia
  • -> VEGF –> neovascularization –> leakage, bleeding, tractional retinal detachment

T1DM: more likely to progress to ischemia, detachment, vision loss

T2DM: more likely to progress to macular edema (distorted central vision)

45
Q

diabetic eye disease sx and screening

A

early stages asymptomatic

  • screen in T1DM starting @ 5 yr after dx
  • in T2DM @ dx
  • both f/u yearly

sx:

  • blurred vision
  • scotomas
  • visual field cuts
  • acute visual loss
46
Q

tx diabetic eye disease

A

anti-VEGF

  • most effective tx for macular edema and preventing proliferative retinopathy (neovascularization)
  • less helpful once damage is already progressed to ischemia, detachment, vision loss

pan-retinal photocoagulation (laser therapy) may also help

47
Q

diabetic nephropathy prevention and tx

A

screening

  • yearly
  • asymptomatic in early stages

prevention

  • glycemic and bp control
  • ACEi or ARB

tx - slow progression in T2DM

  • SGLT2i
  • GLP-1R agonists
  • finerenone (mineralocorticoid aNTagonist)
48
Q

leptin

A 
adipokine
more fat = more leptin
"energy sufficiency" signal
reduces appetite
long term - doesn't do much meal-to-meal

obesity is associated with leptin resistance

49
Q

adiponectin

A

protective adipokine
inversely correlated with fat (less fat = more adiponectin)
less inflammation, IR, atherosclerosis

50
Q

resistin

A

adipokine
more fat = more resistin
promotes IR, hepatic gluconeogenesis

51
Q

RAAS and obesity

A

RAAS (all of those peptides) produced by adipocytes

links obesity to htn

52
Q

PAI-1 and obesity

A

prothrombophilin
inhibits fibrinolysis (promotes thrombosis)
produced by adipocytes (among other tissues)
links obesity to atherosclerosis

53
Q

ghrelin

A

released by stomach
signals hunger
highest when fasting, suppressed by food ingestion

obesity linked to increased ghrelin sensitivity (increased hunger response to lower ghrelin levels)

54
Q

GLP-1

A

secreted by L cells of SI following nutrient uptake
promote satiety
inhibits gastric emptying and intestinal motility
promotes glucose-mediated insulin release
antagonized by somatostatin

55
Q

PYY

A 
secreted by L cells of intestine
co-secreted with GLP-1
signals satiety at hypothalamus
inhibits gastric emptying and intestinal mobility
no effect on glucose
56
Q

weight loss and ghrelin

A

increase in baseline and post-prandial ghrelin for 1+ years following/during weight loss
(increases hunger during this time)

57
Q

weight loss and PYY

A

decreased baseline and post-prandial PYY for 1+ years following/during weight loss
(decreases satiety/increases hunger during this time)

58
Q

POMC

A

cells of melanocortin system in arcuate nucleus of hypothalamus
reduces food intake when activated

59
Q

NPY/AgRP

A

cells of melanocortin system in arcuate nucleus of hypothalamus
increases food intake when activated

60
Q

beta-endorphins

A

inhibit POMC

increases food intake

61
Q

obesity pharmacotherapy

A

gastric/pancreatic lipase inhibitor

  • induces fat maldigestion/malabsorption
  • binds lipases in intestinal lumen

sympathomimetic amines

  • e.g. amphetamines
  • NE (and dopamine, serotonin) release in ht to induce satiety

GLP-1 analogues

  • stimulate POMC (satiety)
  • reduce gastric transit/emptying (satiety)
  • reduce glucose-mediated insulin release
62
Q

roux en Y gastric bypass

A

stapling or transecting stomach
make 10-30 ml proximal gastric pouch
anastomose pouch to jejunum via “roux en Y limb”

  • bypasses duodenum, maldigestion
  • decreases food intake
  • reduced ghrelin (hunger), increased PYY and GLP-1 (satiety, glycemic improvement)

complications:

  • vitamin and mineral deficiencies
  • B1, B2, B6, B12, B9 (folate)
  • iron
  • zinc
  • vitamin A
  • vitamin D
63
Q

sleeve gastrectomy

A

vertical resection of a portion of the stomach

  • decreases food intake
  • reduced ghrelin (hunger), increased PYY and GLP-1 (satiety, insulin sensitivity)
64
Q

alpha cells

A

glucagon

65
Q

beta cells

A

insulin

66
Q

delta cells

A

somatostatin

67
Q

pp cells

A

pancreatic polypeptide

68
Q

distinguishing islet cell types

A

requires IHC

69
Q

insulinoma

A

usually non-malignant, sx (hypoglycemia) arise from insulin production

  • may be overt hypOglycemia
  • may be more subtle, e.g. diarrhea or weight loss

on histology look like an exceptionally large islet (up to 7-10 cm) surrounded by a capsule
IHC can distinguish them from other endocrinomas of pancreas

SFM5 (14 decks)

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