First Aid 78-101 Flashcards
Cheilosis
Corneal vascularization
Vitamin deficiency?
Riboflavin - B2
Function of ribovflavin
component of flavins FAD and FMN
used as cofactors in redox reactions
Uses 2 ATP
Synthesis of Niacin requires what other vitamins?
B2 and B6
Glossitis
what vitamin deficiency?
Niacin - B3
Isoniazid therapy can also cause both B6 and B3 deficiency
How does malignant carcinoid syndrome cause niacin deficiency?
Increase in tryptophan metabolism
Hyperpigmentation of sun-exposed limbs;
Dermatitis of C3-C4 - “broad collar” rash
Niacin deficiency
3D’s
How to prevent facial flushing from taking excess niacin?
Take aspirin with the niacin to prevent the prostaglandin reaction
What vitamin is an essential component of CoA and fatty acid synthase?
B5 - pantothenic acid
Dermatitis Alopecia Enteritis Adrenal insufficiency What vitamin deficiency?
Pantothenic acid - B5
A vitamin that is converted to PLP and used as a cofactor in:
transamination
decarboxylation
glycogen phosphorylase
synthesis of: cystathione, heme, niacin, histamine, serotonon, GABA, norepinephrine, dopamine, epinephrine
Pyridoxine - B6
**cofactor for homocysteine –> cysteine (from protein catabolism) and
succinyl CoA –> heme (from FA catabolism)
Rare vitamin deficiency due to antibiotic use or excessive ingestion of raw egg whites (avidin in eggs)
Vitamin B7 - biotin
used in adding 1 carbon group rxns:
pyruvate –> oxaloacetate (3-4)
Acetyl CoA –> malonyl CoA (2-3)
Propionyl CoA –> methylmalonyl CoA (3-4)
Vitamin important for DNA and RNA bases reaction
Vitamin B9 - folate
Absorbed in the jejunum
Small reserve in liver
Converted to THF
Phenytoin, Methotrexate, Sulfonamides, can all cause what vitamin deficiency?
Folate - B9
hypersegmented neutrophils, glossitis, macrocytic, megaloblastic anemia
most common vitamin deficiency in the US
Cofactor for methionine synthesis and methylmalonyl-CoA mutase
B12 cobalamin
large pool stored in the liver
Anti-intrinsic factor antibodies
pernicious anemia
increases in homocysteine deplete…
vitamins B12 and B9
homocystein –> methionine - methionine synthase is enzyme that simultaneously with B12 also turns THF-CH3 –> THF
What neurological symptoms are found in B12 deficiency?
Degeneration of dorsal columns, lateral corticospinal tracts, spinal cerebellar tracts due to abnormal myelin
If prolonged, deficiency in irreversible
Increased levels of homocysteine increase the risk for
cardiovascular events, via endothelial damage
Build up of what compound, in the absence of B12, is neurotoxic, and causes lethargy, hypotonia, seizures and parasthesias?
Methylmalonyl-CoA
Vitamin necessary for dopamine beta-hydroxylase
Vitamin C
converts dopamine –> NE
Vitamin C is an ancillary treatment for
methemoglobinemia
Reduces Fe3+ to Fe2+
Hemarthrosis
Corkscrew hair
Weakened immune response
what vitamin deficiency?
Vitamin C
Excess vitamin C, give 3 things.
Calcium oxalate kidney stones
can increase risk of iron toxicity in people with excess iron;
nausea, vomiting, fatigue, diarrhea
What are the effects of vitamin D on bone at low and high levels?
Low vitamin D –> increases bone mineralization
High vitamin D –> increases bone resorption
Ergocalciferol
D2
plants
Cholecalciferol
D3
milk, made in sun-exposed skin
Why would vitamin D deficiency cause hypocalcemic tetany?
Low calcium (and phosphate) absorption from the intestine
Breastfed infants should receive oral
Vitamin D
risk factors are hyperpigmentation, low sun exposure, prematurity
Vitamin D excess can be seen in what disease?
Granulomatous diseases –> activation of vitamin D by epithelioid macrophages
Excess - hypercalcemia, hypercalciuria
Vitamin E deficiency looks similar to B12 deficiency except:
no megaloblastic anemia, no hypersegmented neutrophils, no increased serum methylmalonic acid
deficiency E - hemolytic anemia, acanthocytosis, muscle weakness, posterior column (loss of proprioception and vibratory sense) and spinocerebellar tract demyelination (ataxia)
Tocopherol
Tocotrienol
other names for vitamin E
Phytomenadione
Phylloquinone
Phytonadiona
other names for vitamin K
Vitamin K is needed for the ________ which matures clotting factors II, VII, IX, X, C and S
gamma-carboxylation of glutamic acid residues
Prolonged use of antibiotics can cause what deficiency?
Vitamin K
Neonatal hemorrhage due to K deficiency will show what bleeding studies
increased PT, aPTT
normal bleeding time
Delayed wound healing Hypogonadism Decreased adult hair Dysgeusia Anosmia Acrodermatitis Enteropathica what vitamin deficiency?
Zinc
Fatty change in the liver can be caused by what deficiency
Protein
Kwashiorkor
Malnutrition - edema - anemia - fatty liver
Marasmus results in
muscle wasting
total calorie intake down
emaciation
Antidote for methanol or ethylene glycol poisoning, what is it and what does it do?
Fomepizole
inhibits alcohol dehydrogenase
(etOH–> acetaldehyde)
What is the limiting reagent for ethanol metabolism, both steps:
- ethanol –> acetaldehyde (cytosol)
- acetaldehyde –> acetate (mitochondria)
NAD+
- *by using up NAD+ in the liver:
1. pyruvate –> lactate to regenerate NAD+ –> lactic acidosis
2. oxaloacetate –> malate to regenerate NAD+ –> prevents gluconeogenesis –> fasting hypoglycemia
3. dihydroxyacetone phosphate –> glycerol-3-phosphate –> FA made –> hepatosteatosis
Where does heme synthesis take place?
Both cytoplasm and mitochondria
(same with urea cycle and gluconeogenesis)
HUGs take 2
Rate limiting enzyme in glycolysis, what is it and what is the step?
Phosphofructokinase (PFK-1)
cat Fructose-6-P –> Fructose-1,6-P
heavily regulated - ATP and citrate inhibit PFK-1;
Fructose-2,6-phosphate and AMP induce PFK-1
Rate limiting enzyme in gluconeogenesis?
Fructose-1,6-bisphosphatase
cat backward step from glycolysis: Fructose-1,6-P –> Fructose-6-P
inhibited by AMP and Fructose-2,6-P
Rate limiting step and enzyme in TCA
isocitrate dehydrogenase
cat isocitrate –> alpha-ketoglutarate
ATP and NADH inhibit
Insulin and thyroxine stimulate what enzyme?
HMG-CoA reductase
rate limiting and first step in cholesterol synthesis
NADPH is mainly made via
HMP shunt
NADPH is the major reducing equivalent in the cytosol
G6PD is the rate limiting enzyme of
the HMP shunt
glucose-6-P can either go to gycolysis (fwd), glucose (backward, gluconeogenesis), or sideways to 6-phosphogluconolactone (HMP shunt)
it can also go left to glycogenesis, for which glycogen synthase is the rate-limiting enzyme
Gene associated with maturity-onset diabetes of the young
Glucokinase liver and beta cells of pancreas cat glucose to glucose-6-P induced by insulin no feedback inhibition by glucose-6-phosphate
Garlic breath
vomiting
rice-water stools
inhibition of:
lipoic acid by arsenic
mitochondrial enzyme complex = pyruvate dehydrogenase complex - TLCFN cofactors
TLCFN cofactors
TPP (thiamine B1) Lipoic Acid CoA (pantothenic acid B5) FAD (riboflavin B2) NAD (niacin B3)
Purely ketogenic amino acids
Lysine
Leucine
diets high in these aa’s needed to treat pyruvate dehydrogenase deficiency (X-linked)
Rotenone inhibits
ETC complex I
Antimycin A inhibits
ETC complex III
Cyanide, CO, inhibit
ETC complex IV
Oligomycin inhibits
ETC complex V
directly inhibits mitochondrial ATP synthase –> increase in proton gradient
Uncoupling agents - ATP synthesis stops, ETC continues - heat produced, permeability of membrane increased:
2,4-dinitrophenol
aspirin (fevers if OD)
thermogenin in brown fat
Which FA chains can make glucose and why?
Odd chain only, bc can enter Krebs as succinyl-CoA –> oxaloacetate
Pathogenesis of G6PD deficiency
Low G6PD –> low NAPDH –> RBC has no NADPH for detoxification –> infection, drugs, fava beans make free radicals that diffuse into RBCs and damage them –> Hgb denatured –> Heinz bodies/hemolytic anemia
Drugs to be avoided in G6PD
Sulfonamides
Isoniazid
Primaquine
Fructokinase deficiency
benign
AR
cat fructose –> fructose-1-P
causes fructosuria
Aldolase B deficiency
fructose intolerance
AR
fructose-1-P build up, uses up phosphates, inhibits glycogenolysis AND gluconeogenesis
hypoglycemia, cirrhosis, vomiting, jaundice
Tx of fructose intolerance
limit intake of fructose and sucrose
Infant fails to track objects or develop a social smile
AR
galactokinase deficiency
only issue if galactose in diet –> build up of galactitol can cause cataracts
Fructose is to Aldolase B as Galactose is to
Uridyltransferase
classic galactosemia - failure to thrive, jaundice, intellectual disability, hepatomegaly, infantile cataracts, E. Coli sepsis risk
Tx: exclude galactose and lactose from diet
Schwann cells, retina and kidneys have only aldose reductase, for enzymes involving sorbitol. What does this mean?
Can make glucose –> Sorbitol but not sorbitol –> fructose
Build up of sorbitol –> osmotic damage –> cataracts, retinopathy, neuropathy seen in hyperglycemia in diabetes
Arginase
location
fx
deficiency results in
location - urea cycle - cytoplasm of liver
fx - cat arginine –> ornithine (urea cycle) and urea
spastic diplegia, progressive, growth delay, abnormal movements
tx with low protein diet
How is ammonia transported?
Amino acids, glutamate and alanine
hyperammonemia depletes alpha-ketoglutarate (involved in alanine-glutamate transfer of NH3), resulting in what?
low TCA cycle
somnolence, asterixis tremor, cerebral edema
from urea cycle deficiencies or liver disease
tx w/ low protein diet
MOA Benzoate, phenylacetate, phenylbutyrate
bind NH4+ leading to excretion
tx of hyperammonemia
MOA rifaximin
reduce colonic ammoniagenic bacteria
tx of hyperammonemina
MOA Lactulose
acidifies GI tract to trap NH4+ for excretion
tx of hyperammonemia
N-acetyglutamate synthase deficiency (urea cycle) presents in infants with intellectual disability, developmental delay, poorly regulated body temperature and respiration, poor feeding, and results from hyperammonemia. What other enzyme deficiency, also involved in the urea cycle, presents this way?
Carbamoyl phosphate synthetase I deficiency
Both AR
Most common urea cycle disorder
Ornithine transcarbamylase deficiency X-linked recessive orotic acid in urine and blood BUN down symptoms of hyperammonemia **NO megaloblastic anemia (distinguish from orotic acid uria)
Derivatives of Phenylalanine
–(Bh4)–> Tyrosine –(BH4) –> Dopa –(B6)–> Dopamine –>(vit C)–> NE –(SAM)–> Epi
Tyrosine –> Thyroxine
Dopa –> Melanin
Derivatives of Tryptophan
(via niacin, B2, B6) - NAD+, NADPH
(via serotonin, BH4, B6) - Melanin
Derivative of Histidine
Histamine (B6)
Derivative of Glycine
(via porphyrin, B6) - Heme
Derivatives of Glutamate
GABA (B6)
Glutathione
Derivatives of Arginine
Creatine
Urea
NO (BH4)
The deficiency in PKU is Phenylalanine hydroxylase. What step?
Phenylalanine –(BH4)–> Tyrosine
Small percentage of PKU from deficiency in Dihydropterodine reductase which recycles BH2–> BH4 = “malignant PKU”
Pallor of substantia nigra, locus ceruleus and vagal nucleus dorsalis seen in what enzyme deficiency?
PKU;
low dopamine –> low NE, serotonin, epi;
progressive neurological deterioration
AR
Musty body odor
hypopigmentation of hair, skin, eyes
PKU;
Tyrosine becomes essential;
Avoid anything containing phenylalanine (ie artificial sweeteners);
Phenylketones in urine - phenylacetate, phenyllactate, phenylpyruvate (also in blood, contributes to neurological symptoms)
Treat what disorder with restriction of isoleucine, leucine, valine restriction, and thiamine supplementation, and why?
Maple Syrup Urine disease;
deficiency in branched-chain alpha-ketoacid;
dehydrogenase (requires B1);
needed to degrade proteins to enter TCA cycle;
severe CNS defects and intellectual disability;
AR
AR
Bluish black connective tissue and sclerae (ochronosis)
Alkaptonuria
(remember osteogenesis imperfecta is most commonly AD);
urine turns black on prolonged exposure to air;
homogentisic acid toxic to cartilage;
Usually benign
Step inhibited in Alkaptonuria
Tyrosine –> Homogentisic acid –(homogentisate oxidase)–> maleylacetoacetic acid –> fumarate –> TCA
Enzyme defective in tyrosine catabolism pathway
AR lens subloxation marfanoid habitus intellectual disability osteoporosis thombosis atherosclerosis
Homocystinuria
Cystathionine synthase deficiency OR methionine synthase deficiency result in homocystinuria. High amounts of homocystine are found in the urine. What is the pathway?
Methionine cystathionine –> cysteine
Treat CSD version by reducing methionine in diet (to push rxn that way), increase cysteine and B12 and folate
Treat MSD version by increasing methionine in diet
Hereditary (AR) defect in PCT;
Precipitation of hexagonal cystine stones;
Defect name and situation
Prevents reabsorption of COLA: Cystine, Ornithine, Lysine, Arginine in PCT AND intestine;
Cystine forms from 2 cysteines (disulfide bond) –> precipitates;
Urinary cyanide-nitroprusside test to diagnose;
Treat with urinary alkanization is acetozolamide, potassium citrate, and chelating agents - ie penicillamine - to increase stone solubility, plus good hydration
Albinism is a deficiency of tyrosinase. What pathway and step?
DOPA –> Melanine in the catecholamine synthesis pathway
Glycogen branches have what bonds?
alpha (1,6)
Glycogen linkages have what bonds?
alpha (1,4)
What stain identifies glycogen and is useful for diagnosing glycogen storage diseases?
PAS
Why are beta blockers not administered during decompensated HF?
The heart is dependent on sympathetic input in this state
What diuretic class is associated with ototoxicity?
Loop diuretics ie furosemide, torsemide, bumetanide
especially when combined with other potentially ototoxic drugs: aminoglycosides, salicylates, cisplatin
TATA (aka Hogness) box
CAAT box
Eukaryotic promoter regions
TATA box 0 25 bp upstream;
CAAT box 70-80 bp upstream
Enhancers bind activator sequences that have what effect:
Bend DNA –> activator proteins can then access TFs and RNA Pol II at promoter site –> increases RATE of transcription
Classic galactosemia is caused by
impaired metabolism of glacatose-1-P (to UDP galactose via galactose-1-P uridyl transferase);
vomiting, lethargy, failure to thrive soon after birth
Deficiency in glucose-6-phosphatase
can’t make glucose from glycogenolysis;
Von Gierke disease (type I);
glycogen build up in liver –> hepatomegaly;
high uric acid, triglycerides, blood lactate;
severe fasting hypoglycemia
AR
What is the tx for Von Gierke disease?
frequent oral glucose/cornstarch to prevent severe fasting hypoglycemia
avoid fructose and galactose
Explain “Pome trashes the pump”
Pompe disease;
AR;
cardiomegaly, hypertrophic cardiomyopathy, exercise intolerance, hepatomegaly, early death
Can’t debranch glycogen - deficiency alpha-1,6-glucosidase AND deficiency lysosomal alpha-1,4-glucosidase (aka acid maltase)
Cori disease (III) is a milder form of Von Gierke disease. What is the deficient enzyme?
Debranching enzyme - alpha-1,6-glucosidase;
gluconeogenesis OK;
Normal blood lactate levels
Explain McCardle = Muscle
McArdle disease - type V glycogen storage disease
Enzyme: skeletal muscle glycogen phosphorylase (Myophosphorylase);
Increased glycogen in muscle, can’t break it down –> muscle cramps, myoglobinuria, (red urine) with strenuous exercise;
AR
What is a cardiac complication of McArdle disease?
Arrhythmia - electrolyte abnormalities
Fabry Gaucher Niemann-Pick Tay-Sachs Krabbe Metachromatic leukodystrophy Hurler Hunter all?
Lysosomal storage diseases;
Hurler and Hunter are mucopolysaccharidoses
GM2 –(Hexosaminidase A)–> GM3 –> Glucocerebroside
Ceramide trihexoside –(alpha-galactosidase A)–> Glucocerebroside;
Glucocerebroside –(Glucocerebrosidase aka beta-glucosidase)–> Ceramide
Sulfatides –(Arylsulfatase A)–> Galactocerebroside –(Galactocerebrosidase)–> Ceramide
Sphingomyelin –(Sphingomyelinase)–> Ceramide
Lysosomal storage pathway
GM2 –(Hexosaminidase A)–> GM3 –> Glucocerebroside
What disease when enzyme deficient?
Tay-Sachs (AR)
Accumulation of GM2 ganglioside results in what clinical picture?
Cherry-red spot on macula;
Lysosomes with onion skin;
Progressive neurodegeneration;
Developmental delay;
“Tay SaX lacks HeXosaminidase”
Ceramide trihexoside –(alpha-galactosidase A)–> Glucocerebroside;
What disease when enzyme deficient?
Fabry disease
only lysosomal storage disease with X-linked inheritance;
Accumulate ceramide trihexoside (Gb3)
Triad of episodic peripheral neuropathy (TIA, stroke possible), angiokeratomas (rash), hypohidrosis (not sweating)
What disease?
What later complications?
Fabry disease;
Progressive renal failure;
LV hypertrophy –> CV disease
Ceramide trihexoside –(alpha-galactosidase A)–> Glucocerebroside
Sulfatides –(Arylsulfatase A)–> Galactocerebroside
What disease when deficient?
Metachromatic leukodystrophy (AR);
Accumulation of cerebroside sulfate;
Central and peripheral demyelination with ataxia, dementia
Galactocerebroside –(Galactocerebrosidase)–> Ceramide
What disease when deficient?
Krabbe disease (AR) Accumulation of galactocerebroside and psychosine
Peripheral neuropathy
Developmental delay
Optic atrophy
Globoid cells
Krabbe disease
Galactocerebroside –(Galactocerebrosidase)–> Ceramide
If given Ashkenazi Jewish AR disease, what three should you consider?
Tay-Sachs;
Niemann-Pick
Gaucher
Glucocerebroside –(Glucocerebrosidase aka beta-glucosidase)–> Ceramide
What disease when deficient?
Gaucher disease (AR) **most common**
Histology of lipid-laden macrophages resembling crumpled tissue paper
Gaucher disease
deficiency in glucocerebrosidase
“Gaucher cells”
Massive splenomegaly from pancytopenia;
Hepatomegaly;
Osteoporosis;
Aseptic necrosis of femur and bone crises
Gaucher disease
deficiency in glucocerebrosidase
Sphingomyelin –(Sphingomyelinase)–> Ceramide
What symptoms when deficient?
Niemann-Pick disease;
Progressive neurodegeneration;
hepatosplenomegaly, foam cells, cherry-red spot on macula
Cherry red spot on macula WITH hepatomegaly
Niemann-Pick - deficiency sphingomyelinase
WITHOUT hepatomegaly - Tay-Sachs - deficiency of hexosaminidase A
The mucopolysaccharidoses are comprised of Hurler and Hunter syndromes. Both result in accumulation of heparan sulfate and dermatan sulfate. Which is XR and which is AR?
Hunter - XR - Mild hurler with aggressive behavior and NO corneal clouding
Hurler - AR - developmental delay, gargoylism, airway obstruction, corneal clouding, hepatosplenomegaly
alpha-L-iduronidase deficiency
Hurler - AR - developmental delay, gargoylism, airway obstruction, corneal clouding, hepatosplenomegaly
Iduronate sulfatase deficiency
Hunter - XR - Mild hurler with aggressive behavior and NO corneal clouding
Carnitine-dependent transport into the mito matrix required for
long chain fatty acid degradation
CARnitine = carnage of FA
carnitine shuttle
Fatty acid synthesis requires
citrate from mito –> cytosol
citrate shuttle
Hypoketotic hypoglycemia with weakness and hypotonia suggests a toxic accumulation of fatty acids in the mitochondria. What deficiency?
Systemic primary carnitine deficiency;
cannot shuttle long chain FA out of mito for degradation
Avoid fasting in medium-chain acyl-CoA dehydrogenase deficiency bc
cannot breakdown FA to ketone bodies or to enter TCA
Acetone
Acetoacetate
beta-hydroxybutyrate
Ketone bodies
Urine test for ketone bodies can only detect
acetoacetate
