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73 Cards in this Set

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Name the 3 factors that affect the rate of deoxygenation in sickle cells?
Cellular degree of deoxygenation
Intracellular [HbS]
[HbF]
Why does rapid deoxygenation not cause sickle cell?
Because it causes clumping of Hb, not polymer formation
Why do reticulocytes stick in sickle cell?
They have integrin complex a4b1 which binds to fibronectin on endothelial cell. They also have CD36 which binds to thrombospondin released by platelets.
What causes dehydration in sickle cell?
Polymerization damages the membrane and the KCl channel becomes activated.
What does Mg2+ do for a sickle cell?
It inhibits the KCl channel which prevents dehydration which causes increased polymerization
What is the Gardos channel? What activates it and what inhibits it?
The Gardos channel is a Ca2+ activated K channel. When cells sickle, Ca2+ is released from vesicles which causes dehydration through K efflux. It is inhibited by clotrimazole.
Discuss treatments for sickle cell
1) Induce hyponatremia to cause RBC swelling (need to constantly monitor
2) Clotrimazole to inhibit the Gardos Channel
3) Mg2+ to block KCl channel
4) Increase HbF with azacytidine
5) Hydroxyurea to increase HbF
6) Butyric acid to prolong HbF
7) Bone marrow transplant
What are the 2 primary causes of gout?
20% over production of uric acid
80% renal clearance problem
What are secondary causes of gout?
Diuretics, aspirin, dehydration, acidosis and lead all cause renal clearance problems.
Psoriasis, leukemia, lymphoma, SS
What are sources of uric acid?
1/3 daily turnover
2/3 denovo synthesis
1/3 diet
How is type I glycogen storage disease related to hyperuricemia?
Blocking G6P to glycogen causes, it to push through the pentose phosphate shunt which increases R5P which increases PRPP which stimulates PRPP synthetase to make purines
Which joints are affected by gout first?
Big toe, foot, ankle, knee, hands, elbows, shoulders then hips
What causes the pain in gout?
PMN chemotaxis to deposits of uric acid crystals. PMN's cause inflammation
Presentation of gout?
Rapid onset (wake up with it). Extremely painful joint with erythema. Fever may accompany. Renal stones and maybe even tophi
How do you diagnose gout?
Joint aspirate > 10,000 PMNs
Needle shaped negatively birefringent crystals (MUST BE INTRACELLULAR CRYSTALS)
Serum uric acid - NOT HELPFUL
Treatment for gout
1) Drain the joint
2) Corticosteroid injection in joint
3) NSAIDS - Indomethacin
4) Colchicine - Must give within 24 hours and orally. In IV will kill patient
5) Probenacid while still on colchicine
6) Allopurinol - watch for hepatitis and severe skin reactions. Can also cause an attack if patient isn't on colchicine already
What is pseudogout? Diagnosis? Treatment?
Calcium pyrophosphate deposits
Rhomboid shaped positively birefringent crystals.
NSAIDS and corticosteroid injection
What are the genetics of Lesch Nyhan?
X-linked recessive deficiency in HGPRT enzyme
What is the clinical presentation of Lesch Nyhan?
MR, cerebral palsy, hyperuricemia, compulsive self-biting and injury. Hypoxanthine accumulates in CSF. URIC ACID IS NOT IN CSF
Diagnosis of Lesch Nyhan?
Suggested by self-mutilation, serum uric acid high, test HGPRT enzyme level with erythrocyte lysate test.
Treatment of Lesch Nyhan?
Psych meds for anxiety, dental procedure to remove teeth, allopurinol for gout.
How are cyclobutane-pyrimidine dimers fixed? What about pyrimidine(6,4)photoproducts?
CPDs are repaired by transcription coupled NER
PPD are repaired by global gene NER.
Discuss the repair proteins of NER?
XPA, XPC and XPE detect the dimer. Helicase despirals DNA double strand and this involved XPB and XPD. XPF makes 5' incision, XPG makes 3' incision
Say 2 things about each XP complementation group
XPA most frequent neurological disorders and common in Japan
XPC also prevalent and associated with squamous along with XPA
XPD most associated with malignant melanoma and neurological disorders.
XPV prevalent and associated with basal cell.
XPE basal cell and frequent in Germany
Treatment of XP
Light protected lifestyle
Photolyase cream
5-Fluorouracil for actinic keratosis.
Surgical intervention for carcinomas
Presentation of XP?
Begins with sunburn, black lentigines, teleangectasias, atrophic and dry. Cancer is 1000X more prevalent than normal population. Neurological defects in 14-40% of population.
Ocular manifestations occur 40% of the time
Presentation of classic PKU
Presentation of malignant PKU
MR with phe levels > 1mM
Blond hair, blue eyes.
Mousy smell to urine
Malignant have lower serum phe levels but neurological defects are more significant even when phe levels are controlled.
Genetics of PKU?
Autosomal recessive with a lesion on chromosome 12
Presentation of MSUD
Decorticate rigidity at birth, caramel smell to the urine, feeding difficulties at birth
What is the enzyme deficiency in MSUD? What does it normally do? What cofactors are required for the enzyme?
Branched chain a-ketoacid dehydrogenase
Breaks down Leucine, Valine and Isoleucine
Thiamine, Lipoic acid, CoA, NAD
Diagnosis for classic PKU
Step 1: Heel stick - serum [phe]
Step 2: Phe >350um or phe:tyr ratio > 1.5
Step 3: DNA test for HPA mutation
Step 4: Restrict Phe, if problems persist then test for BH4 deficiency
Diagnosis for malignant PKU
Assay BH4 levels in fibroblasts, amniocytes or erythrocytes
Diagnosis for MSUD
Heel stick screen for branched chain a-ketoacids
Then use dinitrophenylhydrazine reagent
Measure enzyme levels in fibroblasts
Treatment for classic and malignant PKU?
Restrict diet phe < 250-500mg/day. Goal: keep levels below 350um
For BH4, constantly provide the cofactor
Treatment for MSUD
Restrict branched chain aa's trying not to over restrict isoleucine and valine. Thiamine supplements help the enzyme and high caloric diet to ensure growth.
Classic galactosemia presentation
Neonatal jaundice, bleeding diathesis, feeding intolerance, lethargy, hypotension.
What is the enzyme deficiency in classic galactosemia?
Galactose-1-phosphate uridyl transferase (GALT)
How does GALE present? What enzyme is deficient?
Intellectual dysfunction later in life and hepatomegaly
Epimerase enzyme
Primary symptom in GALK deficiency? What enzyme is deficient?
Cataracts due to increased galactitol.
Galactokinase
How does fructokinase deficiency present?
Asymptomatic although Clinitest will be positive in which case Clinistix should be done to differentiate from DM.
How does Aldolase A present?
At birth with MR, short stature, hemolytic anemia and abnormal facies.
How does Aldolase B present?
Following ingestion of fructose, vomiting and hypoglycemia result. Later on, liver failure, renal dysfunction
What is the enigma with classic galactosemia?
Even if you remove galactose from the diet individuals could still develop ovarian failure, reduced IQ, verbal dyspraxia and cataracts.
What is found in the blood and urine of someone with GALT?
Increase galactose and gal-1P in the blood. Increased galactose and galatitol in the urine. Increased galactose causes a positive Clinitest.
What is found in the blood of someone with GALE?
Increased erythrocyte galactose-1-phosphate and galactose
What is found in the urine of someone with GALK?
Galactitol
What does increased galactose-1-phosphate do to cells?
It inhibits glucose-1-phosphate pyrophosphorylase which decreases UDP glucose. W/o UDP glucose, you are unable to conj bilirubin or modify proteins which leads to kernicterus and Ecoli sepsis.
What GLUT transporter does the intestine have for fructose uptake?
GLUT5
Diagnosis for GALT?
GALT enzyme activity is measure in heel stick with serum measurements of GAL and GAL1P.
CO2 breath test < 5%, prognosis is good.
Diagnosis for GALE?
Similar serum results as GALT so test for GALE enzyme deficiency
Diagnosis for GALK?
Urine galactitol measurements initially.
Follow this with RBC, fibroblast or lymphoblast GALK activity
Diagnosis for fructose intolerance?
Positive Clinitest but negative Clinistix.
Individual will also have hypoglycemia, elevated uric acid, chronic hyperbilirubinemia and lactic acidosis.
Genetic testing is viable because of the number of mutations
Treatment for Galactosemia
Eliminate milk products, some fruits (watermelon,tomatoes)
Additional Ca2+ supplements
Monitor serum GAL1P and urine galactitol
Treatment for Fructose intolerance
Restrict dietary fructose
What is the main difference between DKA and HHNS?
Level of dehydration, ketoacidosis.
What is the effect of glucagon in DKA?
It lowers liver malonyl-CoA which stimulates B-oxidation through loss of CPT1 inhibition and inhibits fa synthesis.
It stimulates gluconeogenesis/glycogenolysis and inhibits insulin mediated glucose uptake.
What is the effect of catecholamines on DKA?
Antagonizes insulin action, stimulates gluconeogenesis and glycogenolysis.
What is the effect of growth hormone and cortisol on DKA?
Antagonizes insulin action
What is the difference in hormone levels between DKA and HHNS?
In HHNS, Insulin is high enough to prevent lipolysis which also prevents ketogenesis but not high enough to stop gluconeogenesis in the liver.
List the precipitating causes of DKA in order?
Infection 35%
Insulin omission 15-30%
New onset DM 20-25%
Misc 10-20%
List the precipitating causes of HHNS in order?
Infection 60%
New onset 25%
Misc. 10-15%
Insulin omission 5%
Typical patient is in nursing home where dehydration can cause HHNS or stroke/MI causes stress hormone release.
What are the diagnostic criteria for DKA?
BGL > 250mg/dl (might not be high if patient has had insulin or has liver failure)
Arterial pH < 7.3
HCO3- < 15
Ketonemia > 3mmol
Anion gap > 12Meq/L
What does a ∆gap < -6 mean? What about > 6?
Hyperchloremic metabolic acidosis
Metabolic alkalosis due to vomiting
When do you consider DKA resolved?
When 2 of 3 acid base parameters are met. Bicarb > 18, pH > 7.3 and anion gap < 14
How do you detect ketonemia?
Use the nitroprusside test but this can't be used after DKA has been diagnosed because clearance of acetone lags behind insulin therapy.
What are the diagnostic criteria for HHNS?
BGL > 600mg/dl
Increased serum osm > 320
Dehydration w/o ketones
pH > 7.3
HCO3- 18-24
How do you calculate serum osm?
(2xNa + Glucose)/18 + BUN/2.8
How do you calculate ∆gap? What about anion gap?
∆gap = ∆anion gap - ∆bicarb
Anion gap = Na-(Cl+HCO3)
What is the number 1 treatment for DKA?
Fluid replacement
What is the main point of providing insulin in DKA?
Reduce the production of ketones and mobilization of fats. Effect on reducing BGL not as good as hydration therapy.
When do you withhold insulin therapy?
When the patient has arterial hypotension and severe BGL.
When the patient has severe hypokalemia.
What is the effect of HCO3 infusion in patients with DKA?
Worsens hypokalemia
CNS acidosis
Intracellular acidosis due to increased CO2
Overshoot alkalosis
When should you administer PO4?
When PO4 < 1-1.5 to prevent cardiac dysfunction, anemia and respiratory depression.