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8 Cards in this Set

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Gilbert's Syndrome


(congenital)

Basic Cause: Hyperbilirubinemia. Benign, Intrahepatic autosomal recessive liver disorder. Occurrence: 1 in 20. 1/2 inherit , 1/2 gain spontaneous mutation. Defect in bilirubin metabolism. Typically asymptomatic except in times of fasting or stress - then jaundice manifests.


Biochemical Cause: 70-80% reduction in UDP glucuronyl transferase activity, resulting in mild, fluctuating increases in unconjugated bilirubin. Often correlated with fasting or illness.


Effect: Jaundice. Not all individuals exhibit symptoms. Onset in teens-30s (rarely detected before puberty when bilirubin production greatly increases). Males more frequently affected than females (because produce more bilirubin).


Treatment: Small doses of phenobarbital to stimulate UDP glucuronyl transferase activity & increase liver metabolism.

Neonatal Jaundice

Basic Cause: Hyperbilirubinemia. Common & transient condition, particularly in premature infants (50%). Occurs due to immaturity of enzymes involved in bilirubin conjugation.


Biochemical Cause: Defect in bilirubin metabolism - enzymes involved in bilirubin conjugation are not yet mature.


Effect: High levels of unconjugated bilirubin are toxic to the newborn - due to its hydrophobicity it can cross the BBB & cause kernicterus, a type of mental retardation.


Treatment: Phenobarbital used to be administered to the mother prior to induced labor of a premature infant - crosses the placenta & enhances the 3 steps in hepatic bilirubin metabolism independently: uptake & storage of unconjugated bilirubin by the hepatocyte, conjugation, & biliary secretion. Jaundice within the first 24 hours of life, or which requires phototherapy needs to be further investigated. Jaundice that presents later than 10 days after birth is almost always abnormal.

Crigler-Najjar Syndrome


(congenital)

Basic Cause: Autosomal recessive, intrahepatic deficiency in bilirubin metabolism. Hyperbilirubinemia. Very rare.


Biochemical Cause: Characterized by complete absence or marked reduction in bilirubin conjugation. Type I = 0% UDP glucuronyl transferase activity. Type II = 10% UDP glucuronyl transferase activity.


Effect: A severe unconjugated hyperbilirubinemia that usually presents at birth. Afflicted individuals are at a high risk for kernicterus if left untreated.


Treatment: Type I can be fatal when the enzyme is completely absent & left untreated: Treated by phototherapy (10-12 hrs/day) & liver transplant by age 5. Type II responds to phenobarbital as there is still a small amount of UDP glucuronyl transferase activity present.

Post-Hepatic Jaundice

Basic Cause: Caused by an obstruction of the biliary tree.


Biochemical Cause: Plasma bilirubin is conjugated, & other biliary metabolites, such as bile acids accumulate in the plasma.


Effect: Characterized by pale colored stools (absence of fecal bilirubin or urobilin), and dark urine (increased conjugated bilirubin). In complete obstruction, urobilinogen is absent from the urine.


Treatment: Surgery to unblock bile duct.

Hemochromatosis


(Several different types & causes)

Basic Cause: Iron overload - disorder in iron metabolism that is characterized by excess absorption, saturation of iron-binding proteins & deposition of hemosiderin in the tissues.


Biochemical Cause: Most commonly caused by defects in HFE (Human hemochromatosis protein: disease-causing mechanism unknown, but may be result of increased iron absorption in intestines, or dysregulation of hepcidin production) affecting hepcidin production, hepcidin-ferroportin interactions or the genes involved in iron sensing.


Effect: Hemosiderin deposits affect primarily the liver, heart, & pancreas. Can cause liver cirrhosis, hepatocellular carcinoma, diabetes, arthritis & heart failure. Skin can turn "bronze" colored.


Treatment: Repeat phlebotomy to induce a mild anemia reducing RBC mass & inducing RBC formation & iron usage for Hb synthesis. Avoidance of alcohol, vitamin C additives, & raw seafood. Low iron diet is not recommended.

Fluoride

Fluoride is a strong competitive inhibitor of enolase [enzyme in glycolysis pathway] - used to inhibit anaerobic glycolysis in blood collection.


{RBCs can metabolize glucose to lactate, so in sample glucose will be consumed & lactate will be produced, acidifying sample.}



In addition to its ability to inhibit glycolysis, fluoride is also used to prevent tooth decay (at levels too low to inhibit enolase). When fluoride is combined with hydroxyapatite, fluoroapatite is formed, which is more resistant to demineralization.

Pyruvate Kinase Deficiency

Basic Cause: Autosomal recessive disorder. Most common hemolytic anemia caused by a glycolytic enzyme. RBC breakdown without sufficient ATP to keep the cell healthy.


Biochemical Cause: Thermal lability of enzyme[PK, which converts PEP to pyruvate], Increased Km for PEP, decreased activation by fructose-1,6-biphosphate.


Effect: Afflicted individuals can accumulate 2,3-BPG, affecting O2 delivery.


Treatment: Severe cases require transfusions.

Arsenic & GAPDH

Basic Cause: Arsenate inhibits substrate-level phosphorylation, reducing net yield of ATP in anaerobic glycolysis to zero. {Arsenic/arsenite also toxic, but have different mechanism f action: react with thiol groups in sulfhydryl enzymes - GAPDH & enzymes of heme synthesis, irreversibly inhibiting their activity.}


Biochemical Cause: Arsenate does not inhibit any enzymes of glycolysis, it dissipates the redox energy available from the GADPH rxn & prevents formation of ATP by substrate-level phosphorylation at the PGK rxn. In effect, arsenate uncouples the GAPDH & PGK rxns.


Effect:


Treatment: