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213 Cards in this Set

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Lesch-Nyhan Disease
84. Lesch- Nyhan syndrome (deficiency of hypoxanthine p-ribosyl transferase.) Impairs salvage of guanine to GMP (purine salvage).
Energy deficits in HMP shunt or glycolysis enzymes may result in:
Hemolytic anemias. Common defecits include glucose-6-phosphate dehydrogenase and pyruvate kinase deficiency.
#1. Glucose 6-phosphate dehydrogenase deficiency
There is a defect in an HMP shunt step. NADPH produced by HMP shunt normally acts to reduce glutathione in RBCs, which products oxidation of hemoglobin. G6PD deficiency may lead to hemolytic anemia attack. Abnormally oxidized hemoglobin can precipitate as Heinz bodies in red blood cells, and hemolysis occurs. G6PD deficiency is protective against malaria, as malarial organisms need NADPH and HMP shunt for growth.
#2. Hexokinase defiency
Glucose cannot be phosphorylated, and various glycolytic intermediatesare deficient. This is associated with hemolytic anemia.
#3. Glucose phosphate isomerase defiency.
Associated with a hemolytic anemia.
#4. Phosphofructokinase deficiency (Type VII glycogen storage disease)
Phosphofructokinase is deficient at this step in muscle. Glucose cannot be used efficiently, and the patient experiences muscle cramps. RBCs normally have a form of this enzyme (so patients may have hemolytic anemia or myoglobinuria. Muscle biopsy reveals enzyme defect. Increased muscle glycogen stores, since glucose is shunted toward glycogen in absence of functioning glycolytic pathway. Increase in muscle fructose-6-phosphate and glucose-6-phosphate, but decrease in fructose 1,6, bisphosphate).
#5. Aldolase deficiency.
Associated with a hemolytic anemia, sometimes, muscle weakness.
#6. Triose-phosphate isomerase deficiency.
Associated with hemolytic anemia.
#7. Phosphoglycerate kinase deficiency.
Associated with hemolytic anemia.
#8. Diphosphoglyceromutase deficiency.
This side step in the glycolytic chain is particularly important in red cell metabolism as 2,3-diphosphoglycerate (2,3-DPG) decreases the O2 affinity of hemoglobin and stabilizes oxygenated form of hemoglobin. DPG mutase results in deficiency of 2,3-DPG, w/excess affinity for O2, and anemia. Conversely pyruvate kinase deficiency leads to excess 2,3-DPG and low oxygen affinity, which may allow better delivery of oxygen to tissues but is associated with anemia.
#9. Enolase deficiency
Associated with hemolytic anemia.
#10. Pyruvate kinase deficiency
The cell cannot produce ATP that normally is produced during this rx. And is needed for the cell's Na+/K+ pump. There is hemolytic anemia. Assay for pyruvate kinase in RBCs (autosomal recessive inheritance).
Glycogen storage diseases
Glycogen accumulates in liver or muscle or both. Glycogen accuulates either because it can't be broken down properly, or because xs. Glycogen is shunted into storage (as glucose 6-phosphate can't be metabolized somewhere.
#11. Glucose 6-phosphatase deficiency
(Type I GSD; Von Gierke's Disease). There is a deficiency at this step in the formation of glucose by the liver. Glucose 6-phosphate instead forms other things and flow of reactions shifts to the following paths: (1) Glycogen accumulates in liver which becomes enlarged (2) There is excess uric acid to shunting through the HMP shunt to form purines. Uric acid stones may deposit in the urinary tract) (3) There is a buildup of pyruvate and lactic acid (4) Since the liver is not turning out glucose, alternate sources of energy must be increased: Triglycerides breakdown in fat cells to release fatty acids (elevation of serum lipids), fatty deposits (xanthomas) in various body parts. Excess pyruvate (pyruvic acid) and lactate ) can result in serum acidosis. Enlarged liver, hypoglycemia, elevated uric acid, serum acidosis with elevated pyruvate and lactate, hyperlipidemia, and growth retardation may also be present. Dx: confirm absence of glucose 6-phosphatase on liver biopsy. Liver cells are full of glycogen and fat.
#12. Deficiency of branching enzyme
(Type IV GSD; Anderson Disease): Without branching enzyme, liver produces abnormal glycogen with long chains. Result: Enlarged liver w/ cirrhosis and poor prognosis. Assay for deficient in liver biopsy or assay leukocytes or cultured skin fibroblasts. Glycogen in liver biopsy is also abnormal.
#13. Muscle phosphorylase deficiency
(Type V GSD; McArdle's Disease): Liver phosphorylase is normal, but muscle phosphorylase is deficient. Thus the patient can't breakdown muscle glycogen and experiences muscle cramps and weakness with exercise. Muscle biopsy may confirm the deficient enzyme. No specific rise in lactate in an ischemic exercise test. MRI--> dx muscle fx.
#14. Liver phosphorylase deficiency (Type VI GSD; Hers' Disease)
Glycogen accumulates in liver w/ resulting liver enlargement. Growth retardation, as amino acids are shunted toward gluconeogenesis (not growth).
#15. Liver phosphorylase kinase deficiency (Type VIII GSD)
Since the kinase that activates liver phosphorylase is inactive, it prevents activation of liver phosphorylase. There is resulting accumulation of glycogen in the liver and liver enlargement. Dx. Made by assay for defective enzyme in liver biopsy or in leukocytes/erythrocytes.
#16. Deficiency of debranching enzyme (Type III GSD; Cori's Disease)
Hypoglycemia is not too bad as the outer chain of glycogen can be at least broken down. The 1-6's though can't be broken, however, and short chained glycogen accumulates. Sxs: Liver enlargement, muscle weakness/cramps, xs fat breakdwn-->hyperlipidemia. Dx: liver biopsy reveals glycogen accumulation and absence of debranching enzyme. Rx: supplement diet w/ protein, fructose, and galactose which can be converted to glucose.
#17. Deficiency of Lysosomal alpha-glucosidase (Type II GSD; Pompe's Disease)
Maltase, apart from its location in small intestinal cells, is found in lysosomes throughout the body called lysosomal alpha-glucosidase. Rather than changing maltose to glucose, lysosomal alpha-glucosidase directly changes glycogen to glucose. Deficiency in lysosomal alpha glucosidase results in glycogen accumulation in liver, skeletal and cardiac muscle (and in other tissues). There is liver enlargement, heart, and tongue w/ poor muscle tone and early death due to cardiac failure or respiratory infection. Dx. made w/ muscle biopsy, shows glycogen accumulation and absence of lysosomal alpha-glucosidase activity.
#18. Essential fructosuria (fructokinase deficiency)
This is a benign condition in which high fructose levels, while not toxic, may be detected in testing the urine for sugar. Both glucose and fructose are reducing substances, capable of reducing chemical reagents that are used for urinary test for reducing sugars (like clinitest tablets).
#19. Hereditary fructose intolerance (deficiency in fructose-1-phosphate aldolase)
Unlike essential fructosuria, this is a significant clinical disorder. Fructose 1-phosphate accumulates and may be toxic to liver/kidney. Accumulation of fructose-1-phosphate ties up inorgnic phosphorus needed to form ATP (from ADP). Fructose 1-phosphate inhibits liver phosphorylase. Liver cells then function poorly and there may be liver "enlargement", "jaundice", and "hypoglycemia." Decreased renal function (protein in urine) and poor growth. Ingestion of fructose causes hypoglycemia and vomiting. Tx. involves removal of fructose from diet. (Don't administer large doses of fructose, xylitol or sorbitol by IV).
#20. Lactase deficiency
Lactase produced in intestinal microvilli, and deficiency results in poor digestion of lcatose, bloating, ab cramps, and diarrhea on ingestion of milk. Can be hereditary, but may be acquired by intestinal disease that affect small bowel. Dx: small bowel biopsy or lactose tolerance test (where blood glucose doesn't rise after lactose administration). Hydrogen breath test is also diagnostic, because bacteria act on lactose and produce hydrogen (which can be detected at increased levels in breath).
#21. Galactokinase deficiency:
Galactitol accumulates-->cataracts-->RBCs decreased galactokinase activity.
#22. Classic galactosemia
Defect in galactose 1-P-uridyl transferase that normally allows galactose 1-P to change to UDP-galactose. This backup in galactose metabolism results in accumulation of galactose and galactose 1-p in liver, causing cirrhosis. Kidney failure and mental retardation may result. Galactose-1-P is especially toxic. Cataracts from galactitol in lenses may accumulate. Infants w/ failure to thrive and non-glucose sugar in urine is suspicious. Newborn blood commonly screened for elevation in galactose. Tx: reduce galactose intake.
#23. Essential pentosuria (deficiency of xylitol dehydrogenase)
A benign accumulation of xylulose develops, which may be confused with glucose when detected in urine.
#24. Pyruvate dehydrogenase deficiency.
Children who develop lactic acidosis with buildup of pyruvate and alanine. Severe neurological disturbances. Tx: decrease carbohydrate intake and increase intake of ketogenic nutrients (nutrients will bypass pyruvate dehydrogenase step in forming acetyl CoA).
#25.. Cyanide poisoning
Interferes with electron transport. Cyanide binds to the Fe+++ of cytochrome oxidase (cyt a + cyt a3)--prevents Oxygen from combining with cytochrome oxidase. Combines with iron of methemoglobin (Fe+++). Tx: sodium nitrite. Nitrite converts hemoglobin (Fe++) to methemoglobin (Fe+++) which in turns competes to remove cyanide from cytochrome oxidase. Subsequent sodium thiosulfate administration. this reacts with cyanide to form benign thiocyanate, excreted as urine.
#26. Antimycin A, Retenone, and Amytal
(1) Antimycin A is a fungal antibiotic blocks e. transport at step between cytochromes b and c1. (2) Rotenone- A toxic plant derivative used as a fish poison (3) Amytal- a barbituate sedative, both interrupt e. transport at step between NADh and FMN.
#27. Fluroacetate (rat poison)
Acts by converting to fluorocitrate and then inhibiting aconitase at this step. Arsenic, prevents transofmration of G-3P to 3-P glycerate. Arsenate resembles phosphate and can substitute for it in oxidative phosphorylation, and also attach to glyceraldehyde 3-P in place of phosphate.
#28. fumaraase deficiency.
There is a deficit in transformation of fumarate to malate. Infant has developmental retardation, with abnormal neuromuscular function, lactic acidemia, and fumarate aciduria (the krebs cycle can back up all the way to lactate). Lactic acidosis may also be present in rare disorders of cytochrome oxidase. Dx: absence of fumarase activity in liver and skeletal muscle mitochondria assay.
#29. Excess alcohol intake
May result in hypoglycemia. Alcohol metabolism produces NADH when ethanol converts to acetaldehyde. NADH xs prevents lactate from being transformed to glucose (in gluconeogenesis) and may lead to lactate accumulation. Excess of NADH also inhibits conversion of malate-->oxaloacetate (which is then unavailable for conversion to glucose.) Steroids raise blood glucose by stimulating PEP carboxykinase, which facilitates conversion of oxaloacetate to PEP in gluconeognesis. Hypoglycemia and aldehyde toxicity may in part be implicated in fetal alcohol syndrome (infants born to alcoholic mothers).
What two enzymes catalyze the conversion of ethanol to acetaldehyde and acetic acid?
Alcohol dehydrogenase and aldehyde dehydrogenase.
#30. Diabetic Ketosis.
Insulin= fed state-->clear xs glucose in blood, promotion of glucose entry into cells, stimulation of glycogen storage, lipid storage, and protein synthesis. Insulin stimulates glycolysis and decreases gluconeogenesis. In diabetes, lack of insulin activity leads to tendancy for gluconeogenesis and pulling of oxaloacetate from krebs cycle. This leads to tapping into triglycerides as alternate source of acetyl CoA for Krebs cycle; however, even this can't get into krebs cycle as a result of oxaloacetate depletion, and it becomes acetoacetyl coA-->ketones. Since insulin is needed to form malonyl CoA, deficit in malonyl CoA synthesis leads to acetyl CoA accumulation. Without malonyl CoA, we can't inhibit fatty acid oxidation, and the resulting fatty acid breakdown leads to more ketone formation. XS acetyl CoA cannot avoid ketosis by reverting to glucose, because the pyruvate-->acetylCoA step is irreversible. XS fatty acids may travel to liver as VLDL, but they are overhwlmed and fatty liver/elevated blood lipids may develop. Insulin stimulation production of LDL (lipoprotein lipase). Without insulin there is insufficient LPL to release fatty acids from VLDL and chylomicrons and may lead to increase in serum triglycerides, apart from increased VLDL production in liver. Starvation ma lead to ketone elevation as well (oxaloacetate depletion in an effort to make glucose, but not being able to make it past Acetyl CoA (no fatty liver though). Kwashiorkor is absence of protein leading to inability for lipids to undock and lipid accumulation in liver-->enlarged liver and ascites that results from ypoalbuminemia.
#31. Pancreatitis
Pancreatic lipase is a lipolytic enzyme that releases fatty acids from glycerides. Improper activation of pancreatic zymogens can lead to activation of enzymes with resultant pancreatic damage.
#32. Carnitine deficiency
Fatty acid oxidation occurs in mitochondria. Fatty acids stored as triglycerides outisde of the mitochondria; however, CARNITINE, can transport long fatty acid chains into the mitochondria for oxidation. Without carnitine or enzyme combination, fats cannot be properly utilized for energy. The patient experiences muscle cramps on fasting or exercising. (Note:this illustrates the importance of fatty acid oxidation for muscle function.) In some variants there may be encephalopathy (due to hypoketotic hypoglycemia) and cardiomyopathy.
#33. Respiratory distress system
Lecithin (phosphatidylcholine) is important phosphoglyceride. In the lung, one of the lecithins reduces surface tension in the pulmonary alveoli. Lecithin deficiency reduces surface tension in pulmonary alveoli. Lecithin deficiency inm the premature infant results in the respiratory distress syndrome, in which alveoli are collapsed and there is difficulty with air exchange.
#34. Niemann-Pick Disease
Sphingomyelin collects in brain due to deficiency in sphingomyelinase (which normally removes phosphocholine from sphingomyelin. Mental retardation and early childhood death.
#35. Nerve gas
Nerve gas and organophosphate insecticides inhibit AChE (acetylcholinesterase) an enzyme important in degradation of acetylcholine to choline. This can cause paralysis through inhibiting AChE at the junction between peripheral nerves and muscle. (death via respiratory paralysis).
#36. Myasthenia gravis
Patients with this condition produce auto-antibodies against Ach receptors-->poor communication between nerve and muscle.
#37. HMG CoA reductase
Rate-limiting step in cholesterol synthesis. Drugs that inhibit HMG CoA reductase can lower blood cholesterol (normally xs cholesterol body inhibits HMGCoA Reductase via negative feedback--a natural control mechanism). Some people don't have a spike in serum cholesterol after a meal and others due, and those differences may be baesd on the natural activity of the negative feedback loop between cholesterol and HMGCoA reductase.
#38. Refsum's disease
Inability to break down phytanic acid (from phytol in chlorophyl isoprenoid--a branched fatty acid) in peroxisomes. This leads to severe neuro symptoms.
#39. Cholesterol desmolase
A partial block at this control step reduces the levels of all the steroid hormones.
#40. Cytochrome P-450
Like cytochromes a, b, and c is part of an electron transport chain. However, rather than the electron transport associated with ox phos, it functions in hydroxylation. This is crtical in the combining of O2 with cholesterol and its derivatives.
#41. 3-Beta hydroxysteroid dehydrogenase deficiency
Decrease in mineralocorticoid and glucocorticoid production, and abnormal sexual development.
#42 21-hydroxylase deficiency
This is the most common hereditary enzyme defect in steroid biosynthesis. There is decreased glucocorticoid and mineralocorticoid production, as the enzyme is comon to both pathways. This leads to increased ACTH production, which in turn causes adrenal hyerplasia and increased pregnenolone production. This results in increased androgen production/virilization. Tx = glucorticoid administration. This decreases ACTH production by negative feedback.
#43 11-beta hydroxylase deficiency
As in 21-hydroxylase deficiency, decrease in mineralocorticoids and glucocorticoids, with virilization.
#44 18-dehydrogenase and 18-hydroxylase deficiency
There is a deficiency of mineralocorticoids
#45 17-alpha hydroxylase deficiency
There is a decrease in both glucocorticoid and androgen production. The mineralocorticoid path is open and this may cause hypertension through xs mineralocorticoids.
#46 17,20 lyase deficiency
Decrease in androgen productoin
#47 Gallstones.
Most gallstones are composed mainly of cholesterol. Bile salts/phospholipids normally prevent the precipitation of cholesterol, but cholesterol stones may form when the cholesterol/bile-salt-phospholipid ratio increases excessively. Tx: chenodeoxycholate = oral tx. for cholesterol gallstones (provides extra bile acids but inhibits RL step in cholesterol synth.
#48 Hyperammonemia
XS ammonia levels drives rx. From 2-ketoglutarate toward glutamate. This depletes 2-ketoglutarate from kreb's cycle and reduces ATP output. This can impair brain function with hyperammonemia (brain deprived of ATP).
#49 Phenylketonuria (deficiency of phenylalanine hydroxylase)
Elevated phenylalanine (buildup and excretion of phenylpyruvate in urine, giving it a mousy odor. Mental retardation is the prominent feature. Tx: with low-phenylalanine diet and sometimes tetrahydrobiopterin deficiency can be tx. With biopterin).
#50 Alkaptonuria (defect in homogentisate oxidase)
Defect in homogentisate oxidase at this step. There is a buildup of homogentisate, which spills out into the urine. The excess homogentisate polymerizes as it stands (especially in alkaline urine), causing a dark-colored urine. The condition is generally benign but may result in arthritis in later years. Polymer binds to cololagen and may result in ochronosis, in which connective tissue acquires a darker color; the ears, for instance may adopt a bluish coloration through transmitted light.
#51 Tyrosinemia
There are enzyme defects at steps in the metabolism of tyrosine. These result in the accumulation of tyrosine and its metabolites in the urine and serum. Liver and kidney dysfunction, and mental retardation are common. The condition may be treated by lowering tyrosine and phenylalanine intake. Vitamin C may be helpful as it is a cofactor for hydroxyphenylpyruvate hydroxylase at this step.
#52 Albinism (tyrosinase deficiency)
Tyrosinase deficiency at this steps blocks steps necessary to produce melanin (and individual lacks malanin pigment in skin hairs, iris, and RPE. In oculocutaneous albinism, the individual is sensitive to bright light and sunburns easily. There is an increased incidence of skin cancer. Tx: = avoidance of prolonged, direct sun exposure. Ocular albinism= eyes alone involved.
#53 Parkinson's Disease
There is a deficiency of dopamine in the brain stem, particularly in midbrain where this is marked loss of substantia nigra cells. This leads to -->slowness, stiffness, and tremor. Tx: with L-DOPA (dopamine precursor) rather than dopamine because L-DOPA can cross blood-brain barrier. Carbidopa is commonly added to L-DOPA in tx. Carbidopa inhibits dopa decarboxylase (the enzyme active at this step in the formation of dopamine), but does not cross the blood brain barrier. Thus administered L-DOPA is free to act in the brain but inhibited from acting in the periphary where unwanted side effects can occur.
#54 Cystinuria
This is a genetic disease affecting epithelial cell transport of cystine and certain other amino acids, resulting in cystine excess and cystine stones in urine.
#55 Hartnup's Disease
This is a defect in epithelial transport of neutral amino acids (e.g. tryptophan) leading to poor absorption and excess excretion of these amino acids. Clinical sxs. Resemble those of niacin deficiency (tryptophan is precursor of niacin), namely the 3 D's: "Diarrhea, Dementia, Dermatitis." Tx: nicotinamide administration. Fanconi's syndrome is more generalized defect in molecular transport, involving a multitude of amino acids, glucose, calcium, phosphate, proteins, and other molecules. there may be decreased growth and rickets.
#56 Carcinoid Tumor
Elevated 5-hydroxyindole acetate (5-HIAA) occurs in carcinoid tumors of the intestine, where argentaffin cells secrete excess 5-hydroxytryptamine (serotonin). The patient experiences flushing, diarrhea, hypotension, and bronchoconstriction.
#57 Excess xanthurenate in urine.
Xanthurenate levels in urine increase in vitamin B6 deficiency, because B6 (as pyridoxal phosphate) is necessary for chemical transformation of 3-hydroxykynurenine. Pyridoxine deficiency may be defected by giving patient a loading dose of tryptophan. If pyridoxine deficiency is present, there will be xs xanthurinate in the urine. Oral contraceptives may increase urinary xanthurenate levels, possibly because estrogens increase tryptophan dioxygenase levels. Isoniazid (for TB) interacts with and inhibits pyridoxal phosphate--so patients taking isoniazid should take pyridoxine supplements.
#58 Maple Syrup Urine Disease
There is a block in degradation of branched chain amino acids. Leucine, isoleucine, valine, and their ketoic acids are elevated in the blood and urine. The urine acquires a "maple syrup" aroma. Infants have a variety of neurological problems, including mental retardation. Tx: dietary restriction of select amino acids.
#59 Hypervalinemia
There is a suspected defect in valine transaminase, which acts at one of the steps in valine metabolism.
#60 Isovaleric acdemia
Defect in the step from isovaleryl CoA to beta-methyl crotonyl CoA, in the metabolism of leucine. The urine has an odor of "sweaty feet." The patient has various neurological disturbances and mental retardtion. Isovaleric acid is elevated in the plasma. It is treated by restricting dietary intake of leucine.
#61 Methylcrotonic aciduria
There is, among other things, xs secretion of beta-methylcrotinic acid, a substrate in the course of leucine breakdown. Possibly the defect may lie in the enzyme at this step. Biotin (which normally functions at this step in leucine breakdown) may help improve symptoms.
#62 Homocysteinuria
(Defect in cystathionine synthase at this step). This is the most common form of homocysteinuria. The defect leads to elevated homocysteine, which can be detected in urine. Serum methionine is also elevated. Clinical sx: dislocation of lens, mental retardation, various skeletal and neurological problems. Tx: administration of pyridoxine, decreasing dietary methionine, and increasing cysteine. Elevated blood homocysteiene is a risk factor for heart disease.
#63 Hypermethioninuria
Decrease in methionine adenosyl transferase at this step. The condition is relatively benign, whereas cystathionine deficiency is not.
#64 Variant of homocysteinuria
Homocysteine cannot be converted to methionine in this variant. The ineffectiveness of enzyme may be due to the inability of vitamin B12 to form the necessary enzyme cofactor, methylcobalamin. Alternatively, lack of enzyme that forms 5-methyl THF 9which is a methyl donor in the rx.) Lack of folate or vitamin b12 may also result in elevated blood homocysteine levels.
#65 Cystathioninuria (deficiency of cystathioninase)
Cystathionine is elevated in the urine. Treatment with B6 may reduce urinary levels of cystathionine, but generally such tx. Is unnecessary as the condition tends to be benign.
#66 Histidinemia (lack of histidase)
Histidine cannot be changed to urocarnate. Blood and urine histamine are elevated, and urocarnate (normally found in sweat) is absent. The patients may be retarted. Dx: check blood and urine for histidine and its minor derivatives. On adding ferric chloride to urine, "if the urine turns green there is histidine"
#67 Histamine
Histamine is widespread in the body organs. Largely found in mast cells/basophils. Degranulation in response to: presence of certain drugs, tissue trauma, and antigen-antibody allergic interction. Actions include: artriolar relaxation, hypotension/shock if excessive, excitation of smooth muscle-->bronchospasm, stimulation of sensory nerve endings, and gastric secretion. Tx: chromolyn sodium to inhibit histamine release from mast cells. Tx with : Cimetidine (histamine-like drug (competes with histamine receptors in stomach-->useful for reducing gastric acid secretion in tx. of pep. ulcers).
#68 Formiminotransferase deficiency
This results in increased urinary levels of FIGlu (formiminoglutamate). The patient may have significant neurological and other physical defects. FiGlu is also an indicator for folate deficiency, just as xanthurenate is for B6 deficiency, and urinary methylmalonate is for B12 deficiency.
#69 Scurvy (deficiency of Vit C)
Collagen is an important intercellular structural protein that contains hydroxyproline and hydroxylysine, amino acids that are rare in other kinds of protein. The concentration of glycine is also very high in collagen. In scurvy, there is defective collagen formation, as vitamin C is necessary for the hydroxylation of proline. The patient with scurvy bruises easily and has decaying gums. Defects in collagen synthesis may occur at steps other than that of hydroxylation of proline.
Steps in collagen synthesis (intracellular/extracellular steps)
(A) synth of initial polypeptide in fibroblast (B) Hydroxylation--ie formation of hydroxyproline and hydroxylysine-- and glycosylation --addition of sugar to-- the polypeptide--vitamin C is a cofactor that is necessary for proline hydroxylation (C) Formation of a procollagen triple helix, each containing 3 peptide strands (D) Release of the procollagen triple helix from the fibroblast. (Extracellular steps): (E) TRImming the ends of the procollagen TRIple helix to form a TROpocollagen triple helix. (F) Linine up of many tropocollagen triple helices to form a collagen fiber. The particular staggering of tropocollagen helices within the collagen fiber accounts for the periodicity oflines seen when viewing a collgaen fiber through electron microscope. (G) Cross-linking of tropocollagen bundles within the collagen fiber.
Ehler's-Danlos Syndrome
Problems at later stages in the structuring of collagen. Trimming of the procollagen triple helix to form a tropocollagen triple helix may be defective. There may also be defects in collagen cross-linking. The patient has very elastic skin and is double-jointed.
Osteogenesis imperfecta
The child has "brittle bones" that fracture easily. There may be blue sclerae, hearing defects, and dental abnormalities. Variety of forms of this condition that involve defects in collagen structure.
Collagen digestion
Collagenase. Certain bacteria (e.g. clostridium histolyticum) produce collagenase to faciliate spread through tissue. Important for tissue restructuring during growth/generation.
#70 Hyperhydroxyprolinemia
Defect in the oxidation of hydroxyproline. Sx: mental retardation and elevated plasma hydroxyproline.
#71 Propionyl CoA carboxylase deficiency.
The serum shows elevated propionate. The patient may have mental retardation, ketoacidosis, protein intolerance and other defects. Holocarboxylase synthetase is the enzyme that liniks biotin to propionyl-CoA-carboxylase. If it is deficient, the child has vomiting, lethargy, hypotonia, seizures and other problems that can be treated by administration of biotin.
#72. Defective metabolism of methylmalonyl CoA.
Infants with this may present with acidosis. There is an xs of methylmalonate in urine, as methylmaolonyl CoA cannot change to succinyl CoA. Sometimes this is due to defect in Vitamin B12 metabolism and sometimes to a defect in methylmalonyl CoA mutase, for which B12 is a coenzyme. XS urinary methylmalonate is also an indicator of B12 deficiency.
Clinical fundamentals and treatment of urea cycle defects:
The general trend is elevated ammonia levels-->neurological disturbances including mental retardation. Tx: lower protein intake, and tx. With benzoic acid to incrase ammonia elmination. Arginine supplementation is needed except in hyperarginemia.
#73 Carbamoyl phosphate synthetase deficiency
Ammonia cannot effectively enter the urea cycle and there is hyperammonemia.
#74 Ornithine transcarbamoylase deficiency
Another cause of hyperammonemia; the most common of the urea cycle metabolic disorders; it is x-linked.
#75 Arginosuccinate synthetase deficiency.
There are elevated citrulline levels in the blood, urine, and CSF, and there may be hyperammonemia.
#76 Arginosuccinic aciduria.
There is decreased arginosuccinate activity. Arginosuccinate is elevated arginosuccinate in blood and urine, whereas arginine is lower. For some reason, the hair is very dry and brittle
#77 Hyperargininemia
There is defective arginase activity. Blood arginine levels are increased. The patient may have vomiting, seizures, ataxia, and protein intolerance. Restriction of argining in the diet may be beneficial.
Most common causes of hyperlipidemia:
Excess alcohol intake (alcohol is converted to acetyl CoA, which can convert to lipids) and diseases of lipid metabolism.
Clinical presentation of hyperlipidemia
Hyperlipidemia presents as blood vessel wall plaques (artheromata), fatty skin lessions in eye lides (xanthelesmae) and lipid deposits in tendons (xanthomas) and the cornea (corneal arcus). Pancreatitis may also result from elevated triglycerides, as pancreatic lipase may be needed to act on elevated blood triglycerides to form breakdown products that may injure the pancreas.
Cholesterol Ratios
Cholesterol is relatively concentrated in LDL and HDL (triglycerides in chylomicrons and VLDL). Heart disease correlated with increased LDL and decreased HDL. HDL is cholesterol dense, and is good because it shunts excess cholesterol back to liver. Chylomicrons, VLDL, and LDL carry cholesterol to periphery.
Tx. of Lipid Disorders
(A) Decrease cholestero/saturated fat intake. Consume unsaturated fats (B) Use cholestyramine or Colestipol--bind and prevent bile salt resorption (C) Nicotinic acid-->decrease VLDL production (D) Inhibitors of HMG CoA reductase (e.g. simvastatin, Zocor) to decrease the production of cholesterol. (E) Clofibrate-->activates lipoprotein lipase to help clear VLDL and chylomicrons. Also reduces cholesterol/triglyceride biosynthesis, and stimulate fatty acid ox (F) Ezetimibe--> inhibits cholesterol absorption in small intestine (G) Ingesting medium fatty acids. They can be administered without requiring lipoprotein lipase for processing (attach to albumin and are absorbed directly into portal system).
Lipoprotein disorders
(A) Familial lipoprotein Lipase Deficiency (Dx: electrophoresis, Type I lipoprotein pattern). Serum triglycerides become elevated with particular elevation of chylomicrons. Xanthomas are present (not arthersclerosis). Pancreatitis may develop due to chylomicrons. (B) Familial hypercholesterolemia --Type IIa or IIb pattern on electrophoresis-- This involves an elevation in LDL and sometimes VLDL due to a defect in cell LDL receptor (C) Familial dysbetalipoproteinemia (Type III pattern)--A defect in the remnent particle apoprotein, which results in the loss of remnant ability to bind to liver cells. Xanthomas and early artherosclerosis. --Broad beta band seen on electrophoresis. (D) Familial hypertriglyceridemia (Type IV or V)-- There is elevated VLDL but the mechanism is unclear. Xanthomas, pancreatitis and premature artherosclerosis. (E) Multiple lipoprotei-type (IIa, IIB or IV pattern)= elevated LDL, possibly due to excess production of VLDL. There is premature atherosclerosis.
Hypolipoproteinemia disorders
(F) abetalipoproteinemia--absence of apoproteins. Chylomicrons not found and there is fat malabsorption with lipid accumulation in intestinal cells. There are various neurologic abnormalities and distorted, "thorny" erythrocytes (acanthocytosis) (G) Familial hypobetalipoproteinemia- decrease but not a total absence of apoB and its lipoprotein--relatively benign. (H) Tangier disease--absence of HDL due to defect in cholesterol efflux regulatory protein, which plays a role in intracellular cholesterol transport. Serum cholesterol low/cellular cholesterol is high. Unfortunately, since cholesterol can't be transported back to the liver, it accumulates in phagocytic cells. Tonsils are orange and enlarged. Various neurologic problems/corneal opacities may be seen. (I) LCAT deficiency--Cholesterol in HDL particle cannot be esterified. This leads to buildup of unesterified cholesterol, corneal opacities, renal insufficiency, hemolytic anemia, and premature atherosclerosis. Dx. by enzyme assay for plasma LCAT.
#79. Tay-Sachs Disease
Deficiency in hexosaminidase A, which normally breaks down gangliosides. XS ganglioside in the accumulates in the brain of the infant. The child appears normal at birth but experiences progressive neurologic deficits-->death in a few years.
#80. Gaucher's disease
Results from deficiency of beta-glucosyl ceramidase, which normally breaks down glycosyl cerebroside to ceramide. Glucosylcerebroside then accumulates in the brain, liver, and spleen. Bone marrow exam for "gaucher's cells" w/ xs cerebroside.
Krabbe's Disease
Globoid Leukodystrophy--accumulation of galactocerebroside in white matter of CNS, as lysosomes lack lack the enzyme galactocerebrosidase.
Fabry's disease
X-linked gluboside breakdown disorder. The defect is in alpha-galactosidase A (patient has painful neuropathy and progressive renal failure with accumulation of globoside in the kidneys.
#81 Mucopolysaccharidoses
Proteoglycan disorders (hereditary lysosomal defect that can degrade mucopolysaccharides-->heparin sulfate and dermatan sulfate. Mucopolysaccharide buildup can lead to mental retardation and skeletal abnormalities. "Pulmonary alveolar proteinosis" can cause excess glycoprotein to fill the alveoli.
#82. Gout
Uric acid elevation can lead to urate crystal precipitation in blood/urine. Urate crystals deposit in joints and urine. Hyperuricemia (elevation of uric acid in blood) may develop from excess uric acid and/or decreased excretion.

Causes of excess production of uric acid include:
a. lesch nyham syndrome (#84)
b. PRPP synthetase overactivity (#83)
c. glucose-6-phophatase deficiency (#11)

* various malignancies may result in elevated uric acid via cell breakdown or conversion of excess nucleic acids to uric acid. Renal disease may block excretion of uric acid (result in hyperuricemia. Alcohol can precipitate gout by decreasing excretion and increasing production of uric acid).
Overactivity of PRPP synthetase or amidotransferase
PRPP synthetase acts between Ribose 5-P and PRPP. Amidotransferase acts between PRPP and ribosylamine.

Overactivity may lead to hyperuricemia.
#84 Lesch-Nyhan Syndrome
Lesch Nyhan syndrome is a deficiency of hypoxanthine p-ribosyl transferase. It's an X-linked defect in the salvage pathway that normally changes hypoxanthine and guanine to IMP and GMP.

In the absence of salvage, there are urate and PRPP accumulation and subsequently gout (PRPP normally combines with hypoxanthine and guanine to form IMP and GMP)-->gout
#85 Xanthine oxidase deficiency
The inability to change xanthine to urate actually results in xanthinuria with decreased blood and urine urate. Sometimes you can get xanthine stone formation. Absent enzyme confirmed on liver biopsy. (It's like the opposite of gout)
#86 APRT (adenine p-ribosyl transferase) deficiency
Absence of APRT between adenine and AMP steps shunts adenine toward 2,8-dioxyadenine--> possible urinary stones
#87. Adenosine deaminase deficiency
This is associated with low numbers of lymphocytes, SCID (severe combined immunodeficiency disease) and sometimes liver disease.

There is an overproduction of ATp and dATP, which leads to an imbalance that upsets the proliferation of immune cells.

Gene replacement? Other therapies?
#88. Purine nucleoside phosphorylase deficiency
Associated with immune system deficiency and decreased numbers of T lymphocytes.
#89. Orotic aciduria
Blocks in steps leading to pyrimidine synthesis may result in deficient production of pyrimidine nucleotides.

Results?: Anemia, immune deficiency (from decreased red and white cell production), excess orotic acid and precipitation in urine.

Treatment with uridine may help supply missing pyrimidine, but can decrease the level of orotate by uridine's negative feedback on steps that lead to orotate production.

Tx: leflunamide-->immunosuppressive drug that inhibits dihidroorotate dehydrogenase, an enzyme which facilitates the synthesis of orotate from dihydroortate.

This UMP synthesis is blocked, as is immune cell proliferation, which requires UMP synthesis.
#90 Pyrimidine 5'-nucleotidase deficiency
RNA, in this condition, cannot be completely degraded in maturing red blood cells. The nucleotides of uridine and cytidine accumulate--> hemolytic anemia.

In lead poisoning, lead inhibits 5'-nucleotidase and may also result in an anemia.

In both lead poisoning and pyrimidine 5'-nucleotidase deficiency, the red cells have the microscopic appearance of "basophilic stippling", which may be due to incompletely degraded RNA.

Lead inhibits iron incorporation during heme synthesis.
#91 Xeroderma pigmentosum
Defect in normal DNA repair due to deficiency in any of many proteins involved in DNA repair, including an endonuclease.

Ataxia telangiectasia and Fanconi's anemia also may be related to endonuclease deficiency.
#92 Protein disorders
1. enzyme defects
2. diseases of transport proteins
3. disorders of immune system
4. blood clotting disturbances
5. abnormalities of cell membranes
6. and abnormalities of those hormones that are proteins.
#93. Vitamin B6 Deficiency
By reducing pyridoxal phosphate availability at the entrance to porphyrin synthesis pathways, an anemia may result through decreased ability to form heme.
#94. Uroporphyrinogen I synthase deficiency
Acute intermitent porphyria
#95 Uropophyrinogen III cosynthase deficiency
(congenital erythropoetic porphyria)
#96. Uropophyrinogen decarboxylase deficiency
Porphyria cutanea tarda. Blistering of skin in sun exposed areas.
#97. Coproporphyrinogen oxidase deficiency
(Variegate porphyria)
#99 Ferrochelatase (heme synthetase) deficiency
There is a defect in the ability of Fe++ to combine with protoporphy
#100. Hemoglobinopathies
Mutations that change amino acids in hemoglobin may cause abnormally functioning red blood cells and anemia.
Sickle cell anemia
Abnormal hemoglobin is produced that results in sickle-shaped red cells, particularly under conditions of oxygen deprivation.

10% of blacks heterozygous and 0.4% homozygous.

Normal Hemoglobin (HbA) is alpha2beta 2. In sickle cell ther is change in beta chain, and these individuals have mixture of HbS and HbA. Homozygous have HbS only.
Thalassemias
Alpha thallassemia--alpha chain is underproduced.

Beta thallassemia--beta chain is underproduced (gene mutation forms a stop codon)

Thallassemia minor--heterozygous type of beta thallassemia

Thalassemia major--homozygous thallassemia.
Metabolic causes of anemias:
Red blood cells do not have mitochondia (or Krebs cycle-->ATP poduction) and from HMP shunt (NADPH production).

Defects either in glycolysis or HMP shunt may result in red cell abnormalities.
When red cells get old and are destroyed (mainly in spleen), the heme ring is broken and Fe++ is released forming:
Biliverdin, an open-chain molecule with no iron.
How might hemolytic anemias affect levels of circulating unconjugated bilirubin?
Excessive blood breakdown can overwhelm liver and result in elevation of circulating unconjugated bilirubin. This non-polar molecule is not excreted, but te secondary rise in water-soluble urobilinogen may be detected in the urine as a laboratory test consistent with hemolytic anemia and certain liver disorders that involve poor urobilinogen reprocessing.

Unconjugated (as well as conjugtaed) bilirubin, may be deposited in a number of tissues-->jaundice. Unconjugated (lipid-soluble) bilirubin can cross the blood brain barrier and can cross blood-brain barrier and cause toxic effects when deposited in the brain (kernicterus) particularly when deposited in lipid-rich basal ganglia.
Consequence of poor liver uptake/conjugation of unconjugated bilirubin?
Results in increased serum unconjugated bilirubin. Decreased excretion of bilirubin in bile will result in light-colored stools, as the by-product of urobilinogen metabolism, stercobilin, will not be so present.
Inadequate release of conjugated bilirubin into bile OR bile duct obstruction may result in what?
As bilirubin is already conjugated, one may find a rise in the blood of conjugated (water soluble) bilirubin.

Conjugated bilirubin can be excreted in the urine (urine tests positive for bilirubin).

Hepatitis and Cirrhosis damage liver-->rise in both unconjugated and conjugated bilirubin (more so of conjugated form).
#101. Decrease in UDP-glucuronyl transferase activity
The liver normally conjugates "indirect" bilirubin to conjugated ("direct") bilirubin, which can be readily excreted through the bile.

Impaired conjugation leads to unconjugated (lipid soluble) bilirubin accumulating in blood-->jaundice. Passing to brain can cause brain dysfunction.
"Gilbert's Syndrome" and "Crigler-Najjar syndrome"
Mild decrease in UDP-glucuronyl transferase.

Gilbert's (asymptomatic but mildly elevated unconjugated bilirubin)

"Crigler-Najjar syndrome" (enzyme defect more severe. Phenobarbital induces synthesis of glucuronyl transferase and may be useful in reducing jaundice).
#102. What kind of reactions can the liver utilize to detoxify drugs?
a. "Conjugation (w/ glucuronate, etc.)
b. Oxidation
c. Reduction
d. hydrolysis
Why are babies so susceptible to side effects from the drug chloramphenicol?
"Grey baby syndrome" UDP-glucuronyl transferase levls low-->toxic effect-->avoidance of chloramphenicol.
#103 Dubin-johnson and Rotor syndromes
Defective excretion of conjugated bilirubin into bile. This leads to hyperbilirubinemia of conjugated type --> extrahepatic obstruction of biliary ducts (as by tumor or gallstones)
#104 Vitamin B1 (thiamine)
Deficiency results in

1) beri-beri:
2) Wernicke-Korsakoff syndrome: alcoholism-->psychosis/confabulation, memory loss/neurologic findings
#105 Vitamin B2 (riboflavin)
Deficiency results in : angular stomatitis (cracks in corner of mouth), tongue inflammation, seborrheic dermatitis, and anemia
#106 Vitamin B6 (pyridoxine, pyridoxal; pyridoxamine)
Deficiency results in:

Dermatitis, glossitis, anemia, and neurological disturbances (peripheral neuropathy and convulsions)
#107 Vitamin B12 (cyanocobalamin)
Deficiency results in:

*pernicious anemia. Deficiency in intrinsic factor can worsen.

Macrocytic anemia, hypersegmented leukocytes, and neurosensory deficits related to posterior column degeneration. Positive Schilling test in which radioactive B12 is ingested, with subsequent assays of degree of absorption; elevated urine methylmalonate;

Tx: B12 tablets or injections.
#108 Vitamin C (ascorbic acid)
Deficiency: Scurvy-->swollen gums, easy bruisability, defective collagen formation. Serum levels of ascorbic acid may be tested for diagnosis.
#109 Folacin (=folate=folic acid)
Deficiency: resembles B12 (anemia) w/o neurologic abnormalities.

Unlike B12 (folate needs continued replacement-->poor diet)
#110 Biotin
Biotin must be broken down by biotinidase to use biotin.

In biotinidase deficiency, there may be nerve damage and mental retardation.

If biotin supplements are started within the first few weeks of life, the child may be normal.
#111 Niacin (= nicotinic acid)
Nicotinamide is a related amide compound with similar activity as niacin.

Deficiency leads to : PELLAGRA (3D's): Diarrhea, Dermatitis, and Dementia.
#112. Pantothenate (=pantothenic acid)
Deficiency results in: fatigue, nausea, vomiting, abdominal pain, and neurosensory disturbances.
#113 Vitamin A (retinal) deficiency
Deficiency: night blindness, xeropthalmia (dry cornea/conjunctiva) Dry skin and mucous membranes. Vit. A deficiency secondary to poor protein intake may occur due to poor carrier complex formation.

Toxicity: vomiting, headache, mental status, hair loss, skin peel, *death sometimes*
#114 Vitamin D
Deficiency causes hypocalcemia and hypophosphatemia-->rickets

Osteomalacia (decalcification/softening of bones in adults)

Osteoporosis (reduction in bone mass as a whole)

Toxic: hypercalcemia/renal stones
#115 Vitamin E
Deficiency: Inconclusive--dystrophic changes in muscle/hemolysis?

Toxicity: an excess may interfere with action of various hormones, with vitamin K and blood clotting, and white blood cell functioning
#116 Vitamin K
Deficiency: important in blood clotting-->deficiency results in hemorrhages (especially in newborns) and elevated prothrombin time on lab testing.

Toxicity: hemolytic anemia, kernicterus (bilirubin in brain)

(note: dicoumarol looks like vitamin K, is an anticoagulant/interferes with blood clotting).
# 117 Thyroxine
Deficiency: Results in dwarf, cenlarged tongue/abdomen, mental retard.

adult results in myxedema (dry, edematous skin, mental and physical sluggishness, decreased tendon reflexes, decreased metabolism, a goiter. (underproduction, rarely due to iodine in USA and is due to autoimmune process in most cases)

Excess: Grave's disease, goiter, exopthalmos, hyperactivity, increased basal metabolic rate. Due to overproduction by thyroid.
#118. Glucocorticoids (cortisol)
Excess: Cushing's syndrome. Opposite effects to insulin. Causes gluconeognesis and fat/protein breakdown. Has an anti-inflammatory effect.

Cushing's syndrome results in:
1. high plasma cortisol-->abnormal glucose metabolism (diabetes mellitus)
2. abnormal fat distribution (obesity, buffalo hump, "moon face")
3. abnormal protein breakdown (osteoporosis, myopathy, purple stria on abdomen)
4. coinciding increase in androgen secretion (hursutim, amenorrhea)

Hypertension and hypokalemia may reslut. Ulcers, decreased inflammatory response, and psychosis may occur.

XS glucorticoids may be due to ACTH-secreting tumor.
#119 Mineralocorticoids (aldosterone)
Deficiency: Addison's disease--> adrenal cortisol insufficiency of both glucocorticoids and mineralocorticoids. Patient may have hypotension, low serum sodium, weakness, and excess skin pigmentation. Secondary to autoimmune disease against adrenal gland, or infection (AIDS).

Excess: Conn's Syndrome-->patient has hypertension and low serum potassium.. May be secondary to hormone-producing tumor.
#120 Epinephrine
Excess: (pheochromocytoma)-->hormone producing tumor. Patient experiences episodes of hypertension, cardiac palpitations, and anxiety, Urinary VMA may be elevated.
# 121 Androgens (testosterone)
Deficiency: (In utero-->failure of male genital development. Male pseudohermaphroditism-->cellular recognition proteins for androgen leading to androgen insensitivity).

Excess: Testosterone in adults can lead to increase body mass, cardiac and liver disease + testicular atrophy.
#122 Estrogens (estradiol most important)
Deficiency: In childhood (e.g. turner's syndrome) results in failure to develop secondary female sex characteristics. In adults, loss of menstruation results (following menopause or ovary removal).

Excess: In childhood, may occur with a hormone-producing tumor-->precocious puberty-->early epiphesial closure.
Insulin Deficiency and Excess
Insulin defciency: results in diabetes mellitus (hyperglycemia, glycosuria, and ketoacidosis in some caess.

XS blood sugar-->osmotic fluid loss/coma.

Vascular disease and neuropathy partly due to glycosylation of membrane proteins (HbA etc).

Diabetes may be 2ndary to underproduction or to defective insulin. (Type I= insulin dependent, insulin can be used as tx.). (Type II= non-insulin dependent often results in cell receptor for insulin being defective. Such cases may be resistant).

Excess: Hypoglycemia, coma. Occurs with xs insulin administration (but insulin secreting tumors can cause this).
Glucagon
Excess: May occur in glucagon secreting tumor-->result in life threatening hyperglycemia.
Growth Hormone
Deficiency: childhood normally proportioned midget.

Excess: can result in normally proportioned giant when overproduction occurs in childhood.

Overproduction in an adult results in acromegaly. (These adults have abnormally proportioned growth features, especially enlarged hands, feet, and jaw. there may be hyperglycemia as growth hormone is also involved in glucose metabolism)
Antidiuretic hormone (ADH; vasopressin)
Deficiency: Diabetes insipdus. In which the patient may excrete large volumes of urine and drink constantly.

Excess: Results in water retention, hyponatremia. ADH secreted by certain tumors (and in response to certain inflammations) by normal lung or pituitary tissues.
Calcitonin
Excess: found in medullary thyroid carcinoma-->mild hypocalcemia.
Parathyroid Hormone
PTH acts to increase serum calcium.

Deficiency: Results in hypocalcemia and tetany (spasms on flexion of the wrists and joints)

Excess: Results in hypercalcemia, calcium may deposit in various tissues or precipitate as renal stones-->bone demineralization.
ACTH, TSH, LH, FSH, AND RENIN
Deficiencies and excesses are refleected in changes in activity of their respective target organs.
Prolactin
Excess: Galactorrhea (excess lactation) ; may result from hormone-secreting tumor.
Gastrin
Excess: Results in gastric hyperacidity and ulcers; occurs with gastrin-producing tumors (zollinger-ellison syndrome)
Sodium
Most abundant extracellular cation. Influences water retention in body, and important part of control of acid-base balance.

Deficiency: neuromuscular dysfunction
excess: hypertension/fluid retention
Potassium
Main intracellular cation. Mycordial depolarization/contraction.

Deficiency: NM dysfunction
XS: myocardial dysfunction
Chloride
Important anion (negative ion) in maintenance of fluid/electrolyte balance; an important component of gastric juice.
Calcium
Most abundant mineral (bones and death), important participant in regulation of many metabolic processes. When bound to regulatory protein (calmodulin) calcium helps modulate activities of many enzymes.

When bound to calmodulin (regulatory protein) calcium helps modulate enzyme activity.

Important for blood clotting, neural and muscular activity, cell motility, hormone actions, and other activities.

Deficiency: rickets osteomalacia, tetany, and othre NM problems.

XS: hypercalcemia and renal stones
Phosphorus
Important component of bone, and universally important in the structure and functioning of cells.

Deficiency: associated with rickets in children, and osteomalacia in adults. Other defects occur in functioning of red and white blood cells, platelets, and liver.
Magnesium
Important participant in reactions that involve ATP.

Deficiency: metabolic and neurologic dysfunction.

Excess: associated with CNS system toxicity.
Chromium
Enhances effect of insulin
Deficiency: defective glucose metabolism
Excess: chromium dust may lead to carcinoma of lung
Cobalt
Part of B12 molecule
excess: GI distress + neuro/cardiac dysfunction
Copper
Part of number of enzymes, including cytochrome oxidase and lysyl oxidase (important in collagen cross-linking)

Deficiency (anemia/mental retardation. Menkes' Disease-->defect in copper transport/utilization, associated with brittle kinky hair, cerebral degeneration, and infant death.

Excess-->results in liver disease, various neurologic disturbances, dementia, copper cataracts. These occur in Wilson's disease where there is excess copper deposition in brian, liver cornea, lens, and kidney.
Fluoride
Contributes to harndess of bones and death

Deficiency: dental caries
Excess: associated with stained teeth, nausea, GI disturbances, and tetany
Iodide
Part of hormone thyroxine
Deficiency: hypothyroidism
Excess: results in hyperthyroidism in susceptible persons
Iron
Functions in hemoglobin molecule, certain enzymes, and the cytochromes.

Deficiency: anemia
Excess: hemochromatosis (abnormal iron deposits and damage to liver, pancreas, and other tissues)
Manganese
Needed to activate variety of enzymes, including enzyes involved in the synthesis of glycoproteins, proteoglycans and oligosaccharides.

Deficiency: result in underproduction of latter molecules.

Excess: may result in Parkinson-like symptoms (shaking, slowness, stiffness) and psychosis.
Molybdenum
Important component of certain enzymes (e.g. xanthine oxidase, sulfite oxidase)
Nickel
May stabilize the structure of nucleic acids and cell membranes.

Excess: association with carcinoma of lung?
Selenium
Part of enzyme glutathione peroxidase (like Vit E) acts as an antioxidant. Component of T4-deiodinase, which converts T4 to T3.

Deficiency- may result in Cong. Heart Failure

XS: causes "garlic" breath body odor and skeletal muscle degeneration
Silicon
Associated with many mucopolysaccharides and may be important in the structuring of connective tissue. Excess silca particle inhalation may result in silcosis (pulmonary inflammation).
Zinc
Component of many DNA-binding proteins, including steroid receptors, and of many enzymes, including lactate dehydrogenase, alkaline phosphatase, and DNA polymerases.

Deficiency: problems include poor wound healing, hypoganadism, decreased taste and smell, and poor growth).

Excess: vomiting from Gi irritation.
Penicillins
Many gram negative bacteria are resistant to peniccilin as the outer membrane of gram negative blocks penicillin entry.

Bacteria may produce penicillinase that can break beta-lactam ring of molecule.

Variants of peniccilin hvae been developed that are effective even in the presence of peniccilinase.
What antibiotic acts on bacterial cytoplasmic membranes?
Polymyxin antibiotics
What bacteria interferes with protein synthesis in bacteria?
CLE TAG
(e.g. erythromycin and the tetracyclines)
What antibiotics interfere with other aspects of cytoplasmic metabolism?
Sulfonamides interfere with bacterial incorporation of PABA (para-aminobenzoid acid) in formation of folic acid.
#124 Erythromycin and tetracyclines
Act, in part, by interfering with bacterial protein synthesis
#125. Sulfonamides
Bacteria need PABA to form folic acid. Humans don't need PABA (folic acid comes from diet)

Sulfonamides are competitive antagonists of PABA and thus can affect bacteria while not harming human cells.
Trimethoprim
acts on the dihydrofolate reductase step (between 7,8 dihydrofolate, and 5,6,7,8 tetrahydrofolate. Trimethorpim has a more damaging effect on bacteria and protzoans.

It is often coadministered with trimethoprim (which inhibits PABA incorporation)
#127 Adenine arabinoside
Purine adenine analogue. Acts on DNA viruses by inhibiting viral DNA polymerase.
Idoxyuridine
Acts on DNA viruses. a derivative of pyrimidine deoxyuridine, becomes incorporated into DNA and blocks viral multiplication.
Acyclovir
A purine nucleoside analogue of guanine, converts to triphosphate form which interferes with herpes simplex viral DNA polymerase.
Azidothymidine (AZT)
A thymidine analog, and DDI, an inosine analog, are antivral agents used in AIDS therpay. They stop DNA synthesis in viruses, such as AIDS, that do not have a 3'-->5' exonuclease
#128 Methotrexate
Antitumor folic acid antagonist. It looks like folic acid (inhibits transformation of dihydrofolate to THF.

Without THF, we can't form dTMP from dUMP (pyrimidine biosynthesis) and we can't even enter purine ring biosynthesis (to IMP).

Inhibiting these steps interferes with DNA formation/tumor cell division.
#129 Asparaginase.
For therapy of tumors. Certain tumors require exogenous asparagine for their survival whereas normal cells can produce their own asparagine.

Asparaginase may be useful in inducing remission in patients with acute lymphoblastic leukemia by reducing the availability of exogenous asparagine to maligant cells.
#130 5-fluorouracil (5-FU)
Antitumor drug that acts at the same map area as does methotrexate in pyrmidine biosynthesis (but acts by different mechanism).

Because of its resemblance to uracil, it inhibits thymidilate synthase, and prevents the formation of thymidine (a pyrimidine)
Thymidilate synthase
converts dUMP to dTMP (uracil to thymidine, a pyrimidine).

5-fluoracil, which resembles uracil, inhibits thymidilate synthetase and prevents thymidine formation.
#131 Mercaptopurine
Antitumor, analog of adenine (purine) and acts by interfering with adenine's incorporation into nucleic acids.
#132 Thioguanine
Is an antitumor agent that resembles purine guanine and acts by abnormally substituting for guanine in RNA and DNA
#134 Allopurinol
Allopurinol (tx of gout). Allopurinol looks like hypoxanthine, and thereby reduces urate production (xanthine oxidase acts on hypoxanthine-->xanthine and xanthine-->uric acid)
Xanthine oxidase
Facilitates steps that lead to the production of urate. (allopurinol looks a lot like hypoxanthine, and thereby reduces urate production)
#135. Hyaluronidase
Cleaves hyaluronic acid. It is produced by certain bacteria and may facilitate their spread through tissue planes.

Sometimes administered with drug injections to facilitate spread of drug through injected tissues.
#136. Heparin
Interferes with activity of number of clotting enzymes in clotting cascade.
# 137 Phenformin
Prevents lactic acid from undergoing gluconeogenesis in the liver.

Antidiabetic drug (but has discuntinued due to its tendancy to cause lactic acidosis.

The sulfoureas are other antidiabetic drugs that act partly by stimulating insulin release and partly by increasing number of insulin receptors in periphral tissues).
# 138 Antabuse
Tx for alcoholism. Prevents acetaldehyde-->acetate.

This results in a marked buildup of acetaldehyde in the blood, making the patient feel sick when alcohol is ingested.

Metronidazole is an antibiotic having a similar action, and patients must be cautioned not to drink alcohol while taking this drug.
#139 Monoamine oxidase (MAO) inhibitors
Drugs that inhibit monoamine oxidase are used as antidepressants in certain patients.
#140 Aspirin
Decrease inflammation pain and fever. Prolongs bleedings (inhibits platelet aggregation). Aspirin inhibits cyclooxygenase (enzyme important in prostaglandin and thromboxane synthesis.
Indomethacin and phenylbutazone
NSAIDs that inhibit cyclooxygenase (COX). There are two forms of COX, COX-1 and COX-2.
COX-2
Found primarily in inflamed tissue. thus more recent drugs that specifically inhibit COX-2 are accompanied by fewer general side effects.

Steroidal antiinflammatory agents appear to inhibit cyclooxygenase snthesis.
Physiological effect if fish oils
Special polyunsaturated fatty acids (in certain respects look like arachidonic acid)

These "omega-3" fatty acids are so called because they have a C=C bond between 3rd and 4th carbons from the omega end (non-carboxylic end) of the fatty acid.

They can be converted to prostaglandin-like compounds which appear to have an effect in lowering blood pressure, decreasing platelet aggregation and , to some degree, increasing the HDL/LDL ratio.
#141 Thiouracil
Used to tx. hyperthyroidism. Thiouracil inhibits organic binding of iodide needed in the formation of mono-, di-, tri(T3) and tetraiodothyronine (T4)
#143. CPK Creatinine phosphokinase
changes ADP to ATP when needed.

Leakage of creatinine phosphokinase is merely a detectable marker of cell injury--and raises the attention of the physician for such.

3 types: MM, MB, and BB.

MB elevation suggests heart attack.

Elevation of MM is suspicious for muscle damage.
#144. Creatinine
Test of renal function. Creatinine is derived from creatine phosphate (normally is excreted almost totally by the kidney).

Blood levels of serum creatinine, as well as urea, are useful indices of renal function (their elevation often a sign of renal insuficiency)
#145. SGOT
(serum glutamate oxaloacetate transaminase).

Enzyme is found many areas of the body, but it is most useful as a marker of liver or cardiac injury. It leaks out of the damaged cell and increases in the serum after heart attack and liver injury (hepatitis) and may be the clue that these conditions are present.
#146. SGPT
(serum glutamate pyruvate transaminase) This enzyme is concentrated in the liver; it leaks out of the liver cell and rises in the serum with liver damage, as in hepatitis and mononucleosis. It does not significantly increase in MI and, hence, the test is more specific than SGOT for liver disease.
Serum alkaline phosphatase
Liver and bone disease.

Alkaline phosphatases catalyze reactions in which a phosphate is removed from a phosphate ester, especially at alkaline pH.

These levels rise with bone breakdown (tumor infiltration) and in liver disease and with bile duct obstruction.
Acid phosphatase
rich in the prostate. A rise in serum levls tests for the presence of prostate carcinoma. (Replaced by PSA, a serine protease that is elevated in prostatic carcinoma and prostatitis).
Serum LDH (Lactate Dehydrogenase elevation)
Widespread intracellular enzyme. Detection of high serum levels is rather nonspecific for localizing damage site, but its measurement is helpful in confirming MI or liver injury, skeletal muscle injury, or certain other tissues.

5 different isozymes of LDH helps to further localize injury, and these are tissue specific.
#148. Sorbitol dehydrogenase
Elevation of serum levels useful sign of liver cell damage.

Elevated glucose in diabetes may result in sorbital deposition in the lens and neural tissues, contributing to cataracts and peripheral neuropathy.
A/G (albumin/globulin) ratio
Useful index of liver dysfunction. Albumin is produced by the liver, whereas gamma globulin is produced by cells of the immune system.

Thus A/G ratio may be decreased in liver disease
#149 Amylase
Elevated in serum in mumps or pancreatitis (but peptic ulcer, intestinal obstruction, or gallstones can cause an elevation in amylase)
#150 Clinitest tablets and Clinistix testing or urinary sugar
Monosaccharides are ex. of reducing sugars. Reducing sugars reduce oxidizing agents such as cupric ion Cu++-->Cu+.

Lactose and maltose are reducing sugars (but table sugar is not).

Clinitest tests for reducing sugars in the blood (but will not detect sucrose.

This test has led to the failure of individuals to deceive the physician into thinking they have diabetes by pouring table sugar into their urine.Clinistic are specific for glucose (because they have glucose oxidase). Abscorbic acid can yield false positive.