Metabolism Flashcards
Fomepizole
inhibits alcohol dehydrogenase and is an antidote for methanol or ethylene glycol poisoning
Disulfiram
inhibits acetaldehyde dehydrogenase (acetaldehyde accumulates, contributing to hangover symptoms)
Ethanol metabolism increases NADH/NAD+ ratio in
liver, causing:
- Pyruvate lactate (lactic acidosis).
- Oxaloacetate malate (prevents gluconeogenesis fasting hypoglycemia)
- Dihydroxyacetone phosphate glycerol-3-phosphate (combines with fatty acids to make triglycerides hepatosteatosis)
Increased NADH/NAD+ ratio disfavors…
TCA production of NADH increasing the utilization of acetyl-CoA for ketogenesis (leading to ketoacidosis) and
lipogenesis (leading to hepatosteatosis)
Metabolism products in mitochondria
Fatty acid oxidation (β-oxidation), acetyl-CoA production, TCA cycle, oxidative phosphorylation, ketogenesis.
Metabolism products in cytoplasm
Glycolysis, fatty acid synthesis, HMP shunt, protein synthesis (RER), steroid synthesis (SER), cholesterol synthesis.
Metabolism products in both mitochondria and cytoplasm
Heme synthesis, urea cycle, gluconeogenesis
Electron transport inhibitors
Directly inhibit electron transport, causing a decrease of proton gradient and block of ATP synthesis.
+Rotenone, cyanide, antimycin A, CO
ATP synthase inhibitors
Directly inhibit mitochondrial ATP synthase, causing an increase in proton gradient. No ATP is produced because electron transport stops.
+Oligomycin
Uncoupling agents
Increase in permeability of membrane, causing a reduced proton gradient and increased O2 consumption. ATP synthesis stops, but electron transport continues.
-Produces heat.
+2,4-Dinitrophenol (used illicitly for weight loss), aspirin (fevers often occur after aspirin overdose), thermogenin in brown fat.
Glucose-6-phosphate dehydrogenase deficiency
+X-linked recessive disorder; most common human enzyme deficiency; more prevalent among blacks. malarial resistance.
+Heinz bodies—denatured Hemoglobin precipitates within RBCs due to oxidative stress.
+Bite cells—result from the phagocytic removal of Heinz bodies by splenic macrophages.
-Think, “Bite into some Heinz ketchup.”
NADPH is necessary to…
keep glutathione reduced, which in turn detoxifies free radicals and peroxides. NADPH in RBCs leads to hemolytic anemia due to poor RBC defense against oxidizing agents (e.g., fava beans, sulfonamides, primaquine, antituberculosis drugs). Infection can also precipitate hemolysis (free radicals generated via inflammatory response can diffuse into RBCs and cause oxidative damage)
Essential fructosuria
Involves a defect in fructokinase. Autosomal recessive. A benign, asymptomatic condition, since fructose is not trapped in cells.
+Symptoms: fructose appears in blood and urine.
+Disorders of fructose metabolism cause milder symptoms than analogous disorders of galactose metabolism.
Fructose intolerance
Hereditary deficiency of aldolase B. Autosomal recessive. Fructose-1-phosphate accumulates, causing a increase in available phosphate, which results in inhibition of glycogenolysis and gluconeogenesis.
-Symptoms present following consumption of fruit, juice, or honey. Urine dipstick will be ⊝ (tests for glucose only); reducing sugar can be detected in the urine (nonspecific test for inborn errors of carbohydrate metabolism).
+Symptoms: hypoglycemia, jaundice, cirrhosis, vomiting.
+Treatment: intake of both fructose and sucrose (glucose + fructose).
Galactokinase deficiency
Hereditary deficiency of galactokinase. Galactitol accumulates if galactose is present in diet.
-Relatively mild condition. Autosomal recessive.
+Symptoms: galactose appears in blood and urine, infantile cataracts. May present as failure to track objects or to develop a social smile.
Classic galactosemia
Absence of galactose-1-phosphate uridyltransferase. Autosomal recessive. Damage is caused by accumulation of toxic substances (including galactitol, which accumulates in the lens of the eye).
+Symptoms: failure to thrive, jaundice, hepatomegaly, infantile cataracts, intellectual disability. Can lead to E. coli sepsis in neonates.
+Treatment: exclude galactose and lactose (galactose + glucose) from diet.
Lactase deficiency
Insufficient lactase enzyme leads to dietary lactose intolerance. Lactase functions on the brush border to digest lactose (in human and cow milk) into glucose and galactose.
+Primary: age-dependent decline after childhood (absence of lactase-persistent allele), common in people of Asian, African, or Native American descent.
+Secondary: loss of brush border due to gastroenteritis (e.g., rotavirus), autoimmune disease, etc.
-Congenital lactase deficiency: rare, due to defective gene.
+Stool demonstrates decreased pH and breath shows elevatedhydrogen content with lactose tolerance test. Intestinal biopsy reveals normal mucosa in patients with hereditary lactose intolerance.
Hyperammonemia
Can be acquired (e.g., liver disease) or hereditary (e.g., urea cycle enzyme deficiencies).
+Results in excess NH4, which depletes α-ketoglutarate, leading to inhibition of TCA
cycle.
+Treatment: limit protein in diet. Lactulose to acidify the GI tract and trap NH4 for excretion. Rifaximin to reduce colonic ammoniagenic bacteria. Benzoate or phenylbutyrate (both of which bind amino acid and lead to excretion) may be given to reduce ammonia levels
N-acetylglutamate synthase deficiency
Required cofactor for carbamoyl phosphate synthetase I. Absence of N-acetylglutamate leads to hyperammonemia.
Presents in neonates as poorly regulated respiration and body temperature, poor feeding, developmental delay, intellectual disability (identical to presentation of carbamoyl phosphate synthetase I deficiency)
Ornithine transcarbamylase deficiency
Most common urea cycle disorder. X-linked recessive (vs. other urea cycle enzyme deficiencies, which are autosomal recessive). Interferes with the body’s ability to eliminate ammonia. Often evident in the first few days of life, but may present later. Excess carbamoyl phosphate is converted to orotic acid (part of the pyrimidine synthesis pathway).
+Findings: elevated orotic acid in blood and urine, diminishedBUN, symptoms of hyperammonemia. No megaloblastic anemia (vs. orotic aciduria).
Phenylketonuria
Due to low phenylalanine hydroxylase or low tetrahydrobiopterin cofactor (malignant PKU). Tyrosine becomes essential.
-High phenylalanine leads to excess phenylketones in
urine.
-Findings: intellectual disability, growth retardation, seizures, fair skin, eczema, musty
body odor.
-Treatment: low phenylalanine and high tyrosine in
diet, tetrahydrobiopterin supplementation.
+Maternal PKU—lack of proper dietary therapy during pregnancy. Findings in infant: microcephaly, intellectual disability, growth retardation, congenital heart defects.
+Autosomal recessive. Incidence ≈ 1:10,000.
+Screening occurs 2–3 days after birth (normal at birth because of maternal enzyme during fetal life).
+Phenylketones—phenylacetate, phenyllactate, and phenylpyruvate.
+Disorder of aromatic amino acid metabolism leads tomusty body odor.
+PKU patients must avoid the artificial sweetener aspartame, which contains phenylalanine.
Maple syrup urine disease
Blocked degradation of branched amino acids (Isoleucine, Leucine, Valine) due to low α-ketoacid dehydrogenase (B1). Causes high α-ketoacids in the blood, especially those of
leucine.
-Causes severe CNS defects, intellectual disability, and death.
-Treatment: restriction of isoleucine, leucine, valine in diet, and thiamine supplementation.
-Autosomal recessive.
-Urine smells like maple syrup/burnt sugar.
Alkaptonuria (ochronosis)
Congenital deficiency of homogentisate oxidase in the degradative pathway of tyrosine to fumarate leading to pigment-forming homogentisic acid accumulates in tissue A . Autosomal recessive. Usually benign.
+Findings: dark connective tissue, brown pigmented sclerae, urine turns black on prolonged exposure to air. May have debilitating arthralgias (homogentisic acid toxic to cartilage).
Homocystinuria
Types (all autosomal recessive):
+Cystathionine synthase deficiency (treatment: low methionine, high cysteine, high B12 and folate in diet)
+Lowaffinity of cystathionine synthase for pyridoxal phosphate (treatment: very high B6 and high cysteine in diet)
+Homocysteine methyltransferase (methionine synthase) deficiency (treatment:
high methionine in diet)
-All forms result in excess homocysteine.
+Findings: very high homocysteine in urine, intellectual disability, osteoporosis, marfanoid habitus, kyphosis, lens subluxation (downward and inward), thrombosis, and atherosclerosis (stroke and MI).
Cystinuria
Hereditary defect of renal PCT and intestinal amino acid transporter that prevents reabsorption of Cysteine, Ornithine, Lysine, and Arginine (COLA).
-Excess cystine in the urine can lead to recurrent precipitation of hexagonal cystine stones.
+Treatment: urinary alkalinization (e.g., potassium citrate, acetazolamide) and chelating agents (e.g., penicillamine)
+High solubility of cystine stones; good hydration.
+Autosomal recessive. Common (1:7000).
+Urinary cyanide-nitroprusside test is diagnostic.
+Cystine is made of 2 cysteines connected by a disulfide bond.
Von Gierke disease
type I
Severe fasting hypoglycemia, very highglycogen in liver, highblood lactate, high triglycerides, high uric acid, and hepatomegaly
+Deficient: Glucose-6-phosphatase
+Autosomal recessive
-Treatment: frequent oral glucose/cornstarch; avoidance of fructose and galactose
Pompe disease (type II)
Cardiomegaly, hypertrophic cardiomyopathy, exercise intolerance, and systemic findings leading to early death
+Deficient: Lysosomal α-1,4-glucosidase (acid maltase)
+Autosomal recessive
-Pompe trashes the Pump
(heart, liver, and muscle)
Cori disease (type III)
+Milder form of type I with normal blood lactate levels
+Deficient: Debranching enzyme (α-1,6-glucosidase)
+Autosomal recessive
-Gluconeogenesis is intact
McArdle disease (type V)
High glycogen in muscle, but
muscle cannot break it down leading to painful muscle cramps, myoglobinuria (red urine) with strenuous exercise, and arrhythmia from electrolyte
abnormalities
+Deficient: Skeletal muscle glycogen phosphorylase (myophosphorylase)
+Autosomal recessive
+Blood glucose levels typically unaffected
-McArdle = Muscle
+Treat with vitamin B6 (cofactor)
