Metabolism

Question 1

Fomepizole

Answer 1

inhibits alcohol dehydrogenase and is an antidote for methanol or ethylene glycol poisoning

Question 2

Disulfiram

Answer 2

inhibits acetaldehyde dehydrogenase (acetaldehyde accumulates, contributing to hangover symptoms)

Question 3

Ethanol metabolism increases NADH/NAD+ ratio in

liver, causing:

Answer 3

• Pyruvate Ž lactate (lactic acidosis).
• Oxaloacetate Ž malate (prevents gluconeogenesis Ž fasting hypoglycemia)
• Dihydroxyacetone phosphate Ž glycerol-3-phosphate (combines with fatty acids to make triglycerides Ž hepatosteatosis)

Question 4

Increased NADH/NAD+ ratio disfavors…

Answer 4

TCA production of NADH increasing the utilization of acetyl-CoA for ketogenesis (leading to ketoacidosis) and
lipogenesis (Žleading to hepatosteatosis)

Question 5

Metabolism products in mitochondria

Answer 5

Fatty acid oxidation (β-oxidation), acetyl-CoA production, TCA cycle, oxidative phosphorylation, ketogenesis.

Question 6

Metabolism products in cytoplasm

Answer 6

Glycolysis, fatty acid synthesis, HMP shunt, protein synthesis (RER), steroid synthesis (SER), cholesterol synthesis.

Question 7

Metabolism products in both mitochondria and cytoplasm

Answer 7

Heme synthesis, urea cycle, gluconeogenesis

Question 8

Electron transport inhibitors

Answer 8

Directly inhibit electron transport, causing a decrease of proton gradient and block of ATP synthesis.
+Rotenone, cyanide, antimycin A, CO

Question 9

ATP synthase inhibitors

Answer 9

Directly inhibit mitochondrial ATP synthase, causing an increase in proton gradient. No ATP is produced because electron transport stops.
+Oligomycin

Question 10

Uncoupling agents

Answer 10

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.

Question 11

Glucose-6-phosphate dehydrogenase deficiency

Answer 11

+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.”

Question 12

NADPH is necessary to…

Answer 12

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)

Question 13

Essential fructosuria

Answer 13

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.

Question 14

Fructose intolerance

Answer 14

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).

Question 15

Galactokinase deficiency

Answer 15

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.

Question 16

Classic galactosemia

Answer 16

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.

Question 17

Lactase deficiency

Answer 17

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 elevatedhydrogen content with lactose tolerance test. Intestinal biopsy reveals normal mucosa in patients with hereditary lactose intolerance.

Question 18

Hyperammonemia

Answer 18

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

Question 19

N-acetylglutamate synthase deficiency

Answer 19

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)

Question 20

Ornithine transcarbamylase deficiency

Answer 20

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).

Question 21

Phenylketonuria

Answer 21

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.

Question 22

Maple syrup urine disease

Answer 22

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.

Question 23

Alkaptonuria (ochronosis)

Answer 23

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).

Question 24

Homocystinuria

Answer 24

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).

Question 25

Cystinuria

Answer 25

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.

Question 26

Von Gierke disease

type I

Answer 26

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

Question 27

Pompe disease 
(type II)

Answer 27

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)

Question 28

Cori disease  
(type III)

Answer 28

+Milder form of type I with normal blood lactate levels
+Deficient: Debranching enzyme (α-1,6-glucosidase)
+Autosomal recessive
-Gluconeogenesis is intact

Question 29

McArdle disease  
(type V)

Answer 29

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)