BIOCHEMISTRY: BOARDS AND BEYOND

Question 1

Removes the amine group from adenosine and converts into inosine (a amanation reaction). This enzime is dysfunctional or deficient in many cases of severe combined immunodeficiency syndrome.

Answer 1

Adenosine deaminase

Question 2

Treatment of gout

Answer 2

Inhibit xanthine oxidase (allopurinol)

Question 3

Metabolized by xanthine oxidase, caution with allopurinol. May boost effects and increase toxicity.

Answer 3

Azathioprine and 6-MP

Question 4

Lesch-Nyhan syndrome

Answer 4

Absence of the HGPRT enzyme. Purines cant be saved and are shunted into uric acid. JUVENILE GOUT. Increase of novo purine synthesis (+ PRPP, + IMP), Neurologic impairment: chorea, hypotonia, self mutilating behavior,

Question 5

This enzyme converts inosine monophosphate (IMP) to guanosine monophosphate (GMP).

Answer 5

IMP deshydrogenase

Question 6

An inhibitor of IMP dehydrogenase

Answer 6

Ribavirin

Question 7

Is an X-linked recessive enzyme deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) characterized by hyperuricemia, self-mutilation/aggression, dystonia, and intellectual impairment. HGPRT is an enzyme in the purine salvage pathway necessary for the conversion of hypoxanthine and PRPP into IMP, as well as the conversion of guanine and PRPP into GMP.

Answer 7

Lesch-Nyhan syndrome

Question 8

HGPRT enzyme activity less than 1.5% of normal is diagnostic for

Answer 8

Lesch-Nyhan syndrome

Question 9

This enzyme catalyzes the rate limiting step in synthesis of pyrimidine nucleotides. Found in the cytosol. This enzime is inhibited by uridine triphosphate (UTP).

Answer 9

Carbomoyl phosphate synthetase II

Question 10

Made of 2 N and 4 C

Answer 10

Pyrimidine ring

Question 11

Sources of the ring of pyrimidines

Answer 11

Carbamoyl phosphate and aspartate

Question 12

Autosomal recessive, defect in UMP synthase. Orotic acid in urine. Megaloblastic anemia (no response to B12/folate), growth retardation. Treatment: uridine

Answer 12

Orotic aciduria

Question 13

Key urea cicle enzime, combines carbamoyl phosphate with ornithine to make citrulline

Answer 13

Ornithine transcarbamylase (OTC)

Question 14

High nevels of carbamoil phophate get converted to orotic acid. High nevels of ammonia (urea cycle dysfunctional) = encephalopathy

Answer 14

OTC deficiency

Question 15

Chamotherapy agent, converted to araCTP, mimics dCTP and inhibits DNA polymerase.

Answer 15

ARA-C (Cytarabine or cytosine arabinoside)

Question 16

Sinthesized from deoxyuridine (converted by ribonucleotide reductase), deoxythymidine is only required nucleotide.

Answer 16

Thymidine

Question 17

Inhibits ribonucleotide reductase, blocks formation of deoxynucleotides. Can be used in polycitemia vera, essential thrombocytosis, sickle cell anemia (increase in fetal Hb).

Answer 17

Hydroxyurea

Question 18

Converts dUMP in dTMP (adding 1 C), involves use of N5,N10 tetrahydrofolate

Answer 18

Thymidylate synthase

Question 19

Converts DHF to THF

Answer 19

Dihydrofolate reductase

Question 20

Chemotherapy agent mimics uracil. Inhibits thymidylase synthase. Thymidylase death.

Answer 20

5-FU (5-fluorouracil)

Question 21

Chemotherapy agent, immunosupressent. Mimics DHF, inhibits dihydrofolate reductase = blocks synthesis of dTMP. Bone marrow can be rescued with leucovorin (folinic acid, converted to THF).

Answer 21

Metrotrexate

Question 22

Competitors inhibitors of Dihydropteroate synthase, Mimics PABA (paraaminobenzoic acid that is used for bacteria to create THF). No effect in human cells (dietary folate).

Answer 22

Sulfonamide antibiotics

Question 23

Blocks bacteria dihydrofolate reductase. No THF.

Answer 23

Trimethoprim

Question 24

Loss in dTMP production. Macrocytic anemia (fewer but larger RBCs). Neural tube defects in pregnancy.

Answer 24

Folate deficiency

Question 25

Required to regenerate THF from N5-Methyl THF. (Deficiency Methyl folate trap), loss of dTMP synthesis (megaloblastic anemia), neurological dysfunction (demyelination)

Answer 25

Vitamin B12

Question 26

Elevated ? in vitamin B12 and folate deficiency

Answer 26

Homocysteine

Question 27

Elevated MMA level (no convertion to succynil CoA)

Answer 27

B12 Deficiency

Question 28

Low crit, large RBC (increased MCV, mean corpuscular volume), hypersegmented neutrophils, caused by defective DNA production.

Answer 28

Megaloblastic anemia

Question 29

Causes of megaloblastic anemia

Answer 29

Folate deficiency B12 (neuro symptoms, MMA) Orotic aciduria Drugs (MTX, 5-FU, hydroxyurea) Zidovudine (HIV NRTIs)

Question 30

Classically presents as a pearly nodule with rolled borders and central ulceration. Treatment can include 5-Fluorouracil (5-FU). This drug is a pyrimidine analog that is activated to 5-fluoro-deoxy-uridine monophosphate (5-FdUMP) which binds N5, N10-tetrahydrofolate and inhibits thymidylate synthase.

Answer 30

Basal cell carcinoma

Question 31

Inhibition of thymidylate synthase by 5-FU decreases intracellular thymidine and increases

Answer 31

Intracellular uridine

Question 32

Is a myeloproliferative disorder of megakaryocyte proliferation leading to elevated platelet counts. One of the symptoms that may occur is erythromelalgia, or redness and burning pain of the hands and feet (this syndrome may also be seen in polycythemia vera). Low-risk cases can be observed without treatment. High-risk cases are treated with drug therapy to prevent complications such as thrombosis or bleeding.

Answer 32

Essential thrombocytosis (ET)

Question 33

Reduces the platelet count in ET. In clinical trials, it has been shown to reduce rates of thrombosis. Inhibits pyrimidine synthesis via inhibition of the enzyme ribonucleotide reductase. When pyrimidine synthesis is inhibited, DNA production is limited. This leads to megaloblastic anemia, including a low red cell count and high mean corpuscular volume. In fact, a rise in the MCV can be used to establish that patients are taking the medicine, and that the therapy is exerting a biologic effect.

Answer 33

Hydroxyurea

Question 34

Two nucleotides, carries electrons.

Answer 34

NADH (Nicotinamide adenine dinucleotide)

Question 35

Accepts electrons

Answer 35

NAD+

Question 36

Donate electrons, can donate to electron transport chain = ATP.

Answer 36

NADH

Question 37

At this stage of glycolylis, the glucose molecule is split into two three carbon molecules

Answer 37

Glyceraldehyde-3-phosphate

Question 38

Reactions not reversible in glycolysis.

Answer 38

Glucose to glucose-6-phosphate. Glucose 6-phosphate to Fructose-1,6-biphosphate. Phosphoenolpyruvate to pyruvate.

Question 39

Low km, quickly reach Vm (relatively low Vm compared to glucokinase)

Answer 39

Hexokinase

Question 40

Found in liver and pancreas, not inhibited by G6P. Induced by insulin (it promotes transcription). Inhibited by F6P (overcome by glucose).

Answer 40

Glucokinase

Question 41

Enzime inactive when low glucose and high F6P. The liver favor gluconeogenesis. High Km (rate varies with glucose). Sigmoidal curve (cooperativity)

Answer 41

Glucokinase

Question 42

Glucokinase: high Vm level

Answer 42

After meals

Question 43

In presence of Fructose-6-phosphate translocates glucokinase to nucleus, inactivating it.

Answer 43

Glucokinase regulatory protein or GKRP

Question 44

Often exacerbated by pregnancy

Answer 44

Glucokinase deficiency

Question 45

The rate limiting step for glycolysis.

Answer 45

Catalized by Phosphofructokinase-1, conversion of Fructose-6-phosphate to Fructose-1,6-biphosphate

Question 46

Key inducers of glycolysis

Answer 46

AMP, Fructuose-2,6-bisphosphate (insulin and glucagon)

Question 47

Is the rate limiting enzyme for gluconeogenesis.

Answer 47

Fructose-1,6-bisphosphate 1

Question 48

Likes to drive PKK2/FBPASE2 phosphorylated to favor glycolisis

Answer 48

Glucagon

Question 49

Fructose-1,6-phosphate to 2 GAP, reversible for gluconeogenesis.

Answer 49

Splitting stage of glycolisis

Question 50

Total ATP per glycolisis

Answer 50

4 (2 ATP per GAP) 2 ATP net

Question 51

Inhibitors of piruvate kinase

Answer 51

ATP, alanine

Question 52

Plasma elevations are common in hemolysis, myocardial infarction and some tumors

Answer 52

Lactate deshidrogenase (LDH)

Question 53

Sepsis, bowel ischemia, seizures. Elevated anion gap acidosis. - HCO3, -pH.

Answer 53

Lactic acidosis

Question 54

Too much exercise = too much NAD consumption (exceed capacity to TCA cycle/electron transport). Elevated ratio NADH/NAD. Favors piruvate to lactate (pH = falls in muscle)

Answer 54

Muscle cramps

Question 55

Autosomal recessive disorder, RBCs (most affected, lack mitochondria, membrane failure = phagocytosis in spleen.) New born with extravascular hemolysis and splenomegaly

Answer 55

Piruvate kinase deficiency

Question 56

Synthesized as an offshot of glycolisis. Alters hemoglobin binding and helps the red cell deliver oxygen to tissues in certain setings.

Answer 56

2, 3 - Bisphosphoglycerate

Question 57

Malate aspartate shuttle is used for oxidate phosphorylation (liver, heart)

Answer 57

32 ATP

Question 58

Glycerol 3-phosphate shuttle (muscle)

Answer 58

30 ATP

Question 59

No oxygen, no mitochondria

Answer 59

2 ATP + 2 lactate + 2 H2O

Question 60

Insulin is standard therapy for ?. Insulin drives potassium into cells, lowering the serum potassium level.

Answer 60

Hyperkalemia.

Question 61

Insulin is always given together with glucose when treating hyperkalemia. If given alone, insulin can cause

Answer 61

Hypoglycemia, seizures, or death.

Question 62

Fructose 1,6 Bisphosphatase1 is the rate-limiting enzyme in gluconeogenesis. In the fed state, when insulin levels rise, this enzyme will become

Answer 62

Less active

Question 63

Sources of glucose

Answer 63

Pyruvate, lactate, amino acids, propionate (odd chains fats), glycerol (fats)

Question 64

Inactive without Acetyl-CoA (allosteric activator of gluconeogenesis)

Answer 64

Piruvate Carboxylase

Question 65

Enzimes used in step 1 of gluconeogenesis (piruvate to phospoenolpiruvate (PEP))

Answer 65

Piruvate carboxylase (ATP, CO2 donate COOH, Biotin: in mitochondria) PEP carboxykinase (GTP donate a phosphate)

Question 66

Used by the mitochondria in the gluconeogenesis to get out to the cytosol the oxalacetate (OAA)

Answer 66

Malate shuttle

Question 67

Deficiency of biotin

Answer 67

Massive consumption of raw egg whites (avidin); dermatitis, glossitis, loss of appetite, nausea

Question 68

Pyruvate carboxylase deficiency

Answer 68

Presents in infancy with failure to thrive, high levels of pyruvate and lactate, and a lactic acidosis.

Question 69

Rate limiting step of gluconeogenesis

Answer 69

Fructose-1,6-bisphosphate to fructose-6-phosphate (catalyzed by Fructose 1, 6 bisphosphate 1 tend to be activated by high levels of ATP, inhibited by AMP)

Question 70

ON/OFF switch glycolysis. High: favors glycolisis Low: favor gluconeogenesis. Manipulates enzimes PFK1 and Fructose-1,6-bisphosphate 1.

Answer 70

Fructose-2,6-bisphosphate

Question 71

Levels rise with high insuline (fed state) Levels fall with high glucagon (fasting state)

Answer 71

Fructose-2,6-bisphosphate

Question 72

Converts glucose-6-phosphatase to glucose. Occurs mainly in the kidneys and liver. Endoplasmic reticulum.

Answer 72

Glucose-6-phosphatase

Question 73

Can become glucosa

Answer 73

Odd chain fatty acids

Question 74

The body stores fatty acids as

Answer 74

Triacylglycerol

Question 75

Raises blood glucose. Gluconeogenesis and glycogen breakdown.

Answer 75

Epinephrine

Question 76

Increases gluconeogenesis enzymes, hyperglycemia common side effect steroid drugs.

Answer 76

Cortisol

Question 77

Increases gluconeogenesis

Answer 77

Thyroid hormone

Question 78

Enzime only present in the liver that can mantain glucose levels during fasting

Answer 78

Glucose-6-phosphatase

Question 79

Creates glucose-1-phosphate Stops when glycogen branches decreased to 2-4 linked glucose molecules (limit dextrins). Stabilized by vitamin B6.

Answer 79

Phosphorylase

Question 80

Cleaves limits dextrins

Answer 80

Debranching enzime

Question 81

Elevated in fasting or fight or flight, they favor the breakdown of glycogen into glucose

Answer 81

Glucagon, epinephrine

Question 82

When its phosphorilazed it's activity falls

Answer 82

Glycogen synthase

Question 83

When its phosphorilazed it increases it activity, breaks down more glycogen into glucose

Answer 83

Glycogen phosphorilase

Question 84

Desphosphorylazation of glycogen synthase and glycogen phosphorilase

Answer 84

Insulin

Question 85

Has a tyrosine kinase bound to it. This tyrosine kinase will phosphorylate an enzyme called protein phosphatase 1. The phosphorylated protein phosphatase 1 can remove the phosphate group from GP kinase A (= DECREASE IN GLYCOGEN BREAKDOWN)

Answer 85

Insulin receptor

Question 86

Can directly activate GP kinase A which will phosphorylate glycogen phosphorylase and lead to glycogen breakdown.

Answer 86

Calcium/calmodulin

Question 87

When AMP levels are high, this means that the cell is breaking down lots of ATP and it needs more energy. So this will activate the

Answer 87

Breakdown of glycogen into glucose

Question 88

A deficiency of the enzyme glucose-6-phosphatase (type Ia) Glucose transporter deficiency (type Ib)

Answer 88

Von Gierke's Disease (Glycogen storage disease type 1)

Question 89

Results in deficient breakdown of glycogen in lysosomes leading to glycogen accumulation. This disorder can be classified as a lysosomal storage disease and a glycogen storage disease. In the classic infantile form of Pompe disease, glycogen accumulates in lysosomes in the heart and muscles. It causes primarily muscle dysfunction with no direct effects on the liver. A baby with cardiomegaly and hypotonia should bring this disorder immediately to mind. Often presents in the first few months of life. An enlarged tongue is a classic finding. On blood work, creatine kinase is usually elevated indicating muscle damage. In contrast to other glycogen storage diseases, hypoglycemia is not present.

Answer 89

Acid alpha-glucosidase (also called acid maltase) deficiency, also known as Pompe disease.

Question 90

Because glycogen is stored in the liver, many glycogen storage diseases result in hepatomegaly from glycogen accumulation. That is not usually the case in ?, however. In ?, heart failure results from cardiac glycogen buildup. This leads to pulmonary edema and congestion of the liver.

Answer 90

Pompe disease

Question 91

Glycogen debranching is impaired in ? which is associated with hypoglycemia.

Answer 91

Cori's disease (glycogen storage disease type III)

Question 92

Thrombosis of the hepatic vein causes the ?. This can lead to liver enlargement and ascites. This is seen in hypercoagulable states and in patients with hepatocellular carcinoma.

Answer 92

Budd Chiari syndrome

Question 93

Is caused by a debranching enzyme deficiency. The debranching enzyme cleaves limit dextins as part of glycogen breakdown. In absence of this enzyme, limit dextrins accumulate in the liver causing hepatomegaly.

Answer 93

GSDIII (Cori disease)

Question 94

Liver enlargement also occurs in GSDI due to

Answer 94

Accumulation of glycogen (not just limit dextrins).

Question 95

Often presents at an older age (early childhood) than GSDI (newborn) as the liver is capable of some degree of glycogen breakdown.

Answer 95

GSDIII

Question 96

Muscle weakness in GSDIII occurs because muscle glycogen stores are ineffective at generating energy for myocytes. In contrast, muscle weakness is not typical in ? because this disorder disrupts glycogen metabolism in the liver but not in muscle.

Answer 96

GSDI

Question 97

Growth restriction, hepatomegaly, and elevated AST/ALT from liver damage occur in both disorders.

Answer 97

GSDI I and III

Question 98

Post-prandial hyperglycemia is seen in ? (sometimes called glycogen storage disease type 0).

Answer 98

Glycogen synthase deficiency

Question 99

GSDI can be managed with dietary modifications.

Answer 99

Cornstarch

Question 100

The alanine cycle converts the amino acid alanine into glucose in the liver. This is disrupted in GSDI and, therefore,

Answer 100

Elevated serum alanine levels occur.

Question 101

Occurs in urea cycle disorders and organic acidemias.

Answer 101

Hyperammonemia

Question 102

Occur in the fatty acid disorder, medium chain acyl-CoA dehydrogenase (MCAD) deficiency.

Answer 102

Urinary dicarboxylic acids

Question 103

In this disorder, myocytes cannot break down glycogen which leads to exercise intolerance, myalgias, and weakness. Muscle damage with exercise (rhabdomyolysis) may occur leading to myoglobinuria, dark urine, and an elevated creatine kinase level.

Answer 103

Myophosphorylase deficiency (McArdle disease).

Question 104

Creatine kinase is a muscle enzyme that converts creatine to phosphocreatine. Its presence in the serum is used as

Answer 104

A marker of muscle damage

Question 105

The HMP shunt serves two major purposes in cellular metabolism. It generates ribose 5-phosphate used in the synthesis of nucleic acids. It also produces NADPH, a substance used in a number of synthetic pathways. NADPH protects red cells against oxidative damage. It is also used as part of the respiratory burst in phagocytes. In addition, the enzyme fatty acid synthase requires NADPH.

Answer 105

Fatty acid synthesis will be impaired in the absence of normal NADPH production by the HMP shunt

Question 106

Ribose-5-phosphate

Answer 106

Nucleic acids/DNA/RNA

Question 107

NADPH

Answer 107

Red cell oxidative protection Respiratory burst in phagocytes Fatty acid synthesis

Question 108

Red blood cell membranes are vulnerable to oxidative damage in patients with ?. Synthesis of membrane proteins, however, is not directly impaired by inhibition of the HMP shunt.

Answer 108

Glucose-6-phosphate dehydrogenase deficiency

Question 109

Do not require NADPH or other metabolites produced by the HMP shunt.

Answer 109

The TCA cycle and oxidative phosphorylation

Question 110

Among chronic alcohol users with thiamine deficiency, only 13% develop the Wernicke-Korsakoff syndrome. This subset of patients has been found to have an altered form of the enzyme ?. It is an enzyme of the HMP shunt.

Answer 110

Transketolase in fibroblasts

Question 111

Is an irreversible encephalopathy associated with chronic alcohol use and thiamine (vitamin B1) deficiency.

Answer 111

The Wernicke-Korsakoff (WK) syndrome

Question 112

May be seen among alcohol users with and without WK syndrome.

Answer 112

Hypomagnesemia, folate deficiency, alcohol withdrawal, and increased serum AST

Question 113

Is the most common red cell enzyme disorder. An inherited condition, it is caused by a defect in the enzyme ? which generates NADPH as part of the HMP shunt.

Answer 113

G6PD deficiency

Question 114

In the absence of normal G6PD function, red cells are vulnerable to oxidative damage. Many foods (fava beans) and drugs (antibiotics used for urinary infections like sulfa drugs or nitrofurantoin) generate hydrogen peroxide in red cells. NADPH is required to metabolize hydrogen peroxide into ?. In absence of sufficient NADPH, patients with G6PD deficiency develop hemolysis due to oxidative membrane damage from hydrogen peroxide.

Answer 114

Water

Question 115

G6PD deficiency: Glutathione is metabolized to glutathione disulfide by the enzyme glutathione peroxidase in red cells. In absence of NADPH, glutathione becomes trapped as glutathione disulfide, and cannot be regenerated into glutathione. This results in

Answer 115

Increased levels of glutathione disulfide in red cells.

Question 116

Deficiency of the glycolysis enzyme pyruvate kinase may lead to hemolysis. This presents in

Answer 116

The newborn period

Question 117

Patients with CGD are deficient in the enzyme ? used as part of the respiratory burst by phagocytes (neutrophils and macrophages). In the absence of this enzyme, superoxide (O2-), hydrogen peroxide, and hypochlorous acid cannot be generated for bacterial and fungal killing. This leaves patients vulnerable to infection by catalase-positive organisms.

Answer 117

NADPH oxidase

Question 118

Diagnosis is made through neutrophil function testing (dihydrorhodamine 123 fluorescence; Nitroblue tetrazolium test).

Answer 118

CGD

Question 119

Are found in large amounts in cells of the liver, adipose tissue, the adrenal cortex, the testes, and mammary glands. The common theme among these tissues is the need to synthesize fatty acids or steroids in large quantities. High levels of ? are also found in neutrophils and macrophages which use NADPH for the respiratory burst.

Answer 119

HMP shunt enzymes

Question 119

The rate-limiting enzyme of the HMP shunt. The HMP shunt generates NADPH for steroid and fatty acid synthesis.

Answer 119

Glucose-6-phosphate dehydrogenase (G6PD)

Question 120

The HMP shunt occurs in the ? like glycolysis.

Answer 120

Cytoplasm

Question 121

Pyruvate is shunted into lactate and alanine. This causes a severe lactic acidosis and hyperalaninemia. Hyperventilating in response to acidosis. Secondary hyperammonemia has occurred due to liver dysfunction. Note that serum glucose is normal. Fasting does not worsen the condition.

Answer 121

Pyruvate dehydrogenase (PDH) deficiency

Question 122

Babies with PDH deficiency develop worsening symptoms after eating ? like glucose or starch. These are metabolized into pyruvate which is shunted to lactic acid leading to vomiting, hyperventilation, and other symptoms.

Answer 122

Carbohydrates like glucose or starch. These are metabolized into pyruvate which is shunted to lactic acid leading to vomiting, hyperventilation, and other symptoms.

Question 123

Prolonged fasting should be avoided in ? where fasting metabolism is abnormal. In PDH deficiency, fasting does not worsen the condition.

Answer 123

Glycogen storage diseases and fatty acid disorders

Question 124

Are recommended in PDH deficiency since beta-oxidation can generate acetyl-CoA without need for PDH.

Answer 124

High-fat diets

Question 125

Cofactors for the PDH complex

Answer 125

Vitamins B1, B2, B3, and B5

Question 126

Mutations in genes coding for the E1 subunit of pyruvate dehydrogenase (PDH) lead to PDH deficiency. In this disorder, pyruvate cannot be metabolized into acetyl-CoA for entry into the TCA cycle. When carbohydrates are ingested, pyruvate is shunted to lactic acid causing a severe lactic acidosis. This results in an increased anion gap metabolic acidosis with

Answer 126

Low serum bicarbonate.

Question 127

¿Why Hypoglycemia is not a prominent feature of PDH deficiency?

Answer 127

Gluconeogenesis and glycogenolysis are intact.

Question 128

Occur in disorders of beta-oxidation such as medium-chain acyl-CoA dehydrogenase (MCAD) deficiency

Answer 128

Urinary dicarboxylic acids and hypoketosis

Question 129

In the fasting state, beta-oxidation of fatty acids leads to increased levels of acetyl-CoA in liver cells. High acetyl-CoA levels inhibit ? by activating kinase enzymes that phosphorylate PDH to render it less active.

Answer 129

Pyruvate dehydrogenase (PDH) activity

Question 130

High levels of acetyl-CoA also activate ? which diverts pyruvate towards gluconeogenesis. Pyruvate is converted into oxaloacetate, the first step towards liver synthesis of glucose.

Answer 130

Pyruvate carboxylase (PC)

Question 131

Arsenic has several toxic effects on cellular metabolism. One of them is binding to ?, a co-factor for the pyruvate dehydrogenase complex and the alpha-ketoglutarate complex (TCA cycle). Cells exposed to arsenic cannot generate ATP leading to cell death.

Answer 131

Lipoic acid

Question 132

In exercising muscle, calcium release from the sarcoplasmic reticulum activates several enzymes of the TCA cycle including isocitrate dehydrogenase. Isocitrate dehydrogenase catalyzes ?. Its activity is increased by calcium and ADP, and inhibited by ATP and NADH. Increased TCA cycle activity leads to more ATP generation for exercising muscle.

Answer 132

The rate limiting step of the TCA cycle

Question 133

Fats and amino acids can be used as substrates for gluconeogenesis in the liver through conversion into ?. A number of non-carbohydrate substances can be converted to glucose in the liver via ?. These include odd chain fatty acids and some amino acids. Once converted to ?, they can be metabolized into succinate which can enter the TCA cycle. Through the TCA cycle, succinate is metabolized to oxaloacetate which can enter gluconeogenesis.

Answer 133

Succinyl-CoA

Question 134

This woman is twenty-four hours into the fasting state. At this point in time, glycogen stores will be depleted. Fatty acids will be metabolized via beta oxidation in the liver raising the level of acetyl-CoA. The rise in acetyl-CoA will have several effects to direct the metabolism of the fasting state.

Answer 134

First, pyruvate dehydrogenase is inhibited to prevent pyruvate metabolism into acetyl-CoA. Also, pyruvate carboxylase is activated directing pyruvate metabolism into oxaloacetate and, therefore, into gluconeogenesis. A final effect of increased acetyl-CoA is the synthesis of ketones by the liver, a normal finding in the fasting state.

Question 135

Glycolysis converts glucose into

Answer 135

2 pyruvate 2 ATPs 2 NADH

Question 136

Acetyl CoA can then enter the TCA cycle and be converted to:

Answer 136

1 GTP 3 NADH 1 FADH2

Question 137

The first step is conversion of oxaloacetate into malate, in doing this NADH is converted to NAD plus and what this essentially means is that NADH transfers its electrons to oxaloacetate, and that creates a molecule of malate.

Answer 137

Malate shuttle

Question 138

The major pathologic effect of CO is

Answer 138

Binding to iron in the Fe2+ state in hemoglobin. This creates a functional anemia by rendering many of the oxygen-binding sites unavailable for oxygen. A secondary pathologic effect of carbon monoxide occurs in the mitochondria where CO inhibits electron transport. CO binds to Fe2+ iron found in cytochromes of the electron transport complexes. This renders them unable to transport electrons to generate protons in the intermembrane space. As a result, the electrochemical gradient for ATP production falls.

Question 139

Uncouplers

Answer 139

Allow protons to move out of the intermembrane space without generating ATP. They do not disrupt the transfer of electrons between the complexes of the electron transport chain.

Question 140

Occurs in glycolysis when ATP is synthesized from ADP via enzymes.

Answer 140

Substrate level phosphorylation

Question 141

CO binds to iron in the Fe2+ state, not

Answer 141

The Fe3+ state

Question 142

Is a highly-lethal, mitochondrial poison that binds to Fe3+ iron in complex IV of the electron transport chain.

Answer 142

Cyanide

Question 143

The most common mechanism of exposure is from fires where cyanide is liberated from rubber and other substances. Presenting signs are often non-specific including

Answer 143

Headache, agitation, or confusion. The smell of almonds on the breath is a classic finding (the “funny smell” this man detects). Because mitochondria are poisoned by cyanide, oxygen is not consumed by tissues and remains in the blood. As a result, venous blood is highly oxygenated and develops a bright red color. This gives the skin a characteristic pink discoloration.

Question 144

Mitochondrial poisoning by cyanide will interrupt the electron transport chain. This will stall the TCA cycle and, thus, metabolism will be shunted towards

Answer 144

The production of lactate.

Question 145

Venous oxyhemoglobin levels are increased in cyanide toxicity. As a result, the difference between arterial and venous blood is

Answer 145

Decreased

Question 146

Salicylates directly stimulate the respiratory center in the medulla. This leads to hyperventilation and a respiratory alkalosis. The second effect is the uncoupling of oxidative phosphorylation. As a result, protons in the mitochondrial intermembrane space are transported abnormally across the inner membrane such that they do not generate ATP. This creates heat and causes a fever. Mitochondrial dysfunction also shifts cells to anaerobic metabolism. This leads to an anion gap metabolic acidosis due to an accumulation of lactic acid in addition to the respiratory alkalosis.

Answer 146

Aspirin

Question 147

Is an uncoupler of electron transport that disrupts ATP production by allowing protons to leave the intermembrane space without generating ATP. Oxygen consumption via the electron transport chain will proceed normally as it is undisturbed by ?

Answer 147

2,4 dinitrophenol

Question 148

Will halt both ATP production and oxygen consumption.

Answer 148

An inhibitor of electron transport (e.g., cyanide)

Question 149

Inhibitors shut down ATP production by shutting down electron transport (and, therefore consumption of oxygen).

Answer 149

Uncouplers allow electron transport (i.e., oxygen consumption) to proceed normally but ATP production is inhibited through proton escape from the intermembrane space.

Question 150

Is a rapid-active vasodilator with effects on arterioles and veins. It is used in the treatment of hypertensive emergency. A potentially life-threatening adverse effect is cyanide toxicity which may occur since nitroprusside contains cyanide moieties.

Answer 150

Nitroprusside

Question 151

Cyanide is an inhibitor of electron transport. When the electron transport chain shuts down in the setting of cyanide toxicity, glucose metabolism is directed toward the formation of lactate. As a result, lactic acidosis develops. The hallmarks of cyanide toxicity from nitroprusside are delirium and lactic acidosis. An unexplained fall in the bicarbonate level indicating acidosis is a concerning finding in a patient on nitroprusside. Risk factors for cyanide toxicity include

Answer 151

Prolonged treatment (>24 hours), renal failure, and excessive dosages.

Question 152

Treatment of cyanide toxicity includes withdrawal of the offending drug and administration of an antidote. ? is the first line and acts by directly binding cyanide molecules.

Answer 152

Hydroxocobalamin

Question 153

Is an adjunctive agent that is used with hydroxocobalamin. This compound provides sulfur groups to enzymes that can detoxify cyanide. If these agents are not available, nitrites can be used to induce methemoglobinemia, which has a high affinity for cyanide.

Answer 153

Sodium thiosulfate

Question 154

Is used in the treatment of methemoglobinemia

Answer 154

Methylene blue

Question 155

Is a chelating agent used in a variety of heavy metal toxicities, including lead and iron.

Answer 155

Dimercaprol

Question 156

Is used in the treatment of acetaminophen toxicity.

Answer 156

N-acetylcysteine

Question 157

Elevated liver enzymes, hyperammonemia, hypoglycemia, and hypoketosis. These findings are consistent with a

Answer 157

Beta-oxidation disorder

Question 158

Is required to shuttle fatty acids into the mitochondria. ? is esterified with fatty acids to form acylcarnitines (i.e., “carnitine esters”) as part of lipid metabolism.

Answer 158

Carnitine

Question 159

Lead to poor beta-oxidation of lipids.

Answer 159

Deficient carnitine levels

Question 160

In a carnitine deficiency, serum carnitine is low (absence of carnitine) and acylcarnitine levels are also low. In a beta-oxidation enzymatic defect,

Answer 160

acylcarnitines accumulate

Question 161

Primary carnitine deficiency

Answer 161

impaired membrane transport prevents carnitine uptake by cells. Carnitine is also lost in the urine leading to low serum carnitine levels. Babies with this condition develop hypoketotic hypoglycemia, liver failure, and hyperammonemia (secondary to liver failure). Symptoms worsen during fasting when fatty acid metabolism is required for fuel.

Question 162

May cause secondary carnitine deficiency but is unlikely to have developed in a newborn baby.

Answer 162

Prolonged malnutrition

Question 163

Is an enzymatic disorder of beta-oxidation. It can present similarly to this case, however, medium-chain acylcarnitines will be increased.

Answer 163

MCAD (medium-chain acyl-CoA dehydrogenase) deficiency

Question 164

Is a gluconeogenesis enzymatic defect. This may cause hypoglycemia but not hypoketosis as fatty acid metabolism is normal.

Answer 164

Pyruvate carboxylase deficiency

Question 165

Such as propionic acidemia or methylmalonic acidemia. In these disorders, certain amino acids and odd-chain fatty acids cannot be metabolized into succinyl-CoA. This leads to accumulation of organic acids causing an anion gap metabolic acidosis (low pH, low bicarb). The amino acids affected include isoleucine, valine, threonine, and methionine. Feeding protein to babies with this condition may cause a life-threatening acidosis by exposing the child to these amino acids.

Answer 165

Organic acidemia

Question 166

The major clinical features of organic acidemias are

Answer 166

Lethargy, vomiting, poor muscle tone, and failure to thrive (all non-specific). Serum testing shows anion gap acidosis from the accumulation of organic acids (e.g., propionic acid or methylmalonic acid). The accumulation of these acids in the liver leads to hepatomegaly and liver dysfunction including hyperammonemia. Hypoglycemia with ketosis may also occur. The presence of elevated organic acids in the serum or urine is used for diagnosis. This baby likely has methylmalonic acidemia given the high plasma levels of an isomer of succinate (methyl malonate is an isomer of succinate).

Question 167

High plasma levels of an isomer of succinate (methyl malonate is an isomer of succinate).

Answer 167

Methylmalonic acidemia

Question 168

Is caused by the inability to metabolize fructose due to deficiency of aldolase B.

Answer 168

Hereditary fructose intolerance (HFI)

Question 169

Is not present in breast milk. HFI presents when babies are weaned from breast milk and begin consuming foods containing fructose.

Answer 169

Fructose i

Question 170

In HFI, reducing sugars are present in

Answer 170

The urine

Question 171

Is a disorder of pyrimidine synthesis. It presents as megaloblastic anemia due to the abnormal synthesis of nucleotides.

Answer 171

Orotic aciduria

Question 172

Urea metabolism is disrupted in urea cycle disorders including ornithine transcarbamylase deficiency. These disorders present as

Answer 172

Isolated hyperammonemia without acidosis

Question 173

Suggests an organic acidemia or beta-oxidation disorder.

Answer 173

Acidosis in a newborn with elevated ammonia

Question 174

Urea cycle disorders do not cause

Answer 174

Acidosis, ketosis, or hypoglycemia.

Question 175

The presence of ketones excludes

Answer 175

Fatty acid disorders.

Question 176

There are a number of inborn disorders of beta-oxidation that can lead to the inability to metabolize fatty acids. Some involve long-chain fatty acids, others involve medium-chain, and others involve short-chain. The best test to sort this out is

Answer 176

An acylcarnitine profile

Question 177

May occur secondarily to other disorders including malnutrition and hemodialysis. It can lead to aerobic exercise intolerance due to poor muscle metabolism of fatty acids.

Answer 177

Carnitine deficiency

Question 178

Is a glycogen storage disease caused by the deficiency of the enzyme myophosphorylase. In this disorder, myocytes cannot breakdown glycogen which leads to a nearly identical presentation to that described in this question. Biopsy shows accumulation of glycogen (carbohydrates) not lipids.

Answer 178

McArdle disease

Question 179

May present with weakness and creatine kinase elevation. Muscle biopsy shows inflammatory cells.

Answer 179

Myositis

Question 180

May present with weakness but onset is usually in childhood around ages 2 to 3 years. Biopsy can show lipid accumulation in late stages but also shows myofiber size variation and fibrosis.

Answer 180

Duchenne muscular dystrophy

Question 181

Toxicity from statins may cause

Answer 181

Weakness and elevation of creatine kinase.

Question 182

The hallmark finding of a beta-oxidation disorder

Answer 182

Hypoketotic hypoglycemia

Question 183

Common feature of impaired beta-oxidation.

Answer 183

Urinary dicarboxylic acids

Question 184

Treatment of long-chain fatty acid disorders involves

Answer 184

Avoidance of fasting and a low-fat diet. Medium-chain triglycerides may also be used since the metabolism of these lipids is normal. Carnitine supplementation may be necessary if carnitine levels remain low after other dietary interventions.

Question 185

In the fasting state, fatty acid metabolism in the liver generates lots of acetyl-CoA (more than glucose can generate). The accumulation of acetyl-CoA leads to

Answer 185

Ketone synthesis

Question 186

Purine metabolism generates

Answer 186

Uric acid

Question 187

Glycine is a glucogenic amino acid. It is converted into ? in the fasting state for entry into gluconeogenesis.

Answer 187

Pyruvate

Question 188

The treatment of acute pancreatitis includes placing the patient in a fasting state (“NPO status”) to avoid stimulating the release of pancreatic enzymes. In this setting, fatty acids are metabolized in the liver into ? via beta oxidation. This generates more acetyl-CoA than can be handled by the TCA cycle. As a result, acetyl-CoA accumulates in the liver and is diverted into synthesis of ketones.If the TCA cycle could metabolize more acetyl-CoA, less would be available for ketone synthesis

Answer 188

Acetyl-CoA

Question 189

Is the rate-limiting enzyme of the TCA cycle. Increased activity of this enzyme would consume more acetyl-CoA in liver cells, leaving less available for ketone synthesis

Answer 189

Isocitrate dehydrogenase

Question 190

Is the rate-limiting enzyme of the urea cycle.

Answer 190

Carbamoyl phosphate synthetase I

Question 191

An anion-gap metabolic acidosis in the setting of abdominal pain and hyperglycemia. These findings are classic for diabetic ketoacidosis (DKA) which can be an initial presentation of new-onset diabetes. In DKA, insulin levels are extremely low. Liver cells behave as if in the fasting state despite the presence of hyperglycemia. As a result, fatty acid metabolism via beta-oxidation increases. This generates high levels of acetyl-CoA in hepatocytes. Normally, much of this acetyl-CoA would be metabolized by the TCA cycle. In DKA, however, the TCA cycle is stalled and acetyl-CoA is shunted toward ketone synthesis. Levels of ketones may become so high that a life-threatening acidosis occurs.

Answer 191

The TCA cycle stalls in DKA because oxaloacetate (OAA) is depleted. OAA is diverted towards gluconeogenesis even though glucose levels are high. In addition, fatty acid metabolism generates NADH which favors conversion of OAA to malate, further decreasing the pool of OAA for the TCA cycle. Thus, the TCA cycle generates decreased amounts of NADH in the setting of DKA.

Question 192

Can inhibit the enzime Isocitrate Dehydrogenase and a-KG Dehydrogenase

Answer 192

High levels of NADH

Question 193

Shunts oxaloacetate to malate (driving the TCA Cycle backwards). This leads to high levels of Acetyl CoA = Ketones. Less gluconeogenesis (because less oxaloacetate is available)

Answer 193

NADH

Question 194

Glucose Aminoacids Fatty acids Ethanol: Acetate

Answer 194

Molecules that can be converted to Acetyl CoA

Question 195

Is depleated by etOH metabolism

Answer 195

NAD+

Question 196

Overwhelms the electron transport chain (NAD+ tied up in NADH) = Pyruvate shunted to lactate (this regenerates NAD+). A lactic acidosis can develop.

Answer 196

Excess alcohol consumption

Question 197

Inhibited when NADH is high = less FA breakdown.

Answer 197

B-oxidation

Question 198

In the cytosol is used to synthesis fatty acids

Answer 198

Citrate (is high when the TCA is inhibited)

Question 199

Acetyl CoA is converted to Malonyl CoA by Acetyl-CoA carboxylase

Answer 199

Rate limiting step of fatty acids synthesis

Question 200

Activator of Acetyl-CoA carboxylase. Results in increase in Fatty acids synthesis.

Answer 200

Citrate

Question 201

Powerful inhibitor of B-oxidation

Answer 201

Malonyl-CoA

Question 202

Accumulation also contributes to FA levels. Used to generate NADPH (that favors FA synthesis)

Answer 202

Malate

Question 203

Uses carbons from Acetyl-CoA and malonyl-CoA to create 16 carbon fatty acid Palmitate (requires NADPH)

Answer 203

Fatty acid synthase

Question 204

Glycerol + fatty acids

Answer 204

Trygliceride

Question 205

Normally, glycerol is metabolized into glycerol-3-phosphate and then glycerol-3-phosphate is further metabolized into ?, which can enter glycolysis or gluconeogenesis.

Answer 205

Dihydroxyacetone phosphate

Question 206

The conversion of glycerol-3-phosphate requires NAD+ and in alcoholics, all the NAD+ is tied up in NADH. This means that this step will not occur. And therefore, you will have high levels of glycerol-3-phosphate and glycerol-3-phosphate can be combined with fatty acids to form triglycerides.

Answer 206

Why you get high levels of triglycerides in the liver cells of patients who are alcoholics?

Question 207

Excreted by the proximal tubule.

Answer 207

Uric acid and lactate

Question 208

More lactate in plasma

Answer 208

Less excretion of uric acid (URAT1)

Question 209

High NADH slows ethanol metabolism * Result: buildup of acetaldehyde: toxic to liver cells

Answer 209

* Acute: Inflammation → Alcoholic hepatitis * Chronic: Scar tissue → Cirrhosis

Question 210

Alternative pathway for ethanol * Normally metabolizes small amount of ethanol * Becomes important with excessive consumption Cytochrome P450-dependent pathway in liver: Generates acetaldehyde and acetate (consumes NADPH and Oxygen) * Oxygen: generates free radicals * NADPH: glutathione cannot be regenerated (loss of protection from oxidative stress)

Answer 210

Microsomal ethanol-oxidizing system (MEOS)

Question 211

This is the enzyme that catalyzes the first step in ethanol metabolism, the conversion of ethanol into acetaldehyde. - Zero order kinetics (constant rate) * Also metabolizes methanol and ethylene glycol * Inhibited by fomepizole (antizol): Treatment for methanol/ethylene glycol intoxication

Answer 211

Alcohol dehydrogenase

Question 212

Inhibited by disulfiram (antabuse) * Acetaldehyde accumulates triggers catecholamine release = sweating, flushing, palpitations, nausea, vomiting

Answer 212

Aldehyde Dehydrogenase

Question 213

Skin flushing when consuming alcohol * Due to slow metabolism of acetaldehyde * Common among Asian populations * Inherited deficiency aldehyde dehydrogenase 2 (ALDH2) * Possible ↑risk esophageal and oropharyngeal cancer

Answer 213

Alcohol Flushing

Question 214

Alcohol depletes NAD+ which shunts oxaloacetate into malate. This inhibits gluconeogenesis leading to hypoglycemia.

Answer 214

Consuming alcohol when glycogen stores are low after strenuous exercise is a classic cause of hypoglycemia via this mechanism.

Question 215

Chronic ethanol consumption activates the microsomal ethanol-oxidizing system (MEOS) in the liver. This is associated with a rise in ?. The acetaminophen metabolite NAPQI (N-acetyl-p-benzoquinone imine) is produced via p450 metabolism and is toxic to liver. NAPQI is produced in higher quantities among chronic ethanol users. Heavy alcohol users like this man are at risk for acetaminophen toxicity even when consuming standard dosages of the drug.

Answer 215

Cytochrome P-450 enzyme metabolism

Question 216

Metabolism of ethanol generates high levels of NADH. Recall that NADH is normally high when cells are replete with energy. Thus, high NADH triggers energy storage by the liver including synthesis of fatty acids. Fatty acids accumulate leading to alcoholic fatty liver disease.

Answer 216

Alcoholic fatty liver disease

Question 217

Malonyl-CoA is produced by the rate-limiting enzyme of fatty acid synthesis, acetyl-CoA carboxylase. The activity of this enzyme is increased among chronic alcohol users, leading to increased levels of

Answer 217

Malonyl-CoA

Question 218

Glycerol is normally metabolized into glycerol-3-phosphate in the liver for entry into glycolysis. In the setting of high NADH from alcohol consumption, glycerol metabolism is inhibited. Glycerol-3-phosphate levels increase, leading to the

Answer 218

Production of triglycerides which contribute to fatty acid buildup in the liver.

Question 219

Is an inhibitor of alcohol dehydrogenase which will halt the metabolism of ethanol.

Answer 219

Fomepizole

Question 220

Creatine

Answer 220

* Present in muscles as phosphocreatine * Source of phosphate groups * Important for heart and muscles * Can donate to ADP → ATP * Reserve when ATP falls rapidly in early exercise

Question 221

Elevated levels of ? are seen in patients who have a myocardial infarction.

Answer 221

Creatine kinase

Question 222

The purpose of ? inside your muscle cells is to donate this phosphate group to ADP, to create molecules of ATP, very rapidly, without having to wait for glycolysis and the TCA cycle.

Answer 222

phosphocreatine

Question 223

* Spontaneous conversion * Amount proportional to muscle mass * Excreted by kidneys (used to estimate the glomerular filtration rate.)

Answer 223

Creatinine

Question 224

* Consumed within seconds of exercise * Used for short, intense exertion * Heavy lifting * Sprinting

Answer 224

ATP and Creatine

Question 225

* Stimulates metabolism * Activates glycogenolysis * Activates TCA cycle

Answer 225

Calcium release from muscles

Question 226

The calcium/calmodulin complex can stimulate glycogen phosphokinase A. This will phosphorylate glycogen phosphorylase, which makes the enzyme more active, and that speeds up

Answer 226

Glycogen breakdown (exercising.)

Question 227

Can activate isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase (increase the speed of TCA cycle)

Answer 227

Calcium

Question 228

* Long distance running * Co-ordinated effort by organ systems * Multiple potential sources of energy

Answer 228

Aerobic exercise

Question 229

* Sprinting, weight lifting * Purely a muscular effort * Blood vessels in muscles compressed during peak contraction * Muscle cells isolated from body * Muscle relies on it’s own fuel stores

Answer 229

Anaerobic exercise

Question 230

ATP and creatine phosphate (consumed in seconds) - Fast pace cannot be maintained * Creatinine phosphate consumed * Lactate accumulates

Answer 230

Anaerobic Exercise

Question 231

* ATP and creatine phosphate (consumed in seconds) * Glycogen: metabolized to CO2 (aerobic metabolism) * Slower pace than sprint * Decrease lactate production * Allow time for TCA cycle and oxidative phosphorylation * “Carbohydrate loading” by runners * Increases muscle glycogen content

Answer 231

Moderate Aerobic Exercise

Question 232

* Co-operation between muscle, liver, adipose tissue * ATP and creatine phosphate (consumed in seconds) * Muscle glycogen: metabolized to CO2 * Liver glycogen: Assists muscles → produces glucose * Often all glycogen consumed during race * Conversion to metabolism of fatty acids: Slower process * Maximum speed of running reduced * Elite runners condition to use glycogen/fatty acids

Answer 232

Intense Aerobic Exercise

Question 233

Glucagon epinephrine inhibit the rate-limiting step in fatty acid synthesis. They inhibit the enzyme acetyl-CoA carboxylase. As a result of inhibiting this enzyme, levels of malonyl-CoA will fall, and malonyl-CoA is a powerful inhibitor of beta oxidation. So by lowering its level, you will speed up beta oxidation.

Answer 233

This ensures that fatty acid synthesis will not occur, during a long race like a marathon.

Question 234

Normally, malonyl-CoA inhibits this enzyme

Answer 234

CPT1 (Carnitine palmitoyl transferase I)

Question 235

When you exercise too intensely, you consume all of your NAD. Normally, electron transport convert NADH back into NAD, but if you exercise too intensely, you exceed the capacity of the TCA cycle and electron transport, and all of your NAD is tied up in NADH. When you have an elevated NADH to NAD ratio, this favors the conversion of pyruvate to lactate. As a result, all that lactic acid makes the pH fall in muscles, and this leads to

Answer 235

Cramps.

Question 236

They have lots of mitochondria, and their electron transport chain has lots of capacity, in the hopes of preventing lactic acid buildup in their muscles.

Answer 236

Distance runners condition

Question 237

In the fed state, insulin promotes glycogen synthesis in the liver and in muscle cells.

Answer 237

The rate of glycolysis and inhibits gluconeogenesis.

Question 237

Promotes glucose → adipose tissue * Used to form triglycerides * Promotes uptake of amino acids by muscle * Stimulates protein synthesis/inhibits breakdown

Answer 237

Insulin

Question 238

Is an enzyme found in the liver and in the pancreas. It's function is induced by insulin. Insulin can promote its transcription. The purpose of glucokinase is to phosphorylate glucose so that it becomes glucose-6 phosphate and is locked inside of liver and pancreas cells so that it can undergo further metabolism.

Answer 238

Glucokinase

Question 239

The rate-limiting enzyme of glycolysis is

Answer 239

Phosphofructokinase-1 (PFK1)

Question 240

he rate-limiting enzyme of gluconeogenesis is

Answer 240

Fructose 1,6-bisphosphate1.

Question 241

Insulin influences both of these enzymes, via an intermediate called fructose 2,6-bisphosphate.

Answer 241

- Phosphofructokinase-1 (PFK1) - Fructose 1,6-bisphosphate1.

Question 242

Functions as an on-off switch for glycolysis. When the level is high, glycolysis is turned on, and when the level is low, there's less glycolysis. This favors gluconeogenesis.

Answer 242

Level of fructose 2,6-bisphosphate inside of cells

Question 243

Insulin can activate the enzyme glycogen synthase so that glucose will be converted into glycogen. Conversely, when glucagon levels are high and insulin levels are low, the enzyme ? becomes active so that glycogen is broken down into glucose.

Answer 243

Glycogen phosphorylase

Question 244

The rate-limiting step in fatty acid synthesis is the conversion of acetyl-CoA to malonyl-CoA. The enzyme that catalyzes this step is called

Answer 244

Acetyl-CoA carboxylase

Question 245

This enzyme is activated by insulin so that you get more fatty acid synthesis, when insulin levels are high. Conversely, when insulin levels are low, and glucagon rises, this enzyme will become inhibited.

Answer 245

Acetyl-CoA carboxylase

Question 246

* Glycogen breakdown in liver * Maintains glucose levels in plasma * Dominant source glucose between meals

Answer 246

Key effect of glucagon

Question 247

* Inhibits fatty acid synthesis * Stimulates release of fatty acids from adipose tissue * Stimulates gluconeogenesis

Answer 247

Other effects of glucagon

Question 248

Alanine Lactate Glycerol Odd Chain FAs

Answer 248

Gluconeogenesis

Question 249

Glycogen exhausted after ~

Answer 249

24 hours

Question 250

Is one source of carbon for gluconeogenesis. This comes from the alanine cycle. Muscle cells break down proteins and generate ammonia. The ammonia is passed to alanine, which is secreted from the muscle cells and goes to the liver. In the liver, the ammonia is removed and enters the urea cycle, and the alanine is converted into pyruvate. Pyruvate can enter gluconeogenesis and become glucose, and then it can be secreted from the liver and go back to the muscles, to supply the muscles with glucose.

Answer 250

Alanine

Question 251

is another source of carbon for gluconeogenesis. This comes from the Cori cycle. In the Cori cycle, muscle and also red blood cells metabolize glucose into lactic acid.

Answer 251

Lactate

Question 252

Is generated when triglycerides are broken down. The fatty acids are removed, and this releases molecules of glycerol, which can go to the liver where an enzyme called glycerol kinase converts the glycerol into glycerol-3-phosphate. Glycerol-3-phosphate can then be converted into dihydroxyacetone phosphate, which is an intermediate in gluconeogenesis, and this can then be converted back into glucose.

Answer 252

Glycerol

Question 253

Can also be used as a source of carbons for glucose via gluconeogenesis. Normally, beta oxidation completely consumes fatty acids, but this is different in the case of odd chain fatty acids that have an odd number of carbons, for example, 9 or 11 or 13.

Answer 253

Odd chain fatty acids

Question 254

In the case of odd chain fatty acids, beta oxidation stops when three carbons remain. The structure that will be left when three carbons remain is called ?, and this can be converted through a series steps into succinyl-CoA. Succinyl-CoA, is an intermediate in the TCA cycle, and it can be used as a source of carbons for gluconeogenesis.

Answer 254

Propionyl-CoA

Question 255

Only ? fatty acids can be converted into glucose via gluconeogenesis. That's because even chain fatty acids are completely consumed via beta oxidation.

Answer 255

Odd chain

Question 256

* Glycolysis slows (low insulin levels) * Less glucose utilized by muscle/liver * Shift to fatty acid beta oxidation for fuel * Spares glucose and maintains glucose levels

Answer 256

Starvation

Question 257

* Inadequate protein intake * Hypoalbuminemia → edema * Swollen legs, abdomen

Answer 257

Kwashiorkor

Question 258

Inadequate energy intake, not enough intake of total calories. This is like kwashiorkor without the edema. There's muscle and fat wasting. Many people describe it as skin and bones. And this is a picture of a father and his son who are suffering from marasmus, in an impoverished country. Finally, let's talk about hypoglycemia between meals. As I explained before, the body has a number of mechanisms to maintain the blood sugar level, during times of fasting and starvation.

Answer 258

Marasmus

Question 259

* Hypoglycemia * Ketosis * Usually after overnight fast

Answer 259

Glycogen storage diseases

Question 261

* Deficiency of aldolase B * Build-up of fructose 1-phosphate * Depletion of ATP * Usually a baby just weaned from breast milk

Answer 261

Hereditary fructose intolerance

Question 262

Lack of ketones in setting of ↓ glucose during fasting * Occurs in beta oxidation disorders * FFA → beta oxidation → ketones (beta oxidation) * Tissues overuse glucose → hypoglycemia

Answer 262

Hypoketotic Hypoglycemia

Question 263

Low serum carnitine and acylcarnitine levels

Answer 263

Carnitine deficiency

Question 264

* Dicarboxylic acids 6-10 carbons in urine * High acylcarnitine levels

Answer 264

MCAD deficiency (Medium chain acyl-CoA dehydrogenase)

Question 265

Are the two ketogenic amino acids. They can generate acetyl-CoA to be used in the TCA cycle like even chain fatty acids. They cannot, however, be used by gluconeogenesis to synthesize glucose.

Answer 265

Leucine and lysine

Question 266

Kwashiorkor (or edematous malnutrition) and marasmus. The two forms are distinguished by the presence of edema which only occurs in

Answer 266

Kwashiorkor

Question 267

Involves total calorie insufficiency involving all nutrients, not just protein. This leads to muscle and fat wasting in the absence of edema.

Answer 267

Marasmus

Question 268

High output heart failure may be caused by a ?. This can be seen in malnourished children. It presents with tachycardia, pulmonary edema, elevated jugular venous pressure, and peripheral edema.

Answer 268

Deficiency of vitamin B1 (thiamine)

Question 269

Is the cause of peripheral edema among patients with heart failure.

Answer 269

Increased capillary hydrostatic pressure

Question 270

2 molecules of carbon dioxide (CO2) are produced for each molecule of acetyl-CoA that enters the TCA cycle. In exercising muscles, calcium activates ?, both TCA cycle enzymes that produce CO2.

Answer 270

Isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase

Question 271

Its serum level is used as an indicator of muscle damage.

Answer 271

Creatine kinase

Question 272

Myocytes contain phosphocreatine which serves as a reservoir for phosphate groups. When ATP is hydrolyzed to ADP for muscle contraction, phosphocreatine donates phosphate groups to ADP to regenerate ATP.

Answer 272

The supply of phosphocreatine is depleted within the first few seconds of sustained muscle contraction.

Question 273

Explains the stablity of cellular ATP levels during early muscle contraction.

Answer 273

Use of phosphocreatine to synthesize ATP

Question 274

Under these conditions, fatty acids stored in adipose tissue will be metabolized in the liver into acetyl-CoA for entry into the TCA cycle. Increased levels of acetyl-CoA will activate gluconeogenesis and inhibit glycolysis. Pyruvate kinase catalyzes the final step in glycolysis. Its activity will be decreased in the fasting state. Fructose 2,6 bisphosphate is a regulator of glycolysis. Its level is an “on-off switch” for glycolysis and will be low when gluconeogenesis is activated during a fast. Glucose-6-phosphatase catalyzes the final step of gluconeogenesis in the liver, the conversion of glucose-6-phosphate into glucose. Its activity will be high in the fasting state.

Answer 274

Fasting and starvation

Question 275

* Defects in metabolic pathways * Often present in newborn period * Often non-specific features: * Failure to thrive, hypotonia * Lab findings suggest diagnosis: - Hypoglycemia - Ketosis - Hyperammonemia - Lactic acidosis

Answer 275

Inborn Errors in Metabolism

Question 276

* Glycogen storage diseases * Galactosemia * Hereditary fructose intolerance * Organic acidemias * Disorders of fatty acid metabolism

Answer 276

Causes of newborn Hypoglycemia

Question 277

Some have no hypoglycemia: * Only affect muscles * McArdle’s Disease (type V) * Pompe’s Disease (type II) Hypoglycemia seen in others: * Von Gierke’s Disease (Type I) * Cori’s Disease (Type III)

Answer 277

Glycogen Storage Diseases

Question 278

So babies who have a glycogen storage disease develop

Answer 278

Fasting hypoglycemia

Question 279

Fasting hypoglycemia * Hours after eating * Not in post-prandial period Ketosis * Absence of glucose during fasting * Fatty acid breakdown (NOT a fatty acid disorder) * Ketone synthesis Hepatomegaly * Glycogen buildup in liver

Answer 279

Glycogen Storage Diseases

Question 280

* Severe hypoglycemia * Lactic acidosis (disruption of the Cori Cycle)

Answer 280

Von Gierke’s Disease (Type I)

Question 281

* Gluconeogenesis intact * Mild hypoglycemia (problems breaking down glycogen) * No lactic acidosis (the Cori Cycle is not disrupted)

Answer 281

Cori’s Disease (Type III)

Question 282

* Deficiency of aldolase B * Build-up of fructose 1-phosphate * Depletion of ATP: Loss of gluconeogenesis and glycogenolysis * Hypoglycemia * Lactic acidosis * Ketosis * Hepatomegaly (glycogen buildup)

Answer 282

Hereditary Fructose Intolerance

Question 283

* Starts after weaned from breast milk No fructose in breast milk * “Reducing sugars” in urine: Glucose, fructose, galactose

Answer 283

Hereditary Fructose Intolerance

Question 284

Reducing sugars in urine with hypoglycemia

Answer 284

Hallmark of hereditary fructose intolerance

Question 285

Classic galactosemia

Answer 285

Is a disorder of galactose metabolism. * Deficiency of galactose 1-phosphate uridyltransferase: Galactose-1-phosphate accumulates: Depletion of ATP * 1st few days of life * Breast milk contains lactose * Lactose = galactose + glucose

Question 286

* Vomiting/diarrhea after feeding * Similar presentation to HFI - Hypoglycemia - Lactic acidosis - Ketosis - Hepatomegaly (glycogen buildup) - “Reducing sugars” in urine

Answer 286

Classic Galactosemia

Question 287

After feedings (you will find reducing sugars in the urine) : Galactosemia, HFI Fasting: Glycogen Storage Diseases

Answer 287

Hypoglycemia Lactic Acidosis Ketosis

Question 288

* Abnormal metabolism of organic acids: Propionic acid and Methylmalonic acid * Buildup of organic acids in blood/urine that leads to acidosis * Hyperammonemia

Answer 288

Organic Acidemias

Question 289

if you see a newborn baby who has some unexplained acidemia and hyperammonemia, think of

Answer 289

Organic Acidemias

Question 290

A number of amino acids (Isoleucine, Valine, Threonine and Methionine), also cholesterol, and also odd chain fatty acids. All of these things can be metabolized to Propionyl-CoA. Then via an enzyme that requires biotin as a co-factor, Propionyl-CoA is converted to Methylmalonyl-CoA, and then via another enzyme that requires vitamin B12 as a cofactor, Methylmalonyl-CoA is converted to Succinyl-CoA.

Answer 290

So in the organic acidemia is one of the steps in this process is disrupted due to an enzyme deficiency. So in methylmalonic acidemia, this enzyme is deficient. As a result, all of these molecules are funneled into Methylmalonyl-CoA, but then cannot go any further. And therefore, methylmalonic acid builds up in the blood. In propionic acidemia, all of these substances at the bottom of the screen here are metabolized to Propionyl-CoA, but they can't go any further because this enzyme is deficient. That leads to high levels of proprionic acid in the blood.

Question 291

The organic acidemias generally present in the ?, usually the first few weeks or months of life. The babies will develop non-specific symptoms like poor feeding, vomiting, hypotonia, and lethargy. These babies can have hypoglycemia which can lead to ketosis.

Answer 291

Newborn period

Question 292

The mechanism of this is complex, but it's believed to involve liver damage from the acids that shut down gluconeogenesis. These babies will have an anion gap metabolic acidosis. That's because one of the organic acids is building up in the plasma.

Answer 292

Organic acidemias

Question 293

The hallmark of these disorders to make the diagnosis is to identify elevated levels in the urine or plasma of one of the organic acids.

Answer 293

Organic acidemias

Question 294

In propionic acidemia, there is deficiency of an enzyme called ?. This is a biotin dependent enzyme that metabolizes Propionyl-CoA.

Answer 294

Propionyl-CoA carboxylase

Question 295

In methylmalonic acidemia, there is deficiency of ?. This is a vitamin B12 dependent enzyme that converts Methylmalonyl-CoA into Sccinyl-CoA.

Answer 295

Mehtylmalonyl-CoA mutase

Question 296

Methylmalonyl-CoA and Succinyl-CoA are

Answer 296

Isomers

Question 297

* Branched chain amino acid disorder: valine, leucine, and isoleucine. These amino acids cannot be metabolized due to deficiency of an enzyme called alpha ketoacid dehydrogenase. * Multi-subunit complex * Cofactors: Thiamine, lipoic acid

Answer 297

Maple syrup urine disease

Question 298

* Amino acids and α-ketoacids in plasma/urine * α-ketoacid of isoleucine gives urine sweet smell

Answer 298

Maple syrup urine disease

Question 299

- Carnitine deficiency - MCAD (Medium-chain-acyl-CoA dehydrogenase) deficiency

Answer 299

THE 2 key fatty acid disorders

Question 300

Both cause hypoketotic hypoglycemia when fasting: * Lack of fatty acid breakdown → low ketone bodies * Overutilization of glucose → hypoglycemia * Lack of acetyl-CoA for gluconeogenesis (there's not much Acetyl-CoA around in these disorders because fatty acids aren't being broken down and they produce Acetyl-CoA. )

Answer 300

- Carnitine deficiency - MCAD deficiency

Question 301

In newborn babies, these disorders usually present from three months to two years of age.

Answer 301

Fatty Acid Disorders

Question 302

* Failure to thrive, altered consciousness, hypotonia * Hepatomegaly * Cardiomegaly * Hypoketotic hypoglycemia

Answer 302

Fatty Acid Disorders

Question 303

Only occurs when there's a problem with fatty acid metabolism

Answer 303

Hypoketotic hypoglycemia

Question 304

* Carnitine necessary for carnitine shuttle * Links with fatty acids forming acylcarnitine * Moves fatty acids into mitochondria for metabolism

Answer 304

Primary Carnitine Deficiency

Question 305

* Muscle weakness, cardiomyopathy * Low carnitine and acylcarnitine levels

Answer 305

Primary Carnitine Deficiency

Question 306

Hallmark, biochemically, that you will use to make the diagnosis is that the levels of carnitine and acylcarnitine in the plasma will be low.

Answer 306

Primary Carnitine Deficiency

Question 307

In an MCAD deficiency, there is poor oxidation of medium chain fatty acids. These are fatty acids that are six to 10 carbons in length. And the hallmark of an MCAD deficiency is

Answer 307

The presence of structures called dicarboxylic acids that are six to 10 carbons in length in the urine.

Question 308

Will be high in an MCAD deficiency and this is in contrast to a carnitine deficiency.

Answer 308

The level of acylcarnitines of medium chain length

Question 309

* Onset in newborn period (first 24 to 48 hours): Feeding → protein load → symptoms * Poor feeding, vomiting, lethargy * May lead to seizures

Answer 309

Urea Cycle Disorders

Question 310

* Lab tests: Isolated severe hyperammonemia * Normal < 50 mcg/dl * Urea disorder may be > 1000 * No other major metabolic derangements

Answer 310

Urea Cycle Disorders

Question 311

* Most common urea cycle disorder * ↑ carbamoyl phosphate * ↑ orotic acid (derived from carbamoyl phosphate)

Answer 311

OTC Deficiency (Ornithine transcarbamylase deficiency)

Question 312

The level of ammonia will get high, and the level of carbamoyl phosphate will get high.

Answer 312

OTC Deficiency

Question 313

Is also an intermediate in the pyrimidine synthesis pathway, and it is metabolized to orotic acid.

Answer 313

Carbon oil phosphate

Question 314

* Disorder of pyrimidine synthesis * Also has orotic aciduria * Normal ammonia levels * No somnolence, seizures * Major features: Megaloblastic anemia, poor growth

Answer 314

Orotic Aciduria

Question 315

* Inborn errors of metabolism * Loss of ability to metabolize pyruvate → acetyl CoA * All cause severe lactic acidosis * All cause elevated alanine (amino acid) * Pyruvate shunted to alanine and lactate * Pyruvate dehydrogenase complex deficiency

Answer 315

Mitochondrial Disorders

Question 316

* Pyruvate shunted to alanine, lactate - Key findings (infancy): * Poor feeding * Growth failure * Developmental delays - Labs: * Elevated alanine * Lactic acidosis * No hypoglycemia

Answer 316

PDH Complex Deficiency

Question 317

Branched-chain amino acids cannot be metabolized and accumulate in the plasma. This leads to metabolic acidosis. Keto acids also accumulate and spill into the urine. These can be detected as ketones on standard urinalysis. Symptoms develop in the first 48 hours after birth when proteins and amino acids are consumed in breast milk. Features are usually nonspecific and include irritability, poor feedings, or lethargy. A metabolite of the branched chain amino acid isoleucine leads to urine that smells like maple syrup. Neurologic dysfunction is a prominent feature which may develop after the first 4 to 7 days. This includes the possibility of seizures.

Answer 317

MSUD

Question 318

Key features include (1) presentation in the first 24-48 hours after birth, (2) severe hyperammonemia (3) absence of acidosis or other metabolic derangements.

Answer 318

Urea cycle disorder

Question 320

The most common urea cycle disorder is ?. As a result, ammonia cannot be metabolized into urea. This leads to marked hyperammonemia. Ammonia accumulation causes cerebral edema which often leads to hyperventilation and respiratory alkalosis. The absence of acidosis and other metabolic derangements helps distinguish urea cycle disorders from other inborn errors of metabolism.

Answer 320

The deficiency of the enzyme ornithine transcarbamylase

Question 321

Develop in the first few days of life because breast milk contains proteins and amino acids. These cannot be metabolized and hyperammonemia occurs.

Answer 321

Urea cycle disorders

Question 322

Babies with urea cycle disorders

Answer 322

Should avoid breastfeeding and consume a very low protein diet. The diet is adjusted in these children to maintain normal serum levels of amino acids.

Question 323

Frequent feedings

Answer 323

Are helpful in glycogen storage diseases and beta-oxidation disorders where fasting hypoglycemia may occur.

Question 324

Is helpful in children with beta-oxidation disorders who cannot metabolize fatty acids.

Answer 324

A fat-restricted diet

Question 325

Is helpful in children with classic galactosemia who cannot metabolize galactose. This disorder also presents in the newborn period when babies consume breast milk with galactose. Prominent features are hypoglycemia and lactic acidosis after feeding.

Answer 325

A galactose-free diet

Question 326

Children with this disorder lack the normal activity of the enzyme glucose-6-phosphatase. As a result, the liver cannot metabolize glycogen into glucose. Glycogen accumulates in the liver causing hepatomegaly. Fasting hypoglycemia (as occurred when the baby had a long nap) with ketosis and lactic acidosis occurs. This disorder classically presents in infancy at approximately 3 to 6 months of age.

Answer 326

Glycogen storage disease type I (von Gierke disease).

Question 327

Is caused by the inability to metabolize fructose due to deficiency of aldolase B. HFI can present with hypoglycemia, ketosis, and hepatomegal. In addition, HFI presents when babies are weaned from breast milk and begin consuming foods containing fructose. Reducing sugars are present in the urine.

Answer 327

Hereditary fructose intolerance (HFI)

Question 328

Is a beta-oxidation disorder of fatty acids. It can present with fasting hypoglycemia similar to this case, however, ketones are absent (hypoketotic hypoglycemia).

Answer 328

Medium chain acyl-CoA dehydrogenase deficiency

Question 329

Is the most common urea cycle disorder. It presents with isolated severe hyperammonemia.

Answer 329

Ornithine transcarbamylase (OTC) deficiency

Question 330

Methylmalonic acidemia due to ? is an organic acidemia. The main presenting features are severe acidosis and markedly elevated ammonia. Organic acids will be present in the urine. This disorder usually presents within the first two weeks after birth.

Answer 330

Deficiency of methylmalonyl CoA mutase

Question 331

This baby has many classic findings of an organic acidemia such as methylmalonic acidemia caused by the deficiency of the enzyme methylmalonyl-CoA mutase. Key features of this disorder are

Answer 331

(1) presentation in the first weeks of life, (2) severe acidosis, and (3) severe hyperammonemia. The diagnosis is confirmed through the identification of methylmalonic acid in the urine.

Question 332

Urinary dicarboxylic acids will be present in the urine. These acids are produced by omega oxidation of fatty acids which occurs when beta-oxidation cannot proceed normally.

Answer 332

Beta-oxidation disorder involving fatty acid metabolism

Question 333

Most of the lysosomal storage diseases involve

Answer 333

Abnormal processing of sphingolipids

Question 334

Most of the molecules that accumulate in lysosomal storage disorders are ?. They all contain sphingosine and they're all examples of sphingolipids.

Answer 334

Ceramide derivatives

Question 335

If you modify a ceramide molecule by adding a head group to the hydroxyl on ceramide, you can get many other structures like A

Answer 335

Glycosphingolipids and sulfatides.

Question 336

* Three sugar head group on ceramide * Broken down by α-galactosidase A * Fabry’s Disease - Deficiency of α-galactosidase - Accumulation of ceramide trihexoside

Answer 336

Ceramide Trihexoside Globotriaosylceramide (Gb3)

Question 337

Sphingosine

Answer 337

Long chain “amino alcohol” - Addition of fatty acid to NH2 = Ceramide

Question 338

* X-linked recessive disease * Slowly progressive symptoms * Begins child → early adulthood

Answer 338

Fabry’s Disease

Question 339

* Neuropathy: classically pain in limbs, hands, feet * Skin: angiokeratomas, small dark, red to purple raised spots * Dilated surface capillaries * Decreased sweat

Answer 339

Fabry’s Disease

Question 340

* Renal disease - Proteinuria, renal failure * Cardiac disease - Left ventricular hypertrophy - Heart failure

Answer 340

Fabry’s Disease

Question 341

* CNS problems - TIA/Stroke (early age) * Often misdiagnosed initially * Enzyme replacement therapy available: Recombinant galactosidase

Answer 341

Fabry’s Disease

Question 342

Fabry’s Disease: Classic case

Answer 342

* Child with pain in hands/feet * Lack of sweat * Skin findings - Deficiency of α-galactosidase A - Accumulation of ceramide trihexoside

Question 343

* Glucose head group on ceramide * Broken down by glucocerebrosidase * Gaucher’s disease - Deficiency of glucocerebrosidase - Accumulation of glucocerebroside

Answer 343

Glucocerebroside

Question 344

* Most common lysosomal storage disease * Autosomal recessive * More common among Ashkenazi Jewish population * Lipids accumulate in spleen, liver, bones

Answer 344

Gaucher’s Disease

Question 345

Most common initial sign of Gaucher's disease

Answer 345

Splenomegaly

Question 346

- Hepatosplenomegaly: * Splenomegaly: most common initial sign - Bones * Marrow: Anemia, thrombocytopenia, rarely leukopenia * Often easy bruising from low platelets * Avascular necrosis of joints (joint collapse) - CNS (rare, neuropathic forms of disease) * Gaze palsy * Dementia * Ataxia

Answer 346

Gaucher’s Disease

Question 347

Macrophage filled with lipid “Crinkled paper”

Answer 347

Gaucher Cell

Question 348

Gaucher's disease: * Severe bone pain * Due to bone infarction (ischemia) * Infiltration of Gaucher cells in intramedullary space * Intense pain, often with fever (like sickle cell)

Answer 348

Bone Crises

Question 349

A 10-month-old boy is brought for evaluation of abnormal facial features. Over the past several months, his mother has noted distortion of his facial bones. In addition, he does not crawl like the other children his age. Since birth, he has had six sinus infections. On exam, the boy has an enlarged skull, wide nasal bridge, and flattened midface. He lays flat on the floor and is unable to push up or get to a sitting position. Examination of the eyes reveals corneal clouding. On abdominal exam, the liver is palpable below the costal margin and there is splenomegaly. This boy’s findings may be explained by abnormal accumulation of which of the following?

Answer 349

Carbohydrates. Typical features of the lysosomal storage disease, Hurler’s syndrome.

Question 350

Children born with this condition lack the enzyme alpha-L-iduronidase and accumulate heparan and dermatan sulfate. These substances are glycosaminoglycans, a type of complex carbohydrate.

Answer 350

Hurler’s syndrome

Question 351

Hunter's and Hurler's are examples of mucopolysaccharidoses, disorders involving the accumulation

Answer 351

Glycosaminoglycans

Question 352

Children with Hurler’s syndrome are usually normal at birth. Over the first year of life, coarse facial features develop including an ?. Developmental delay occurs including failure to meet appropriate milestones. These children often have recurrent sinus and respiratory infections caused by soft tissue enlargement in the airways due to the accumulation of glycosaminoglycans. Other common features are corneal clouding and hepatosplenomegaly. A pattern of skeletal abnormalities can be identified on x-ray called dysostosis multiplex. Diagnosis is suggested by glycosaminoglycans in the urine.

Answer 352

Enlarged skull, wide nasal bridge, and flattened midface.

Question 353

Is not seen in lysosomal storage diseases which are disorders of complex lipid or carbohydrate structures.

Answer 353

Accumulation of proteins or nucleic acids

Question 354

Sphingosine is a component of sphingolipids including ceramide. Ceramide accumulates in the sphingolipidosis disorder,

Answer 354

Fabry disease

Question 355

A 15-year-old boy is evaluated for paresthesias. For the past three months, he has woken with a burning and tingling sensation in his hands and feet. Sometimes it feels like “pinpricks all over my hands.” The symptoms wax and wane during the day. When he runs during gym class, the symptoms also get worse. Vitals signs are within normal limits.

Answer 355

Fabry disease

Question 356

Disorder is caused by a deficiency of the lysosomal enzyme alpha-galactosidase A leading to accumulation of ceramide trihexoside. Ceramides are complex lipids made of sphingosine and fatty acids.

Answer 356

Fabry disease

Question 357

The classic phenotype of Fabry disease presents in adolescence or young adulthood. The first features to occur are usually ?. Lack of sweat (hypohidrosis) may also be present at diagnosis although this feature is not always obvious. Some patients will complain of heat intolerance due to lack of sweat. Later in life, as the disease progresses, other features develop including renal failure, hypertrophic cardiomyopathy, and TIA or stroke. These are unlikely to be described at the time of presentation.

Answer 357

Acroparaesthesias (pain, burning, tingling, pinpricks) and angiokeratomas

Question 358

The diagnosis of Fabry disease is often missed for many years due to the vague presenting symptoms. Diagnosis can be made by measuring ?. Treatment is available with enzyme replacement therapy.

Answer 358

Alpha-galactosidase A enzyme activity

Question 359

In contrast to some lysosomal storage diseases like Tay-Sachs, patients with Fabry live into adulthood although lifespan is reduced due to

Answer 359

Heart failure, stroke, and kidney disease.

Question 360

Is caused by the deficiency of the enzyme UDP-N-acetylglucosamine-1-phosphotransferase in the Golgi apparatus which adds mannose-6-phosphate (M6P) to lysosomal enzymes. This causes an error in intracellular trafficking. In the absence of M6P, enzymes are secreted into the extracellular space rather than directed to lysosomes. Enzymes can be detected in the plasma of children with I-cell disease, one of the hallmarks of this disorder.

Answer 360

I-cell disease

Question 361

In I-cell disease, complex molecules that are normally degraded in lysosomes accumulate within cells. These are visible as cellular “?” under the microscope hence the name “inclusion cell” or I-cell disease.

Answer 361

Inclusions

Question 362

Whereas most lysosomal storage diseases involve deficient activity of a lysosomal enzyme, I-cell disease involves an enzyme in the ?. Deficient activity of this enzyme causes a secondary functional deficiency of multiple lysosomal enzymes which are trafficked to the extracellular space instead of lysosomes.

Answer 362

Golgi apparatus

Question 363

Clinical features of I-cell disease are similar to Hurler’s syndrome. Many babies appear normal at birth although the diagnosis can be made prenatally through detection of skeletal and bony abnormalities. Over the first year of life, coarse facial features develop including an ?Developmental delay occurs. These children often have recurrent sinus and respiratory infections caused by soft tissue enlargement in the airways. Other potential features are corneal clouding and hepatosplenomegaly. A pattern of skeletal abnormalities can be identified on X-ray called dysostosis multiplex.

Answer 363

Enlarged skull, wide nasal bridge, and flattened midface.

Question 364

The majority of lysosomal enzymes in I-cell disease are found in the

Answer 364

Extracellular space

Question 365

Gaucher’s disease, a lysosomal storage disease caused by the absence of the enzyme ? with the accumulation of glucocerebroside.

Answer 365

Glucocerebrosidase

Question 365

A macrophage that has accumulated excessive glucocerebroside. This is a classic finding on bone marrow biopsy of those with Gaucher’s disease. The nucleus is pushed to the side. The cytoplasm has the appearance of “crumpled tissue paper.” Macrophages are a type of phagocyte.

Answer 365

Gaucher cell

Question 366

The clinical features of Gaucher's disease are caused by infiltration of Gaucher cells into the liver, spleen, and bone marrow. The presentation may occur at any age but most cases are diagnosed before age 20. The majority of patients have splenomegaly on exam at presentation. Bone marrow suppression may cause ? Bone pain and fractures are common.

Answer 366

Anemia, thrombocytopenia, or leukopenia.

Question 367

Is made by demonstrating reduced glucocerebrosidase activity in leukocytes. Prognosis is variable but many patients live into their 60s or 70s.

Answer 367

Diagnosis of Gaucher's disease

Question 368

Recombinant glucocerebrosidase enzyme replacement therapy.

Answer 368

Treatment of Gaucher's disease

Question 369

A family pedigree is evaluated by a geneticist. A married couple emigrated to the United States in 1914 and had three children including one boy and two girls. The boy had lifelong problems with severe neuropathy and ultimately died from suicide. The two girls had a total of six children including two boys who also had neuropathy as well as a skin rash. An abnormal gene is identified on genetic testing among members of the family. This gene is most likely involved in the metabolism of which of the following?

Answer 369

Genetic disorder with X-linked inheritance (only occurs in males). Most lysosomal disorders and glycogen storage diseases are autosomal recessive. One exception is Fabry’s disease which is X-linked. Fabry’s disease is caused by deficiency of the lysosomal enzyme the breaks down ceramide trihexoside. Symptoms include neuropathy and skin rash.

Question 370

Glycogen debranching is abnormal in

Answer 370

Glycogen storage disease type III

Question 371

Sphingomyelin breakdown is abnormal in

Answer 371

Niemann-Pick disease

Question 372

Glucocerebroside breakdown is abnormal in

Answer 372

Gaucher’s disease

Question 373

Ganglioside processing is abnormal in

Answer 373

Tay-Sachs disease.

Question 374

Tay-Sachs disease, a lysosomal storage disease caused by the deficiency of the enzyme hexosaminidase A and accumulation of GM2 ganglioside. The disorder usually presents in the first six months of age. The dominant feature is ? caused by the accumulation of GM ganglioside in neurons. This presents as developmental delay, weakness, hypotonia, or seizures. A cherry-red spot on the macula is a classic finding. Classic histology findings are neurons with ballooned vacuoles in the cytoplasm. Electron microscopy may show lysosomes with whorling (“onion skinning”). There is no treatment, and death usually occurs in childhood.

Answer 374

Neurodegeneration

Question 375

Like most lysosomal storage diseases, Tay-Sachs is autosomal recessive. Since this boy has the disease, both parents must be carriers. The chance of a second child with the disease is therefore ?. The chance the next child will be a carrier of the abnormal gene is 50%

Answer 375

25%

Question 376

A lysosomal storage disease caused by the deficiency of galactocerebrosidase and abnormal metabolism of galactocerebroside. With this enzyme deficiency, galactocerebroside is not catabolized normally and is shunted into a toxic substance, galactosylsphingosine. As a result, the brain shows a loss of myelin and oligodendrocytes. This is a similar pattern to other demyelinating diseases like multiple sclerosis.

Answer 376

Krabbe disease

Question 377

Demyelination in Krabbe is rapid and survival beyond Demyelination in Krabbe is rapid and survival beyond 2 years is uncommon ? is uncommon.

Answer 377

2 years

Question 378

A 5-month-old boy is evaluated after a seizure. He was born by vaginal delivery after an uncomplicated pregnancy. He was healthy at birth with normal Apgar scores. Development had been normal up to this point. Earlier in the day, his mother was rocking him when he developed tonic-clonic activity. On exam, the baby’s arms and wrists are stiff and flexed.

Answer 378

Krabbe disease

Question 379

The dominant clinical features of Krabbe disease are neurologic including ?. Some of these features resemble Tay-Sachs disease, however, Tay-Sachs presents with muscle weakness with hypotonia and a cherry-red spot on the macula.

Answer 379

Seizures, stiffness, and weakness

Question 380

Friedewald Formula

Answer 380

LDL-C = Total Chol -HDL-C - TG/5

Question 381

As long as the triglyceride level is relatively normal, this formula is accurate.

Answer 381

Friedewald Formula

Question 382

* Elevated total cholesterol, LDL, or triglycerides * Risk factor for coronary disease and stroke * Modifiable – often related to lifestyle factors * Sedentary lifestyle * Saturated and trans-fatty acid foods * Lack of fiber

Answer 382

Hyperlipidemia

Question 383

Nephrotic syndrome (LDL) Alcohol use (TG) Pregnancy (TG) Beta blockers (TG) HCTZ (TC, LDL, TG)

Answer 383

Secondary Hyperlipidemia

Question 384

* Most patients have no signs/symptoms * Physical findings occur in patients with severe ↑lipids * Usually familial syndrome

Answer 384

Signs of Hyperlipidemia

Question 385

* Xanthomas - Plaques of lipid-laden histiocytes - Appear as skin bumps or on eyelids * Tendinous Xanthoma - Lipid deposits in tendons - Common in Achilles * Corneal arcus - Lipid deposit in cornea - Seen on fundoscopy

Answer 385

Signs of Hyperlipidemia

Question 386

* Elevated triglycerides (>1000) → acute pancreatitis * Exact mechanism unclear, may involve increased chylomicrons in plasma * Chylomicrons usually formed after meals and cleared * Always present when triglycerides > 1000mg/dL * May obstruct capillaries → ischemia * Vessel damage can expose triglycerides to pancreatic lipases * Triglycerides breakdown → free fatty acids * Acid → tissue injury → pancreatitis

Answer 386

Pancreatitis

Question 387

* Autosomal recessive * ↑↑↑TG (>1000; milky plasma appearance) * ↑↑↑ chylomicrons

Answer 387

Familial Dyslipidemias: Type I – Hyperchylomicronemia

Question 388

* Severe LPL dysfunction -LPL deficient - LPL co-factor deficient (apolipoprotein C-II) * Recurrent pancreatitis * Enlarged liver, xanthomas * Treatment: Very low fat diet - Reports of normal lifespan - No apparent ↑risk atherosclerosis

Answer 388

Type I – Hyperchylomicronemia

Question 389

* Autosomal dominant * Few or zero LDL receptors * Very high LDL (>300 heterozygote; >700 homozygote) * Tendon xanthomas, corneal arcus * Severe atherosclerosis (can have MI in 20s)

Answer 389

Type II - Familial Hypercholesterolemia

Question 390

* Apo-E2 subtype of Apo-E * Poorly cleared by liver * Accumulation of chylomicron remnants and VLDL (collectively know as β-lipoproteins) * Elevated total cholesterol and triglycerides * Usually mild (TC>300 mg/dl) * Xanthomas * Premature coronary disease

Answer 390

Type III – Familial Dysbetalipoproteinemia

Question 391

Decreased risk of Alzheimer’s

Answer 391

ApoE2

Question 392

Increased risk of Alzheimer’s

Answer 392

ApoE4

Question 393

* Autosomal dominant * VLDL overproduction or impaired catabolism * ↑TG (200-500) * ↑VLDL * Associated with diabetes type II * Often diagnosed on routine screening bloodwork * Increased coronary risk/premature coronary disease

Answer 393

Type IV Hypertriglyceridemia

Question 394

Fasting is often recommended prior to serum lipid measurement (although newer data suggest this may not be necessary). The reason for fasting is to ?. Most fat in our diet is in the form of triglycerides, and these levels transiently increase after a meal. In clinical practice, the most common reason for a new finding of elevated triglycerides is a non-fasting blood sample (i.e., patient forgets to fast prior to blood draw). Repeat testing after emphasizing the need to fast often reveals normal triglyceride levels or levels unchanged from prior testing.

Answer 394

Avoid high triglyceride levels

Question 395

Metoprolol is a beta blocker which can modestly increase triglycerides, an effect that occurs

Answer 395

Shortly after starting the medication.

Question 396

Modestly elevated triglycerides as described in this case are often secondary to another cause such as a

Answer 396

Non-fasting sample, alcohol consumption, estrogen therapy, thyroid disease or drugs (beta blockers, HCTZ, HIV medications).

Question 397

Increased liver VLDL secretion leads to ? as these are the major component of VLDL.

Answer 397

Elevated triglycerides

Question 398

Lipoprotein lipase deficiency causes ?, also a condition of elevated triglycerides.

Answer 398

Hyperchylomicronemia

Question 399

Is an enzyme that breaks down LDL receptors in the liver. Inhibition leads to reduced LDL cholesterol. This is the mechanism of action of the drug, evolocumab (trade name Repatha).

Answer 399

Proprotein convertase subtilisin/kexin type (PCSK9)

Question 400

Evidence of pancreatitis

Answer 400

Elevated amylase and lipase

Question 401

Deficiency of lipoprotein lipase (LPL). A small number of cases are also caused by apolipoprotein C-II deficiency. Apo C-II is a required cofactor for LPL. When absent, a functional LPL deficiency occurs despite a normal LPL gene.

Answer 401

Hyperchylomicronemia (type I dyslipidemia)

Question 402

LDL receptor deficiency leads to familial hypercholesterolemia with

Answer 402

Markedly elevated total and LDL cholesterol