BIOCHEMISTRY: BOARDS AND BEYOND Flashcards
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.
Adenosine deaminase
Treatment of gout
Inhibit xanthine oxidase (allopurinol)
Metabolized by xanthine oxidase, caution with allopurinol. May boost effects and increase toxicity.
Azathioprine and 6-MP
Lesch-Nyhan syndrome
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,
This enzyme converts inosine monophosphate (IMP) to guanosine monophosphate (GMP).
IMP deshydrogenase
An inhibitor of IMP dehydrogenase
Ribavirin
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.
Lesch-Nyhan syndrome
HGPRT enzyme activity less than 1.5% of normal is diagnostic for
Lesch-Nyhan syndrome
This enzyme catalyzes the rate limiting step in synthesis of pyrimidine nucleotides. Found in the cytosol. This enzime is inhibited by uridine triphosphate (UTP).
Carbomoyl phosphate synthetase II
Made of 2 N and 4 C
Pyrimidine ring
Sources of the ring of pyrimidines
Carbamoyl phosphate and aspartate
Autosomal recessive, defect in UMP synthase. Orotic acid in urine. Megaloblastic anemia (no response to B12/folate), growth retardation. Treatment: uridine
Orotic aciduria
Key urea cicle enzime, combines carbamoyl phosphate with ornithine to make citrulline
Ornithine transcarbamylase (OTC)
High nevels of carbamoil phophate get converted to orotic acid. High nevels of ammonia (urea cycle dysfunctional) = encephalopathy
OTC deficiency
Chamotherapy agent, converted to araCTP, mimics dCTP and inhibits DNA polymerase.
ARA-C (Cytarabine or cytosine arabinoside)
Sinthesized from deoxyuridine (converted by ribonucleotide reductase), deoxythymidine is only required nucleotide.
Thymidine
Inhibits ribonucleotide reductase, blocks formation of deoxynucleotides. Can be used in polycitemia vera, essential thrombocytosis, sickle cell anemia (increase in fetal Hb).
Hydroxyurea
Converts dUMP in dTMP (adding 1 C), involves use of N5,N10 tetrahydrofolate
Thymidylate synthase
Converts DHF to THF
Dihydrofolate reductase
Chemotherapy agent mimics uracil. Inhibits thymidylase synthase. Thymidylase death.
5-FU (5-fluorouracil)
Chemotherapy agent, immunosupressent. Mimics DHF, inhibits dihydrofolate reductase = blocks synthesis of dTMP. Bone marrow can be rescued with leucovorin (folinic acid, converted to THF).
Metrotrexate
Competitors inhibitors of Dihydropteroate synthase, Mimics PABA (paraaminobenzoic acid that is used for bacteria to create THF). No effect in human cells (dietary folate).
Sulfonamide antibiotics
Blocks bacteria dihydrofolate reductase. No THF.
Trimethoprim
Loss in dTMP production. Macrocytic anemia (fewer but larger RBCs). Neural tube defects in pregnancy.
Folate deficiency
Required to regenerate THF from N5-Methyl THF. (Deficiency Methyl folate trap), loss of dTMP synthesis (megaloblastic anemia), neurological dysfunction (demyelination)
Vitamin B12
Elevated ? in vitamin B12 and folate deficiency
Homocysteine
Elevated MMA level (no convertion to succynil CoA)
B12 Deficiency
Low crit, large RBC (increased MCV, mean corpuscular volume), hypersegmented neutrophils, caused by defective DNA production.
Megaloblastic anemia
Causes of megaloblastic anemia
Folate deficiency
B12 (neuro symptoms, MMA)
Orotic aciduria
Drugs (MTX, 5-FU, hydroxyurea)
Zidovudine (HIV NRTIs)
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.
Basal cell carcinoma
Inhibition of thymidylate synthase by 5-FU decreases intracellular thymidine and increases
Intracellular uridine
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.
Essential thrombocytosis (ET)
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.
Hydroxyurea
Two nucleotides, carries electrons.
NADH (Nicotinamide adenine dinucleotide)
Accepts electrons
NAD+
Donate electrons, can donate to electron transport chain = ATP.
NADH
At this stage of glycolylis, the glucose molecule is split into two three carbon molecules
Glyceraldehyde-3-phosphate
Reactions not reversible in glycolysis.
Glucose to glucose-6-phosphate.
Glucose 6-phosphate to Fructose-1,6-biphosphate.
Phosphoenolpyruvate to pyruvate.
Low km, quickly reach Vm (relatively low Vm compared to glucokinase)
Hexokinase
Found in liver and pancreas, not inhibited by G6P. Induced by insulin (it promotes transcription). Inhibited by F6P (overcome by glucose).
Glucokinase
Enzime inactive when low glucose and high F6P. The liver favor gluconeogenesis. High Km (rate varies with glucose). Sigmoidal curve (cooperativity)
Glucokinase
Glucokinase: high Vm level
After meals
In presence of Fructose-6-phosphate translocates glucokinase to nucleus, inactivating it.
Glucokinase regulatory protein or GKRP
Often exacerbated by pregnancy
Glucokinase deficiency
The rate limiting step for glycolysis.
Catalized by Phosphofructokinase-1, conversion of Fructose-6-phosphate to Fructose-1,6-biphosphate
Key inducers of glycolysis
AMP, Fructuose-2,6-bisphosphate (insulin and glucagon)
Is the rate limiting enzyme for gluconeogenesis.
Fructose-1,6-bisphosphate 1
Likes to drive PKK2/FBPASE2 phosphorylated to favor glycolisis
Glucagon
Fructose-1,6-phosphate to 2 GAP, reversible for gluconeogenesis.
Splitting stage of glycolisis
Total ATP per glycolisis
4 (2 ATP per GAP)
2 ATP net
Inhibitors of piruvate kinase
ATP, alanine
Plasma elevations are common in hemolysis, myocardial infarction and some tumors
Lactate deshidrogenase (LDH)
Sepsis, bowel ischemia, seizures. Elevated anion gap acidosis. - HCO3, -pH.
Lactic acidosis
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)
Muscle cramps
Autosomal recessive disorder, RBCs (most affected, lack mitochondria, membrane failure = phagocytosis in spleen.) New born with extravascular hemolysis and splenomegaly
Piruvate kinase deficiency
Synthesized as an offshot of glycolisis. Alters hemoglobin binding and helps the red cell deliver oxygen to tissues in certain setings.
2, 3 - Bisphosphoglycerate
Malate aspartate shuttle is used for oxidate phosphorylation (liver, heart)
32 ATP
Glycerol 3-phosphate shuttle (muscle)
30 ATP
No oxygen, no mitochondria
2 ATP + 2 lactate + 2 H2O
Insulin is standard therapy for ?. Insulin drives potassium into cells, lowering the serum potassium level.
Hyperkalemia.
Insulin is always given together with glucose when treating hyperkalemia. If given alone, insulin can cause
Hypoglycemia, seizures, or death.
Fructose 1,6 Bisphosphatase1 is the rate-limiting enzyme in gluconeogenesis. In the fed state, when insulin levels rise, this enzyme will become
Less active
Sources of glucose
Pyruvate, lactate, amino acids, propionate (odd chains fats), glycerol (fats)
Inactive without Acetyl-CoA (allosteric activator of gluconeogenesis)
Piruvate Carboxylase
Enzimes used in step 1 of gluconeogenesis (piruvate to phospoenolpiruvate (PEP))
Piruvate carboxylase (ATP, CO2 donate COOH, Biotin: in mitochondria)
PEP carboxykinase (GTP donate a phosphate)
Used by the mitochondria in the gluconeogenesis to get out to the cytosol the oxalacetate (OAA)
Malate shuttle
Deficiency of biotin
Massive consumption of raw egg whites (avidin); dermatitis, glossitis, loss of appetite, nausea
Pyruvate carboxylase deficiency
Presents in infancy with failure to thrive, high levels of pyruvate and lactate, and a lactic acidosis.
Rate limiting step of gluconeogenesis
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)
ON/OFF switch glycolysis.
High: favors glycolisis
Low: favor gluconeogenesis.
Manipulates enzimes PFK1 and Fructose-1,6-bisphosphate 1.
Fructose-2,6-bisphosphate
Levels rise with high insuline (fed state)
Levels fall with high glucagon (fasting state)
Fructose-2,6-bisphosphate
Converts glucose-6-phosphatase to glucose. Occurs mainly in the kidneys and liver. Endoplasmic reticulum.
Glucose-6-phosphatase
Can become glucosa
Odd chain fatty acids
The body stores fatty acids as
Triacylglycerol
Raises blood glucose. Gluconeogenesis and glycogen breakdown.
Epinephrine
Increases gluconeogenesis enzymes, hyperglycemia common side effect steroid drugs.
Cortisol
Increases gluconeogenesis
Thyroid hormone
Enzime only present in the liver that can mantain glucose levels during fasting
Glucose-6-phosphatase
Creates glucose-1-phosphate
Stops when glycogen branches decreased to 2-4 linked glucose molecules (limit dextrins).
Stabilized by vitamin B6.
Phosphorylase
Cleaves limits dextrins
Debranching enzime
Elevated in fasting or fight or flight, they favor the breakdown of glycogen into glucose
Glucagon, epinephrine
When its phosphorilazed it’s activity falls
Glycogen synthase
When its phosphorilazed it increases it activity, breaks down more glycogen into glucose
Glycogen phosphorilase
Desphosphorylazation of glycogen synthase and glycogen phosphorilase
Insulin
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)
Insulin receptor
Can directly activate GP kinase A which will phosphorylate glycogen phosphorylase and lead to glycogen breakdown.
Calcium/calmodulin
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
Breakdown of glycogen into glucose
A deficiency of the enzyme glucose-6-phosphatase (type Ia)
Glucose transporter deficiency (type Ib)
Von Gierke’s Disease (Glycogen storage disease type 1)
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.
Acid alpha-glucosidase (also called acid maltase) deficiency, also known as Pompe disease.
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.
Pompe disease
Glycogen debranching is impaired in ? which is associated with hypoglycemia.
Cori’s disease (glycogen storage disease type III)
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.
Budd Chiari syndrome
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.
GSDIII (Cori disease)
Liver enlargement also occurs in GSDI due to
Accumulation of glycogen (not just limit dextrins).
Often presents at an older age (early childhood) than GSDI (newborn) as the liver is capable of some degree of glycogen breakdown.
GSDIII
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.
GSDI
Growth restriction, hepatomegaly, and elevated AST/ALT from liver damage occur in both disorders.
GSDI I and III
Post-prandial hyperglycemia is seen in ? (sometimes called glycogen storage disease type 0).
Glycogen synthase deficiency
GSDI can be managed with dietary modifications.
Cornstarch
The alanine cycle converts the amino acid alanine into glucose in the liver. This is disrupted in GSDI and, therefore,
Elevated serum alanine levels occur.
Occurs in urea cycle disorders and organic acidemias.
Hyperammonemia
Occur in the fatty acid disorder, medium chain acyl-CoA dehydrogenase (MCAD) deficiency.
Urinary dicarboxylic acids
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.
Myophosphorylase deficiency (McArdle disease).
Creatine kinase is a muscle enzyme that converts creatine to phosphocreatine. Its presence in the serum is used as
A marker of muscle damage
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.
Fatty acid synthesis will be impaired in the absence of normal NADPH production by the HMP shunt
Ribose-5-phosphate
Nucleic acids/DNA/RNA
NADPH
Red cell oxidative protection
Respiratory burst in phagocytes
Fatty acid synthesis
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.
Glucose-6-phosphate dehydrogenase deficiency
Do not require NADPH or other metabolites produced by the HMP shunt.
The TCA cycle and oxidative phosphorylation
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.
Transketolase in fibroblasts
Is an irreversible encephalopathy associated with chronic alcohol use and thiamine (vitamin B1) deficiency.
The Wernicke-Korsakoff (WK) syndrome
May be seen among alcohol users with and without WK syndrome.
Hypomagnesemia, folate deficiency, alcohol withdrawal, and increased serum AST
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.
G6PD deficiency
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.
Water
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
Increased levels of glutathione disulfide in red cells.
Deficiency of the glycolysis enzyme pyruvate kinase may lead to hemolysis. This presents in
The newborn period
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.
NADPH oxidase
Diagnosis is made through neutrophil function testing (dihydrorhodamine 123 fluorescence; Nitroblue tetrazolium test).
CGD
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.
HMP shunt enzymes
The rate-limiting enzyme of the HMP shunt. The HMP shunt generates NADPH for steroid and fatty acid synthesis.
Glucose-6-phosphate dehydrogenase (G6PD)
The HMP shunt occurs in the ? like glycolysis.
Cytoplasm
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.
Pyruvate dehydrogenase (PDH) deficiency
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.
Carbohydrates like glucose or starch. These are metabolized into pyruvate which is shunted to lactic acid leading to vomiting, hyperventilation, and other symptoms.
Prolonged fasting should be avoided in ? where fasting metabolism is abnormal. In PDH deficiency, fasting does not worsen the condition.
Glycogen storage diseases and fatty acid disorders
Are recommended in PDH deficiency since beta-oxidation can generate acetyl-CoA without need for PDH.
High-fat diets
Cofactors for the PDH complex
Vitamins B1, B2, B3, and B5
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
Low serum bicarbonate.
¿Why Hypoglycemia is not a prominent feature of PDH deficiency?
Gluconeogenesis and glycogenolysis are intact.
Occur in disorders of beta-oxidation such as medium-chain acyl-CoA dehydrogenase (MCAD) deficiency
Urinary dicarboxylic acids and hypoketosis
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.
Pyruvate dehydrogenase (PDH) activity
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.
Pyruvate carboxylase (PC)
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.
Lipoic acid
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.
The rate limiting step of the TCA cycle
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.
Succinyl-CoA
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.
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.
Glycolysis converts glucose into
2 pyruvate
2 ATPs
2 NADH
Acetyl CoA can then enter the TCA cycle and be converted to:
1 GTP
3 NADH
1 FADH2
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.
Malate shuttle
The major pathologic effect of CO is
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.
Uncouplers
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.
Occurs in glycolysis when ATP is synthesized from ADP via enzymes.
Substrate level phosphorylation
CO binds to iron in the Fe2+ state, not
The Fe3+ state
Is a highly-lethal, mitochondrial poison that binds to Fe3+ iron in complex IV of the electron transport chain.
Cyanide
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
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.
Mitochondrial poisoning by cyanide will interrupt the electron transport chain. This will stall the TCA cycle and, thus, metabolism will be shunted towards
The production of lactate.
Venous oxyhemoglobin levels are increased in cyanide toxicity. As a result, the difference between arterial and venous blood is
Decreased
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.
Aspirin
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 ?
2,4 dinitrophenol
Will halt both ATP production and oxygen consumption.
An inhibitor of electron transport (e.g., cyanide)
Inhibitors shut down ATP production by shutting down electron transport (and, therefore consumption of oxygen).
Uncouplers allow electron transport (i.e., oxygen consumption) to proceed normally but ATP production is inhibited through proton escape from the intermembrane space.
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.
Nitroprusside
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
Prolonged treatment (>24 hours), renal failure, and excessive dosages.
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.
Hydroxocobalamin
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.
Sodium thiosulfate
Is used in the treatment of methemoglobinemia
Methylene blue
Is a chelating agent used in a variety of heavy metal toxicities, including lead and iron.
Dimercaprol
Is used in the treatment of acetaminophen toxicity.
N-acetylcysteine
Elevated liver enzymes, hyperammonemia, hypoglycemia, and hypoketosis. These findings are consistent with a
Beta-oxidation disorder
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.
Carnitine
Lead to poor beta-oxidation of lipids.
Deficient carnitine levels
In a carnitine deficiency, serum carnitine is low (absence of carnitine) and acylcarnitine levels are also low. In a beta-oxidation enzymatic defect,
acylcarnitines accumulate
Primary carnitine deficiency
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.
May cause secondary carnitine deficiency but is unlikely to have developed in a newborn baby.
Prolonged malnutrition
Is an enzymatic disorder of beta-oxidation. It can present similarly to this case, however, medium-chain acylcarnitines will be increased.
MCAD (medium-chain acyl-CoA dehydrogenase) deficiency
Is a gluconeogenesis enzymatic defect. This may cause hypoglycemia but not hypoketosis as fatty acid metabolism is normal.
Pyruvate carboxylase deficiency
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.
Organic acidemia
The major clinical features of organic acidemias are
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).
High plasma levels of an isomer of succinate (methyl malonate is an isomer of succinate).
Methylmalonic acidemia
Is caused by the inability to metabolize fructose due to deficiency of aldolase B.
Hereditary fructose intolerance (HFI)
Is not present in breast milk. HFI presents when babies are weaned from breast milk and begin consuming foods containing fructose.
Fructose i
In HFI, reducing sugars are present in
The urine
Is a disorder of pyrimidine synthesis. It presents as megaloblastic anemia due to the abnormal synthesis of nucleotides.
Orotic aciduria
Urea metabolism is disrupted in urea cycle disorders including ornithine transcarbamylase deficiency. These disorders present as
Isolated hyperammonemia without acidosis
Suggests an organic acidemia or beta-oxidation disorder.
Acidosis in a newborn with elevated ammonia
Urea cycle disorders do not cause
Acidosis, ketosis, or hypoglycemia.
The presence of ketones excludes
Fatty acid disorders.
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
An acylcarnitine profile
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.
Carnitine deficiency
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.
McArdle disease
May present with weakness and creatine kinase elevation. Muscle biopsy shows inflammatory cells.
Myositis
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.
Duchenne muscular dystrophy
Toxicity from statins may cause
Weakness and elevation of creatine kinase.
The hallmark finding of a beta-oxidation disorder
Hypoketotic hypoglycemia
Common feature of impaired beta-oxidation.
Urinary dicarboxylic acids
Treatment of long-chain fatty acid disorders involves
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.
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
Ketone synthesis
Purine metabolism generates
Uric acid
Glycine is a glucogenic amino acid. It is converted into ? in the fasting state for entry into gluconeogenesis.
Pyruvate
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
Acetyl-CoA
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
Isocitrate dehydrogenase
Is the rate-limiting enzyme of the urea cycle.
Carbamoyl phosphate synthetase I
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.
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.
Can inhibit the enzime Isocitrate Dehydrogenase and a-KG Dehydrogenase
High levels of NADH
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)
NADH
Glucose
Aminoacids
Fatty acids
Ethanol: Acetate
Molecules that can be converted to Acetyl CoA
Is depleated by etOH metabolism
NAD+
Overwhelms the electron transport chain (NAD+ tied up in NADH) = Pyruvate shunted to lactate (this regenerates NAD+). A lactic acidosis can develop.
Excess alcohol consumption
Inhibited when NADH is high = less FA breakdown.
B-oxidation
In the cytosol is used to synthesis fatty acids
Citrate (is high when the TCA is inhibited)
Acetyl CoA is converted to Malonyl CoA by Acetyl-CoA carboxylase
Rate limiting step of fatty acids synthesis
Activator of Acetyl-CoA carboxylase. Results in increase in Fatty acids synthesis.
Citrate
Powerful inhibitor of B-oxidation
Malonyl-CoA
Accumulation also contributes to FA levels. Used to generate NADPH (that favors FA synthesis)
Malate
Uses carbons from Acetyl-CoA and malonyl-CoA to create 16 carbon fatty acid Palmitate (requires NADPH)
Fatty acid synthase
Glycerol + fatty acids
Trygliceride
Normally, glycerol is metabolized into glycerol-3-phosphate and then glycerol-3-phosphate is further metabolized into ?, which can enter glycolysis or gluconeogenesis.
Dihydroxyacetone phosphate
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.
Why you get high levels of triglycerides in the liver cells of patients who are alcoholics?
Excreted by the proximal tubule.
Uric acid and lactate
More lactate in plasma
Less excretion of uric acid (URAT1)
High NADH slows ethanol metabolism
* Result: buildup of acetaldehyde: toxic to liver cells
- Acute: Inflammation → Alcoholic hepatitis
- Chronic: Scar tissue → Cirrhosis
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)
Microsomal ethanol-oxidizing system (MEOS)
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
Alcohol dehydrogenase
Inhibited by disulfiram (antabuse)
* Acetaldehyde accumulates triggers catecholamine release = sweating, flushing, palpitations, nausea, vomiting
Aldehyde Dehydrogenase
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
Alcohol Flushing
Alcohol depletes NAD+ which shunts oxaloacetate into malate. This inhibits gluconeogenesis leading to hypoglycemia.
Consuming alcohol when glycogen stores are low after strenuous exercise is a classic cause of hypoglycemia via this mechanism.
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.
Cytochrome P-450 enzyme metabolism
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.
Alcoholic fatty liver disease
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
Malonyl-CoA
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
Production of triglycerides which contribute to fatty acid buildup in the liver.
Is an inhibitor of alcohol dehydrogenase which will halt the metabolism of ethanol.
Fomepizole
Creatine
- 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
Elevated levels of ? are seen in patients who have a myocardial infarction.
Creatine kinase
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.
phosphocreatine
- Spontaneous conversion
- Amount proportional to muscle mass
- Excreted by kidneys (used to estimate the glomerular filtration rate.)
Creatinine
- Consumed within seconds of exercise
- Used for short, intense exertion
- Heavy lifting
- Sprinting
ATP and Creatine
- Stimulates metabolism
- Activates glycogenolysis
- Activates TCA cycle
Calcium release from muscles
The calcium/calmodulin complex can stimulate glycogen phosphokinase A. This will phosphorylate glycogen phosphorylase, which makes the enzyme more active, and that speeds up
Glycogen breakdown (exercising.)
Can activate isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase (increase the speed of TCA cycle)
Calcium
- Long distance running
- Co-ordinated effort by organ systems
- Multiple potential sources of energy
Aerobic exercise
- 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
Anaerobic exercise
ATP and creatine phosphate (consumed in seconds)
- Fast pace cannot be maintained
* Creatinine phosphate consumed
* Lactate accumulates
Anaerobic Exercise
- 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
Moderate Aerobic Exercise
- 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
Intense Aerobic Exercise
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.
This ensures that fatty acid synthesis will not occur, during a long race like a marathon.
Normally, malonyl-CoA inhibits this enzyme
CPT1 (Carnitine palmitoyl transferase I)
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
Cramps.
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.
Distance runners condition
In the fed state, insulin promotes glycogen synthesis in the liver and in muscle cells.
The rate of glycolysis and inhibits gluconeogenesis.
Promotes glucose → adipose tissue
* Used to form triglycerides
* Promotes uptake of amino acids by muscle
* Stimulates protein synthesis/inhibits breakdown
Insulin
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.
Glucokinase
The rate-limiting enzyme of glycolysis is
Phosphofructokinase-1 (PFK1)
he rate-limiting enzyme of gluconeogenesis is
Fructose 1,6-bisphosphate1.
Insulin influences both of these enzymes, via an intermediate called fructose 2,6-bisphosphate.
- Phosphofructokinase-1 (PFK1)
- Fructose 1,6-bisphosphate1.
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.
Level of fructose 2,6-bisphosphate inside of cells
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.
Glycogen phosphorylase
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
Acetyl-CoA carboxylase
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.
Acetyl-CoA carboxylase
- Glycogen breakdown in liver
- Maintains glucose levels in plasma
- Dominant source glucose between meals
Key effect of glucagon
- Inhibits fatty acid synthesis
- Stimulates release of fatty acids from adipose tissue
- Stimulates gluconeogenesis
Other effects of glucagon
Alanine
Lactate
Glycerol
Odd Chain FAs
Gluconeogenesis
Glycogen exhausted
after ~
24 hours
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.
Alanine
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.
Lactate
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.
Glycerol
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.
Odd chain fatty acids
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.
Propionyl-CoA
Only ? fatty acids can be converted into glucose via gluconeogenesis. That’s because even chain fatty acids are completely consumed via beta oxidation.
Odd chain
- 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
Starvation
- Inadequate protein intake
- Hypoalbuminemia → edema
- Swollen legs, abdomen
Kwashiorkor
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.
Marasmus
- Hypoglycemia
- Ketosis
- Usually after overnight fast
Glycogen storage diseases
- Deficiency of aldolase B
- Build-up of fructose 1-phosphate
- Depletion of ATP
- Usually a baby just weaned from breast milk
Hereditary fructose intolerance
Lack of ketones in setting of ↓ glucose during fasting
* Occurs in beta oxidation disorders
* FFA → beta oxidation → ketones (beta oxidation)
* Tissues overuse glucose → hypoglycemia
Hypoketotic Hypoglycemia
Low serum carnitine and acylcarnitine levels
Carnitine deficiency
- Dicarboxylic acids 6-10 carbons in urine
- High acylcarnitine levels
MCAD deficiency (Medium chain acyl-CoA dehydrogenase)
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.
Leucine and lysine
Kwashiorkor (or edematous malnutrition) and marasmus. The two forms are distinguished by the presence of edema which only occurs in
Kwashiorkor
Involves total calorie insufficiency involving all nutrients, not just protein. This leads to muscle and fat wasting in the absence of edema.
Marasmus
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.
Deficiency of vitamin B1 (thiamine)
Is the cause of peripheral edema among patients with heart failure.
Increased capillary hydrostatic pressure
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.
Isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase
Its serum level is used as an indicator of muscle damage.
Creatine kinase
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.
The supply of phosphocreatine is depleted within the first few seconds of sustained muscle contraction.
Explains the stablity of cellular ATP levels during early muscle contraction.
Use of phosphocreatine to synthesize ATP
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.
Fasting and starvation
- 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
Inborn Errors in Metabolism
- Glycogen storage diseases
- Galactosemia
- Hereditary fructose intolerance
- Organic acidemias
- Disorders of fatty acid metabolism
Causes of newborn Hypoglycemia
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)
Glycogen Storage Diseases
So babies who have a glycogen storage disease develop
Fasting hypoglycemia
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
Glycogen Storage Diseases
- Severe hypoglycemia
- Lactic acidosis (disruption of the Cori Cycle)
Von Gierke’s Disease (Type I)
- Gluconeogenesis intact
- Mild hypoglycemia (problems breaking down glycogen)
- No lactic acidosis (the Cori Cycle is not disrupted)
Cori’s Disease (Type III)
- 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)
Hereditary Fructose Intolerance
- Starts after weaned from breast milk
No fructose in breast milk - “Reducing sugars” in urine: Glucose, fructose, galactose
Hereditary Fructose Intolerance
Reducing sugars in urine with hypoglycemia
Hallmark of hereditary fructose intolerance
Classic galactosemia
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
- Vomiting/diarrhea after feeding
- Similar presentation to HFI
- Hypoglycemia
- Lactic acidosis
- Ketosis
- Hepatomegaly (glycogen buildup)
- “Reducing sugars” in urine
Classic Galactosemia
After feedings (you will find reducing sugars in the urine) : Galactosemia, HFI
Fasting: Glycogen Storage Diseases
Hypoglycemia
Lactic Acidosis
Ketosis
- Abnormal metabolism of organic acids: Propionic acid and Methylmalonic acid
- Buildup of organic acids in blood/urine that leads to acidosis
- Hyperammonemia
Organic Acidemias
if you see a newborn baby who has some unexplained acidemia and hyperammonemia, think of
Organic Acidemias
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.
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.
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.
Newborn period
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.
Organic acidemias
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.
Organic acidemias
In propionic acidemia, there is deficiency of an enzyme called ?. This is a biotin dependent enzyme that metabolizes Propionyl-CoA.
Propionyl-CoA carboxylase
In methylmalonic acidemia, there is deficiency of ?. This is a vitamin B12 dependent enzyme that converts Methylmalonyl-CoA into Sccinyl-CoA.
Mehtylmalonyl-CoA mutase
Methylmalonyl-CoA and Succinyl-CoA are
Isomers
- 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
Maple syrup urine disease
- Amino acids and α-ketoacids in plasma/urine
- α-ketoacid of isoleucine gives urine sweet smell
Maple syrup urine disease
- Carnitine deficiency
- MCAD (Medium-chain-acyl-CoA dehydrogenase) deficiency
THE 2 key fatty acid disorders
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. )
- Carnitine deficiency
- MCAD deficiency
In newborn babies, these disorders usually present from three months to two years of age.
Fatty Acid Disorders
- Failure to thrive, altered consciousness, hypotonia
- Hepatomegaly
- Cardiomegaly
- Hypoketotic hypoglycemia
Fatty Acid Disorders
Only occurs when there’s a problem with fatty acid metabolism
Hypoketotic hypoglycemia
- Carnitine necessary for carnitine shuttle
- Links with fatty acids forming acylcarnitine
- Moves fatty acids into mitochondria for metabolism
Primary Carnitine Deficiency
- Muscle weakness, cardiomyopathy
- Low carnitine and acylcarnitine levels
Primary Carnitine Deficiency
Hallmark, biochemically, that you will use to make the diagnosis is that the levels of carnitine and acylcarnitine in the plasma will be low.
Primary Carnitine Deficiency
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
The presence of structures called dicarboxylic acids that are six to 10 carbons in length in the urine.
Will be high in an MCAD deficiency and this is in contrast to a carnitine deficiency.
The level of acylcarnitines of medium chain length
- Onset in newborn period (first 24 to 48 hours): Feeding → protein load → symptoms
- Poor feeding, vomiting, lethargy
- May lead to seizures
Urea Cycle Disorders
- Lab tests: Isolated severe hyperammonemia
- Normal < 50 mcg/dl
- Urea disorder may be > 1000
- No other major metabolic derangements
Urea Cycle Disorders
- Most common urea cycle disorder
- ↑ carbamoyl phosphate
- ↑ orotic acid (derived from carbamoyl phosphate)
OTC Deficiency (Ornithine transcarbamylase deficiency)
The level of ammonia will get high, and the level of carbamoyl phosphate will get high.
OTC Deficiency
Is also an intermediate in the pyrimidine synthesis pathway, and it is metabolized to orotic acid.
Carbon oil phosphate
- Disorder of pyrimidine synthesis
- Also has orotic aciduria
- Normal ammonia levels
- No somnolence, seizures
- Major features: Megaloblastic anemia, poor growth
Orotic Aciduria
- 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
Mitochondrial Disorders
- Pyruvate shunted to alanine, lactate
- Key findings (infancy):
- Poor feeding
- Growth failure
- Developmental delays
- Labs:
- Elevated alanine
- Lactic acidosis
- No hypoglycemia
PDH Complex Deficiency
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.
MSUD
Key features include (1) presentation in the first 24-48 hours after birth, (2) severe hyperammonemia
(3) absence of acidosis or other metabolic derangements.
Urea cycle disorder
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.
The deficiency of the enzyme ornithine transcarbamylase
Develop in the first few days of life because breast milk contains proteins and amino acids. These cannot be metabolized and hyperammonemia occurs.
Urea cycle disorders
Babies with urea cycle disorders
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.
Frequent feedings
Are helpful in glycogen storage diseases and beta-oxidation disorders where fasting hypoglycemia may occur.
Is helpful in children with beta-oxidation disorders who cannot metabolize fatty acids.
A fat-restricted diet
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.
A galactose-free diet
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.
Glycogen storage disease type I (von Gierke disease).
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.
Hereditary fructose intolerance (HFI)
Is a beta-oxidation disorder of fatty acids. It can present with fasting hypoglycemia similar to this case, however, ketones are absent (hypoketotic hypoglycemia).
Medium chain acyl-CoA dehydrogenase deficiency
Is the most common urea cycle disorder. It presents with isolated severe hyperammonemia.
Ornithine transcarbamylase (OTC) deficiency
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.
Deficiency of methylmalonyl CoA mutase
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
(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.
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.
Beta-oxidation disorder involving fatty acid metabolism
Most of the lysosomal storage diseases involve
Abnormal processing of sphingolipids
Most of the molecules that accumulate in lysosomal storage disorders are ?. They all contain sphingosine and they’re all examples of sphingolipids.
Ceramide derivatives
If you modify a ceramide molecule by adding a head group to the hydroxyl on ceramide, you can get many other structures like A
Glycosphingolipids and sulfatides.
- Three sugar head group on ceramide
- Broken down by α-galactosidase A
- Fabry’s Disease
- Deficiency of α-galactosidase
- Accumulation of ceramide trihexoside
Ceramide Trihexoside
Globotriaosylceramide (Gb3)
Sphingosine
Long chain “amino alcohol”
- Addition of fatty acid to NH2 = Ceramide
- X-linked recessive disease
- Slowly progressive symptoms
- Begins child → early adulthood
Fabry’s Disease
- Neuropathy: classically pain in limbs, hands, feet
- Skin: angiokeratomas, small dark, red to purple raised spots
- Dilated surface capillaries
- Decreased sweat
Fabry’s Disease
- Renal disease
- Proteinuria, renal failure
- Cardiac disease
- Left ventricular hypertrophy
- Heart failure
Fabry’s Disease
- CNS problems
- TIA/Stroke (early age)
- Often misdiagnosed initially
- Enzyme replacement therapy available: Recombinant galactosidase
Fabry’s Disease
Fabry’s Disease: Classic case
- Child with pain in hands/feet
- Lack of sweat
- Skin findings
- Deficiency of α-galactosidase A
- Accumulation of ceramide trihexoside
- Glucose head group on ceramide
- Broken down by glucocerebrosidase
- Gaucher’s disease
- Deficiency of glucocerebrosidase
- Accumulation of glucocerebroside
Glucocerebroside
- Most common lysosomal storage disease
- Autosomal recessive
- More common among Ashkenazi Jewish population
- Lipids accumulate in spleen, liver, bones
Gaucher’s Disease
Most common initial sign of Gaucher’s disease
Splenomegaly
- 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
Gaucher’s Disease
Macrophage filled with lipid
“Crinkled paper”
Gaucher Cell
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)
Bone Crises
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?
Carbohydrates. Typical features of the lysosomal storage disease, Hurler’s syndrome.
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.
Hurler’s syndrome
Hunter’s and Hurler’s are examples of mucopolysaccharidoses, disorders involving the accumulation
Glycosaminoglycans
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.
Enlarged skull, wide nasal bridge, and flattened midface.
Is not seen in lysosomal storage diseases which are disorders of complex lipid or carbohydrate structures.
Accumulation of proteins or nucleic acids
Sphingosine is a component of sphingolipids including ceramide. Ceramide accumulates in the sphingolipidosis disorder,
Fabry disease
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.
Fabry disease
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.
Fabry disease
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.
Acroparaesthesias (pain, burning, tingling, pinpricks) and angiokeratomas
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.
Alpha-galactosidase A enzyme activity
In contrast to some lysosomal storage diseases like Tay-Sachs, patients with Fabry live into adulthood although lifespan is reduced due to
Heart failure, stroke, and kidney disease.
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.
I-cell disease
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.
Inclusions
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.
Golgi apparatus
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.
Enlarged skull, wide nasal bridge, and flattened midface.
The majority of lysosomal enzymes in I-cell disease are found in the
Extracellular space
Gaucher’s disease, a lysosomal storage disease caused by the absence of the enzyme ? with the accumulation of glucocerebroside.
Glucocerebrosidase
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.
Gaucher cell
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.
Anemia, thrombocytopenia, or leukopenia.
Is made by demonstrating reduced glucocerebrosidase activity in leukocytes. Prognosis is variable but many patients live into their 60s or 70s.
Diagnosis of Gaucher’s disease
Recombinant glucocerebrosidase enzyme replacement therapy.
Treatment of Gaucher’s disease
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?
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.
Glycogen debranching is abnormal in
Glycogen storage disease type III
Sphingomyelin breakdown is abnormal in
Niemann-Pick disease
Glucocerebroside breakdown is abnormal in
Gaucher’s disease
Ganglioside processing is abnormal in
Tay-Sachs disease.
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.
Neurodegeneration
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%
25%
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.
Krabbe disease
Demyelination in Krabbe is rapid and survival beyond Demyelination in Krabbe is rapid and survival beyond 2 years is uncommon ? is uncommon.
2 years
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.
Krabbe disease
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.
Seizures, stiffness, and weakness
Friedewald Formula
LDL-C = Total Chol -HDL-C - TG/5
As long as the triglyceride level is relatively normal, this formula is accurate.
Friedewald Formula
- 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
Hyperlipidemia
Nephrotic syndrome (LDL)
Alcohol use (TG)
Pregnancy (TG)
Beta blockers (TG)
HCTZ (TC, LDL, TG)
Secondary Hyperlipidemia
- Most patients have no signs/symptoms
- Physical findings occur in patients with severe ↑lipids
- Usually familial syndrome
Signs of Hyperlipidemia
- 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
Signs of Hyperlipidemia
- 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
Pancreatitis
- Autosomal recessive
- ↑↑↑TG (>1000; milky plasma appearance)
- ↑↑↑ chylomicrons
Familial Dyslipidemias: Type I – Hyperchylomicronemia
- 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
Type I – Hyperchylomicronemia
- 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)
Type II - Familial Hypercholesterolemia
- 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
Type III – Familial Dysbetalipoproteinemia
Decreased risk of Alzheimer’s
ApoE2
Increased risk of Alzheimer’s
ApoE4
- 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
Type IV Hypertriglyceridemia
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.
Avoid high triglyceride levels
Metoprolol is a beta blocker which can modestly increase triglycerides, an effect that occurs
Shortly after starting the medication.
Modestly elevated triglycerides as described in this case are often secondary to another cause such as a
Non-fasting sample, alcohol consumption, estrogen therapy, thyroid disease or drugs (beta blockers, HCTZ, HIV medications).
Increased liver VLDL secretion leads to ? as these are the major component of VLDL.
Elevated triglycerides
Lipoprotein lipase deficiency causes ?, also a condition of elevated triglycerides.
Hyperchylomicronemia
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).
Proprotein convertase subtilisin/kexin type (PCSK9)
Evidence of pancreatitis
Elevated amylase and lipase
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.
Hyperchylomicronemia (type I dyslipidemia)
LDL receptor deficiency leads to familial hypercholesterolemia with
Markedly elevated total and LDL cholesterol
