proteins

Question 1

urea cycle

Answer 1

1. Ornithine ->Citrulline (catalyzed by Carbamoyl phosphate synthetase I ). 2. Citrulline + Aspartate ->Argininosuccinate (catalyzed by Arginonosuccinate synthase) 3. Argininosuccinate ->Arginine (catalyzed by Argininosuccinate lyase)
2. Arginine ->Ornithine + Urea (catalyzed by Arginase)

Question 2

Carbamoyl phosphate synthetase I

Answer 2

initial step in urea cycle. located in mitochondira.  Reaction: bicarbonate + ammonia -> carbamoyl phosphate uses 2 of the 3 ATPs in urea cycle. N-acetylglutamate is an allosteric activator of carbamoyl phosphate synthetase I.

Question 3

N-acetylglutamate

Answer 3

an allosteric activator of carbamoyl phosphate synthetase I.  Arginine is an activator of N-acetylglutamate synthase, which catalyzes the following reaction: acetyl CoA + glutamate to N-acetylglutamate

Question 4

transport of ammonia

Answer 4

Glutamine serves as a means of transport, since it can “hold” two ammonia groups. Glu dehydrogenase serves as a control pt for protein metabolism specifically by controlling the direction of either nitrogen removal or incorperation into amino acids. Most tissues use glutamine synthetase to convert glutamate to glutamine for transport to the liver (to enter the urea cycle). Muscle is different where alanine is used instead of glutamine for transport in the Alanine-Glucose Cycle. This is because in muscle there is a build-up of pyruvate from glycolysis and pyruvate can be converted to alanine for transport to liver (transamination). The liver, in turn, can use the alanine to convert back to pyruvate (transamination) and glucose remade (gluconeogenesis).

Question 5

Arginine in nerve and muscle function

Answer 5

NO synthase converts arginine -> citrulline to produce NO. In the urea cycle, arginine -> ornithine, which is catalyzed by arginase or enzymes that produce creatine phosphate for energy in muscles.

Question 6

Ketogenic amino acids

Answer 6

no production of glucose. Lysine and leucine are the ketogenic amino acids since breadown gives Acetyl-CoA (i.e. only 2 carbons).

Question 7

glucogenic amino acids

Answer 7

produces pyruvate or Kreb Cycle intermediates. Oxaloacetate in Kreb Cycle comes from aspartate transamination

Question 8

Decarboxylation of branched-chain amino acids

Answer 8

Branched Chain Amino Acids include leucine, valine, and isoleucine.  First, these three amino acids are deaminated by branched-chain aminotransferase to produce a-keto acids. Second, they are decarboxylated by branched-chain a-ketoacid dehydrogenase complex. Maple Syrup Urine Disease (MSUD) occurs when this
dehydrogenase complex is deficient and there is consequently a build up of the a-keto acids in urine (“sweet smelling”).

Question 9

thyroid chemistry

Answer 9

tryrosine is used to make T4 (prohormone), which is converted to T3 (hormone).

Question 10

thyroid stimulating hormone

Answer 10

Stimulates iodide (I-) uptake and stimulates release of T4,T3.

Question 11

thyroid peroxidase

Answer 11

Oxidizes iodide (I-) to I2

Question 12

thryoglobulin

Answer 12

contains tyrosine residues that are iodinated to form T4, T3

Question 13

thyroxin binding globulin

Answer 13

transports T4, T3

Question 14

Porphyrin (Heme) Metabolism

Answer 14

are specialized products derived from Gly and TCA intermediate. Porphyrins such as Heme are cyclic molecules made of 4x pyroles primarily produced in liver.  Porphyrins bind Fe2+ (iron).

Question 15

synthesis of porphyrin

Answer 15

1. glycine + succinyl CoA -> δ Aminolevulinic acid (ALA) (catalyzed by δ-Aminolevulinate synthase). 2. 2x ALA -> Porphobilinogen (catalyzed by by δ-Aminolevulinate dehydratase)
2. Porphobilinogen -> - >-> Protoporphyrin IV (catalyzed by 4 enzymes). 4. Protoporphyrin IX -> Heme (catalyzed by Ferrochelatase)

Question 16

Prophyrias

Answer 16

diseases in porphyrin synthesis. Lead inhibits δ-Aminolevulinate dehydratase and ferrochelatase, leading to lead poisoning

Question 17

Porphyrin (Heme) degradation

Answer 17

Reactions Heme -> biliverdin (green) -> bilirubin (red-orange) -> bilirubin diglucuronide (conjugated bilirubin) -> urobilinogen -> stercobilin (brown). Bilirubin is transported in blood via albumin. In liver, bilirubin is conjucated with glucuronic acidbilirubin diglucuronide (or otherwise known as conjugated bilirubin). In intestine, bilirubin diglucuronide is oxidizedstercobilin. Jaundice occurs when bilirubin cannot be processed properly (i.e. hemolytic jaundice occurs when too many RBCs lyse, neonatal jaundice when bilirubin diglucuronide is not produced fast enough by low levels of bilirubin glycuronyltransferase).

Question 18

sulfur containing amino acids

Answer 18

methionine and cysteine

Question 19

cysteine

Answer 19

(an unessential amino acid) is unique in that the –SH can form disulfides with another Cys, which is important for structural intergrity of many proteins (especially extracellular proteins).

Question 20

Glutathione (GSH)

Answer 20

tripeptide that controls redox potential via GSH GSSG, where cysteine is central amino acid that does the redox. thiol acts as redox buffer (“SH buffer”) to maintain proteins in their reduced forms (i.e. intracellular proteins) and regulate activity (i.e. enzymes). Cofactor for several enzymes (i.e. Glutathione transferase, GST). Reduce hydrogen peroxide (H2O2) to water and general protection against ROS (radical oxidizing species).

Question 21

methionine

Answer 21

an essential amino acid. is unique in that it is used to produce S-adenosylmethionine, which is also an intermediate in the production of cysteine.

Question 22

S-adenosylmethionine (SAM)

Answer 22

produced in the first step of methionine degradation and converted to S-adenoyslhomocysteine (SAH). SAM is major Carbon donor and a “high energy storage unit” like ATP.

Question 23

methionine degradation

Answer 23

Met -> SAM -> SAH -> Homocysteine -> Met

 Homocysteine -> Met needs THF and vit B12 to transfer back CH3 group

Question 24

methionine to cysteine conversion

Answer 24

Met -> SAM -> SAH -> Homocysteine -> Cystathionine -> Cysteine

Question 25

hyperhomocysteinemia

Answer 25

elevated homocysteine cause problems like cardiovascular disease. Results from low levels of folate, B6 and B12. Cysteine is now essential.

Question 26

homocysteinuria

Answer 26

results from defect in cystationine-n-synthase (CBS) and cannot convert homocysteine to cystathionine (and eventually cysteine). Leads to mental retardation, osteoporosis and vascular disease. Cysteine is now essential. Can treat with vit B6 to force CBS activity.

Question 27

Cysteinuria

Answer 27

kidney stones due to defective transporter of cysteine (and ornithine, lysine, and arginine) that leads to crystallization in urea, treat with acetazolamide that makes cysteine more soluble.

Question 28

Tetrahydrofolate (THF)

Answer 28

A cofactor used for transferring carbons. Tetrahydrofolate (THF) is synthesized in bacteria and its precursor, folate, is a vitamin for mammals. The different forms of tetrahydrofolate are interconvertible and serve as donors of one-carbon units in a variety of biosynthetic reactions. The one-carbon group, in any of three oxidation states, is bonded to N-5 or N-10 or to both. The most reduced form of the cofactor carries a methyl group, a more oxidized form carrIes a methylene group, and the most oxidized forms carry a methenyl, formyl, or formimino group.

Question 29

Trp metabolism

Answer 29

Trp is metabolized to pyruvate or acetyl-CoA. Trp is first hyroxylated by tryptophan hydroxylase using tetrahydrobiopterin (BH4) as a cofactor. Trp is used to produce serotonin (neurotransmitter), melatonin (hormone), and niacin (energy).

Question 30

Phe and Tyr metabolism

Answer 30

Phe and Tyr are metabolized to fumerate or acetoacetate.

Question 31

phenylalanine hydroxylase

Answer 31

Phe is hydroxylated by phenylalanine hydroxylase to produce Tyr using BH4 as a cofactor.

Question 32

Tyrosine hydroxylase

Answer 32

hydroxylates Tyr to produce DOPA using BH4, which is subsequently metabolized to chatecholamines (DOPA, dopamine, norepinephrine, epinephrine) or melanin, whic is a pigment produced as a complex combination of several molecules derived from tyrosine metabolism.

Question 33

Metabolic diseases in Tyr metabolism

Answer 33

Phenylketonuria (PKU), which is a defect in phenylalanine hydroxylase that leads to build-up of alternative byproducts (phenyllactate, phenylacetate, and phenylpyruvate). Tyrosinemias are defects in the mutli-step tyrosine degradation categorized as types I, II, and III that refer to the particular dysfunctional enzyme involved.

Question 34

Tetrahydrobiopterin (BH4)

Answer 34

a naturally occurring essential cofactor of the three aromatic amino acid hydroxylase enzymes (Phenylalanine hyroxylase, tyrosine hyroxylase, and tryptophan hydroxylase), used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotonin (5-hydroxytryptamine, 5-HT), melatonin, dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline), and is a cofactor for the production of nitric oxide (NO) by the nitric oxide synthases. A deficit in tetrahydrobiopterin biosynthesis and/or regeneration can result in phenylketonuria (PKU) from excess L-phenylalanine concentrations or hyperphenylalaninemia (HPA), as well as monoamine and nitric oxide neurotransmitter deficiency or chemical imbalance.

Question 35

roles of purines and pyrimidines

Answer 35

1. The building blocks that make up the nucleic acids (DNA and RNA) which are critical for cell division and gene transcription/translation. 2. The primary energy carriers in the cell in molecules such as ATP and GTP. 3. The foundation for many coenzymes such as CoA, FAD, NAD, NADP. 4. Important in intracellular signaling such as cAMP, cGMP. 5. Carriers for activated intermediates such as UDP-glucose which is directed to glycogen synthesis and CDP-diacylglycerol which is involved in glycerophospholipid synthesis.

Question 36

nucleoside

Answer 36

a base combined with a pentose sugar.

Question 37

nucleotide

Answer 37

a base combined with a pentose sugar, which is phosphorylated. Nucleotides contain purine and pyrimidine bases. There are five common ones: guanine and adenine (purines); uracil, thymine, and cytosine (pyrimidines). A, G, C, and T are found in DNA, while A, G, C, and U are found in RNA. Unusual bases are found in places like tRNA and rRNA, but these are primarily post-transcriptional modifications of the 5 common bases. Bases, when covalently linked to ribose sugars and phosphates, become nucleotides.

Question 38

phosphoribosyl pyrophosphate synthetase (PRPP synthase)

Answer 38

The secondary regulated step in purine and pyrimidine nucleotide synthesis. an enzyme that converts ribose 5-phosphate into phosphoribosyl pyrophosphate (PRPP)

Question 39

glutamine phosphoribosyl pyrophosphate amidotransferase

Answer 39

PRPP (contains the ribose sugar) and glutamine are used by glutamine phosphoribosyl pyrophosphate amidotransferase to add the first nitrogen to the PRPP. At the start of purine de novo synthesis.

Question 40

Purine nucleotide synthesis

Answer 40

The pathway involves the addition of several amino acids and CO2 to the growing base as well as tetrahydrofolate and ATP as important elements in the pathway. The first base that is produced by this pathway is inosine mono-phosphate (IMP). IMP is then used to make the GMP and AMP bases by the action of enzymes that act on the IMP. Failure of one of the enzymes involved in AMP synthesis can lead to a form of autism. Feedback loops are a critical mechanism of regulation in purine synthesis. Specifically, IMP, GMP, and AMP inhibit enzymes that act early in the pathway.

Question 41

Pyrimidine nucleotide synthesis

Answer 41

The atoms that make up the pyrimidine bases come from both amino acid and small molecule sources. Unlike the purines, the pyrimidine base ring is not made on the ribose sugar, but made separately and then the base ring is added to the sugar. The first step in the synthesis of the pyrimidine ring is the primary source of regulation. The enzyme that catalyzes this key step is carbamoyl phosphate synthetase II. This is different from carbamoyl phosphate synthetase I in the urea cycle in that it is in the cytosol, and it is activated by PRPP and inhibited by UTP. The first nucleotide produced by this pathway is uracil mono-phosphate (UMP). To make cytosine, the nucleotides must first be converted to a triphosphate form. Once UMP is converted to UTP, it can be converted to CTP by the action of the CTP synthase enzyme.

Question 42

Changes in phosphorylation states and conversion of rNDPs to dNDPs

Answer 42

To convert nucleotide monophosphates (NMPs) to the diphosphate (NDP) and triphosphate (NTP) forms, a set of enzymes called kinases are used. The enzymes take phosphate from an ATP donor and transfer it to other nucleotides.

Question 43

ribonucleotide reductase

Answer 43

converts ribose to deoxyribose, needed for DNA. Ribonucleotide reductase operates on diphosphates (NDPs; ADP, GDP, CDP, and UDP). Once UDP is converted to dUDP, it can then be dephosphorylated to make dUMP, which is then converted to dTMP by thymidylate synthase. Kinases can then convert dTMP to dTDP and dTTP.

Question 44

regulation of ribonucleotide reductase

Answer 44

Ribonucleotide reductase is regulated by a complex mechanism that ‘senses’ the concentration of dNTPs. The enzyme has a primary regulation site (“on/off” switch) that controls the overall activity of the enzyme, and a substrate specificity site (“dial”). The primary regulation site is active in the presence of ATP, inactive when dATP builds up. The substrate specificity switch is sensitive to the concentrations of individual dNTPs, and as each builds up, the enzyme changes from operating on one NDP, to operating on another. Equal and adequate amounts of each NDP are converted to dNDP (and then to the dNTPs).

Question 45

Nucleotide degradation

Answer 45

Degradation of purine nucleotides occurs by first removing the base from the sugar, yielding a free base (adenosine or guanine). The free bases are then further broken down to uric acid, which is what is excreted from the body in urine. Failures in this pathway lead to several diseases. Pyrimidines are broken down by first removing the base ring from the ribose, as in purine degradation. However, unlike purine degradation, the base ring is then opened up (the uric acid from purine degradation is a closed ring). Ultimately, the breaking down of the base ring leads to molecules that can be used in other pathways (Succinyl-CoA, Malonyl-CoA, and Acetyl-CoA). These products are water soluble and so do not cause problems like uric acid can.

Question 46

Salvage pathways of nucleotides

Answer 46

Nucleotides can be made de novo from other molecules in the body, but in addition, they can be made through salvage pathways, in which partially degraded nucleotides are reused. The salvage pathways involve enzymes that take free bases and attach them to ribose sugar in the form of PRPP. Failure of these enzymes (transferases) can lead to disease.

Question 47

Severe Combined immunodeficiency syndrome

Answer 47

caused by a mutation in the gene encoding adenosine deaminase, an enzyme used in the purine degradation pathway. This leads to a buildup of dATP, which inhibits ribonucleotide reductase, which prevents enough dNTPs from being made. Rapidly proliferating cells (such as those
in the immune system) are affected.

Question 48

Gout

Answer 48

caused by a buildup of uric acid in the blood. Uric acid is the result of the
purine degradation pathway. This disease can be caused by deficiencies or hyperactivities of some enzymes, and several risk factors (age, diet, etc.) are associated with the disease.

Question 49

Lesch-Nyhan syndrome

Answer 49

caused by a deficiency in one of the primary enzymes in the purine salvage pathway (HGPRT), leading to higher rates of de novo synthesis of purines. Patients may have gout symptoms, self-mutilating behavior and other severe mental disorders.

Question 50

Methotrexate and 5-florouracil

Answer 50

targets the thymidylate synthase/folate metabolism cycle (anti cancer)

Question 51

6-mercaptopurine

Answer 51

inhibits AMP synthesis (anti cancer)

Question 52

Azidothymidine (AZT)

Answer 52

inhibits viral polymerase (anti HIV)

Question 53

Cytosine arabinoside (araC)

Answer 53

targets DNA polymerase (anti leukeia)

Question 54

Acyclovir (ACV)

Answer 54

targets viral DNA polymerase and reverse transcriptase (anti

Herpes simplex virus)

Question 55

Acivicin

Answer 55

glutamine analog, inhibits nucleotide synthesis (mostly GMP; anti cancer)

Question 56

Phenylketonuria

Answer 56

Liver phenylalanine hydroxylase (PAH) deficiency. Autosomal recessive inheritance. 1:16,000 live births. Pathophysiology is due to elevated total body phenylalaine. No direct pathologic effect on the liver. Rare variants of biopterin synthesis or recycling (about 1% of severe hyperphenyalaninemia.

Question 57

Phenylketonuria phenotype

Answer 57

severe: plasma phe greater than 1200 micro moles. moderate: 600-1200. benign: below 600. Mental retardation and autistic behaviors. White matter hyperintensities (pseudoleukodystrophy). seizures.

Question 58

Dietary therapy for PKU

Answer 58

Restrict dietary protein. Phe tolerance depends on residual enzyme activity. Supplement with phenylalanine-free medical beverage. maternal PKU can lead to microcephaly, low birth weight, mental retardation, and malformations in infants of mothers with poorly controlled PKU.

Question 59

long term management of PKU

Answer 59

restrict Phe, but do not eliminate it. Provide adequate calories; provide adequate protein, vitamins, minerals (phe-free formula). maintain normal growth and development. treatment for life.

Question 60

maple syrup urine disease

Answer 60

branched chain ketoacid dehydrogenase (BCKD) deficiency. Autosomal recessive inheritance. Incidence is 1/185,000 births. Enzyme is composed of four subunits and mutations are known in all four genes. p.Y391N substitution in E1α protein is a common foundermutation in the Mennonite population. Mutations in E2 subunit most likely to be thiamine (vitamin B1) responsive.

Question 61

acute treatment of MSUD

Answer 61

eliminate dietary protein intake. supplement valine and isoleucine. provide adequate non-protein energy source and amino acids that are not BCAA. Avoid hypotonic fluids. Treat cerebral edema if symptoms develop. Hemodialysis maybe.

Question 62

chronic therapy of MSUD

Answer 62

protein restricted diet supplemented with branched chain amino acid free medical foods. Leucine intake about 400-600 mg per day in severe neonatal forms. then 600-800 after adolescence. supplement valine and isoleucine (rapid depletion with dietary exclusion). Thiamine supplementation in some cases of E2 subunit deficiency. Valine, isoleucine, and their corresponding ketoacids are more readily excreted than leucine and ketoleucine. That explains the usual need of Val and ileu in excess of leu.

Question 63

tyrosinemia type 1

Answer 63

fumarylacotoacetate hydrolase (FAH) deficiency. Autosomal recessive inheritance. Often due to founder affect (quebecois, finland). 3 presenting forms: early in infancy (1 to 6 months), with liver disease (hepatic failure or cholestatic jaundice or cirrhosis with renal tubulopathy) (As a rule a liver failure presenting in the first 2 weeks of life is NOT due to tyrosinemia type 1); late infancy, presenting with rickets due to renal tubulopathy (Fanconi syndrome) with no obvious liver failure; prophyria like attack at any age (can be presenting sign).

Question 64

Fanconi syndrome

Answer 64

a disease of the proximal renal tubules of the kidney in which glucose, amino acids, uric acid, phosphate and bicarbonate are passed into the urine, instead of being reabsorbed. Fanconi syndrome affects the proximal tubule, which is the first part of the tubule to process fluid after it is filtered through the glomerulus. It may be inherited, or caused by drugs or heavy metals.

Question 65

rickets

Answer 65

Rickets is defective mineralization or calcification of bones before epiphyseal closure in immature mammals due to deficiency or impaired metabolism of vitamin D, phosphorus or calcium, potentially leading to fractures and deformity.

Question 66

Succinylacetone

Answer 66

Succinylacetone, an abnormal metabolite of the tyrosine metabolic pathway, is produced in patients with hereditary tyrosinemia because of a genetic deficiency of fumarylacetoacetase. This metabolite greatly inhibits the activity of ALA dehydratase and accounts for the elevated excretion of ALA in urine in this disease, leading to porphyria like abdominal pain crisis and peripheral neuropathy. Tyrosine is very proximal to the block and is only moderately elevated

Question 67

cellular effects of tyrosinemia type 1

Answer 67

toxic compounds such as fumarylacetoacetate, maleylacetoacetate, and succinylacetone accumulate. hepatocullular damage occurs leading to cirrhosis, hepatocellular carcinoma, high alpha fetoprotein (unreliable as marker in neonates).

Question 68

Urine dinitrophenylhydrazine (DNPH) test

Answer 68

DNPH precipitates with branched chain ketoacids.2-hydroxyisoleucine is responsible for the maple syrup urine odor.

Question 69

Valine: Leucine ratio in MSUD

Answer 69

Normally valine is greater than leucine. During fasting or ketosis, branched chain amino acids may be mobilized from muscle back to liver to support gluconeogenesis but the ratios of three amino acids in the blood remain normal. In MSUD, the valine:leucine ratio is inverted.

Question 70

Treatment of Tyrosinemia type 1

Answer 70

2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexane-dione (NTBC) inhibits 4-hydroxyphenylpyruvic acid dioxygenase, which further increases plasma tyrosine. Decreased production of FAA and succinylacetone may not prevent hepatocellular carcinoma. Phe and Tyr restriction necessary to avoid excessive hypertyrosinemia (risk of keratitis and palmoplantar keratosis). Liver transplant if hepatocellular carcinoma develops

Question 71

2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexane-dione (NTBC)

Answer 71

The mechanism of action of nitisinone involves reversibile inhibition of 4-Hydroxyphenylpyruvate dioxygenase (HPPD),. This is a treatment for patients with Tyrosinemia type 1 as it prevents the formation of maleylacetoacetic acid and fumarylacetoacetic acid, which have the potential to be converted to succinyl acetone, a toxin that damages the liver and kidneys. This causes the symptoms of Tyrosinemia type 1 experienced by untreated patients.

Question 72

Alkaptonuria

Answer 72

Alkaptonuria is an inherited condition that causes urine to turn black when exposed to air. Ochronosis, a buildup of dark pigment in connective tissues such as cartilage and skin, is also characteristic of the disorder. This blue-black pigmentation usually appears after age 30. People with alkaptonuria typically develop arthritis, particularly in the spine and large joints, beginning in early adulthood. Mutations in the HGD gene cause alkaptonuria. The HGD gene provides instructions for making an enzyme called homogentisate oxidase. This enzyme helps break down the amino acids phenylalanine and tyrosine. As a result, a substance called homogentisic acid, which is produced as phenylalanine and tyrosine are broken down, accumulates in the body.

Question 73

cystathionine beta synthase deficiency

Answer 73

an increased excretion of the thiol amino acid homocysteine in urine and is characterized by nearsightedness (myopia), dislocation of the lens at the front of the eye, an increased risk of abnormal blood clotting, and brittle bones that are prone to fracture (osteoporosis) or other skeletal abnormalities. Some affected individuals also have developmental delay and learning problems. Eye abnormalities: Ectopia lentis, Myopia, May be an isolated presenting sign in children or adults. Developmental disability and neuropyschiatric symptoms

Question 74

Cystathionine-β-synthase

Answer 74

It catalyzes the first step of the transsulfuration pathway, from homocysteine to cystathionine.
CBS uses the cofactor pyridoxal-phosphate (PLP) and can be allosterically regulated by effectors such as the ubiquitous cofactor S-adenosyl-L-methionine (adoMet).

Question 75

Diagnostic evaluation of homocystaturia

Answer 75

Plasma amino acids: Methionine = 180 µM (normal 10–35 µM); Homocystine = 2 µM (normally undetectable); Total homocysteine = 150 µM. Urine amino acids: Homocystine = 20 mmol/mg creatinine; Normally undetectable. Urine organic acids normal (no MMA). Urine cyanide-nitroprusside test positive

Question 76

Signs of classical untreated homocystinuria

Answer 76

Skeletal malformations: Marfanoid habitus, Osteoporosis, Scoliosis, Most common in B6 non-responsive forms

Question 77

treatment of homocystinuria

Answer 77

No specific cure has been discovered for homocystinuria; however, many people are treated using high doses of vitamin B6 (also known as pyridoxine). Slightly less than 50% respond to this treatment and need to take supplemental vitamin B6 for the rest of their lives. Those who do not respond require a Low-sulfur diet (especially monitoring methionine), and most will need treatment with trimethylglycine.

Question 78

Recurrent thromboembolism with homocystinuria

Answer 78

May be a isolated presenting sign in late onset B6 responsive forms. Thromboembolism (venous/arterial) can be presenting sign; also phlebitis, pulmonary embolism, cerebrovascular accident. Environmental triggers: Anesthesia, Catabolism, Smoking, and Oral contraceptives

Question 79

Classical homocystinuria

Answer 79

Cystathionine β-synthase deficiency. Autosomal recessive inheritance. Incidence = 1/200,000 to 1/400,000 births; Incomplete ascertainment. Cases often missed on newborn screens obtained during the first week of life. 50% of CBS mutations are pyridoxine (vitamin B6) responsive

Question 80

Homocystinuria treatment

Answer 80

Pyridoxine (B6) challenge: 750 mg orally per day for one week; Monitor plasma methionine, total homocysteine; Hyperhomocysteinemia will normalize in pyridoxine responsive forms. Restrict dietary protein. Supplemented with methionine free medical foods. Oral betaine. Consider supplementation with B12, folate, and/or cysteine

Question 81

Urea Cycle Disorders (UCD)

Answer 81

The urea cycle rids waste ammonia from the body. It is a scaffold of amino acids that accept ammonia and release urea. In the absence of a functioning urea cycle (primary failure, secondary inhibition, liver failure), ammonia rises and is toxic to the central nervous system. Encephalopathy, coma, irreversible neurologic damage, or death may result. Urea cycle defects can present at any age (check an ammonia level for unexplained vomiting, seizures, progressive obtundation). Newborn screening does not detect all disorders of the urea cycle; always test if there is a clinical concern: plasma ammonia, plasma amino acids, urine orotic acid, urine amino acids

Question 82

Ammonia (NH3)

Answer 82

It is crucial to identify hyperammonemia early in order to prevent the devastating consequences of markedly elevated levels. Unless an ammonia level is checked, the diagnosis will be missed. May be elevated in: Urea cycle disorders (primary), Organic acidemias, Fatty acid oxidation disorders, Carnitine cycle disorders, Transient hyperammonemia of the newborn (THAN), Liver failure, Asparaginase treatment, Valproate therapy

Question 83

Ornithine Transcarbamylase (OTC) Deficiency

Answer 83

The most common urea cycle disorder. X-linked. Male hemizygotes with no enzyme activity may not survive the newborn period. 15% of female heterozygotes will have clinical symptoms ranging from mild to severe (dependent on pattern of X-inactivation)

Question 84

Diagnosis of Ornithine Transcarbamylase (OTC) Deficiency

Answer 84

Plasma amino acids: Low citrulline and Elevated glutamine (>1200 uM). Urine organic acids: Elevated orotic acid. Molecular genetic testing of OTC: Hemizygote for p.T178M mutation, Diagnostic for OTC deficiency

Question 85

diagnostic testing for urea cycle disorder

Answer 85

Specific disorder may be suspected on basis on biochemical findings, which may be pathognomonic for one disorder (eg. very high ASA in arginosuccinate lyase deficiency). DNA testing may be used for diagnosis and to guide genetic counseling. Diagnosis may require enzyme assay if DNA testing is negative; skin or liver biopsy may be required

Question 86

Ammonia Scavenging Agents

Answer 86

Intravenous arginine (argininosuccinase deficiency) sodium phenylbutyrate and sodium benzoate (ornithine transcarbamoylase deficiency) are pharmacologic agents commonly used as adjunctive therapy to treat hyperammonemia in patients with urea cycle enzyme deficiencies.[1] Sodium phenylbutyrate and sodium benzoate can serve as alternatives to urea for the excretion of waste nitrogen. phenylbutyrate, which is the prodrug of phenylacetate, conjugates with glutamine to form phenylacetylglutamine, which is excreted by the kidneys. Similarly, sodium benzoate reduces ammonia content in the blood by conjugating with glycine to form hippuric acid, which is rapidly excreted by the kidneys.

Question 87

treatment of urea cycle disorder

Answer 87

Dietary protein restriction. Ammonia scavenging medications. L-arginine or L-citrulline supplementation (depending on the specific defect). Acute, severe hyperammonemia may require hemodialysis or intravenous scavengers. Consider liver transplantation for patients with recurrent hyperammonemia or brittle disease refractory to medical management.

Question 88

Glycolipids

Answer 88

Glycolipids are molecules that contain both carbohydrate and lipid components. Glycolipids have roles in cell signaling, cell membranes, and as an energy source. In higher organisms, most glycolipids are glycosphingolipids, but glycoglycerolipids and other types exist. The synthesis, functions, and degradation of glycolipids involve complex pathways involving dozens of substrates, and enzymes, cofactors. They are important in many cell types, especially nervous tissues.

Question 89

Lysosomes

Answer 89

Lysosomes are single-membrane bound, intracellular organelles found in all mammalian cells except red blood cells. Lysosomes are acidic, hydrolase-rich organelles that are capable of degrading most biological macromolecules. ‘Hydrolases’ refer to enzymes that can function in the acid environment of the lysosome; hydrolases are targeted to the lysosomes by Mannose-6-Phosphates (M6P) on the hydrolases that are recognized by M6P receptors. Lysosomes receive input from both the endocytotic and biosynthetic pathways, which means they can degrade biological macromolecules from extracellular (endocytic) and intracellular (biosynthetic) sources.

Question 90

Lysosomal Storage Diseases (LSDs)

Answer 90

LSDs are a group of disorders where defects in lysosomal ‘function’ are present and one (or more) biomolecules cannot be properly degraded and/or processed. In most cases, LSDs are due to the absence of one or more lysosomal enzymes. As a result, undigested glyco-lipids and extracellular components that would normally be degraded by lysosomal enzymes accumulate in lysosomes as large inclusions. In most of these conditions, substrate storage is manifested clinically as an increase in the mass of the affected tissues and organs. When the brain is affected, however, as is often the case, the picture is one of neurodegeneration. The different presentations of LSDs is driven in part by which enzyme(s) is defective and what material(s) accumulate in which organ(s).

Question 91

LSD Inheritance

Answer 91

The majority of LSDs are inherited in an autosomal recessive fashion. Three exceptions that are inherited in X-linked fashion are: Fabry disease (alpha-galactosidase) and Hunter syndrome (iduronate-2-sulfatase)

Question 92

Key signs of LSD

Answer 92

macrocephaly, cognitive regression, corneal clouding, cherry red spot (Most commonly a retinal finding connected with Tay Sachs disease), macroglossia, sleep apena, hepatosplenomegaly (Can be massive, protuberant belly; typically does not lead to liver function abnormalities), proteinuria (Fabry), dysostosis multiplex (abnormal bony structure on X-rays; Vertebral ‘beaking’, broad bases of metacarpals and phalanges, scoliosis), joint stiffness, short stature

Question 93

Gaucher Disease

Answer 93

presents with: Hepatosplenomegaly, Aseptic necrosis of the femur, Bone crises, Pancytopenia or thrombocytopenia, Neurological symptoms occur in less frequent sub-types of Gaucher’s disease. Gaucher disease is caused by a deficiency in β-glucocerebrosidase. This leads to an accumulation of glucocerebroside. Gaucher cells are lipid filled macrophages that appear like crumpled paper seen in Gaucher disease. Gaucher disease is the most common lysosomal storage disease. The treatment for Gaucher disease is recombinant glucocerebrosidase.

Question 94

Fabry Disease

Answer 94

presents with: Peripheral neuropathy of the hands and feet, Angiokeratomas ( benign cutaneous lesion of capillaries, resulting in small marks of red to blue color and characterized by hyperkeratosis), Cardiovascular disease, Renal disease, Patients also have a 20-fold increased risk in stroke. X linked recessive. Fabry disease is caused by a deficiency in α-galactosidase A. This leads to an accumulation of ceramide trihexoside.

Question 95

Niemann-Pick Disease

Answer 95

presents with: Progressive neurodegeneration, Hepatosplenomegaly, Cherry-red spots on the macula, and Foam cells (lipid filled macrophages). Niemann-Pick Disease is caused by deficiency in sphingomyelinase. This leads to an accumulation of sphingomyelin, with CNS involvement.

Question 96

Krabbe Disease

Answer 96

presents with: Peripheral neuropathy, Developmental delay, Optic atrophy, Globoid cells, Fever in the absence of infection, Irritability (Krabbe presents with crabbiness). Krabbe Disease has a deficiency in galactocerebrosidase. This leads to an accumulation of galactocerebroside and psychosine.

Question 97

Tay-Sachs Disease

Answer 97

presents with: Progressive neurodegeneration, Developmental delay, Cherry-red spot on the macula, Lysosomes that appear like onion skins (whorled membranes). Note that there is no hepatosplenomegaly. Tay–Sachs disease is caused by insufficient activity of the enzyme hexosaminidase A,

Question 98

Metachromatic leukodystrophy

Answer 98

presents with central and peripheral demyelination with ataxia and dementia. Metachromatic leukodystrophy has a deficiency in Arylsulfatase A. This leads to an accumulation of cerebroside sulfate.

Question 99

Hurler syndrome

Answer 99

presents with: Developmental delay, Airway obstruction, Corneal clouding, Hepatosplenomegaly, “Gargoylism” (a somewhat outdated term that refers to the physical features typical of Hurler syndrome: clawed hands and thick, coarse facial features with a low nasal bridge). Hurler syndrome has a deficiency in α-L-iduronidase. This leads to an accumulation of heparan sulfate and dermatan sulfate. Deposition in coronary arteries leads to ischemic heart disease.

Question 100

Hunter syndrome

Answer 100

presents as a mild form of Hurler’s syndrome, but also includes aggressive behavior and lacks corneal clouding. Mnemonic: “A hunter needs to see clearly” (i.e. no corneal clouding). Hunter syndrome has a deficiency in iduronate sulfatase. This leads to an accumulation of heparan sulfate and dermatan sulfate. Hunter syndrome has X linked recessive inheritance.

Question 101

Pompe’s Disease

Answer 101

presents with left ventricular hypertrophy, which leads to outflow tract obstruction and cardiac failure. Mnemonic: “The pump (heart) gets trashed in Pompe’s”. Pompe’s disease has a deficiency in lysosomal α-1,4-glucosidase. This leads to glycogen deposits in the lysosomes.

Question 102

I-Cell disease

Answer 102

presents with: Growth and developmental delay, Coarse facial features, Gingival hypertrophy, Skeletal abnormalities. Caused by a defective phosphotransferase enzyme which leads to the inability to properly synthesize the mannose-6-phosphate tag required for targeting enzymes to lysosomes. As a result, high levels of lysosomal enzymes build up in the extracellular space. Also, without digestive enzymes in the lysosomes, the lysosomes become engorged and interfere with cellular function. The disease is called I-cell due to cytoplasmic Inclusions in fibroblasts.

Question 103

McArdle’s

Answer 103

caused by defective skeletal muscle glycogen phosphorylase (myophosphorylase). Defective myophosphorylase prevents glycogen breakdown in muscle. Common clinical findings of McArdle disease include: Myoglobinuria, Muscle cramps, No change in blood lactate levels post exercise, Electrolyte abnormalities. Note that blood glucose levels are unaffected. Glycogen structure is unaffected in McArdle disease.

Question 104

general guidelines of when to feed

Answer 104

Previously well nourished adult who cannot eat but who has minimal acute medical illness: Might go 10-14 days without food before they begin to develop potentially serious nutritional deficiencies. Previously undernourished adults with minimal medical illness, or previously well nourished individuals with serious acute medical illness (infection, surgery, cancer): Might go 5-7 days without food before they begin to develop potentially serious nutritional deficiencies. Previously undernourished adults with serious medical illness: may develop potentially serious nutritional deficiencies in 3-5 days if they are not fed. These numbers will be substantially shorter for infants and children as they have smaller pool sizes and increased nutrient needs due to growth and development.

Question 105

how many calories to feed your patient

Answer 105

general ranges for total expenditure of energy are 22-25 kcal/kg/day for someone who is not that sick to 30-32 kcal/kg/day for someone who is very sick. An average protein requirement for sick patients is 0.8-1 g protein/kg body weight/d.

Question 106

Nutritional support in respiratory failure

Answer 106

Breathing brings O2 into the body for oxidative metabolism and excretes CO2 produced by nutrient oxidation. If you overfeed a patient, they will tend to try increase their rate of oxidation of nutrients and as a result consume more oxygen and produce more CO2. With more CO2 production comes the need for more ventilation. If a person is having trouble getting off a ventilator you do not want to over feed them. However you also do not want to underfeed them which could lead to weakness of their respiratory muscles. It turns out that there is more CO2 produced for each O2 consumed when glucose is burned as compared to fat. For this reason some people say that to minimize CO2 production while still giving adequate energy you might consider feeding people on a ventilator a high fat diet. The evidence in favor of this idea is limited.

Question 107

Nutritional support in liver failure

Answer 107

Patients with end stage liver disease may develop “hepatic encephalopathy” which is due in part to high levels of ammonia in their blood which accumulate because of an inability of their liver to incorporate the ammonia into urea. These patients may also have ascites which is due to salt and water retention. For these reasons it may be prudent to limit protein, salt and water intake in a person who has hepatic encephalopathy. This must be weighed against the possible deleterious effects of underfeeding a person who may already be malnourished. Some clinicians think that part of the alterations in consciousness seen in patients with end stage liver disease come from the accumulation of “false neurotransmitters” that derive from high levels of aromatic amino acids seen in these patients. For this reason some advocate the use of diets that are high in branched chain amino acids to both give adequate protein without fostering the production of these “false neurotransmitters” in the brain. Here again, the data in support of this idea is not strong.

Question 108

Nutritional support in renal failure

Answer 108

The kidneys are responsible for excreting urea. If they do not work the levels of blood urea nitrogen (BUN) increases. The source of this nitrogen is protein catabolism. For this reason some clinicians would limit the amount of protein a person with renal failure gets each day. Here again, this must be weighed against the risk of providing too little protein to a person who may already be undernourished. In general, you certainly do not want to overfeed protein to a person with end stage renal disease, but neither do you want to overly restrict it. The calculation of nitrogen balance is more difficult in these individuals but can be done.

Question 109

Nutritional support in cardiac disease

Answer 109

Patients with cardiac disease can be admitted with complications of CAD such as angina or an acute MI or problems of volume overload from congestive heart failure (CHF). For patients with CAD it may be useful to take the opportunity of hospitalization to have a nutritionist discuss a saturated fat restriction in the diet. For overweight or obese patients, restriction of energy may also be important. For patients with CHF, the main dietary constituent to restrict is Na+. A standard approach is to place these patients on a 2 g Na+ diet. A “cardiac diet” is often an option for hospitalized patients. This diet typically is a low fat, low sodium, low saturated fat diet.

Question 110

Nutritional support in diabetes

Answer 110

control of blood glucose levels depends in part on dietary carbohydrate intake as well as the use of glucose lowering medications. Often insulin is used to control glucose in the hospital. The most important thing in dosing insulin with meals is the amount of carbohydrate in the meal. Ideally a hospital will offer a diabetic diet with controlled carbohydrate content with each meal. This is sometimes not available. In this situation, patients should be advised to be aware of the carbohydrate content of the meals that they order from the hospital menu. Some hospitals have a “diabetic diet” as an option for inpatients. These diets are often restricted in calories, fat and simple sugars. While it may be helpful to have patients consume a diet like this, we often adjust anti-diabetic medications in the hospital based on blood sugars obtained in the hospital. If the patient goes home and eats substantially more than they did in the hospital, the program of medications used in the hospital may no longer be appropriate. Another option may be to have the patient to eat in the hospital more like they will eat at home. That way medications can be adjusted to a diet that is more like what they will be eating at home.

Question 111

vitamin A function

Answer 111

essential in photochemical basis of vision (signals in retina􏰄brain visual cortex); maintenance of conjunctival membranes & cornea; critical for epithelial cellular differentiation and proliferation

Question 112

vitamin food source

Answer 112

preformed Vit A (retinol/retinal): liver, dairy products, egg yolks, fish oil (e.g. cod liver oil) precursor (carotenoids e.g. beta-carotene): abundant in deep yellow/orange & green vegetables, eg. spinach, carrots, broccoli, pumpkin

Question 113

vitamin A food source

Answer 113

preformed Vit A (retinol/retinal): liver, dairy products, egg yolks, fish oil (e.g. cod liver oil) precursor (carotenoids e.g. beta-carotene): abundant in deep yellow/orange & green vegetables, eg. spinach, carrots, broccoli, pumpkin

Question 114

risk of vitamin A deficiency

Answer 114

low intake &/or low fat intake (fat

Question 115

risk of vitamin A deficiency

Answer 115

low intake &/or low fat intake (fat

Question 116

biochemical evaluation of vitamin A levels

Answer 116

serum retinol (but levels remain WNL until liver stores nearly exhausted & ↓ w/ Acute Phase Reaction)

Question 117

Vitamin D function

Answer 117

functions as a hormone; maintains intracellular & extracellular Ca++ w/in physiologic range; stimulates intestinal absorption Ca++and P, renal reabsorption of Ca++ and P, mobilization of Ca++ and P from bone; innate immune function (generation of toxic radicals), cellular growth and differentiation through nuclear and plasma membrane vitamin D receptors present in many types of cells, other: active area of scientific inquiry

Question 118

sources of vitamin D

Answer 118

precursor (dehydrocholesterol) in skin, converted to cholecalciferol (Vit D3) by UV light; Dietary sources: a) Natural: fish liver oils, fatty fish, egg yolks; b) fortified milk & formulas D3 from animal sources, D2 ergocalciferol from plant (algae) sources; D3 activity 2-3x > D2

Question 119

Metabolism of Vitamin D

Answer 119

Absorbed via chylomicrons; Vitamin D2 or D3 hydroxylated in liver, to 25-hydroxy- cholecalciferol and then in kidney to 1,25-dihydroxy-cholecalciferol (calcitriol) = active form

Question 120

deficiency of vitamin D

Answer 120

Deficient: 25OH-D /= 30 ng/mL (>80 nmol/L) evidence building of association of sufficiency with decreased risk chronic illnesses. Rickets: (25OH-D

Question 121

risk of vitamin D deficiency

Answer 121

lack of adequate sunshine exposure; low dietary intake; fat malabsorption (cystic fibrosis, liver disease, prox. sm. intest disease, orlistat – intestinal lipase inhibitor); breastfed infant, esp if mother deficient (low infant stores at birth); dark skin (􏰅pigmentation=decreased skin conversion; difficult to quantify); obesity (sequestered in fat); liver or renal disease (unable to activate – need calcitriol). Much recent data/discussion are whether U.S. population levels

Question 122

recommended dose of vitamin D

Answer 122

Supplement (400 IU D3) to all breastfed infants until receiving at least 500 ml(16oz+)/day infant formula or milk; non-breastfed infants/children not receiving > 500 ml infant formula or Vit D fortified milk. Other: 5-15 min unprotected sun exposure or UVB tanning (varies with pigmentation) x 2-3x/wk not recommended by American Academy of Dermatology. RDA = 600 IU/d children and adults 70yrs; Tol Upper Limit 4000 IU/d.

Question 123

Hypervitaminosis of vitamin D

Answer 123

risk with chronic granulomatous diseases (e.g. sarcoidosis)

Question 124

toxicity of vitamin D

Question 125

biochemical evaluation of vitamin D

Answer 125

serum 25(OH) Vit D levels reflect nutritional status

Question 126

function of vitamin E

Answer 126

antioxidant, free radical scavenger; cell membrane stabilizer

Question 127

food source of vitamin E

Answer 127

polyunsaturated vegetable oils, wheat germ

Question 128

vitamin E deficiency

Answer 128

neurologic degeneration: with loss of reflexes (DTR’s), spinocerebellar ataxia, neuropathy, ophthalmoplegia; incoordination, loss of vibration and position sense; hemolytic anemia

Question 129

risk of deficiency of vitamin E

Answer 129

prematurity, fat malabsorption syndromes, short gut syndrome, C.F.

Question 130

toxicity of vitamin E

Answer 130

low; coagulopathy (very large doses inhibit Vit K dependent factors

Question 131

megadoses of vitamin E

Answer 131

for protection against heart disease and/or cancer not supported by most current literature

Question 132

vitamin K function

Answer 132

essential for carboxylation of coagulation proteins (Factors II (prothrombin), VII, IX, X, C, and S)

Question 133

sources of vitamin K

Answer 133

leafy vegetables, fruits, seeds; synthesized by intestinal bacteria

Question 134

deficiency of vitamin K

Answer 134

prolonged coagulation times; hemorrhagic disease of newborn: bleeding into skin (purpura), gi tract, CNS

Question 135

risk of deficiency of vitamin K

Answer 135

newborns (poor placental transport, sterile gut, low clotting factors); late (2-12 wk), esp. breastfed infants (breast milk relatively low) or fat malabsorption syndromes, chronic antibiotic use.

Question 136

recommended dose of vitamin K

Answer 136

All newborns should receive single IM dose of 0.5-1.0 mg (adequacy of oral doses presently not defined)

Question 137

function of vitamin B1 (thiamine)

Answer 137

Thiamine Diphosphate (TDP or thiamin pyrophosphate TPP): coenzyme central to intermediary metabolism in all cells, esp. glycolysis, TCA cycle, amino acid metabolism; decarboxylation and transketolation reactions; TTP thought to bind at Na+ channel in nerve membranes; many function in nerve conduction. Functions as coenzyme for alpha ketogluterate dehydrogenase, pyruvate dehydrogenase, branched chain ketoacid dehydrogenase, and transketolase

Question 138

food sources of thiamine

Answer 138

Esp. rich in whole grains (high in germ) enriched grains lean pork legumes

Question 139

recommended intake of thiamine

Answer 139

1.1-1.2 mg/d. Treatment for deficiency: 50-100 mg intramuscular or intravenous

Question 140

thiamine deficiency

Answer 140

Classical syndrome: Beriberi; Dry (paralytic/nervous) beriberi: peripheral neuropathy w/ impairment of sensory, motor, and reflex functions; affects distal > proximal limbs; muscle tenderness, weakness/ atrophy, foot/wrist drop Wet (cardiac) beriberi: edema and high output cardiac failure (tachycardia, cardiomegaly and CHF) + signs/sxs of dry beriberi Wernicke-Korsakoff syndrome (cerebral beriberi): “Triad” – ocular signs (nystagmus, ophthalmoplegia), ataxia, and amnesia/mental confusion. Retentive memory impaired out of all proportion to other cognitive function; only partially reversible with pharmacologic doses of thiamin; genetic predisposition for different susceptibility, unmasked by EtOH abuse, dietary deficiency. Neuro sxs may be only partially reversible (ophthalmoplegia quickly responds)

Question 141

biochemical evaluation of thiamine

Answer 141

Erythrocyte transketolase activity; blood thiamine levels

Question 142

Populations at risk of thiamine deficiency

Answer 142

Alcoholics most at risk in US (low intake, poor intestinal absorption, defective metabolism); elderly may have relatively high incidence of mild deficiency; chronic renal dialysis patients; adults on high carbohydrate diet derived mainly from milled rice or unenriched grains; anorexia nervosa patients and refeeding after starvation may precipitate deficiency because body “stores” insufficient to handle increased demand to metabolize CHO/energy load; bariatric surgery (assoc. w/ bypass, banding, and gastric sleeve). Dietary deficiency still common in many Asian countries with high reliance on refined rice.

Question 143

Function of vitamin B2 (riboflavin)

Answer 143

Part of 2 co-enzymes, flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) which function in oxidation/reduction reactions in TCA cycle and oxidative phosphorylation; Amino acid & fatty acid metabolism; metabolism of vit K, folate B6, and niacin.

Question 144

food sources of riboflavin

Answer 144

Richest sources: liver, wheat germ; Dairy = largest contribution to intake in US diet (UV light destroys the vitamin), meats & poultry; leafy greens

Question 145

recommended daily intake

Answer 145

1.1-1.3 mg/d

Question 146

deficiency of riboflavin

Answer 146

oral- ocular genital syndrome, chellosis (cracking of lips) and angular stomatitis (sores at corner of mouth), increased vascularization of conjunctiva and photophobia, and seborrheic dermatitis and scrotal dermatitis

Question 147

biochemical evaluation of riboflavin

Answer 147

Erythrocyte glutathione reductase activity co-efficient (EGRAC) (increased in deficiency)

Question 148

risk for riboflavin deficiency

Answer 148

women and infants, elderly, adolescents; Gross isolated deficiencies rare in US, but may be significant incidence of milder deficiency in those ingesting

Question 149

Function of niacin (vitamin B3)

Answer 149

Nicotinamide is substituent of the critical electron carrying substances NAD & NADP; functions in multiple energy related pathways, including glycolysis, TCA cycle and oxidative phosphorylation and fatty acid synthesis and oxidation.

Question 150

food sources of niacin

Answer 150

Meats, poultry, fish, peanut butter, legumes are major sources of preformed niacin. Tryptophan = precursor; diets w/ liberal amounts of milk and eggs (rich in tryptophan) are likely adequate for niacin, even if low in preformed niacin.

Question 151

recommended daily amount of niacin

Answer 151

14-16 mg/d; Niacin equivalents (NE): 1 NE = 1 mg niacin or 60 mg tryptophan. Deficiency treatment: 50-100 mg 3x/day for 3-4 days

Question 152

niacin deficiency

Answer 152

Pellagra: “The 4 D’s:” Dermatitis: characteristic symmetric pattern; aggravated by sun, heat exposure. Dementia - confusion, dizziness, and
hallcucinations. Diarrhea. Death

Question 153

toxicity of niacin

Answer 153

Relatively nontoxic in doses of 3 - 6 grams/d of nicotinic acid; used to lower serum cholesterol (esp LDL); initially causes peripheral vasodilation & flushing; less common: 􏰅 serum uric acid, glucose intolerance, liver damage.

Question 154

biochemical evaluation of niacin

Answer 154

urinary excretion of N1- methylnicotinamide and 2-pyridone (ratio

Question 155

risk of niacin deficiency

Answer 155

appears after months of poor intake; historically, occurred in areas where corn was major source of protein and calories in diet; clinically, may be seen w/ generalized malabsorption; alcoholism; cirrhosis; metabolic “shunting” (eg carcinoid tumors producing excessive serotonin and shunt tryptophan away from usual metabolic pathway); Rx w/ isoniazid (for tuberculosis); may also be seen in Hartnup disease (defective absorption of tryptophan by the intestine and kidneys).

Question 156

function of folate

Answer 156

1-carbon transfers, esp. in synthesis of nucleic acids and for metabolism of certain amino acids; conversion homocysteine 􏰄 methionine. Methyl-donor, epigenetics

Question 157

food sources of folate

Answer 157

“foliage” - deep green leaves, broccoli, orange juice, whole grains
(easily destroyed w/ prolong cooking); fortification of grains in U.S. in 1998 leading to increased intakes

Question 158

recommended daily amount of folate

Answer 158

400 μg/d; women of child bearing age advised to have intake 400 μg/d to prevent neural tube defects; RDA during pregnancy = 600 μg/d.

Question 159

deficiency of folate

Answer 159

Macrocytic anemia, hypersegmented neutrophils, glossitis, increased plasma homocysteine; increased occurrence & recurrence of neural tube defects; risk partly hereditary, partly polygenic; Individuals w/ MTHFR gene increases requirement

Question 160

biochemical evaluation of folate

Answer 160

rbc folate reflects tissue stores & chronic status; serum folate reflects recent intake

Question 161

risk of folate deficiency

Answer 161

Pregnant women, breastfed infant of folate deficient mother; infants/children fed unsupplemented goat’s milk; medications: Dilantin, sulfasalazine; chronic hemolytic anemia or blood loss

Question 162

function of vitamin B12 (cobalamin)

Answer 162

Closely related to folate metabolism & 1-C transfers; Metabolism of odd chain length fatty acids; Re-form tetrahydrafolate from methylfolate (in formation of methionine); Isomerization of methylmalonyl Co-A to succinyl Co-A (essential to lipid & CHO metabolism). Interaction essential for protein & nucleic acid synthesis.

Question 163

food sources of cobalamin

Answer 163

Animal products only

Question 164

recommended daily amount of cobalamin

Answer 164

2.4 μg/d; Slow turnover rates; Intakes in US generally&raquo_space; RDA;

Question 165

cobalamin deficiency

Answer 165

Macrocytic anemia, hypersegmented neutrophils, Neurologic disturbances: paresthesias, gait problems, depression. Note: hematologic effects reversible, but neurologic effects are irreversible with longstanding deficiency. Treatment with folate will correct anemia but has NO effect on neurologic symptoms. Macrocytic anemia should not be treated with folate unless B12 deficiency has been ruled out.

Question 166

absorption and homeostasis with cobalamin

Answer 166

Cleavage of vit from dietary protein & binding to “intrinsic factor” (IF) secreted by gastric parietal cells. Cobalamin - IF complex absorbed from distal ileum. Absorbed into portal circulation, transported bound to transcobalamin II. Liver stores 1-10 mg (vs RDA); Can take years to develop deficiency, unless damage to stomach, ileum, pancreas

Question 167

biochemical evaluation of cobalamin

Answer 167

Serum B12 level; urine or blood methylmelonic acid (increased in defic); Serum homocysteine (increased in deficit);
CBC (increased MCV) (non-specific)

Question 168

risk of cobalamin deficiency

Answer 168

Vast majority of cases of B12 deficiency result from inadequate absorption. Pernicious anemia: hereditary condition with gastric atrophy in which IF is not produced or secreted (may be autoimmune phenomenon), resulting in 􏰆 B-12 absorption; relatively common in elderly; may need more b/c decreased absorption of food-bound B-12 􏰊advised to use fortified foods or supplements. Gastric atrophy associated with aging; may require parenteral administration to correct. Resection of stomach or ileum as in patients with gastric/bariatric surgery or short gut syndrome,; Strict vegetarian diet without supplementation; Breastfed infant of deficient mother (e.g. unsupplemented strict vegetarian mother). Auto-immune conditions 􏰄 antibodies to IF

Question 169

function of vitamin B6 (Pyridoxine)

Answer 169

critical in amino acid metabolism, interconversions

Question 170

food source of B6

Answer 170

animal products, vegetables, whole grains (lost in processing, not enriched)

Question 171

deficiency of B6

Answer 171

anemia, seizures, glossitis; +/- depression?

Question 172

vit B6 toxicity

Answer 172

doses > 500 mg/d associated with sensory ataxia, impaired position/vibratory sensation; symptoms partially reversed with d/c of supplement

Question 173

biochemical evaluation of vit B6

Answer 173

pyridoxal, phosphate, homocysteine

Question 174

risk of vitamin B6 deficiency

Answer 174

Primarily associated with use of Isoniazid medication (INH); end-stage renal diseases/renal insufficiency; malabsorption syndromes, such as celiac disease, Crohn’s disease, ulcerative colitis; Certain genetic diseases, such as homocystinuria; elderly with poor diet

Question 175

vitamin C function

Answer 175

antioxidant/reducing agent (=electron donor); Collagen synthesis; reduction of Fe3+ to Fe2+ & enhanced Fe absorption; Norepinephrine synthesis

Question 176

absorption and homeostasis of vitamin C

Answer 176

Through active (saturable) process; dose dependent: at low doses ( 1.5 g/d, absorption ~50%; at 10 g/d, absorption ~15 %. 􏰊 if large total intake, better to take divided in 
80 mg/d; maximum pool size ~ 2000 mg; intakes > 400-500 mg/d leads to minimal further increase in plasma a.a. concentrations.

Question 177

risk of vitamin C deficiency

Answer 177

diets lacking in fruits and vegetables, 􏰅 requirements for wound healing & burns; low income (associated with poor diet quality), smokers; infants fed cow’s milk (evaporated or pasteurized) without supplementation

Question 178

Function of iron

Answer 178

Oxygen transport in blood (hemoglobin) and muscle (myoglobin). Electron transfer enzymes (cytochromes). Enzymes for activation of oxygen (oxidases and oxygenases)

Question 179

food sources of iron

Answer 179

Heme iron: Cellular animal protein: meats, poultry, liver; (milk is poor source). Non-heme: legumes, nuts, whole grains (esp when enriched/fortified, green leafy vegetables; Note: absorption of non-heme iron, much lower (􏰌􏰉􏰍􏰎 20%)

Question 180

recommended daily amount of iron

Answer 180

8 mg/d adult male; 18 mg/d adult female (8 mg/d post-menopausal); (Pregnancy: 27 mg/d – generally requires supplement)

Question 181

factors affecting iron absorption

Answer 181

Dietary factors that form insoluble complexes (phytate, tannins, phosphate, oxalate). Factors affecting oxidation state (ascorbic acid: Fe3+ to Fe2+; absorption enhanced for reduced state). Chemical form (non-heme/inorganic vs heme (heme iron enhances absorption of non-heme)). Mineral-mineral interactions: excessive Zn or Cu leading to decreased Fe absorption. Host factors: physiologic states (Pregnancy, growth, erythropoiesis); Fe deficiency leads to increased absorption; inflammation: leads to increased hepcidin from liver leads to increased absorption at enterocyte. Quantity present in the meal/gut lumen (inverse relationship)

Question 182

homeostasis of iron

Answer 182

Main site of regulation is intestinal absorption; once absorbed, very efficiently/effectively retained (e.g. recycling from rbc/Hb breakdown); bleeding = major route of iron loss; stores: liver, bone marrow, spleen. Transport: Transferrin. Storage form: ferritin or hemosiderin (aggregated ferritin molecules). Iron distribution: Males: 2500 mg in circulating hemoglobin; 500-1000mg in stores. Females: 1500 mg in circulation; stores 􏰑 500 mg

Question 183

iron deficiency

Answer 183

Most common nutritional deficiency in the world; Populations “at risk”: infants > 6 mo old (low stores, high requirement); premature infants (very low stores, high requirement); adolescents (relatively high requirement + poor intake); pregnant women (increased requirement); populations with chronic infestations (e.g. helminths, causing intestinal blood loss), bariatric surgery patients, hospitalized elderly or elderly in long term care facilities. Deficiency in men or in post-menopausal women merits investigation for source of bleeding. Manifestations: Anemia (microcytic, hypochromic), decreased exercise/work tolerance, fatigue, listlessness; deficiency w/o anemia 􏰄 impaired cognitive function (permanent if onset in infancy?), impaired growth

Question 184

diagnosis of iron deficiency

Answer 184

nutritional deficiency suggested by low Hb/Hct and microcytic/hypochromic rbc (= severe deficiency);
low ferritin (= mild, moderate or severe deficiency; caveat: ferritin is an acute phase protein, and is elevated with inflammatory conditions; need to check inflammatory marker (ESR or CRP) coincidentally w/ ferritin for accurate interpretation); low serum Fe w/ high total Fe binding capacity (TIBC) leading to 􏰐low % saturation

Question 185

treatment of iron deficiency

Answer 185

Oral iron supplements (ferrous sulfate) 30-60 mg/d x 2-6 mo for replenishment of iron stores (infants/children: 2-6 mg/kg/day)

Question 186

iron toxicity

Answer 186

Iron is a potent pro-oxidant 􏰊unnecessary iron supplementation to be avoided; normal individuals generally able to regulate absorption well enough to avoid iron overload syndrome; conditions requiring frequent blood transfusions can lead to iron overload (regular blood donation avoids excessive iron accumulation!). Excess iron deposited mainly as hemosiderin in reticuloendothelial cells. Large doses of supplemental iron interfere with absorption of zinc, copper & possibly other minerals. Hereditary Hemochromatosis –relatively common inherited condition in which Fe absorption is excessive due to defect in hepcidin; individuals accumulate increased Fe stores that are damaging, esp to liver (increased risk of hepatocellular carcinoma); public health concern re common Fe fortification, supplementation programs being harmful to these individuals; Medicinal Fe overdose is esp toxic; effects: hemorrhagic gastroenteritis, shock & acidosis, coagulation defects, hepatic failure; in children, 1-2 grams of iron may be fatal.

Question 187

zinc function

Answer 187

Regulation of gene expression (zinc finger transcription proteins, both RNA & DNA metabolism) Structural roles in membrane stability. Metalloenzymes (> 200). Especially critical during periods of growth and cellular/tissue proliferation (immune system, wound healing, skin & gi tract integrity); physiologic functions for which zinc is essential include normal growth, sexual maturation, sense of taste, immune function, night vision (possibly mediated through Vit A & retinol binding protein)

Question 188

food sources and absorption of zinc

Answer 188

Widely distributed in foods, but richest sources = animal products; (oysters extremely high); beef > poultry > fish, milk, eggs; relatively high in whole grains, legumes, seeds, etc but lower absorption from plant foods; Absorption impaired by phytate (found only in plants; esp high in corn, legumes, nuts). Absorption not increased w/ deficiency (unlike iron)

Question 189

recommended daily amount of zinc

Answer 189

men 11 mg/d; women 8 mg/d (Pregnancy: adolescents: 13 mg/d; adult: 11 mg/d)

Question 190

homeostasis of zinc

Answer 190

Absorption of dietary zinc and excretion of zinc from gi tract are important in regulating body zinc “pool”; Zinc secreted into gi tract w/ digestion, as part of pancreatic-biliary secretions; some reabsorbed, some
excreted, so route to excrete excess Zn exists (vs iron)

Question 191

risk of zinc deficiency

Answer 191

Infants (esp premature) & young children (high growth rate +/- marginal intake); breastfed infants > 6 mo; human milk low [Zn] after 6 mo – need source from foods. Pregnant women (high demand; critical for normal embryogenesis). Monotonous, plant based diets (esp if high in phytate); Bariatric surgery patients (up to 40% may be deficient due to decreased protein intake and malabsorption). Elderly: poor zinc status common and may be associated with higher incidence of pneumonia; increased ratio in elderly associated with higher mortality; may be biomarker of aging. (Age 2011, May 5). GI illness/injury: diarrhea associated w/ increased losses (World Health Organization: 20 mg/d x 10 days for acute diarrhea in young children). Wounds, burns: increased requirement for synthesis of new tissue. Worldwide, prevalence of zinc deficiency likely to be widespread, especially in populations on primarily plant based diet (high phytate); Zn deficiency estimated to account for 0.4 million deaths/yr in children

Question 192

manifestation of zinc deficiency

Answer 192

Mild: growth delays/stunting, anorexia, impaired immune function; impaired neurocognitive development. Moderate – severe: severe, characteristic dermatitis (acro-orificial); diarrhea, immune dysfunction, delayed wound healing, taste impairment, anorexia, personality changes. Acrodermatitis Enteropathica: mutation in enterocyte Zn transporter (ZIP4); fatal condition if not treated; responds to high doses of Zn supplements (lifetime); presents w/ severe dermatitis, growth failure, diarrhea.

Question 193

toxicity of zinc

Answer 193

relatively low; > 50 mg/d can decreased HDL-cholesterol, impair absorption of Fe & Cu, cause nausea, diarrhea

Question 194

other uses of zinc

Answer 194

Lozenges within 24 hr of first symptoms of a cold, may decrease the duration of illness by one to four days & significantly reduce the severity of cold symptoms; more research needed re dose and formulation; postulate Zn may prevent viral replication or attachment to nasal membranes.

Question 195

function of iodine

Answer 195

Integral part of thyroid hormones: thyroxine (tetraiodothyronine) (T4) and triiodothyronine (T3); thyroid gland able to concentrate iodine; amount in the gland 􏰒 intake

Question 196

food sources of iodine

Answer 196

Seafoods & seaweed (most iodine resides in the ocean); I content of crops grown and animal products (esp dairy & eggs) variable, dependent on composition of feeds and/or content of soil (“geochemical distribution”); iodized salt provides substantial source. Iodine content of soil varies (geochemical), depending on glaciation, rainfall, runoff into rivers. Historically in U.S. had “goiter belts” prior to iodization of salt. Worldwide, iodine deficiency remains a major public health issue, esp in mountainous areas. “Goitrogens” – foods containing ions which compete w/ iodide; e.g. thiocyanate (SCN-) ; contained in cassava, a common dietary staple which is associated w/ widespread goiter & hypothyroidism.

Question 197

absorption, metabolism, and excretion of iodine

Answer 197

Readily absorbed from food, reaches circulation as Iodide. In circulation, 95% as organic Iodine, 5% as Iodide; most T4 and T3 trannsported via carrier proteins (eg thyroxine binding globulin). Iodide uptake leads to 􏰐binding to T4 & T3 leading to 􏰐circulation

Question 198

iodine deficiency

Answer 198

common worldwide􏰐 causing endemic goiter & cretinism in children (5.7 million cretins exist; estimate 1 billion persons at risk for I deficiency disorders). Cretin child: (“deaf mutism”) dwarfed, mentally retarded, typical “dull” facies, large tongue; results from I deficiency during pregnancy; fetus: increased 􏰅abortions, stillbirths, congenital anomalies; Goiter: enlarged thyroid gland as compensation for 􏰆 I for thyroid hormone synthesis. In populations w/ endemic iodine deficiency, estimated to be responsible for a mean IQ loss of 13.5 points in the population. “Global Action Plan” adopted by WHO, UNICEF, World Bank to end Iodine Deficiency disorders by year 2000. Estimates from 2003 indicate 35% of world’s population still w/ “insufficient I intake, w/ highest rates in Europe (60%) and SE Asia (40%).

Question 199

Function copper

Answer 199

oxidative enzymes (cytochrome oxidase, ferroxidase, amine oxidase)

Question 200

food sources of copper

Answer 200

shellfish, meats, nuts; low in milk

Question 201

absorption and metabolism of copper

Answer 201

30-40% absorption from mixed diet; stored in liver; excreted in bile

Question 202

functions of selenium

Answer 202

Glutathione peroxidase (GSHx); deiodinase; important anti-oxidant

Question 203

food sources of selenium

Answer 203

Present in foods associated w/ amino acids (e.g. selenomethionine); intake varies widely w/ soil content (“geochemical” distribution). E.g., in areas of China, New Zealand, Finland, Venezuela, soil levels low, populations w/ much lower blood levels - ? functional consequences. Keshan disease, a cardiomyopathy in China which can be prevented w/ Se supplementation may represent interaction w/ other nutritional deficits (e.g. I) and/or viral infection (viral mutation to increase virulence in Se deficient host).

Question 204

absorption and metabolism of selenium

Answer 204

60-80% absorbed from diet; kidneys main site homeostasis & urine excretion

Question 205

Periods of vulnerability according age

Answer 205

0-12 mo: marasmus/severe wasting most common form of PEM, but stunting also very common, and often starts during first year of life. 12-24 mo: kwashiorkor/ edematous PEM more common (per classic descriptions; in U.S., experience is typically in younger infants). Older children: stunting common; typically degree of wasting is milder; Pregnant/lactating women: w/ PEM, effects primarily on fetus, neonates, and infants. Elderly: tend to suffer from PEM. [Adolescents, adult men, and non-pregnant/non-lactating women have lowest rates of PEM]

Question 206

Pathophysiology of Marasmus (“severe acute malnutrition/SAM”)

Answer 206

The “normal” physiologic response to starvation includes: Reduction in energy expenditure (decreased physical activity, bradycardia, hypothermia). Decreased activity of sodium pump. Shift in fuel utilization to mobilization of body fat (increased ketones, decreased gluconeogenesis). Muscle protein catabolism (but w/ 􏰁 overall protein turnover). Decreased inflammatory response & impaired immune function. Impaired function of G-I tract (dysmotility, malabsorption). (Reduced body mass). While these and other responses result in decreased nutrient demands and achieve a new equilibrium, if the nutritional deprivation persists, the patient is less able to adapt to complications, such as an infectious insult. As reserves are depleted, the individual is susceptible to injury that a normal host could withstand with little repercussion: ie, loss of functional reserve and loss of physiological responsiveness to stress are the hallmarks of the adaptation to severe PEM.

Question 207

Pathophysiology of Kwashiorkor

Answer 207

The etiologic mechanisms of kwashiorkor are not completely understood, it is generally considered a failure of the normal adaptive response of protein sparing that is normally seen in a fasting state. As noted above, classically protein deficiency in the face of adequate energy intake was thought to be etiologic, but clearly this is an oversimplification. Contributing factors include infectious stress, cytokine release, relative micronutrient deficiencies and possibly free radical exposure and oxidative damage. Potential role of the enteric microbiome recently highlighted (NEJM, 2013). Fat reserves and muscle mass tend to be unaltered; this may lead to the assumption that nutritional status is adequate. Other characteristic clinical findings include skin lesions (“flaky paint”), hair texture and pigmentation changes (“flag sign”), and generalized edema (“moon facies”). The list below indicates some of the metabolic derangements seen in kwashiorkor, which is associated with a relatively higher mortality than marasmus. Hypoalbuminemia & enlarged fatty liver leading to edema. Increased permeability of biological cell membranes leads to edema. Impaired sodium/potassium homeostasis (sodium excess, potassium deficiency). Hypotransferrinemia (anemia). Impairment of immune system (infection)

Question 208

Principles of Management of Severe PEM

Answer 208

1. Resolving life-threatening conditions: Cautious restoration of circulation – enteral preferred; avoid over-hydration; Potassium supplements ± Mg++; avoid excessive Na+; Treatment of infections (signs/symptoms may be mild/absent); Avoid hypoglycemia (preferably by small, frequent oral feeds). 2. Restoring nutritional status without abruptly disrupting homeostasis: Begin slowly (pt is adapted to malnourished state). Small frequent (􏰣 q 4 hr) feeds, liquid oral or via nasogastric tube. Initial goal = maintenance protein and energy requirements (ie, not catch-up amounts). Diet should be high biologic quality protein, high fat. Replete specific micronutrient deficiencies (especially K, Mg, P, Zn, Vitamin A). 3. Ensuring nutritional rehabilitation. Gradually advance energy intakes to 1.5x normal and 3-4x protein needs; Usually begins 1-2 wk after initial stabilization – after resolution of edema. Restoration of appetite may be prolonged, especially in kwashiorkor. Introduction of familiar foods. Emotional & physical stimulation, including physical activity to enhance recovery of cardiorespiratory and skeletal function.

Question 209

refeeding syndrome

Answer 209

Refeeding a starved person may result in predictable metabolic derangements, esp due to acute shifts from extracellular to intracellular spaces. Most common & potentially dangerous: K+, P, & Mg++. Potassium: increased insulin secretion (in response to feeding) leading to intracellular glucose & K+ causing decreased serum K+ leading to altered nerve/muscle function. Phosphorus: increased insulin secretion causes intracellular P; increased intracellular phosphorylated intermediates; P “trapped” in intracellular space; Magnesium: increased requirements w/ increased metabolic rate (= co-factor for ATPase). Any one of these derangements, if severe, can cause sudden death.

Question 210

classification of obesity

Answer 210

overweight (BMI of 25-29.9 kg/m2) was associated with slightly lower mortality and that stage I obesity (BMI of 30-34.9 kg/m2) had similar mortality, compared with “normal” BMI (BMI 18.5-24.9 kg/m2). However, most studies show that mortality rises as BMI increases above 25 kg/m2 and particularly above a BMI of 30 kg/m2. The relationship between BMI and total mortality and morbidity rises more steeply at cutoffs of 35 kg/m2 and 40 kg/m2. Gender does not substantially alter the relationship between obesity and health risk. Therefore, the same cutoff points are used to define overweight (BMI 25-29.9 kg/m2), obesity (BMI 􏰆 30 kg/m2), and severe obesity (BMI 􏰆 40 kg/m2), and in both men and women. Age does modify this relationship to some extent, with studies showing that the lowest mortality in older individuals may be a BMI of 25-29.9 kg/m2. Ethnic differences exist in disease risk at a given degree of obesity. For example, the International Diabetes Federation recommends a lower waist circumference cutoff for east Asian and south Asian patient to define abdominal obesity, as compared to white populations. Some studies suggest that weight-related disease risk is lower in African-American populations, compared to whites. However, in the U.S., elevated waist circumference definitions currently are the same for all ethnic 􏰊roups (􏰆 􏰍􏰈 inches for women, 􏰆 􏰥􏰉 inches for men)􏰙

Question 211

co-morbidities of obesity

Answer 211

Known co- morbidities associated with obesity include: obstructive sleep apnea, type 2 diabetes, hypertension, hyperlipidemia, cardiovascular disease including heart attack, stroke, and heart failure, non-alcoholic fatty liver disease, erectile dysfunction, polycystic ovarian disease, infertility, certain forms of cancer (e.g., breast, colon), depression, low back pain, and osteoarthritis.

Question 212

Type 2 Diabetes and Impaired Glucose Tolerance

Answer 212

BMI, abdominal fat distribution and weight gain are important risk factors for the development of type 2 diabetes. Data from NHANES III found that almost 70% of adult men and women in the U.S. with type 2 diabetes have a BMI of 27 or greater, and the risk of diabetes increases linearly with BMI. Data from 8 years of follow up of a cohort of over 113,000 US women aged 30-55 in the Nurses’ Health Study found that, among women of BMI 23-23.9 kg/m2, the relative risk of diabetes was 3.6 times that of women having a body mass index less than 22 kg/m2.

Question 213

Dyslipidemia

Answer 213

Visceral obesity is associated with elevated triglycerides, low HDL cholesterol, and increased small, dense LDL particles. Data from NHANES III suggest that prevalence of hypercholesterolemia (total cholesterol > 240 mg/dl) increased progressively with BMI in men. In women, the prevalence was highest at a BMI of 25-27 kg/m2, and did not increase further with increasing BMI.

Question 214

Coronary Artery Disease (CAD)

Answer 214

Obese persons, particularly those with abdominal fat distribution, are at increased risk for CAD. The risk of CAD begins to increase at a BMI of 23 kg/m2 for men and 22 kg/m2 for women. It was previously thought that most of the increased risk was mediated by obesity related increases in risk factors, particularly hypertension, dyslipidemia, impaired glucose tolerance/diabetes, and the metabolic syndrome. However, several long term epidemiologic studies including the Nurses’ Health Study and the Framingham Study have shown that overweight and obesity increased the risk for CAD even after correction for other known risk factors. The American Heart Association has added obesity to its list of major risk factors for CAD.

Question 215

Sleep Apnea

Answer 215

Obese men and women are also at high risk for sleep apnea, in which partial or complete upper airway obstruction during sleep leads to episodes of apnea or hypopnea. The interruption in nighttime sleep and repeated episodes of hypoxemia lead to daytime somnolence, morning headache, systemic hypertension, and can eventually result in pulmonary hypertension and right heart failure. In a study of two hundred obese women and 50 obese men (mean BMI 45.3 kg/m2) and 128 controls matched for age and sex, 40% of obese men and 3% of obese women demonstrated sleep apnea warranting therapeutic intervention. Another 8% of men and 5.5% of women showed apneic activity that warranted recommendation for evaluation in the sleep laboratory. In contrast, none of the 128 controls demonstrated sleep apneic activity severe enough for therapeutic intervention.

Question 216

Non-Alcoholic Fatty Liver Disease

Answer 216

Obesity is associated with a spectrum of liver disease known as non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). Manifestations of this disorder include hepatomegaly, abnormal liver associated enzyme tests, and abnormal liver histology including macrovesicular steatosis, steatohepatitis, fibrosis, and in a worst case scenario, cirrhosis. NAFLD/NASH has become a common cause of cirrhosis in the U.S., along with viral hepatitis and alcohol use. The exact prevalence of NAFLD/NASH in obese patients is not fully known. However data, from autopsy studies suggest that steatohepatitis occurs in approximately 20% of obese patients.

Question 217

Metabolic Syndrome

Answer 217

Metabolic syndrome is a specific body phenotype of abdominal obesity associated with a group of metabolic disorders that are risk factors for cardiovascular disease, including coronary artery disease, stroke, and congestive heart failure. Characteristics of this syndrome include: abdominal obesity, elevated blood pressure/hypertension, high triglycerides, low HDL cholesterol, and impaired glucose tolerance/type 2 diabetes.

Question 218

hypothalamus role in weight control

Answer 218

The hypothalamus is intimately involved in both the control of short- and long-term regulation of body weight. The paraventricular nucleus (PVN), ventromedial nucleus (VMN), arcuate nucleus (Arc), and lateral hypothalamus (LH) regulate food intake and disposition by processing information concerning peripheral energy stores and then stimulating or inhibiting feeding or altering gastric motility and food metabolism/utilization.

Question 219

Short-Term Regulation of Food Intake

Answer 219

Short term regulation of food intake involves cues to initiate feeding (hunger) and cues to stop feeding (satiety). Thus, these are the signals involved in potentially determining meal size and frequency. Early studies identified the lateral hypothalamus as the ‘hunger center’ and the ventromedial nucleus as the ‘satiety center’.

Question 220

lateral hypothalamus (LH)

Answer 220

Stimulation of the lateral hypothalamus (LH) produces voracious eating, even in a food replete animal, and lesions in this region produced aphagia (no eating). Two peptides have been identified that are expressed in the brain only by neurons in the LH: melanin concentrating hormone (MCH) and orexins (also known as hypocretins). These peptides induce feeding when injected into the CNS. The MCH and orexin neurons in the LH have very similar projection patterns, including the brainstem motor systems that support behaviors like chewing, licking, and swallowing. These include cranial nerve motor neurons in the trigeminal, facial, and hypoglossal motor nuclei, as well as the reticular areas that surround them and which constitute pattern generators for these behaviors. The MCH and orexin neurons also innervate sympathetic and parasympathetic preganglionic nuclei in the medulla and the spinal cord.

Question 221

ventromedial nucleus (VMN)

Answer 221

Opposite effects are seen in the ventromedial nucleus (VMN). Evidence that the VMN acts as a ‘satiety’ center comes from the observation that stimulation of this region results in cessation of eating even in hungry animals. Animals with lesions in this region eat excessively and become obese. Lesioned animals may reach 3-4 times normal weight within several months. Once this weight is reached, the animals reduce their food intake to simply maintain their increased weight. If they are force-fed to further increase their weight, they subsequently reduce their eating to lose weight back to the post-lesion level. If they are food-restricted, they subsequently eat to regain the weight. Thus, VMN lesions have the effect of “resetting” the regulated weight to a higher level.

Question 222

arcuate nucleus

Answer 222

The arcuate nucleus contains “first order” neurons that promote either food intake or satiety. Activation of arcuate neurons that produce both neuropeptide Y (NPY) and agouti-related peptide (AgRP) promote feeding while activation of the arcuate neurons that produce both 􏰂-melanocyte stimulating hormone (􏰂-MSH) and cocaine and amphetamine-related transcript (CART) promote satiety. Remember, 􏰂-MSH is a product of the proopiomelanocortin (POMC) precursor molecule. These two neuron populations innervate many of the same targets in the hypothalamus including the paraventricular nuclei (PVN) and LH. In addition, the 􏰂-MSH/CART neurons directly innervate sympathetic preganglionic neurons in the spinal cord. 􏰂-MSH activates melanocortin receptors (MCR) while AgRP blocks the effect of 􏰂-MSH at these receptors. MCRs are expressed in PVN and LH as well as by preganglionic sympathetic and parasympathetic neurons in the medulla and spinal cord. Activation of MCRs induces satiety. NPY increases hunger when injected into the hypothalamus and decreases energy expenditure (via inhibition of the sympathetic nervous system and perhaps by inhibition of thyroxin and growth hormone secretion). Thus, the NPY/AgRP neurons are thought to constitute a potent feeding system that is actively opposed by the 􏰂-MSH/CART satiety system. These neurons express receptors for peripherally generated hormones that participate in regulation of food intake, and these hormones can alter the balance between these opposing systems.

Question 223

Ghrelin

Answer 223

Ghrelin is a 28 a.a. peptide hormone secreted from the stomach that induces feeding. Its blood levels peak prior to a meal, although the factors stimulating its release are poorly understood. Ghrelin receptors are located in the arcuate nucleus, and ghrelin appears to activate the NPY/AgRP arcuate neurons

Question 224

GI signals

Answer 224

Both hormonal and neural signals generated in the GI tract participate in short-term regulation of food intake. Several satiety signals also originate from the GI tract. Rapid eaters, like dogs and some humans, stop a meal long before there has been an appreciable change in blood sugar. Thus, the signal(s) to end a meal, the “full” feeling we all know, must come initially from factors that engage early in the digestion process. Information about gastric distension as well as hepatic levels of glucose and lipids are carried by vagal afferents to the nucleus of the tractus solitarius (NTS) in the brainstem and are relayed to the PVN, arcuate nucleus, and LH, as well as to the amygdala and visceral sensory thalamus. Information from the thalamus is transmitted to the visceral sensory cortex and provides conscious appreciation of gastric fullness. Food in the ileum induces release of a number of peptides, such as glucagon-like peptide (GLP-1) and PYY

Question 225

cholecystokinin (CCK)

Answer 225

The duodenum signals the presence of nutrients to the brain via the release of cholecystokinin (CCK). CCK activates vagal afferents in the peritoneum and also acts via the area postrema to activate brainstem pathways projecting to the hypothalamus.

Question 226

Glucagon-like peptide (GLP-1)

Answer 226

Glucagon-like peptide (GLP-1) is synthesized in the L-cells of the distal ilium in response to nutrients and is an important incretin hormone. GLP-1 also acts on receptors in the area postrema via the NTS to activate pathways leading to reduced food intake.

Question 227

Peptide YY (PYY)

Answer 227

Peptide YY (PYY) is also released from L cells of the distal ilium in response to nutrients. PYY appears to have its anorexic effects by inhibiting hypothalamic NPY/AgRP neurons.

Question 228

Glucose

Answer 228

Glucose has long been recognized to participate in both hunger and satiety. Hypoglycemia stimulates eating and hyperglycemia inhibits eating. Glucose sensitive neurons are located in the VMN and LH as well as elsewhere in the brain (arcuate nucleus, area postrema and NTS). However, the glucose-sensitive neurons in the VMN are stimulated by hyperglycemia while the glucose-sensitive neurons in the LH are inhibited by glucose. The importance of the glucose sensitive cells in VMN for the regulation of food intake and body weight is demonstrated by the observation that obesity develops in mice after selective destruction of these cells. These same neurons are also affected by other circulating nutrients. Although the involvement of these cells in feeding and satiety is recognized, the relative importance of ‘normal’ blood glucose levels in the regulation of appetite and body weight regulation is still under considerable debate.

Question 229

Long-Term Regulation of Food Intake

Answer 229

aining or losing weight in an adult is primarily a matter of gaining or losing total body fat, which suggests that if total body weight (fat) is regulated over the long-term via control of appetite, there must be some signal from adipose cells to the appetite control system in the brain that provides information about adipose tissue mass. Early evidence that a signal from adipose tissue suppresses appetite was that surgically removing adipose tissue (lipectomy) in rats resulted in increased appetite, as if the reduction in total body fat had reduced the level of an appetite-depressing signal. Another finding was that serum from rats made obese by being fed a high-fat diet had an appetite-depressing effect when injected into control rats.

Question 230

Leptin

Answer 230

Recombinant protein made from the normal gene was named “leptin.” Obese mice of the ob/ob type are deficient in leptin and can be cured of their obesity by systemic administration of this protein. Systemic injection of leptin into normal mice also results in decreased appetite (and increased metabolic rate), resulting in weight loss. Minute amounts of leptin injected directly into the brain ventricles also result in weight loss, suggesting that the site of action of systemically-injected leptin is the brain. It has been further demonstrated that another strain of obese mice, the db/db strain, have a supernormal amount of circulating leptin, but are insensitive to it. This strain has a mutation in the leptin receptor.

Question 231

leptin-receptor

Answer 231

The leptin receptor protein is expressed in the arcuate and VMN (as well as other regions). Leptin inhibits the NPY/AgRP neurons in the arcuate and activates the 􏰂-MSH/CART neurons. Thus, it activates the satiety circuits and inhibits the feeding circuits.

Question 232

Insulin

Answer 232

Insulin also functions as a long-term regulator of food intake, energy balance, and adiposity in a similar manner as leptin. Insulin circulates at levels that parallel body fat mass, and both fasting and meal- or glucose-stimulated insulin concentrations are well correlated with body fat content. Insulin receptors are located in the glucose sensitive regions of the hypothalamus and brainstem, and it is transported into the brain by specific transporters.

Question 233

Phentermine

Answer 233

It is chemically related to amphetamine and increases brain norepinephrine levels. It does not have the abuse potential of amphetamine. doses used ranges from 15- 38.5 mg/day. The average weight loss provided is roughly 5% of baseline weight although there is a range of responses with some people losing more and some losing no weight at all. The drug acts centrally to increase satiety and thereby reduce food intake. What the person experiences is fullness at the end of the meal that allows them to reduce portion sizes. The primary side effects are nervousness, difficulty sleeping, headache and dry mouth. The concerning side effect is an increase in blood pressure that occurs in roughly 1-2% of people taking the drug. For this reason it should not be prescribed to patients with uncontrolled hypertension. If a person has a normal blood pressure the drug should be prescribed at a low dose and the blood pressure checked 7-10 days after starting the drug to make sure it has not risen. The low dose should be sustained for at least a month before considering increasing the dose. Phentermine is only FDA approved for 3 months of use.

Question 234

Orlistat (Alli)

Answer 234

Orlistat is a pancreatic lipase inhibitor that blocks dietary fat absorption from the GI tract. The prescription dose is 120 mg taken with each meal. The OTC dose is 60 mg. The weight loss is similar to phentermine, about 5% of baseline weight with some patients losing more some losing less. Since it is not systemically absorbed, there are no systemic side effects. The primary side effects relate to its mechanism of action. The prescription dose blocks roughly one third of dietary fat from being absorbed. The fat that is not absorbed passes into the stool. Patients may notice oily stools, a sense of urgency, some diarrhea or oily leakage. If patients know that these side effects are related to their intake of dietary fat, many are able to control the side effects by reducing dietary fat or not taking the medication if they are in a situation where they will need to consume a high fat meal. The less medication they take however, the less effective it will be. A theoretical side effect is deficiency of fat soluble vitamins. This is not common, but it is recommended that people on this medication take a daily multivitamin. There are important drug interactions with Coumadin (increased INR) and cyclosporine (reduced drug levels). Orlistat is FDA approved for long term use. There is evidence of efficacy in adolescents and there is evidence that orlistat can prevent the development of diabetes in high risk individuals, improves blood lipids and lowers HbA1C in people with diabetes.

Question 235

Lorcasarin (Belviq)

Answer 235

It is a selective serotonin 2C receptor agonist. This is the latest weight loss drug that acts through serotonin. Fenfluramine and dexfenfluramine were older nonspecific serotonin receptor agonists that had moderate efficacy as weight loss drugs. Unfortunately, these drugs were found to cause cardiac valve problems in some patients and so were taken off the market. The thought is that the 2C receptors are only found in the brain and not on the heart and so this newer drug will have the weight loss benefits without the cardiac toxicity. Studies demonstrate that lorcasarin at a dose of 10 mg/d produces 4-5 % weight loss and no evidence of cardiac valve problems in patients followed out to 2 years of exposure to the drug. Fenfluramine had been combined with phentermine (phen/fen) in the late 1990’s and found to produce a 12-15% weight loss.

Question 236

Phetermine/topiramate (Qsymia)

Answer 236

In a number of conditions like hypertension, diabetes and hyperlipidemia we have found that to attain a high level of efficacy, drugs acting by different mechanisms need to be combined. An example is the use of a potent vasodilator with a beta blocker and a diuretic to treat severe hypertension. For some time now many investigators have thought that the same principle will be needed in the treatment of obesity. While a number of combination products have been tested the first to make it to market is the combination of phentermine and topiramate. This combination at doses of 7.5/46 mg phentermine/topiramate and 15/92 mg each taken once daily are now available. There are concerns that topiramate has teratogenic potential and its use needs to be carefully controlled in women of reproductive age. The weight loss is substantially more than with the other currently available weight loss medications and is in the range of 10-12% of baseline weight. The side effects include dry mouth, paresthesias, insomnia, dizziness, anxiety, irritability and disturbance in attention. The idea was that by combining low doses of these 2 medications there would be greater weight loss efficacy and fewer side effects.

Question 237

Naltrexone SR/Bupropion SR(Contrave)

Answer 237

The newest weight loss medication to be approved is the combination of the opioid receptor antagonist naltrexone with the dopamine and norepinephrine reuptake inhibitor bupropion which has mainly been used for the treatment of depression and as an aid in smoking cessation. The average placebo subtracted weight loss is about 5%. It seems to be a bit more effective than phentermine and lorcasarin but less effective than phentermine/topiramate. The medication has a “black box warning” about a risk of increase suicidal ideation. The medication comes in extended-release t tablets with the following amounts of medication: 8 mg naltrexone HCl /90 mg bupropion HCl. The patient is instructed to gradually increase the dose from 1 pill a day up to 2 pills (16/180 BID) twice a day over a month. In general the medication is pretty well tolerated. The serious but uncommon risks are: suicidal ideation, lowering seizure threshold, increased pulse and blood pressure, and rarely increased liver function tests and closed angle glaucoma.

Question 238

Liraglutide 3 mg (Saxenda)

Answer 238

was recently approved by the FDA as a weight loss medication but it is not yet available in pharmacies. This same medication is currently available at 1.2 and 1.8 mg/d doses for the treatment of diabetes. It is a GLP-1 agonist.