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Unit 4 GNA > LGS Week 3 & 4 > Flashcards

LGS Week 3 & 4 Flashcards

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1
Q

When using the delta classification for Carbon numbering, what end do you start from and which double bonds do you indicate in the name?

A

Start from the carboxyl end and indicate all double bonds

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2
Q

When using the omega classification for Carbon numbering, what end do you start form and which double bonds do you indicate in the name?

A

Start from the methyl end and indicate only the first double bond

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3
Q

How many double bonds are present in saturated fats, monounsaturated fats, and polyunsaturated fats?

A

0
1
2+

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4
Q

Hard fat is [a] fat while oil is [b] fat

A

a. Saturated
b. Unsaturated

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5
Q

Most energy dense molecule in the body, 6x more free energy than other sources

A

Fatty acids

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6
Q

What are the different functions of cholesterol

A

Make bile acids
Make Vitamin D2
Make steroid hormones
Add rigidity to cell membranes

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7
Q

What are the two ways you break down fat in the oral cavity?

A

Mastication - emulsification
Lingual lipase - turn triglycerides into di/monoglycerides

(LL important for infants to digest SCFA and MCFA in breast milk)

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8
Q

What is the enzyme released in the stomach to break down fats, and what cells release it?

A

Gastric Lipase secreted by Chief cells

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9
Q

What hormones aid in lipid digestion and in what ways?

A

Secretin - stimulates pancreatic digestive enzymes, and bicarb released from liver

CCK - stimulates bile release from gallbladder and liver, and pancreatic digestive enzymes

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10
Q

What is the role of Bile-Salt Stimulated Lipase?

A

Produced in the break milk - ingested by infant

Breaks down Tri/diglycerides into monoglycerides and FA

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11
Q

What is the role of Pancreatic Lipase and Colipase?

A

Cleave tri/diglycerides into monoglycerides and FA

Colipase is cofactor that binds to fat globule and pancreatic lipase to release bile salts and allow access of enzyme to fat globule

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12
Q

Which lipoprotein has the most:
Protein
Cholesterol
Phospholipids
Triglycerides

A

Protein: HDL
Cholesterol: LDL
Phosholipids: VLDL
Triglycerides: Chylomicron

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13
Q

What are the roles of the apolipoproteins:

ApoA-I
ApoA-II
ApoB-48
ApoB-100
ApoC-II
ApoE

A

ApoA-I : activates LCAT (Lethicin cholesteryl acetyltransferase)
ApoA-II : activates Hepatic Lipase
ApoB-48 : binds to lipoprotein receptors
ApoB-100 : binds with lipoprotein receptors
ApoC-II : activates Lipoprotein Lipase (LPL)
ApoE : binds with lipoprotein receptors (LDL)

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14
Q

What is the major regulator of chylomicron metabolism?

A

LPL

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15
Q

Android obesity is associated with [shape]-d body while gynoid obesity is associated with [shape]-d body

A

apple-shaped body
pear-shaped body

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16
Q

Name the SCFA

A

Acetic acid
Proprionic acid
Butyric acid

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17
Q

Name the MCFA

A

Caprioc acid
Caprylic acid
Capric acid
Lauric acid

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18
Q

Name the LCFA

A

Myristic acid
Palmitic acid
Stearic acid
Arachadic acid

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19
Q

Name the VLCFA

A

Begenic acid
Lignoceric acid

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20
Q

What are the important functions of polyunsaturated fats?

A

Phospholipid bilayer
Precursor for eicosanoids

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21
Q

What are some examples of unhealthy fats?

A

Saturated LCFA - palmitic (dairy, palm oil), stearic (animal fat)
Unsaturated trans - paritally hydrogenated vegetable oil

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22
Q

What are some examples of healthy fats?

A

Monounsaturated fats - olive oil, avocado - omega 9
Polyunsaturated fats - fish and flex - omega 3 and 6
Saturated MCFA - coconut oil
SCFA - microbiota (dairy)

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23
Q

What is the SMASH acronym representing and what are they?

A

Fish highest in omega-3s (DHA)
Salmon
Mackerel
Anchovies
Sardines
Herring

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24
Q

Which PUFAs are used for energy, for hormone precursors, and for nerve and retina function?

A

Energy: ALA (a-linolenic acid)
Hormone: EPA (eicosapentaenoic acid)
Nerve/Retina: DHA (docosahezenoic acid)

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25
Q

Explain the pathogenesis of Atherosclerosis

A

Lipid accumulates in interstitial space –> LDL oxidation by ROS –> endothelial cells recruit monocytes –> differentiate into macrophages –> phagocytose –> formaiton of Foam Cells –> inflammatory response –> cytokines and GF –> smooth muscle migration –> fibrous cap over lipids –> calcification –> plaque formation –> death of foam cells form nectrotic core –> smooth muscle cell death –> rupture of cap –> thrombus formation

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26
Q

Outline Type I familial dyslipidemia

A

Autosomal recessive
LPL or Apo-CII deficiency (can’t activate LPL)
Increased chylomicron, TG, and cholesterol
CF: pancreatitis, hepatosplenomegaly, xanthomas
Dx: creamy layer in test tube overnight

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27
Q

Outline Type II familial dyslipidemia

A

Autosomal dominant
Defective LDL receptors or ApoB-100 (can’t bind to LDL receptor)
Type IIa - increased LDL, cholesterol
Type IIb - increased LDL, cholesterol, VLDL
CF: accelerated atherosclerosis, tendon xanthomas, corneal acrus

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28
Q

Outline Type III familial dyslipidemia

A

Autosomal recessive
Depective ApoE
increased chylomicrons, VLDL
CF: premature atherosclerosis, palmar xanthomas

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29
Q

Outline Type IV familial dyslipidemia

A

Autosomal dominant
Overproduction of VLDL
Increased TG, VLDL
CF: acute pancreatitis, premature atherosclerosis

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30
Q

Outline Abetalipoproteinemia

A

Autosomal recessive
Mutations in MTTP gene –> deficient microsomal triglyceride transfer protein –> lack of ApoB 48 and 100 –> can’t absorb chylo, vldl, ldl
Decreased chylomicrons, VLDL, LDL
CF: presents in infancy, hepatomegaly, kyphoscholiosis, ataxia, loss of DTR’s, peripheral neuropathy
(Lipids crucial for brain formation in babies)

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31
Q

Fatty Acid metabolism does not occur in

A

RBC and very low levels in CNS

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32
Q

What FA are canitine shuttle dependent to get into mitochondria?
Which are not?

A

LCFA depedent on Carnitine shuttle to get into mitochondria

SCFA and MCFA do not need shuttle to get into mitochondria

VLCFA do not start in mitochondria

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33
Q

Outline the Carnitine Shuttle

A

Priming:
Palmitate + Fatty Acyl-CoA Synthetase –> Palmitoyl-CoA

Transport (shuttle):
Palmitoyl-CoA + CPT1 –> Palmitoyl-Carnitine –> CACT (translocase from cytosol to matrix) –> Palmitoyl-Carnitine –> CPTII –> Palmitoyl-CoA

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34
Q

B-oxidation of even chain FA end in

A

No. of Carbons / 2 = n amount of Acetyl-CoA

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35
Q

B-oxidation of odd chain FA end in

A

No. of Carbons / 2 = # of Acetyl-CoA until 3 Carbons remaining (Propionyl-CoA)
Propionyl-CoA –> Succinyl-CoA

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36
Q

When is a-oxidation used?

A

When the b Carbon has a methyl chain on it creating steric hinderance and blocking access of enzymes

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37
Q

What two FA oxidation reactions occur particularly in the brain?

A

Peroxisomal B-oxidation
a-oxidation

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38
Q

Outline ketogenesis

A

2 Acetyl-CoA + MTP –> Acetoacetyl-CoA + HMG-CoA Synthase –> HMG-CoA + HMG-CoA Lyase –> Acetyl-CoA + Acetoacetate –> D-B-Hydroxybutyrate –> released to blood to travel to extrahepatic tissues

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39
Q

Why does someone in ketosis have “fruity breath”

A

Acetone is exhaled by the lungs

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40
Q

Where does ketogenesis take place?

A

Only in Liver mitochondria

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41
Q

Where does ketolysis take place?

A

In mitochondria of all tissues EXCEPT liver and RBC

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42
Q

What are the regulators of Hepatic FA Oxidation and Ketogenesis

A

CPTI directly regulates Hepatic FA oxidation, indirectly Ketogenesis:
Glucagon stimulates transcription
Malonyl-CoA inhibits

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43
Q

What are regulators of Heart and Skeletal muscle FA oxidation

A

LPL
Stimulated by Glucagon
Inhibited by Insulin

CPTI

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44
Q

Outline MCADD

A

Medium-chain acyl-coenzyme A dehydrogenase deficiency
ACADM gene mutation
Elevated C6-10, C10:1 ACP
CF: Hepatic encephalopathy, SIDS
Treatment: avoid fasting, high carb/low fat diet, IV D10

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45
Q

Outline CPTII deficiency

A

CPTII gene mutation - rare
Elevated C16-18, C16/18:1
Low total and free plasma carnitine levels
CF: Adult myopathic form with weakness, fatigue, rhabdo

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46
Q

Outline CPTI deficiency

A

CPTIA gene mutation, 1 in 500,000
Absent 16-18, C16/18:1
Elevated total and free plasma canitine levels
CF: Hepatic encephalopathy, Fatty Liver in Pregnancy

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47
Q

Outline the three main Peroxisomal Disorders

A

Zellweger Spectrum Disorder - mutation in PEX gene
Defect in formation of peroxisomes
Build up of VLCFAs, branched chain FA, Amino acids
Wide fonanelles, dysmorphic facies, unformed eyebrows

Refsum Disease - defect in a-oxidation
Accumutlation of phytanic acid
Fatigue, hypertension, ataxia, night blindness

X-ALD Adrenoleurkodystrophy
Mutation in ABCD1 gene - deficiency in ALD proteins - X-linked in males
Unable to B-oxidize VLCFAs
Adrenal insufficiency, testicular dysfunction, NS demylination

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48
Q

What are the three categories of Peroxisomal disorders?

A
  1. Disorders of peroxisomal biosynthesis
  2. Single enzymatic disorders
  3. Multiple enzymatic disorders - shortened long bones
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49
Q

What is the main enzyme involved in Fatty Acid biosynthesis?

A

Malonyl-CoA

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50
Q

What stimulates fatty acid biosynthesis?
What inhibits it?

A

Stimulates
1. Citrate
2. Insulin

Inhibits
1. Palmitoyl-CoA
2. Glucagon
3. Epinephrine

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51
Q

Outline Fatty Acid Elongation

A

Palmitoyl-CoA (16C) + Malonyl-CoA –> –> –> Stearoyl-CoA (18C) + 2NADP+

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52
Q

Where does lipogenesis occur?

A

Enterocytes of stomach to send diet TGs to other organs

Liver to send lipids to other organs

Adipocytes for storage

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53
Q

What regulates Adipocyte Lipogenesis?

A

Stimulates : Insulin via LPL and GLUT4
Inhibits : Glucagon, Epinephrine via LPL

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54
Q

What regulates Adipocyte Lipolysis?

A

Stimulates: Glucagon, Epinephrine via HSL
Inhibits: Insulin via ATGL (Adpiose TG lipase) and HSL (hormone-sensitive lipase)

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55
Q

What are the byproducts of glycerophospholipid remodeling and degradation?
Where do these reactions occur?

A

PLA1, PLA2, PLD

Occurs at cell membranes and in lysosomes

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56
Q

Where does sphingolipid degredation occur?
What does it degrade into?

A

Lysosomes

Ceramide

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57
Q

Outline the lesser common Lysosomal Storage Diseases (Sphinogolipidoses)

A

Tay-Sachs disease - AR - Hexosaminidase A difieciency
“cherry red” spots on macula, neurodegeneration, developmental delay, no hepatosplenomegaly

Fabry disease - XR - a-galactosidase A deficiency
Peripheral neuropathy, progressive renal failure

Metachromatic Leukodystrophy - AR - Arylsulfatase A deficiency
Central and peripheral demyelination, dementia

Krabbe disease - AR - Galactocerebroside deficiency
peripheral neuropathy, destruction of oligodendrocytes, optic atrophy

Niemann-Pick disease - AR - sphingomyelinase deficiency
Hepatosplenomegaly, progression ND, foam cells, “cherry red” spot on macula

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58
Q

Outline the most common Lysosomal Storage disease

A

Gaucher disease - AR - Glucocerebrosidase deficiency
Hepatosplenomegaly, pancytopenia, osteoporisis, avascular necrossi of femur, bone crises, Gaucher cells
Treat with recombinant Glucocerebrosidase

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59
Q

What is the enzyme that converts Arachodonic Acid into LTA4?

Which enzyme converts it to PGG2?

A

5-Lipoxygenase (5-LOX)

Cyclooxygenase (COX)

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60
Q

Outline the starting and ending molecule of each stage of cholesterol biosynthesis

A

Stage 1: 2 Acetyl-CoA –> Mevalonate
Stage 2: Mevalonate –> Demethylallyl Pyrophosphate
Stage 3: Demethylallyl Pyrophosphate + Isopentenyl Pyrophosphate –> Squalene
Stage 4: Squalene –> (Lanosterol in middle) –> Cholesterol

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61
Q

What are the regulators of Cholesterol Metabolism?

A

Stimulates:
1. Insulin, Estrogen, decreased cholesterol via HMG-CoA Reductase
2. decreases cholesterol via LDLR

Inhibits
1. increased cholesterol, AMPK-P, increased Lanosterol, Glucagon via HMG-CoA reductase
2. increased cholesterol via LDLR

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62
Q

What is the regulatory step of bile acid/salt synthesis?

A

Cholesterol 7a-hydroxylase

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63
Q

Explain Bile Acid/Salt conjugation

A

Addition of a Glycine or Taurine to the Primary Bile Acids (Cholic or Chenodeoxycholic Acid) which drops the pKa from 6 to…
4-5 with Glycine
< 2 with Taurine

Dropping pKa makes molecules more water soluble because being secreted into alkaline environment with make sure all will be ionized

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64
Q

What is the purpose of the Bile Salt Export Pump

A

actively transports conjugated bile salts through hepatocyte apical membrane into bili canaliculi

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65
Q

What actively transports xenobiotics through hepatocyte apical membrane into bile canaliculi?

A

Multidrug resistance protein 1 (MRP1)

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66
Q

ABCG 5 and 8 are used to

A

actively transport cholesterol through hepatocyte apical membrane into bile canaliculi

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67
Q

Ductal bile is modified by [a] by [b] and is then drained out of [c]

A

a. Cholangiocytes

b. Secreting water, HCO3- and IgA into bile, and resorb glucose and AA from bile

c. Right/left hepatic ducts –> common hepatic ducts

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68
Q

When is hepatic bile sent to the gallbladder?

What chemical changes are made to the bile?

A

During times of fasting

Bile is concentrated:
decrease in H2O, Cl-, HCO3-
increase in Bile salt, Na+, Ca2+

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69
Q

What is ASBT?

A

Apical Sodium-Coupled Bile Salt Transporter

Allows bile salts to enter hepatocytes from co-transport of Na+

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70
Q

What does the activation of FXR in hepatocytes do?

A

Transcription factor for Bile Salts

Decreases expression of NCTP
Increases expression of BSEP (Bile Salt Exit Pump)

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71
Q

What inhibits Bile Salt synthesis?

A

Bile Salts entering hepatocytes –> transcription factors stimulate gene expression of FGF19 –> inhibits signal transduction cascade of bile salt synthesis

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72
Q

Outline Bilirubin synthesis

A

Occurs in reticuloendothelial cells (Phagocytes, Kupffer cells, Spleen)

Heme + Heme Oxygenase –> Biliverdin + Biliverdin Reductase –> Bilirubin –> sent into blood –> Binds to Albumin –> Transported to liver

73
Q

What is the purpose of bilirubin conjugation?

A
  1. Increases its water solubility
  2. Prevents its passive reabsorption in intestines
  3. Decreases its albumin affinity
  4. Promotes its elimination
74
Q

What enzyme conjugates bilirubin?

A

UDPGT1A1

75
Q

Compare/Contrast the following syndromes

Crigler-Najjar
Gilbert
Hemolytic Disease of a Newborn
Physiologic jaundice of the newborn
Rotor syndrome

A

Crigler-Najjar : UDP-GT deficiency - can’t convert unconjugated to conjugated - Type I not compatible with life (Type II is minor)

Gilbert syndrome : can’t secrete conjugated bilirubin?

HDONB - autoimmune Rh antibodies attack RBCs - elevated unconjugated bilirubin

PJONB - newborn’s enzymes aren’t working properly yet

Rotor Syndrome - Conjugated hyperbilirubinemia - lack of enzyme that transports bilirubin from hepatocyte to bile duct

76
Q

What disorders will show elevated unconjugated bilirubin levels?

A

Crigler-Najjar Types I and II
Gilbert

77
Q

What disorders will show elevated conjugated bilirubin levels?

A

Dubin Johnson
Rotor

78
Q

What serious disorder will prolonged jaundice in neonates cause?

A

Kernicterus - brain damage caused by prolonged elevated unconjugated bilirubin

Bilirubin is lipophilic and can cross BBB

79
Q

What are the essential AA?

A

His, Isoleucine, Leu, Lys, Met, Phe, Thr, Trp, Val

80
Q

What AA are conditionally essential?

A

Arg, Cys, Gly, Gln, Pro, Tyr

81
Q

What are the nonessential AA?

A

Ala, Asp, Asn, Glu, Ser

82
Q

What enzymes cleave dietary proteins?

A

Gastric acid and pepsin

83
Q

What is the endopeptidase that cleaves all zygomens into active enzymes?

A

Trypsin

84
Q

What enzymes cleave peptides at the small intestine brush border?

A

Aminopeptidase and Dipeptidase

85
Q

Identify the orange receptor and purple enzyme

A

PepT1
Peptidases

86
Q

Outline Hartnup Disease

A

AR mutation of gene SLC6A19 –> encodes for transport protein BOAT 1
No BOAT1 –> deficiency in uptake of neutral AA in intestinal and epithelial cells
CF: Symptoms due to essential AA Try deficiency - no Vit B3 –> photosensitivity, Ataxia, Pellegra-like symptoms
Symptoms based on environment, stress, nutrition, etc
Treat with sunlight, heat, high protein avoidance

87
Q

What is Purple Urine Bag Syndrome, and what disease is it associated with?

A

Excess tryptophan digested in the colon by bacteria releases Indoles in urine
Seen with UTIs and Hartnup Disease

88
Q

Outline Cysteinuria

A

AR gene mutations of SLC7A9 and SLC3A1
Defective tubular resorption of basic AA in intestinal and kidney, including cystine, ornithine, lysine, arginine
CF: Flank pain, hematuria, six-sided stones - episodes every ~2 years
Treat with diet, hydration, surgical intervention, urinary alkalization

89
Q
A
90
Q

What is the role of the proteasome?

A

Protein turnover

91
Q
A
92
Q
A
93
Q

[a] is the only tissue in which all 20 AA are degraded

[b] is the major location for degradation of BCAA (Ile, Leu, Val)

A

a. Liver
b. Muscle

94
Q

Differentiate between deamination and transamination

A

Deamination is removing an NH4+ group from an AA (ex. to send through urea cycle)

Transamination is transferring amino group from one AA to another

95
Q

Outline the Cahill Cycle

A

Glucose in muscle –> Pyruvate
a-KG + aKetoacid –> Glutamate
Glutamate + Pyruvate –> Alanine –> travels through blood to liver –> dissociates into C group and N group –> C group becomes glucose, N group goes to urea cycle

96
Q

Outline Glutamate N transport

A

a-KG in muscle + NH4 and NADPH –> Glutamate + NH4 and ATP –> Glutamine –> travels to liver –> Glutamine + glutaminase –> -NH4 –> Glutamate + glutamate DH –> -NH4 –> aKG
2 NH4 –> urea cycle

97
Q

What are the starting and final products of the urea cycle?

A

Ornithine AA

98
Q

Where does the urea cycle take place?

A

Liver - Partially in mitochondria and partially in cytosol

99
Q

Outline the Urea Cycle

A

HCO3 + NH3 + CPS1 –> Carbomoyl Phosphate
CP + Ornithine + OTC –> Citrulline
Citrulline transported using ORNT1 into cytosol
Citrulline + Aspartate and Argininosuccinate Synthetase –> Argininosuccinate
Argininosuccinate Lyase –> Arginine and Fumarate
+ Arginase –> Ornithine + Urea
Urea filtered into blood, Ornithine transported back into mitochondria via ORNT1

100
Q

What regulates the Urea Cycle

A

Substrate availability (increased NH3 : NH4 –> increased urea)

CPS I - controlled by NAG

Increased expression of urea cycle enzymes (response to increased protein metabolism)

101
Q

Outline Ornithine Transcarbomoylase (OTC) Deficiency

A

X-linked mutation of OTC gene
Triggered by fasting, illness, or stressful event that leads to catabolism
CF: headache, lack of appetite, vomiting - signs of encephalopathy
Labs: Elevated glutamine and Orotic Acid, low BUN, decrease in urea cycle intermediates (Citrulline and Arg)
Treatment: Citrulline and Arg - to bypass Ornithine Transcarbamylase
During crisis - IV D10, lactulose (diarrheal), nitrogen scavengers

102
Q

Why is elevated Orotic Acid seen in OTC deficiency?

A

No OTC enzyme to convery Carbonyl Phosphate into Citrulline –> excess carbomyl phsophate is leaked from mitochondria to cytoplasm –> Cabamoyl Phosphate shunted through pyrimidine synthesis pathway by CPSII –> formation of Orotic Acid

103
Q

Differentiate elevated Orotic Acid in OTC vs Orotic Aciduria

A

Orotic Acidura occurs if there is a mutation in uiridine monophosphate synthase (UMPS) –> no conversion or Orotic acid to Orotidine Phosphate

OTC has elevated ammonia levels
Orotic aciduria will have megaloblastic anemia –> UMPS can’t convert Orotic acid –> no continuation of pyrimidine synthesis –> no DNA for RBC

104
Q

Why is Glutamine elevated in OTC deficiency?

A

Elevations in ammonia in the cell lead to amination of glutamate to glutamine by glutamine synthesis

105
Q

Describe the pathogenesis of encephalopathy in hyperammonemia

A

Elevations in ammonia in the cell lead to amination of glutamate to glutamine by glutamine synthesis
Glutamine can pass the BBB which changes the osmotic gradient, drawing in fluid –> cerebral edema –> electrolyte imbalances, increased ICP –> seizures, confusions, lethargy, coma, etc.

106
Q

Explain the expected BUN results for the following disorders:
Urea cycle defects
Liver failure
Renal failure

A

UCD: absent or low
Liver: low to normal
Renal: high

107
Q

Which AA carbon skeletons are primarily used to make ketone bodies, and what do they give rise to?

A

Phenylalanine
Tyrosine
Isoleucine
Threonine
Leucine
Tryptophan

Acetyl-CoA or Acetoacetyl-CoA

108
Q

Outline Glutamate biosynthesis and degradation

A

Glutamate <–> (Glutamate DH) <–> a-KG <–> TCA cycle

109
Q

Outline Glutamine biosynthesis and degradation

A

Glutamine –> (Glutaminase) –> Glutamate
Glutamate –> (Glutamine synthetase) –> Glutamine

110
Q

Outline Histidine degradation

A

Histidine –> (Histidase) –> —> —> Glutamate

111
Q

Outline Arginine biosynthesis and degradation

A

Arginine –> (Arginase) –> Ornithine <–> <–> Glutamate

Ornithine –> Citrulline –> Argininosuccinate –> Arginine

112
Q

Outline Proline biosynthesis and degradation

A

Proline –>(Prolease Oxidase) –> –> Glutamate
Glutamate –> –> –> Proline

113
Q

Outline Isoleucine degradation

A

Isoleucine –> –> (BCaKDHC) –> –> –> Propionyl-CoA –> –> –> Succinyl-CoA

114
Q

Outline Valine degradation

A

Valine –> (BCaKDHC) –> –> –> Propionyl-CoA –> –> –> Succinyl-CoA

115
Q

Outline Leucine and Lysine degradation

A

Leucine –> (BCaKDHC) –> –> –> HMG-CoA
Lysine –> –> –> Acetoacetyl-CoA –> (HMG-CoA Synthetase) –> HMG-CoA

HMG-CoA –> (HMG-CoA Lyase) –> Acetyl-CoA + Acetoacetate

116
Q

Outline Maple Syrup Urine Disease

A

Branched Chain a-Ketoacid DHC deficiency
AR BCKDHA, BCKDHB, or DBT gene mutation
CF: neonatal period, failure to thrive, delayed milestones, maple syrup odor in urine or ear wax
Dx: accumulation of BCAAs in plasma, and respective branched chain ketoacids in urine
Screen on NBS
Treat with IV D10, close metabolic monitoring, dietary restriction of BCAAs

117
Q

Outline the Methionine Cycle and Degradation

A

Methionine –> S-Adenosylmethionine (SAM) –> S-Adenosylhomocysteine –> Homocysteine –> Methionine

Homocysteine –> Cystathionine –> Cysteine –> Cysteine degradation pathway
Cystathionine –> Propionyl-CoA –> Succinyl-CoA –> TCA cycle

118
Q

Outline Homocystinuria

A

AR disorder leading to elevated homocysteine in blood and urine

CF: Marfanoid habitus, lens dislocation (down and in), increased risk of atherosclerosis, PVD, osteoporosis

Classical pathway: defect in pyridoxine B6 dependent pathway - inability to convert homocysteine to cystathionine
Treat with B6, B12, folate supplementation

Remethylation pathway: inability to convert homocysteine to methionine
Treat with Betaine supplementation to bypass remethylation pathway and create methionine

119
Q

Outline Phenylalanine Degradation and Tyrosine Biosynthesis and Degradation

A

Phenylalanine –> Tyrosine –> –> Homogentisate –> –> –> Fumarate + Acetoacetate

120
Q

Outline Phenylketonuria (PKU) Disorder

A

AR mutation of the PAH gene, deficient phenylalanine hydroxylase
Multiple phenotypes based on enzyme activity level
Detected on NBS

CF: Musty odor from skin and urine, fair skin, eczeme, seixures, tremors, “blonding” of tips of hair, microcephaly, cognitive delays

Labs: Elevated urine ketones, phenylpyruvate, phenylacetate, and phenyllactate; Increased phenylalanine:tyrosine ratio

Treat with low phe-alanine diet, low protein diet
Supplement selenium, copper, Mg2+, Zinc, L-dopa, Carbidopa, 5-HT, and BH4 for malignant type

121
Q

Explain the different pathways of PKU disorder and how they relate to symptoms

A

No PAH –> Build up of phenylalanine –> toxic build up of ketoacids phe-pyruvate, phe-acetate, phe-lactate

No PAH –> no BH4 –>
decreased tyrosine –> rash, eczema
decreased melanin –> hypopigmentation
decreased production of NT dopamine, NE –> cognitive delay

122
Q

Outline Asparagine Biosynthesis & Degradation & Aspartate Biosynthesis & Degradation

A

Asparagine –> (Asparaginase) –> Aspartate <–> (AST) –> OAA
Aspartate –> Argininosuccinate –> Arginine and Fumarate

OAA –> Aspartate –> (Asparagine Synthetase) –> Asparagine

123
Q

Outline Alanine biosynthesis and degradation

A

Alanine <– (ALT) –> Pyruvate

Cysteine Degradation Pathway and Tryptophan Degradation Pathway –> Alanine

124
Q

Outline Cysteine biosynthesis and degradation

A

Cysteine –> (AST) –> Pyruvate
Cysteine –> Alanine –> (ALT) –> Pyruvate

Methionine Degradation Pathway –> Cysteine

125
Q

Outline Tryptophan Degradation

A

Tryptophan –> –> –> Alanine –> (ALT) –> Pyruvate
Tryptophan –> –> –> Acetoacetyl-CoA –> HMG-CoA –> Acetyl-CoA + Acetoacetate

126
Q

Outline the key roles of AA

A

Making protein
Transporting N
Oxidation for fuel
Used as NT
Precursors for NT, hormones, nucleotides, heme, glutathione

127
Q

Albinism is considered what type of metabolic disorder?

A

Tyrosine

128
Q

Outline Albinism - Oculocutaneous Type

A

AR mutation on OCA1 gene
Two types:
OCA1A - complete lack of tyrosinase
OCA1B - decreased tyrosinase activity

Lack of melanocyte formation –> defect in production of eumelanin –> lack of pigment in hair/eyes
Defects in eye development
Increased risk of sun cancer - no protection from UV rays

Treat with sun exposure avoidance, ophthalmology

129
Q

Outline Alkaptonuria

A

AR disorder of HGD gene –> deficiency/absense of honogentisate 1,2-deoxygenase
Homogentiasate acid oxidized and deposited into tissue as benzoquinone acetic acid which is polymer similar to melanin –> deposits into cartilage –> arthralgias, darkened connective tissue, eyes, and ear cartilage

CF: Triad of Alkaptonuria: Onchronosis (deposit into cartilage), aciduria, and onchronotic osteoarthropathy

Dx: Urine test for HGA, genetic testing

Treat with Vit C, low protein diet, Nitisinone (prevents conversion of tyrosine to HGA)

130
Q

Outline the biosynthesis of NADP+, Serotonin and Melanin

A

Tryptophan –> (Tryptophan Hydroxylase) –> –> (DOPA Decarboxylase) –> Serotonin –> –> –> Melatonin

Tryptophan –> —> –> Nicotinamide moiety of NADP+

131
Q

What is the biosynthetic precursor of Histamine?

A

Histidine

132
Q

What is the biosynthetic precursor of GABA?

A

Glutamate

133
Q

```

~~~

Arginine is the biosynthetic precursor of

A

Nitric Oxide

134
Q

What two AA are the biosynthetic precursors to Creatine, Creatine Phosphate and Creatinine?

A

Arginine and Glycine

135
Q

What is y-Glutamyl Transpeptidase used for?

A

AA transport into cells
Glutathione production

136
Q

What AA are the biosynthetic precursors to Purine nucleotides?

A

Glutamine
Aspartate
Glycine

137
Q

What AA are the biosynthetic precursors to Pyrimadine nucleotides?

A

Glutamine
Aspartate

138
Q

What is the recommended dietary allowance of protein intake for adults?

A

0.8 g/kg of bw

139
Q

What patient populations need more than the RDA protein intake for adults?

A

Pediatric pts
Older (70+) pts
Pregnant women
Athletes

140
Q

Which two AA are limited in diet? How do we mitigate this, and who is the target pt population for it?

A

Methionine and Lysine

Eating rice with beans
Vegans, pts with low protein intake, pts with little dietary variety

141
Q

Identify the etiology and clinical presentation of kwashiorkor

A

Dietary deficiency of protein with adequate calories

Muscle wasting - thin limbs
Decreased plasma proteins - edema, abdominal distention

142
Q

What are the risks of high animal protein intake

A

Colorectal cancer
Risk of stroke
Higher mortality, CVD

143
Q

What happens to Na+, Cl- and H2O during bile storage, and after bile secretion?

A

During storage - Na+, Cl- and H2O are rebsorbed into the cells to concentrate the bile

After secretion - they are secreted into the lumen

144
Q

Biliary pain without gallstones; may have low gallbladder ejection fraction

A

Biliary dyskinesia

145
Q

Excessive supersaturated biliary cholesterol (increase of bile salts and lecithins)

A

Biliary sludge

146
Q

Cholesterol crystal nucleation (increase of deoxycholic acid, secondary bile from dysbiotic Clostridia)

A

Cholelithiasis

147
Q

Fatty meals induce gallbladder contraction; gallstone obstructs gallbladder outlet

A

Biliary Colic

148
Q

Gallstone obstructs common bile duct

A

Choledocholithiasis

149
Q

Prolonged obstruction of gallbladder/cystic duct by gallstone –> chmical irritation and inflammation –> potential superimposed secondary bacterial infection

A

Cholecystitis

150
Q

What pathological features would you see with a blocked bile duct?

A

jaundice, clay-colored stool, dark urine

Conjugated bilirubin deposition into skin –> jaundice
Lack of conjugated bilirubin in intestines –> no conversion to stercobilin –> no color to stool
Increased of conjugated bilirubin in blood stream –> excess excretion of urobilin by kidneys –> dark urine

151
Q

Cholesterol gallstones are [color a] while pigmented gallstones are [color b]

A

a. brown

b. black

152
Q

What are the mechanisms in which cholesterol gallstones form?

A
  1. Hypersecretion of biliary cholesterol
  2. Normal cholesterol but decreased bile salts
  3. Gallbladder stasis
  4. Hypersecretion of mucus in the bladder
153
Q

What are the mechanisms in which pigmented gallstones form?

A

Increase in unconjugated bilirubin:

Hemolytic anemia
Infection - converting conjugated –> unconjugated

154
Q

Discuss the potential clinical sequelae of gallstones lodged at location A

A

Cholecystitis - infection/inflammation beings approx 6 hours after getting stuck

Acalculous Cholecystitis - statis and hypoperfusion, seen in critically ill pts

155
Q

Discuss the potential clinical sequelae of gallstones lodged at location B

A

Choledocholithiasis - obstructive jaundice from blocking CBD, clay-colored stool, dark urine

156
Q

Discuss the potential clinical sequelae of gallstones lodged at location C

A

Sphincter of Oddi obstruction would effect gallbladder, liver, and pancreas

Acute pancreatitis, cholecystitis, hepatitis

157
Q

Discuss the potential clinical sequelae of gallstones lodged at location D

A

Kaltskin tumor - rare, primarily effects the liver but gallbladder and pancreas should remain unaffected.

Jaundice from lack of bilirubin secretion

158
Q

What are the biliary effects of exercise?

A

Increases gallbladder motility

159
Q

What are some dietary approaches to biliary health?

A

Unsaturated fats
Fiber
Avoid simple sugars
Coffee
Water

160
Q

What are the indications, MOA and limitations of Ursodeoxycholic Acid?

A

Long-term management of small gallstones
Prophylaxis of gallstones during rapid weight loss

MOA - increase bile acid pool and ratio of bile acids to cholesterol

Limitations - gradual onset, not effective for large gallstones

161
Q

What are some supplements and botanicals that aid in biliary health?

A

Vit C - conversion of cholesterol to bile acids - red pepper, kiwi, strawberries
Mg2+
Ca2+ - Binds deocycholic acid –> decrease enterohepatic reciruclation –> increased bile synthesis
Vit E

Botanicals: peppermint oil, dandelion, milk thistle, turmeric

162
Q

Describe Pancreatic Divisum

A

Congential abnormality of the pancreas in which the pancreatic duct does not join with the common bile duct at the papilla of vater, but rather exits to the duodenum through a minor sphincter

163
Q

Review why is it normally OK for lipase to be secreted in active form in the pancreas

A
164
Q

Discuss the three initiating events and associated pathways regarding the pathogenesis of pancreatitis

A
  1. Duct obstruction: cholelithiasis, chronic alcholoism, ductal secretions –> interstitial edema –> impaired blood flow –> ischemia –> acinar cell injury –> activated enzymes (autodigestion)
  2. Acinar cell injury: alcohol, drugs, trauma, viruses, hypercalcemia –> release of intracellualr proenzymes/lysosomal hydrolases –> activation of enzymes –> acinar cell injury –> activation of enzymes (autodigestion)
  3. Defective intracellular transport: metabolic injury, alcohol, obstruction –> delivery of proenzymes to lysosomal compartment –> intracellular activation –> acinar cell injury –> activated enzymes (autodigestion)
165
Q

Characterize Hepatitis A

A

Picornavirus, ssRNA, naked
Fecal-oral transmission
abrupt onset with mild severity
Incubation period 15-50 days
Acute only
Diagnosis: symptoms and anti-HAV IgM

166
Q

Characterize Hepatitis B

A

Hepadnavirus, pdsDNA, enveloped
Sexual, paraenteral, perinatal
Insidious onset
Incubation 45-160 days
Acute or chronic
Associated with HCC, cirrhosis
Diagnosis: symptoms, HBsAg, HBeAg, anti-HBc IgM

167
Q

Characterize Hepatitis C

A

Flavivirus, ssRNA, enveloped
Paraenteral, sexual, perinatal
Insidious onset
Incubation 14-180 days
Acute or chronic
Associated with HCC, cirrhosis
Diagnosis: symptoms, anti-HCV ELISA

168
Q

Charcterize Hepatitis D

A

Delta agent, circular RNA, enveloped
Paraenteral, sexual
Abrupt onset with co-infections or superinfection with HBV
Incubation 15-64 days
Acute or chronic
Associated with Cirrhosis, fulminant hepatitis
Diagnosis: Anti-HDV ELISA

169
Q

Characterize Hepatitis E

A

Hepevirus, ssRNA, naked
Fecal oral transmission
Abrupt onset with severe severity in pregnant women
Acute only

170
Q

Contrast HBV vs HBC replication

A

Hep B - Attaches to liver receptors to enter hepatocytes –> pdsDNA enters nucleus to form dsDNA circle –> transcribed in nucleus into 4 different mRNAs –> mRNAs sent to cytoplasm –> 3 smaller mRNA translated into proteins, longest mRNA reverse transcribed into -ssDNA –> proteins and DNA get packed into core –> +ssDNA synthesized –> core is packaged and exits cell

Hep C - enters cell through endocytosis –> uncoating –> mRNA undergoes translation into proteins that inhibit apoptosis and expression of antivirals, and replication –> assembly into exosome –> endocytosed from cell

171
Q

What type of hypersensitivity can Hep B and C cause?

A

Type III

172
Q

What is the role of HBsAg and HBeAg

A

Decoy particles of HBV that outnumber virions and bind Abs –> limits body’s ability to clear virus and forms immune complexes that cause vasculitis and arthritis

173
Q

What’s the difference between a Hep B/D co-infeciton and Hep B/D superinfection?

A

Co-infection: HBV and HDV infect at the same time

Superinfection: HBV is already established as a chronic infection, and then HDV infects - much more severe - HDV exacerbates damage

174
Q

What are the different pathways by which HBV can cause HCC?

A

Integration into DNA suppressing p53
Continued damage and repair –> mistakes in replications –> mutations
HBx - major virulence factor - activates oncogenes –> upregulates TNF-B, Jak Stat, B-catenin pathways

175
Q

Explain how to interpret an HBV serology panel

A

HBsAg - if positive, active infection (acute or chronic)
HBeAg - if positive, actively replicating and infectious
HBV DNA - active infection (acute or chronic replicating)
Anti-HBs - recovered or vaccinated
Anti-HBc IgM - acute or window period
Anti-HBc IgG - window period, chronic or recovery
Anti-HBe - chronic non-replicating

176
Q

Explain the vaccines and other preventative measures for each hepatitis

A

Hep A - killed, inactivated vaccine, good hygiene
Heb B - subunit vaccine using HbsAg (and combination vaccines with DTaP/IPV/HiB), good hygiene
Heb C - no vaccine, avoid risky behavior, blood donor screening
Heb D - Hep B vaccine, about risky behavior
Hep E - no vaccine, good hygiene, safe drinking water

177
Q

Outline the different treatment options for each form of Hepatitis

A

Hep A - No treatment; self-limiting
Hep B - IFN-a-2a: increases experssion of MHC-I, inhibits viral entry and increases activity of macrophages; Nucleosides: reverse transcriptase inhibitors
Hep C - Direct acting antiviral drugs - NS3/4 protease inhibitors, NS5A inhibitors, NS5B polymerase inhibitors
Hep D - IFN-a-2a
Hep E - Ribavirin (maybe)

178
Q

Lamivudine, Entecavir, and Tenofovir are what type of medication used for which disorder?

A

Nucleoside analogs, Hepatitis B

179
Q

Medications ending in “-pravir”, “-asvir”, and “-buvir” are what type of medications used for which disorder? Give an example of each.

A

-previr: NS3/4 protease inhibitors (Paritaprevir)

-asvir: NS5A inhibitors (Velpatasvir)

-buvir: NS5B polymerase inhibitors (Sofosbuvir)

Unit 4 GNA (6 decks)

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