LGS Week 3 & 4 Flashcards
(179 cards)
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
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
3
Q
How many double bonds are present in saturated fats, monounsaturated fats, and polyunsaturated fats?
A
0
1
2+
4
Q
Hard fat is [a] fat while oil is [b] fat
A
a. Saturated
b. Unsaturated
5
Q
Most energy dense molecule in the body, 6x more free energy than other sources
A
Fatty acids
6
Q
What are the different functions of cholesterol
A
Make bile acids
Make Vitamin D2
Make steroid hormones
Add rigidity to cell membranes
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)
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
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
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
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
12
Q
Which lipoprotein has the most:
Protein
Cholesterol
Phospholipids
Triglycerides
A
Protein: HDL
Cholesterol: LDL
Phosholipids: VLDL
Triglycerides: Chylomicron
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)
14
Q
What is the major regulator of chylomicron metabolism?
A
LPL
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
16
Q
Name the SCFA
A
Acetic acid
Proprionic acid
Butyric acid
17
Q
Name the MCFA
A
Caprioc acid
Caprylic acid
Capric acid
Lauric acid
18
Q
Name the LCFA
A
Myristic acid
Palmitic acid
Stearic acid
Arachadic acid
19
Q
Name the VLCFA
A
Begenic acid
Lignoceric acid
20
Q
What are the important functions of polyunsaturated fats?
A
Phospholipid bilayer
Precursor for eicosanoids
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
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)
23
Q
What is the SMASH acronym representing and what are they?
A
Fish highest in omega-3s (DHA)
Salmon
Mackerel
Anchovies
Sardines
Herring
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)
25
Explain the pathogenesis of Atherosclerosis
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
26
Outline Type I familial dyslipidemia
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
27
Outline Type II familial dyslipidemia
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
28
Outline Type III familial dyslipidemia
Autosomal recessive
Depective ApoE
increased chylomicrons, VLDL
CF: **premature atherosclerosis**, palmar xanthomas
29
Outline Type IV familial dyslipidemia
Autosomal dominant
Overproduction of VLDL
Increased TG, VLDL
CF: acute pancreatitis, **premature atherosclerosis**
30
Outline Abetalipoproteinemia
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)
31
Fatty Acid metabolism does not occur in
RBC and very low levels in CNS
32
What FA are canitine shuttle dependent to get into mitochondria?
Which are not?
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
33
Outline the Carnitine Shuttle
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
34
B-oxidation of even chain FA end in
No. of Carbons / 2 = *n* amount of Acetyl-CoA
35
B-oxidation of odd chain FA end in
No. of Carbons / 2 = # of Acetyl-CoA until 3 Carbons remaining (Propionyl-CoA)
Propionyl-CoA --> Succinyl-CoA
36
When is a-oxidation used?
When the b Carbon has a methyl chain on it creating steric hinderance and blocking access of enzymes
37
What two FA oxidation reactions occur particularly in the brain?
Peroxisomal B-oxidation
a-oxidation
38
Outline ketogenesis
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
39
Why does someone in ketosis have "fruity breath"
Acetone is exhaled by the lungs
40
Where does ketogenesis take place?
Only in Liver mitochondria
41
Where does ketolysis take place?
In mitochondria of all tissues EXCEPT liver and RBC
42
What are the regulators of Hepatic FA Oxidation and Ketogenesis
CPTI directly regulates Hepatic FA oxidation, indirectly Ketogenesis:
Glucagon stimulates transcription
Malonyl-CoA inhibits
43
What are regulators of Heart and Skeletal muscle FA oxidation
LPL
Stimulated by Glucagon
Inhibited by Insulin
CPTI
44
Outline MCADD
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
45
Outline CPTII deficiency
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**
46
Outline CPTI deficiency
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**
47
Outline the three main Peroxisomal Disorders
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
48
What are the three categories of Peroxisomal disorders?
1. Disorders of peroxisomal biosynthesis
2. Single enzymatic disorders
3. Multiple enzymatic disorders - shortened long bones
49
What is the main enzyme involved in Fatty Acid biosynthesis?
Malonyl-CoA
50
What stimulates fatty acid biosynthesis?
What inhibits it?
Stimulates
1. Citrate
2. Insulin
Inhibits
1. Palmitoyl-CoA
2. Glucagon
3. Epinephrine
51
Outline Fatty Acid Elongation
Palmitoyl-CoA (16C) + Malonyl-CoA --> --> --> Stearoyl-CoA (18C) + 2NADP+
52
Where does lipogenesis occur?
Enterocytes of stomach to send diet TGs to other organs
Liver to send lipids to other organs
Adipocytes for storage
53
What regulates Adipocyte Lipogenesis?
Stimulates : Insulin via LPL and GLUT4
Inhibits : Glucagon, Epinephrine via LPL
54
What regulates Adipocyte Lipolysis?
Stimulates: Glucagon, Epinephrine via HSL
Inhibits: Insulin via ATGL (Adpiose TG lipase) and HSL (hormone-sensitive lipase)
55
What are the byproducts of glycerophospholipid remodeling and degradation?
Where do these reactions occur?
PLA1, PLA2, PLD
Occurs at cell membranes and in lysosomes
56
Where does sphingolipid degredation occur?
What does it degrade into?
Lysosomes
Ceramide
57
Outline the lesser common Lysosomal Storage Diseases (Sphinogolipidoses)
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
58
Outline the most common Lysosomal Storage disease
Gaucher disease - AR - Glucocerebrosidase deficiency
Hepatosplenomegaly, pancytopenia, osteoporisis, avascular necrossi of femur, **bone crises**, Gaucher cells
Treat with recombinant Glucocerebrosidase
59
What is the enzyme that converts Arachodonic Acid into LTA4?
Which enzyme converts it to PGG2?
5-Lipoxygenase (5-LOX)
Cyclooxygenase (COX)
60
Outline the starting and ending molecule of each stage of cholesterol biosynthesis
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
61
What are the regulators of Cholesterol Metabolism?
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
62
What is the regulatory step of bile acid/salt synthesis?
Cholesterol 7a-hydroxylase
63
Explain Bile Acid/Salt conjugation
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
64
What is the purpose of the Bile Salt Export Pump
actively transports conjugated bile salts through hepatocyte apical membrane into bili canaliculi
65
What actively transports xenobiotics through hepatocyte apical membrane into bile canaliculi?
Multidrug resistance protein 1 (MRP1)
66
ABCG 5 and 8 are used to
actively transport cholesterol through hepatocyte apical membrane into bile canaliculi
67
Ductal bile is modified by [a] by [b] and is then drained out of [c]
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
68
When is hepatic bile sent to the gallbladder?
What chemical changes are made to the bile?
During times of fasting
Bile is concentrated:
decrease in H2O, Cl-, HCO3-
increase in Bile salt, Na+, Ca2+
69
What is ASBT?
Apical Sodium-Coupled Bile Salt Transporter
Allows bile salts to enter hepatocytes from co-transport of Na+
70
What does the activation of FXR in hepatocytes do?
Transcription factor for Bile Salts
Decreases expression of NCTP
Increases expression of BSEP (Bile Salt Exit Pump)
71
What inhibits Bile Salt synthesis?
Bile Salts entering hepatocytes --> transcription factors stimulate gene expression of FGF19 --> inhibits signal transduction cascade of bile salt synthesis
72
Outline Bilirubin synthesis
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
What is the purpose of bilirubin conjugation?
1. Increases its water solubility
2. Prevents its passive reabsorption in intestines
3. Decreases its albumin affinity
4. Promotes its elimination
74
What enzyme conjugates bilirubin?
UDPGT1A1
75
Compare/Contrast the following syndromes
Crigler-Najjar
Gilbert
Hemolytic Disease of a Newborn
Physiologic jaundice of the newborn
Rotor syndrome
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
What disorders will show elevated unconjugated bilirubin levels?
Crigler-Najjar Types I and II
Gilbert
77
What disorders will show elevated conjugated bilirubin levels?
Dubin Johnson
Rotor
78
What serious disorder will prolonged jaundice in neonates cause?
Kernicterus - brain damage caused by prolonged elevated unconjugated bilirubin
Bilirubin is lipophilic and can cross BBB
79
What are the essential AA?
His, Isoleucine, Leu, Lys, Met, Phe, Thr, Trp, Val
80
What AA are conditionally essential?
Arg, Cys, Gly, Gln, Pro, Tyr
81
What are the nonessential AA?
Ala, Asp, Asn, Glu, Ser
82
What enzymes cleave dietary proteins?
Gastric acid and pepsin
83
What is the endopeptidase that cleaves all zygomens into active enzymes?
Trypsin
84
What enzymes cleave peptides at the small intestine brush border?
Aminopeptidase and Dipeptidase
85
Identify the orange receptor and purple enzyme
PepT1
Peptidases
86
Outline Hartnup Disease
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
What is Purple Urine Bag Syndrome, and what disease is it associated with?
Excess tryptophan digested in the colon by bacteria releases Indoles in urine
Seen with UTIs and Hartnup Disease
88
Outline Cysteinuria
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
90
What is the role of the proteasome?
Protein turnover
91
92
93
[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. Liver
b. Muscle
94
Differentiate between deamination and transamination
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
Outline the Cahill Cycle
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
Outline Glutamate N transport
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
What are the starting and final products of the urea cycle?
Ornithine AA
98
Where does the urea cycle take place?
Liver - Partially in mitochondria and partially in cytosol
99
Outline the Urea Cycle
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
What regulates the Urea Cycle
Substrate availability (increased NH3 : NH4 --> increased urea)
CPS I - controlled by NAG
Increased expression of urea cycle enzymes (response to increased protein metabolism)
101
Outline Ornithine Transcarbomoylase (OTC) Deficiency
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
Why is elevated Orotic Acid seen in OTC deficiency?
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
Differentiate elevated Orotic Acid in OTC vs Orotic Aciduria
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
Why is Glutamine elevated in OTC deficiency?
Elevations in ammonia in the cell lead to amination of glutamate to glutamine by glutamine synthesis
105
Describe the pathogenesis of encephalopathy in hyperammonemia
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
Explain the expected BUN results for the following disorders:
Urea cycle defects
Liver failure
Renal failure
UCD: absent or low
Liver: low to normal
Renal: high
107
Which AA carbon skeletons are primarily used to make ketone bodies, and what do they give rise to?
Phenylalanine
Tyrosine
Isoleucine
Threonine
Leucine
Tryptophan
Acetyl-CoA or Acetoacetyl-CoA
108
Outline Glutamate biosynthesis and degradation
Glutamate <--> (Glutamate DH) <--> a-KG <--> TCA cycle
109
Outline Glutamine biosynthesis and degradation
Glutamine --> (Glutaminase) --> Glutamate
Glutamate --> (Glutamine synthetase) --> Glutamine
110
Outline Histidine degradation
Histidine --> (Histidase) --> ---> ---> Glutamate
111
Outline Arginine biosynthesis and degradation
Arginine --> (Arginase) --> Ornithine <--> <--> Glutamate
Ornithine --> Citrulline --> Argininosuccinate --> Arginine
112
Outline Proline biosynthesis and degradation
Proline -->(Prolease Oxidase) --> --> Glutamate
Glutamate --> --> --> Proline
113
Outline Isoleucine degradation
Isoleucine --> --> (BCaKDHC) --> --> --> Propionyl-CoA --> --> --> Succinyl-CoA
114
Outline Valine degradation
Valine --> (BCaKDHC) --> --> --> Propionyl-CoA --> --> --> Succinyl-CoA
115
Outline Leucine and Lysine degradation
Leucine --> (BCaKDHC) --> --> --> HMG-CoA
Lysine --> --> --> Acetoacetyl-CoA --> (HMG-CoA Synthetase) --> HMG-CoA
HMG-CoA --> (HMG-CoA Lyase) --> Acetyl-CoA + Acetoacetate
116
Outline Maple Syrup Urine Disease
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
Outline the Methionine Cycle and Degradation
Methionine --> S-Adenosylmethionine (SAM) --> S-Adenosylhomocysteine --> Homocysteine --> Methionine
Homocysteine --> Cystathionine --> Cysteine --> Cysteine degradation pathway
Cystathionine --> Propionyl-CoA --> Succinyl-CoA --> TCA cycle
118
Outline Homocystinuria
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
Outline Phenylalanine Degradation and Tyrosine Biosynthesis and Degradation
Phenylalanine --> Tyrosine --> --> Homogentisate --> --> --> Fumarate + Acetoacetate
120
Outline Phenylketonuria (PKU) Disorder
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
Explain the different pathways of PKU disorder and how they relate to symptoms
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
Outline Asparagine Biosynthesis & Degradation & Aspartate Biosynthesis & Degradation
Asparagine --> (Asparaginase) --> Aspartate <--> (AST) --> OAA
Aspartate --> Argininosuccinate --> Arginine and Fumarate
OAA --> Aspartate --> (Asparagine Synthetase) --> Asparagine
123
Outline Alanine biosynthesis and degradation
Alanine <-- (ALT) --> Pyruvate
Cysteine Degradation Pathway and Tryptophan Degradation Pathway --> Alanine
124
Outline Cysteine biosynthesis and degradation
Cysteine --> (AST) --> Pyruvate
Cysteine --> Alanine --> (ALT) --> Pyruvate
Methionine Degradation Pathway --> Cysteine
125
Outline Tryptophan Degradation
Tryptophan --> --> --> Alanine --> (ALT) --> Pyruvate
Tryptophan --> --> --> Acetoacetyl-CoA --> HMG-CoA --> Acetyl-CoA + Acetoacetate
126
Outline the key roles of AA
Making protein
Transporting N
Oxidation for fuel
Used as NT
Precursors for NT, hormones, nucleotides, heme, glutathione
127
Albinism is considered what type of metabolic disorder?
Tyrosine
128
Outline Albinism - Oculocutaneous Type
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
Outline Alkaptonuria
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
Outline the biosynthesis of NADP+, Serotonin and Melanin
Tryptophan --> (Tryptophan Hydroxylase) --> --> (DOPA Decarboxylase) --> Serotonin --> --> --> Melatonin
Tryptophan --> ---> --> Nicotinamide moiety of NADP+
131
What is the biosynthetic precursor of Histamine?
Histidine
132
What is the biosynthetic precursor of GABA?
Glutamate
133
# ```
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Arginine is the biosynthetic precursor of
Nitric Oxide
134
What two AA are the biosynthetic precursors to Creatine, Creatine Phosphate and Creatinine?
Arginine and Glycine
135
What is y-Glutamyl Transpeptidase used for?
AA transport into cells
Glutathione production
136
What AA are the biosynthetic precursors to Purine nucleotides?
Glutamine
Aspartate
Glycine
137
What AA are the biosynthetic precursors to Pyrimadine nucleotides?
Glutamine
Aspartate
138
What is the recommended dietary allowance of protein intake for adults?
0.8 g/kg of bw
139
What patient populations need more than the RDA protein intake for adults?
Pediatric pts
Older (70+) pts
Pregnant women
Athletes
140
Which two AA are limited in diet? How do we mitigate this, and who is the target pt population for it?
Methionine and Lysine
Eating rice with beans
Vegans, pts with low protein intake, pts with little dietary variety
141
Identify the etiology and clinical presentation of kwashiorkor
Dietary deficiency of protein with adequate calories
Muscle wasting - thin limbs
Decreased plasma proteins - edema, abdominal distention
142
What are the risks of high animal protein intake
Colorectal cancer
Risk of stroke
Higher mortality, CVD
143
What happens to Na+, Cl- and H2O during bile storage, and after bile secretion?
During storage - Na+, Cl- and H2O are rebsorbed into the cells to concentrate the bile
After secretion - they are secreted into the lumen
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Biliary pain without gallstones; may have low gallbladder ejection fraction
Biliary dyskinesia
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Excessive supersaturated biliary cholesterol (increase of bile salts and lecithins)
Biliary sludge
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Cholesterol crystal nucleation (increase of deoxycholic acid, secondary bile from dysbiotic Clostridia)
Cholelithiasis
147
Fatty meals induce gallbladder contraction; gallstone obstructs gallbladder outlet
Biliary Colic
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Gallstone obstructs common bile duct
Choledocholithiasis
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Prolonged obstruction of gallbladder/cystic duct by gallstone --> chmical irritation and inflammation --> potential superimposed secondary bacterial infection
Cholecystitis
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What pathological features would you see with a blocked bile duct?
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
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Cholesterol gallstones are [color a] while pigmented gallstones are [color b]
a. brown
b. black
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What are the mechanisms in which cholesterol gallstones form?
1. Hypersecretion of biliary cholesterol
2. Normal cholesterol but decreased bile salts
3. Gallbladder stasis
4. Hypersecretion of mucus in the bladder
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What are the mechanisms in which pigmented gallstones form?
Increase in unconjugated bilirubin:
Hemolytic anemia
Infection - converting conjugated --> unconjugated
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Discuss the potential clinical sequelae of gallstones lodged at location A
Cholecystitis - infection/inflammation beings approx 6 hours after getting stuck
Acalculous Cholecystitis - statis and hypoperfusion, seen in critically ill pts
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Discuss the potential clinical sequelae of gallstones lodged at location B
Choledocholithiasis - obstructive jaundice from blocking CBD, clay-colored stool, dark urine
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Discuss the potential clinical sequelae of gallstones lodged at location C
Sphincter of Oddi obstruction would effect gallbladder, liver, and pancreas
Acute pancreatitis, cholecystitis, hepatitis
157
Discuss the potential clinical sequelae of gallstones lodged at location D
Kaltskin tumor - rare, primarily effects the liver but gallbladder and pancreas should remain unaffected.
Jaundice from lack of bilirubin secretion
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What are the biliary effects of exercise?
Increases gallbladder motility
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What are some dietary approaches to biliary health?
Unsaturated fats
Fiber
Avoid simple sugars
Coffee
Water
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What are the indications, MOA and limitations of Ursodeoxycholic Acid?
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
What are some supplements and botanicals that aid in biliary health?
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
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Describe Pancreatic Divisum
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
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Review why is it normally OK for lipase to be secreted in active form in the pancreas
164
Discuss the three initiating events and associated pathways regarding the pathogenesis of pancreatitis
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)
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Characterize Hepatitis 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
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Characterize Hepatitis B
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
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Characterize Hepatitis C
Flavivirus, ssRNA, enveloped
Paraenteral, sexual, perinatal
Insidious onset
Incubation 14-180 days
Acute or chronic
Associated with HCC, cirrhosis
Diagnosis: symptoms, anti-HCV ELISA
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Charcterize Hepatitis D
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
Characterize Hepatitis E
Hepevirus, ssRNA, naked
Fecal oral transmission
Abrupt onset with severe severity in pregnant women
Acute only
170
Contrast HBV vs HBC replication
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
What type of hypersensitivity can Hep B and C cause?
Type III
172
What is the role of HBsAg and HBeAg
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
What's the difference between a Hep B/D co-infeciton and Hep B/D superinfection?
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
What are the different pathways by which HBV can cause HCC?
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
Explain how to interpret an HBV serology panel
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
Explain the vaccines and other preventative measures for each hepatitis
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
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Outline the different treatment options for each form of Hepatitis
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)
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Lamivudine, Entecavir, and Tenofovir are what type of medication used for which disorder?
Nucleoside analogs, Hepatitis B
179
Medications ending in "-pravir", "-asvir", and "-buvir" are what type of medications used for which disorder? Give an example of each.
-previr: NS3/4 protease inhibitors (Paritaprevir)
-asvir: NS5A inhibitors (Velpatasvir)
-buvir: NS5B polymerase inhibitors (Sofosbuvir)
