Unit III week 1 Flashcards
1
Q
Categorization of 20 Amino Acids
5 methods to do this
A
1) Acidic or basic
2) Polar or nonpolar
3) Ability to synthesize or not
4) Specific chemical constituents
5) Use in energy synthesis
2
Q
Essential vs. non-essential vs. conditionally essential AAs
A
Essential: cannot be synthesized by body, obtained from diet
Non-essential: can be synthesized from other amino acids
Conditionally essential: can be made by the body, but capacity for their synthesis is limited (especially in state of high consumption - e.g. illness)
3
Q
Specific chemical constituents in AAs can be… (4)
A
Sulfur containing AAs
AAs with nitrogen in side chain (involved in N transport)
Branched amino acids
Aromatic amino acids (precursors for NTs and hormones)
4
Q
How are proteins broken down in the gut?
A
GI tract → Peptidases: activated in gut lumen
Different specificities for specific types of peptide bonds
Sequentially break down long peptide chains into component AAs → absorbed and enter circulation
5
Q
How are proteins broken down in tissues? (2 ways)
A
protein within cells also need to be broken down
1) Ubiquitination: targets proteins for degradation in proteasomes
2) Degradation in lysosomes
6
Q
Amino acids contain a _______ group.
This means it must first be removed before use as a precursor for ___________.
This means it must be added before _______ is made from a carbon skeleton.
A
NH2
gluconeogenesis
Amino acid
7
Q
Transamination reactions:
1) L-Amino acid donates NH3 to ________ –> ________ + ___________
catalyzed by ___________
2) Ammonia released as NH3 with regeneration of _________ –> _________
A
(bidirectional depending on substrate / acceptor availability)
NO production of anything, just shuttling something
1) AA donates NH3 to a-ketoglutarate → L glutamate + a-keto acid
Catalyzed by aminotransferase
2) Ammonia released as NH3 with regeneration of a-ketoglutarate
→ Urea cycle
8
Q
Urea cycle:
1) NH3 –> ___________
catalyzed by ____________
A
NH3 → carbamoyl phosphate
Catalyzed by carbamoyl phosphate synthase 1
*Key regulated step in protein catabolism
9
Q
Urea cycle:
2) Carbamoyl phosphate + __________ –> _________
A
Carbamoyl phosphate + NH3 (from aspartate) → urea
Urea: marker of AA catabolism and oxidation
10
Q
Glutamine
A
nitrogen containing AA, accepts nitrogen from other AAs in peripheral tissues and carries it to liver/kidney
→ donates N to glutamate
→ a-ketoglutarate + NH3
11
Q
Glutamine donates N to _________
Glutamate –> _________ + ________
This reaction is catalyzed by __________
A
glutamate
Glutamate –> a-ketoglutarate + NH3
catalyzed by glutamate dehydrogenase
Second key regulated step
12
Q
Two key regulated steps of urea cycle:
A
1) NH3 → carbamoyl phosphate
Catalyzed by carbamoyl phosphate synthase 1
2) Glutamate → a-ketoglutarate catalyzed by glutamate dehydrogenase
13
Q
Sulfur containing amino acids (2)
A
cysteine (non-essential AA)
methionine (essential AA)
14
Q
Cysteine
A
can form disulfide bridges (change protein conformation)
-SH group
unessential amino acid
15
Q
Glutathione (GSH)
A
highly soluble tripeptide that contains cysteine
1) Redox buffer (SH buffer) that maintains proteins in reduced forms (EX - reduces Fe3+ → Fe2+)
2) ROS protection: reduces hydrogen peroxide (H2O2) → H2O
3) Cofactor for several enzymes
4) uses Cys to control redox potential via GSH ← → GSSG
16
Q
A-adenosylmethionine (SAM)
A
Met used to produce SAM (produced during first step of methionine degradation)
- energy source for some biochemical reactions and important methyl donor
- Precursor for homocysteine (B1 and folate metabolism)
- SAM → S-adenosylhomocysteine (SAH)
17
Q
Tetrahydrofolate
A
important one carbon methyl transfer reactions
18
Q
Ring structure on side chains of what AAs? (3)
These are precursors for what important molecules? (7)
A
tryptophan, phenylalanine, tyrosine
Precursors for serotonin, niacin, dopamine, NE, epinephrine, tetrahydrobiopterin, thyroid hormone
19
Q
Collagen
formation occurs via posttranslational modification from what 2 enzymes?
These reactions are _______ dependent
A
most abundant protein in human body, forms triple stranded helix
1) Prolyl hydroxylase
2) Lysyl hydroxylase
Vitamin C dependent
20
Q
Hydroxyproline (Hyp)
-use?
___________ converts _____ to Hyp
A
used in collagen for H-bonding → increase collagen strength
Prolyl hydroxylase converts Pro to Hyp
21
Q
Hydroxylysine (Hyl)
-use?
___________ converts _____ to Hyl
A
used in collagen for interchain cross-links
Lysyl hydroxylase converts Lys to Hyl
22
Q
Gamma-carboxyglutamate (Gla)
-use?
_________ converts ______ –> ______
This reaction is _______ dependent
A
used to target proteins to membranes via Ca chelation
Glutamyl carboxylase converts Glu → Gla (vitamin K dependent)
23
Q
Scurvy
A
both prolyl hydroxylase and lysyl hydroxylase rely on Vit-C (ascorbate) as a coenzyme
No Vit C → scurvy (Reduced collagen strength)
24
Q
Vitamin C
A
cofactor for prolyl hydroxylase and lysyl hydroxylase enzymes used in collagen synthesis and strengthening
25
Vitamin K
used as cofactor for glutamyl carboxylase
26
Vitamin B6
used to make pyridoxal phosphate (PLP) → used by aminotransferases to “hold” / transfer amino groups during transamination reactions
27
Ubiquitin-Proteasome System
ATP dependent cross-linking of protein to ubiquitin (done by E1, E2 and E3 types)
Ubiquitinated proteins sequestered to proteasome → cellular trash can with proteolytic activity
28
Protein degradation: Lysosomal path
ATP independent, engulfs extracellular proteins (or live pathogen) → broken down by acid hydrolysis and lysosomal proteins (cathepsin)
29
Proteases (6)
secreted as proenzymes and cleaved in order to be activated
1) Pepsin
2) Enteropeptidase
3) Trypsin
4) Chymotrypsin
5) Carboxypeptidase-A
6) Carboxypeptidase-B
30
Pepsin
stomach
pepsinogen cleaved by HCl → pepsin→ cleave proteins
Aspartic protease: hydrolyzes N-terminal side of aromatic residues (Phe, Trp, Tyr)
31
Enteropeptidase
(intestine): cleaves trypsin into active form
Trypsinogen cleaved by enteropeptidase → trypsin
32
Trypsin
produced in pancreas → small intestine
cleaved into active form by enteropeptidase
Serine protease - hydrolyze C-terminal side of basic AA (Arg, Lys)
Trypsin cleaves all other zymogens in SI (chymotrypsinogen → chymotrypsin, pro carboxypeptidases → carboxypeptidase)
33
Chymotrypsin
serine protease - hydrolyzes C-terminal side of aromatic and some hydrophobic residues (Phe, Trp, Tyr, Leu, Met)
cleaved into activated form by trypsin
34
Carboxypeptidase-A
metallocarboxypeptidase - hydrolyzes C- terminal of hydrophobic AAs (Ala, Ile, Leu, Val)
cleaved into activated form by trypsin
35
Carboxypeptidase-B
cleaved into activated form by trypsin
metallocarboxypeptidase - hydrolyzes C-terminal of basic residues AAs (Arg, Lys)
36
Liver problems --> build up of what two enzymes?
Liver problems → build up of aminotransferases (ALT and AST) in blood
37
Alanine aminotransferase (ALT)
catalyzes what reaction
alanine + a-ketoglutarate ← → pyruvate + glutamate
38
Aspartate aminotransferase (AST)
catalyzes what reaction
aspartate + a-ketoglutarate ← → oxaloacetate + glutamate
39
Glu dehydrogenase
catalyzes what reaction?
Glutamate → a-ketoglutarate + NH3+
NH3 --> enters urea cycle
40
Aminotransferases require coenzyme _________ derived from _______
require coenzyme pyridoxal phosphate (PLP)
| PLP is a derivative of B6
41
pyridoxal phosphate (PLP)
PLP is a derivative of B6
PLP “holds” amino group during its transfer
Used by aminotransferases as a conenzyme
42
Urea Cycle general overview
get rid of ammonia by forming less toxic compounds (urea)
-We do NOT store ammonia, and it’s toxic
- Ornithine recycled in urea cycle
- Occurs in mitochondria for part and cytosol for part
Entry points for nitrogen: aspartate and free ammonia
43
Overall reaction of urea cycle
3ATP + HCO3- + NH4+ + aspartate → 2 ADP + AMP + 2Pi + PPi + fumarate + urea
44
Tyrosine
used to make...?
Tyrosine → T4 (prohormone) → T3 (hormone)
45
Thyroid stimulating hormone (TSH)
stimulates iodide uptake + release of T4, T3
46
Thyroid peroxidase
oxidizes iodide (I-) → I2
47
Thyroglobulin (Tg)
contains Tyr residues iodinated to form T4, T3
48
Thyroxin binding globulin (TBG)
transports T3, T4
49
Porphyrin
cyclic molecules made of 4x pyrroles produced in liver
Bind Fe2+ (iron)
50
Heme synthesis
1) ______ + _______ --> __________
catalyzed by what enzyme
where in the cell does this occur?
Gly + succinyl CoA → d-Aminolevulinic acid (ALA)
Catalyzed by d-Aminolevulinate synthase
mitochondria
51
Heme synthesis
2) 2 d-Aminolevulinic acid (ALA) --> _______________
catalyzed by what enzyme
occurs where in the cell?
2 ALA → Porphobilinogen
Catalyzed by d-Aminolevulinate dehydratase
occurs in cytosol
52
Heme synthesis
3) Porphobilinogen --> --> --> --> __________ --> heme
the final step is catalyzed by what enzyme?
where in the cell does this occur?
Porphobilinogen → → → → Protoporphyrin → Heme
(catalyzed by ferrochelatase)
occurs in mitochondria
53
Porphyrin (heme) degradation:
1) Heme --> _______ --> _______
2) Bilirubin is transported in blood with ____________
3) Bilirubin is conjugated with ___________ in the _________ --> ______________
1) Heme → Biliverdin (green) → bilirubin (red-orange)
2) Albumin
3) Bilirubin conjugated with glucuronic acid in liver → bilirubin diglucuronide (conjugated bilirubin)
54
Porphyrin (heme) degradation:
4) Bilirubin diglucuronide (conjugated bilirubin) --> ________ --> _________
this occurs where?
→ bilirubin diglucuronide → urobilinogen → stercobilin (brown)
Occurs in intestine
55
Lead effect on heme - inhibits what two enzymes?
inhibits d-Aminolevulinate dehydratase and ferrochelatase
→ “Lead Poisoning”
Get Zn-protoporphyrin formation → fluorescent haze around RBCs
56
Urea cycle:
1) _______ + _________ --> Citrulline
catalyzed by what enzyme?
where in the cell?
Ornithine + Carbamoyl Phosphate → Citrulline
Catalyzed by Ornithine Transcarbamylase
Found in MITOCHONDRIA
57
Carbamoyl Phosphate Synthetase I
catalyzes what reaction?
located where in the cell?
activated by what?
uses what else in this reaction?
CO2 + NH3 → Carbamoyl Phosphate
**uses 2 ATP
MITOCHONDRIA
Activated by N-acetylglutamate**
58
N-acetylglutamate
Key activator required for carbamoyl phosphate synthetase I kick starting the Urea Cycle
59
How is N-acetylglutamate made?
______ + _______ --> N-acetylglutamate
catalyzed by _________
reaction is activated by ________
Acetyl CoA + Glutamate --> N-acetylglutamate
N-Acetylglutamate synthase
activated by Arginine
60
ORNT1
ornithine IN - citrulline OUT (of mitochondria)
antiporter
61
Urea Cycle
2) Citrulline + _________ --> _____________
catalyzed by what enzyme?
where in the cell does this take place?
what else is used in this reaction?
Citrulline + Aspartate → Argininosuccinate
Catalyzed by Argininosuccinate synthase (ASS)
Occurs in cytosol
uses ATP
62
Urea Cycle:
3) Arginosuccinate --> ________ + __________
catalyzed by what enzyme?
where in the cell does this take place?
what else is used in this reaction?
Argininosuccinate → Arginine + Fumarate
Catalyzed by Argininosuccinate lyase
Occurs in cytosol
doesn't use anything else!
63
Arginine --> ______ + _______
catalyzed by what enzyme?
where in the cell does this take place?
what else is used in this reaction?
Arginine → Ornithine + Urea
Catalyzed by Arginase
Occurs in cytosol
doesn't use anything else!
64
In nerves arginine can be converted directly into ________ and ______ via what enzyme?
Arginine → citrulline + NO (NO synthase)
65
In muscle, arginine can be converted directly into ________ and ________ for what purpose?
Arginine → ornithine → creatine phosphate for muscle energy
66
Four control points for protein catabolism:
1) Directionality of transamination (by ALT and AST) regulated by relative concentrations of “substrates” and “products”
2) N-acetylglutamate required activator of carbamoyl phosphate synthetase
Kick starts Urea Cycle
3) Directionality of oxidative deamination by Glu dehydrogenase depends on relative concentrations of Glu, a-ketoglutarate, NH3
4) ATP and GTP are allosteric inhibitors of Glu dehydrogenase, while ADP and GDP are activators
67
Ammonia is transported in the blood using ______ or _______
urea
| glutamine
68
Glutamine
“holds” two ammonia groups
formed by glutamine synthetase
69
glutamine synthetase
converts glutamate → glutamine for transport to liver → enters urea cycle there
NOT in muscle
70
Glu dehydrogenase
why is it important?
what reaction does it catalyze?
what activates this reaction, what inhibits it?
control point for protein metabolism**
-Controls direction of nitrogen removal vs. incorporation into AAs
Glutamate + H2O ←→ a-ketoglutarate + NH4+
Inhibited by ATP and GTP
Activated by ADP and GDP
71
Cori Cycle
Pyruvate --> Lactate in muscle --> transported in blood to liver
Lactate --> pyruvate --> glucose in liver
Glucose sent to muscle for oxidation into pyruvate
72
Cahill Cycle - Alanine-Glucose Cycle
Glucose --> pyruvate --> alanine (transamination) in MUSCLE
Alanine transported in blood to liver
Alanine --> pyruvate (transamination) --> glucose in LIVER
glucose transported in blood to muscle
73
Gluconeogenic amino acids
| -3 examples
produces pyruvate or TCA intermediates
Oxaloacetate (from aspartate transamination)
Asparagine
Aspartate
74
Ketogenic amino acids
| -2 examples
no net production of glucose
Lysine and leucine → Acetyl CoA (2 carbons)
75
Maple Syrup Disease (MSUD)
deficiency in branched-chain a-ketoacid dehydrogenase complex
→ build up of a-keto acids in urine (“sweet smelling”)
leucine buildup is toxic
76
How are branched chain amino acids (leucine, valine, isoleucine) broken down?
(2 steps)
which one is deficient in MSUD?
1) Deaminated by branched-chain aminotransferase → a-keto acids
2) Decarboxylated by branched-chain a-ketoacid dehydrogenase
* *deficient in MSUD
77
Homocystinuria
defect where?
defect in cystathionine-b-synthase (CBS) or deficiency in Vit-B6
→ cannot convert homocysteine → cystathionine
78
Homocystinuria
presentation (4)
what are abnormal lab values? (2 key ones)
treatment (3) ?
Presentation:
1) DVT, stroke, atherosclerosis
2) Marfan-like habitus
3) Mental retardation
4) Joint contractures
Elevated homocysteine, elevated methionine (no megaloblastic anemia)
*on new born screening
TX:
- Vit-B6 to “force” CBS activity
- restrict methionine
- betaine treatment +/- folate and B12
79
Hyperhomocysteinemia
defect where?
causes what?
elevated levels of homocysteine due to low folate, B6, and B12 (vascular disease)
Cysteine is now essential and treat with folate, B6, and B12
80
Cystinuria
defect where?
treatment?
kidney stones due to defective transporter of cystine → crystallization in urea
TX: acetazolamide (make cystine more soluble)
81
Cys and Met Metabolism (4 steps for Met, 5 steps for Cys)
Met → SAM → SAH → homocysteine → Met
OR
Met → SAM → SAH → homocysteine → cystathionine → cysteine
82
Conversion of homocysteine --> Methionine requires _____ and _____ for CH3 transfer
Homocysteine → Met requires THF and VB12 for CH3 transfer
83
Tetrahydrofolate (THF)
synthesized in bacteria, Folate → THF
One-carbon donor for variety of biosynthetic reactions
(used in homocysteine --> Met reaction)
84
Trp Metabolism:
Trp --> ______ or _______
Trp hydrolyzed by ____________ which uses _______ has a cofator
Trp → pyruvate or acetyl-CoA
hydrolyzed by tryptophan hydroxylase
Uses Tetrahydrobiopterin (BH4) as cofactor
85
Tryptophan is important for the production of what 3 things?
Trp → serotonin, melatonin, niacin
86
Phe and Tyr metabolism:
Phe, Tyr →_____________ or _________
fumarate or acetoacetate
87
Phe (hydroxylated by _________) → ______
Uses ______ cofactor
Phe (hydroxylated by phenylalanine hydroxylase) → Tyr
Uses BH4 cofactor
88
Tyr (hydroxylated by ________) → _______
| Uses ______ as cofactor
Tyr (hydroxylated by tyrosine hydroxylase) → DOPA
Uses BH4 as cofactor
89
DOPA --> _________ or ________
uses _____ as cofactor
DOPA → catecholamines (dopamine, NE, epinephrine) or melanin
Uses BH4 as cofactor
90
BH4
cofactor for...(3)
1) Phenylalanine hydroxylase
2) Tyrosine hydroxylase
3) Tryptophan hydroxylase
91
Phenylketonuria (PKU)
defect in phenylalanine hydroxylase (convertes Phe--> tyrosine)
→ buildup of alternative byproducts (phenyllactate, phenylacetate, phenylpyruvate)
92
Tyrosinemia
defects in multi-step tyrosine degradation
93
Purines vs. Pyrimidines
Purines: guanine, adenine - 2 ringed base
Pyrimidines: uracil, thymine (DNA), cytosine (RNA) - 1 ring base
94
Nucleoside vs. nucleotide
Base = single or double ringed, contains N, C, O, and H
Nucleoside = base + pentose sugar
Nucleotide = base + ribose sugar + phosphate
95
Purine nucleotide synthesis overview
start with sugar, add phosphate (PRPP) to activate sugar --> add base
--> ends at IMP --> AMP, GMP
96
Pyrimidine nucleotide synthesis overview
start by making base --> add activated sugar (PRPP) --> ends at UMP --> UTP or dTMP
Unlike purines, pyrimidine base ring NOT made on ribose sugar - made separately and then base ring is added to sugar
97
Purine nucleotide synthesis:
1) Ribose -5-Phosphate --> __________
catalyzed by _________
uses _____
activated by ______
Inhibited by _______
1) Ribose 5-phosphate → 5-Phosphoribosyl-1-pyrophosphate (PRPP, ACTIVATED SUGAR)
Catalyzed by PRPP Synthetase
Uses ATP
Activated by Pi
Inhibited by purine ribonucleotides
98
Purine nucleotide synthesis:
2) PRPP + _______ --> adds first N to PRPP
```
catalyzed by ___________
inhibited by (3)
activated by (1)
```
RPP (contains ribose sugar) + Glutamine → add first N to PRPP
Via glutamine Phosphoribosylpyrophosphate amidotransferase
KEY STEP
Inhibited by AMP, GMP, IMP
Activated by PRPP
99
What is required for purine synthesis (4)
glycine
glutamine
THF
aspartate
100
What is required for pyrimidine synthesis (1)
aspartate
101
Purine synthesis:
after N is added to PRPP --> --> a few steps later you make _________ which can then generate ______ and _______
Inosine Monophosphate (IMP)
→ GMP + AMP
102
AMP --> ATP how?
| GMP --> GTP how?
AMP* + ATP ← → 2 ADP* (via adenylate kinase)
ADP + CTP ← → ATP* + CDP
GMP* + ATP ← → GDP* + ADP (via guanylate kinase)
GDP + ATP ← → GTP* + ADP
103
Pyrimidine synthesis:
1) ______ + CO2 --> ________
catalyzed by ___________ where in the cell?
inhibited by _____
activated by _______
Glutamine + CO2 --> carbamoyl phosphate
Via Carbamoyl Phosphate Synthetase II: in cytosol
Activated by PRPP
Inhibited by UTP
104
Pyrimidine synthesis:
2) Carbamoyl phosphate + _________ --> --> --> eventually generates _________
Aspartate
Generates Uracil Monophosphate (UMP)
105
Pyrimidine synthesis:
3) Once UMP is made, it can generate...(2 pathways)
1) UMP → UDP --> UTP → CTP (Via CTP synthase)
| 2) UMP --> UDP --> dUTP (via ribonucleotide reductase) --> dUMP --> dTMP
106
Purine breakdown overview
base removed from sugar → free base (adenosine/guanine)
Bases broken down to uric acid → excreted in urine
107
Purine breakdown:
1) AMP --> ______
2) Adenosine --> ________
- what enzyme?
3) -> hypoxanthine --> __________
- what enzyme?
4) Xanthine --> ________
- what enzyme
AMP → Adenosine
Adenosine→ Inosine (Adenosine deaminase)
→ hypoxanthine → xanthine (xanthine oxidase)
Xanthine → uric acid (xanthine oxidase)
108
Pyrimidine breakdown
base ring removed from ribose (same as purines)
→ base ring OPENED UP → Succinyl-CoA, Malonyl-CoA, Acetyl-CoA
NO toxic intermediates
109
Salvage Pathways
-two main enzymes used?
nucleotides made from partially degraded, reused nucleotides
-Free bases attached to ribose sugar (PRPP)
1) Guanine + PRPP → GMP (by HGPRT)
2) Hypoxanthine + PRPP → IMP (HGPRT)
3) Adenine + PRPP → AMP (by adenine phosphoribosyl transferase (APRT))
110
Ribonucleotide Reductase
converts ribose to deoxyribose
Operates on diphosphates (NDPs, ADP, GDP, CDP, UDP)
111
Regulation of ribonucleotide reductase
Primary regulation site (“on/off” switch) for overall enzyme activity → active in presence of ATP, inactive with high dATP
Substrate specificity site (“dial”): sensitive to concentrations of individual dNTPs → enzyme changes specificity based on what NDP is in highest concentration
→ equal amounts of each NDP → dNDP
112
Gout
buildup of uric acid in blood due to deficiency or hyperactivity of enzymes in purine degradation pathway
113
Severe Combined Immunodeficiency Syndrome (SCID)
mutation in adenosine deaminase gene
| → build up of dATP → inhibits ribonucleotide reductase → prevents enough dNTPs from being made
114
Lesch-Nyhan Syndrome
deficiency in what?
presentation? (3)
deficiency in purine salvage pathway (HGPRT) → higher rates of de novo purine synthesis
Presentation: gout symptoms, self-mutilating behavior, severe mental disorders
115
5-Fluorouracil targets _______ and Methotrexate targets __________
targets thymidylate synthase (5-FU)
targets folate metabolism cycle (Methotrexate
116
6-mercaptopurine inhibits ________
inhibits de novo purine synthesis (inhibits AMP synthesis)
117
Azidothymidine (AZT) inhibits ___________
viral polymerase
118
Cytosine arabinoside (araC) targets __________
targets DNA polymerase (anti leukemia)
119
Acyclovir (ACV) targets _______ and _________
targets viral DNA polymerase and reverse transcriptase (anti HSV)
120
Hydroxyurea inhibits __________
ribonucleotide reductase
121
Acute intermittent porphyria is a deficiency in ___________ enzyme.
Inheritance?
Problem with porphobilinogen deaminase (converts porphobilinogen → hydroxymethylbilane)
AD, episodic, variable expression
122
Acute intermittent porphyria
Presentation (5)
1) Late onset
2) Anxiety, confusion, paranoia
3) Acute abdominal pain
4) NO photosensitivity
5) Port-wine urine
123
What should you NEVER give a patient with Acute intermittent porphyria? Why?
NEVER give barbiturates (induce CYP450 → increase heme consumption → decrease [heme] → no ALA synthetase inhibition → build up of heme synthesis intermediates)
124
Porphyria Cutanea Tarda is a deficiency in _________ enzyme
inheritance?
Problem with uroporphyrinogen decarboxylase (converts uroporphyrinogen → coproporphyrinogen)
Most common Porphyria
AD
125
Porphyria Cutanea Tarda
Presentation (5)
1) Late onset
2) Photosensitivity - inflammation, blistering, shearing of skin with sun exposure
3) Hyperpigmentation
4) Exacerbated by alcohol
5) Red/brown urine
126
Albinism is a defect in ________ enzyme, a part of ________ metabolism that produces melanin
defect in tyrosinase (converts tyrosine → melanin)
127
Alcaptonuria is a defect in _________ enzyme, part of the _______ and ______ breakdown pathway
defect in homogentisate oxidase (phenylalanine and tyrosine breakdown pathway)
128
Alcaptonuria
presentation (3)
dark urine (blue/black)**, ochronosis, arthritis
129
How do you differentiate hyperhomocysteinemia due to low folate vs. low B12
Low folate → megaloblastic anemia, elevated homocysteine, decreased methionine, normal methylmalonic acid
Low B12 → megaloblastic anemia, elevated homocysteine, decreased methionine, ELEVATED methylmalonic acid (B12 also a cofactor for methylmalonyl CoA mutase)
130
Methionine degradation and cysteine synthesis
1) Met → _______ via transfer of methyl group
2) SAM → ________
3) SAH → _________
4) Homocysteine broken down into _________ via ________ enzyme and cofactors or _________ requiring _______ enzyme and cofactors
5) finally, cystathionine --> _________
1) Met → SAM (S-adenosylmethionine) via transfer of methyl group
2) SAM → S-adenosylhomocysteine (SAH)
3) SAH → Homocysteine
4) Homocysteine
→Methionine via Homocysteine Methyltransferase (B12 and THF cofactor) **
OR
→ Cystathionine via Cystathionine Synthase (B6 cofactor**)
5) Cystathionine → Cysteine
131
Treatment of PKU
dietary restriction of phenylalanine
- avoid aspartame
- Sapropterin (BH4 cofactor supplement) for patients with some residual enzyme activity
-Must also treat mothers with PKU to prevent problems in infant
132
Manifestations of untreated PKU
intellectual disability, hypopigmentation, eczema, hypomyelination on brain MRI
133
How is PKU usually diagnosed
Newborn screening for PKU: diagnosed nearly 100% of time
- Presence of hyperphenylalaninemia using Guthrie microbial assay on blood spot
- NBS via tandem mass spectrometry (test for PKU + many other diseases)
134
Presentation of Maple Syrup Urine Disease (MSUD)
1) Maple syrup odor in cerumen 12-24 hrs after birth
2) Ketonuria
3) Irritability, poor feeding by age 2-3 days
4) Encephalopathy - lethargy, intermittent apnea, opisthotonus
5) Cerebral edema
6) Stereotyped movements (“fencing”, “bicycling”) by 4-5 days
7) Coma and central respiratory failure by 7-10 days
**Reversible with treatment
135
Diagnosis of MSUD (6)
presence of clinical features
```
+decreased levels of BCKAD enzyme
+presence of all-isoleucine
+elevated leucine
+urine ketones
+gene sequencing
```
**Newborn screening done for MSUD
136
Treatment of MSUD
- dietary leucine restriction
- high calorie BCAA-free formulas
- judicial supplementation with isoleucine and valine (only leucine is toxic)
- frequent monitoring
- Liver transplant
137
Tyrosinemia Type I is due to a deficiency in ____________ enzyme
Deficiency of enzyme fumarylacetoacetate hydrolase (FAH)
138
Tyrosinemia Type I
Presentation
1) Acute liver failure in infancy, later as hepatocellular carcinoma
2) Hyperbilirubinemia, jaundice, ascites, coagulopathy, hepatomegaly
3) Rickets
4) Neurologic crises, abdominal pain
5) Death occurs in untreated child before age 10 from liver failure, neurologic crisis, or hepatocellular carcinoma
139
Urea cycle disorders
Defects in metabolism of waste nitrogen from the breakdown of protein and other nitrogen-containing molecules
Deficiency in the six enzymes of the urea cycle pathways: CPS1, OTC, ASS1, ASL, ARG, NAGS
140
Presentation of urea cycle disorders
severe vs. partial
Severe UCD → accumulation of AMMONIA during first few days of life → normal at birth with rapid progression to cerebral edema, lethargy, anorexia, hyper/hypoventilation, hypothermia, seizures, neurologic posturing, coma
Partial UCD → ammonia accumulation triggered by illness or stress
141
Screening for urea cycle disorders
plasma ammonia concentration > 150 umol/L or higher with normal anion gap and normal plasma glucose
Definitive diagnosis with enzyme activity assay or genetic testing
Certain deficiencies may be present on newborn screening (ASS1, ASL, ARG deficiencies)
*OTC is not
142
Ornithine transcarbamylase deficiency (OTC)
most common urea cycle defect (X-linked)
OTC ONLY expressed in liver
Lethal in neonatal period for boys
**OTC is NOT on newborn screening
143
Diagnosis of OTC deficiency and treatment
Diagnosis: diagnostic metabolite is orotic acid with low citrulline, high glutamine
Treatment: VERY LOW protein diet, supplement citrulline/arginine, close nutritional monitoring
- Dialysis
- Liver transplant is curative
144
Lysosomal Storage Diseases (LSD)
-examples (7)
occur when a lysosomal enzyme is deficient/missing resulting in substrate accumulation (storage) in various organs and dysfunction
PROGRESSIVE diseases that present less acutely than other metabolic conditions
1) Fabry
2) Gaucher
3) Hunter
4) Hurler
5) Pompe
6) Tay Sachs
7) McArdle
145
Key signs of storage/accumulation in lysosomal storage diseases
Macrocephaly, cognitive regression
Coarseness, angiokeratoma
Corneal clouding, cherry red spot (Tay Sachs)
Macroglossia, sleep apnea
Hepatosplenomegaly
Proteinuria
Dysostosis multiplex (vertebral “beaking”, broad bases of metacarpals and phalanges, scoliosis)
Joint stiffness, short stature
146
Inheritance of lysosomal storage diseases
most AR, with a few exceptions
Fabry (alpha-galactosidase) = X-linked Dominant
Hunter syndrome (iduronate-2-sulfatase) = X-linked Recessive
147
Lysosomes
single membrane bound, intracellular organelles
Acidic, hydrolase-rich, capable of degrading macromolecules into smaller components
Hydrolases only active in acidic environment of lysosome
148
Fabry disease
inheritance?
-differences in presentation based on age (teen, adult, older adult)?
X-linked dominant (mostly men)
- Preteen/teen onset with neuro findings
- Adult with renal failure
- Older adult with LVH or stroke
149
Fabry Disease
5 key features
1) ACROPARESTHESIAS** (pain in palms/soles + fever)
2) Proteinuria and RENAL FAILURE**
3) LVH/stroke
4) Dark red, ANGIOKERATOMAS** (bathing suit distribution)
5) Family history of early renal failure in male relatives
150
What enzyme is deficient in fabry disease?
Alpha-galactosidase
151
Is there a treatment for fabry disease?
agalsidase beta
152
Gaucher Disease Type 1
inheritance?
onset at what age?
AR, adult onset
153
Gaucher Disease Type 1
Key features (5)
1) Hepatosplenomegaly (enlarging abdomen)
2) Anemia (fatigue)
3) Thrombocytopenia
4) Looks like “lymphoma” (BIG SPLEEN/anemia) but isn’t
5) BONY PAIN
154
Enzyme deficient in Gaucher Disease Type 1
Beta-glucosidase (aka glucocerebrosidase)
155
Is there a treatment for Gaucher Disease Type 1?
enzyme replacement, oral substrate inhibition
156
Hunter and hurler disease
inheritance?
onset at what age?
Hunter = XR, onset in childhood
Hurler = AR, onset in childhood
157
Key features shared by hunter and hurler synromes (6)
1) Coarse facies
2) Airway disease
3) Ear infections
4) Hoarse voice
5) Hepatosplenomegaly
6) Short stature
158
2 main features that differentiate hunter and hurler syndromes
1) MALE (Hunter), FEMALE (Hurler)**
| 2) NO CORNEAL CLOUDING (Hunter) CORNEAL CLOUDING (Hurler)
159
Enzyme involved in Hunter syndrome
iduronate sulfatase
| treat with recombinant enzyme - Idursulfase
160
Enzyme involved in Hurler syndrome
Alpha iduronidase
| treat with recombinant enzyme - Iaronidase
161
Pompe Disease
inheritance?
key organs involved?
AR
Organs involved: skeletal muscles, heart (infant only)
162
Pompe Disease
Clinical presentation
- Infant with progressive MUSCLE WEAKNESS and SEVERE LVH
- Normal intelligence
- Infant presents at 3-6 months, dead at 1 yr w/o treatment
Adult with proximal MUSCLE WEAKNESS and RESPIRATORY WEAKNESS (sleep apnea)
-Normal intelligence
163
Key features of pompe disease
infant vs. adult
1) Infant with muscle weakness, high CK, and LVH on ECG
| 2) Adult with sleep apnea and trouble climbing stairs
164
Enzyme deficient in pompe disease
alpha-glucosidase
| treat with recombinant enzyme - alglucosidase alfa
165
Tay Sachs Type I
inheritance
age of onset?
AR, infantile/early adulthood onset
166
Ket features of Tay Sachs (6)
1) Increased startle reflex
2) Blindness**
3) Seizures
4) CHERRY RED SPOTS**
5) Mental/motor deterioration
6) Likely will die
167
Enzyme deficient in Tay Sachs
Beta-hexosaminidase A
168
Is there a treatment for Tay Sachs?
No - supportive only
169
McArdle disease
inheritance?
age of onset?
AR, adult onset
170
Key features of McArdle (3)
1) Muscle weakness and cramping with exercise
2) “Second Wind” phenomenon (weak upon initial exercise, then gets “second wind”
3) High CK
171
Enzyme deficient in McArdle
Is there a treatment for McArdle?
glycogen phosphorylase
TX = supportive
172
Feeding a hospitalized patient depends on what 4 factors?
1) Patient’s preexisting nutritional status
2) Patient’s level of illness
3) Consequences to patient of inadequate nutrition
4) Risks of feeding them
173
Enteral administration
tube inserted into GI tract via mouth, nose, or through abdominal wall
Risks: aspiration of food into lungs
Administration:
Start infusion at lower infusion rate, and gradually increase flow rate of diet over a period of days
Check residuals (amount of food still in stomach)
If you cannot give enteral diet at a rate sufficient to meet TEE then give some enteral nutrition with parenteral nutrition
Enteral preferred over parenteral
174
Parenteral administration
IV feeding
Risks: infection from a central line that contains nutrients in high concentration
Should administer enteral when possible
175
What to feed - Estimating calories/day needed
Someone not that sick → 22-25 kcal/kg/day, very sick → 30-32 kcal/kg/day
Multiple by kg, then 1 kcal/ml, then divide by hours → hourly infusion rate
176
How to monitor the adequacy of feeding?
What are signs of overfeeding?
once glycogen stores are filled → pt develops hyperglycemia
→ reduce number of calories they get each day, may take days for situation to reverse itself
177
How to monitor the adequacy of feeding?
What are signs of underfeeding?
Underfeeding → break down muscle to donate AAs to gluconeogenesis → lose weight over time, can measure urinary nitrogen over 24 hrs
Number of grams of protein catabolized = grams urinary nitrogen x 6.25
grams of protein catabolized > protein you are feeding them → underfeeding them
178
Special issues associated with feeding hospitalized patients:
Respiratory failure patient
Overfeeding → increases rate of oxidation of nutrients → consume more O2 and produce more CO2
DO NOT OVERFEED
Consider feeding people on a ventilator a high fat, low calorie diet
More CO2 produced for each O2 consumed when glucose is burned compared to fat
179
Special issues associated with feeding hospitalized patients:
Liver failure patient
High levels of ammonia + high aromatic AA + ascites → limit protein, salt, water intake
180
Special issues associated with feeding hospitalized patients:
Renal failure patient
Kidneys responsible for excreting urea → limit protein catabolism, limit volume and salt
181
Special issues associated with feeding hospitalized patients:
Cardiac disease patient
Low fat, low sodium, low saturated fat diet = “Cardiac diet”
Restrict Na+ due to volume overload (CHF)
Restrict energy in overweight or obese patients
182
Special issues associated with feeding hospitalized patients:
Diabetic patient
“Diabetic diet” = restricted calories, fat, and simple sugars
Control carb content with each meal so insulin dose can be tailored to carbs
May want to feed patient more like how they would eat at home so medications/insulin can be adjusted to a more realistic diet
183
Risk for Nutritional Problems (7)
```
Very young
Very old
Underweight/overweight
Hypermetabolic
Alcoholic
Impoverished/marginalized/altered mental capacity
Chronic conditions
```
184
Chronic conditions that put patients at risk for nutritional problems
Decreased absorption: CF, celiac disease
Increased losses: blood loss, diarrhea
Increased requirements: growth, pregnancy, lactation, pulmonary/cardiac disease
185
Obtaining Diet Intake Information (4)
History - risk, diet
Anthropometry - BMI, waist circumference
Physical Exam - skin (rash, petechiae, bruising, pallor), hair (color, texture), mouth (sores, cracked lips, tongue), extremities
-Loss/gain of subcutaneous fat, muscle wasting, edema, neuro exam, mouth
Labs - albumin, prealbumin, transferrin, CBC, specific nutrient level
186
Estimated Average Requirement (EAR)
estimated adequate intake for 50% of population - used to assess inadequate intakes and planning goal intake for mean intake of POPULATIONS
EX) need X amount if Vit C to prevent scurvy
187
Recommended Dietary Allowance (RDA)
meets requirements for 95-87% of population (i.e. it’s set high) - used as goal for HEALTHY individuals (NOT to assess/plan diets of groups)
Applies to INDIVIDUALS not groups
188
Actual estimates of intakes of food and/or nutrients: (2)
1) 24 hour recall/typical day: quick, easy, good for diets with limited variability, may not be representative of usual intake better assessment of food patterns
2) Diet record (including multiple days): better estimate of average food/nutrient intakes, time consuming, may change eating behavior
189
To achieve change you must...(2)
1) Reduce difficulty
| 2) Increase motivation
190
Readiness to change
importance (is change worthwhile) and confidence (where pt believes he/she can change)
191
How to address dietary and lifestyle changes with a patient:
Traditional dietary counseling focuses on WHAT patient should eat, concept of WHY they eat as they do and impediments to changing dietary behavior less understood and less emphasized
Failure to change diet in most patients is NOT result of inadequate motivation, but of excessive difficulty/barriers
-focus on readiness to change, increasing motivation, and decreasing barriers
192
Aim of US Dietary Guidelines
Target healthy public over age of 2
Promote health and aim to reduce risk of chronic disease, including obesity, cardiovascular disease, diabetes, and some cancers (Ironically doing the opposite of what it is intended to do)
Science-based (more like big money based) advice to promote health and reduce risk for major chronic diseases through diet and physical activity for general public
Yes I am very fucking bitter
193
2015-2020 Dietary Guidelines
5 key messages
1) Healthy eating pattern across a lifetime
2) Focus on variety, nutrient density, amounts
3) Limited calories from added sugars, saturated fats and reduce sodium intake
4) Healthier food and beverage choices (fiber/whole grain, low/non-fat dairy, chips→ nuts, soft drinks → water)
5) Be active
194
Guidelines for sugar, saturated fatty acids, and sodium intake
Added sugar < 10% of total daily calories
< 10% calories from saturated fatty acids, and limit trans fats to as low as possible
Reduce sodium intake to < 2300 mg/d
195
How typical dietary patterns and food choices differ in US from DG
Dietary practices “divergent” from recommendations considered to be 2nd leading cause of preventable death in US
-Unhealthy eating and inactivity contribute to 310,000-580,000 deaths/yr
Consume too few green vegetables, orange vegetables, legumes, and whole grains, fruits, low fat dairy, and seafood
-Only 6% and 8% achieve their recommended target intakes for vegetables and fruits respectively in average day
Excess intake of solid fats and added sugars, refined grains, and sodium
Caloric intake exceeds energy expended
196
3 benefits of a diet rich in vegetables, fruits, whole grains, low fat dairy, healthy oils:
Reduced mortality, cardiovascular disease, and blood pressure
197
Water soluble vitamins
not stored (Except B12), highly absorbed from diet, excreted via urine, low toxicity
Chronic intakes DO alter tissue levels
198
Types of water soluble vitamins (4 categories)
Non B-Complex: Ascorbic acid (Vit C)
B-Complex:
-Energy metabolism: thiamin, niacin, riboflavin, pantothenic acid
- Hematopoietic: folic acid, B12
- Other: B6, Choline, Inositol, Biotin
199
Fat soluble vitamins
accumulate “stores” in body, potential for toxicity with excess intake
Require absorption of dietary fat and carrier system for transport in blood
Includes Vit A, D, E, K
200
```
Vitamin A:
Biochemical function (4)
```
1) Essential photochemical basis of vision
2) Maintains conjunctival membranes and cornea
3) Critical for epithelial cellular differentiation and proliferation
4) Immune regulation (serum levels DECREASED with inflammation = NEGATIVE acute phase reactant)
201
Vitamin A
Major dietary sources
Pre-formed VitA: liver, dairy, egg yolks, fish oil (animal sources)
Precursor (Beta-Carotene): deep yellow/orange and green vegetables (spinach, carrots, broccoli, pumpkin)
202
Vitamin A
Characteristic deficiency findings
1) Night blindness
2) Xerophthalmia (extreme dryness of cornea) → Bitot’s Spots
3) Epithelial linings become flat, dry, and keratinized
4) Immune impairment (ex - treat measles with Vit A)
203
Vitamin A
Characteristic toxicity findings
how does toxicity occur?
can ONLY occur with PREFORMED Vit A intake
-can occur with Accutane
Vomiting, increased ICP, headache, bone pain, bone mineral loss, liver damage, death, birth defects
204
Vitamin A
Lab findings
serum retinol (will be normal until liver stored depleted)
serum levels DECREASED with inflammation = NEGATIVE acute phase reactant
205
Vitamin A
Risk for deficiency
poor or extreme low fat diet
206
Vitamin D
Biochemical function
acts as a hormone (plasma membrane and nuclear receptors in a range of tissues)
1) Maintain intra/extracellular Ca2+
- Stimulate intestinal absorption Ca2+ and P
- Stimulate renal reabsorption of Ca2+ and P
- Mobilize Ca2+ and P from bone
2) Innate immune function (generation of toxic radicals)
3) Cellular growth and differentiation through nuclear and plasma membrane vitamin D receptors
207
Vitamin D
Major dietary sources
Precursor in skin: UVB light → converted to cholecalciferol (D3)
Diet: fish liver oils, fatty fish, egg yolks, fortified milk and formulas
D3 activity 2-3x > D2
208
Vitamin D
Metabolism - 3 steps
1) Absorbed by chylomicrons (requires fat absorption)
2) D2 or D3 hydroxylated in liver → 25-hydroxy-cholecalciferol
3) Kidney → 1,25-dihydroxy-cholecalciferol (calcitriol) = ACTIVE FORM
209
Vitamin D
Characteristic deficiency findings (2)
Rickets (25OH-D < 11 ng/mL) = failure of maturation of cartilage and calcification → bowed legs, widened metaphyses, painful bone fractures
Adult osteoporosis
210
Vitamin D
Characteristic toxicity findings
risk of toxicity increased with what types of diseases?
Hypercalcemia, vomiting, seizures, nephrocalcinosis, soft tissue calcification
Risk of Vit-D toxicity with chronic granulomatous diseases (e.g. sarcoidosis)
211
Vitamin D
Lab findings
serum 25(OH) Vit D levels
TEST 25-OH Vit D → level reflects BODY STORES
212
Vitamin E
Biochemical function (3)
antioxidant, free radical scavenger, cell membrane stabilizer
213
Vitamin E
Major dietary sources
polyunsaturated vegetable oils, wheat germ
214
Vitamin E
Characteristic deficiency findings (2)
Neurologic degeneration (loss of DTRs, neuropathy, ophthalmoplegia, spinocerebellar ataxia) = IRREVERSIBLE
Hemolytic anemia
215
Vitamin E
Characteristic toxicity findings (1)
1) coagulopathy - inhibit Vitamin K dependent clotting factors
(low risk of toxicity)
216
Vitamin E
Risk for deficiency (1)
prematurity
217
Vitamin K
Biochemical function
essential for carboxylation of coagulation factors (2, 7, 9, 10, protein C and protein S)
218
Vitamin K
Dietary sources
leafy vegetables, fruit, seeds, synthesis by intestinal bacteria
219
Vitamin K
Characteristic deficiency findings (2)
1) Prolonged coagulation times (increased PT, increased PTT, normal bleeding time)
2) Hemorrhagic disease of newborn (give Vit-K injection)
220
Vitamin K
Risks for deficiency (3)
Newborn, antibiotics, poor diet
221
High risk of vitamin D deficiency with...(6)
1) Low sun exposure (Winter, dark skin pigmentation)
2) Low dietary intake
3) Fat malabsorption
4) Breastfed infants
5) Obesity (fat sequestration, sedentary)
6) Liver or renal disease → must use calcitriol (active form), because cannot activate VitD
222
Numbers indicating dietary deficiency of Vitamin D
deficient, insufficient, sufficient
Deficiency = 25-OH < 20 ng/mL
Insufficiency - 21-29 ng/mL
Sufficient >/= 30 ng/mL
223
Energy Releasing Vitamins include... (3)
Thiamine (B1), Riboflavin (B2), Niacin (B3)
- All involved in glycolysis / TCA
- TPP, FAD, NAD
- decarboxylation, oxidation-reduction
224
Thiamine (B1)
Function
Thiamine pyrophosphate (TPP or TDP): coenzyme central to metabolism (glycolysis, TCA cycle, AA metabolism, decarboxylation, transketolation reactions)
225
Thiamine (B1)
Dietary sources (3)
rich in whole grains, lean porks, legumes
226
Thiamine (B1)
Deficiency findings:
Beriberi: nervous and cardiovascular effects
227
Thiamine (B1)
3 kinds of BeriBeri
Dry Beriberi = peripheral neuropathy, muscle tenderness (esp legs), weakness, atrophy (foot drop)
Wet Beriberi = cardiac → edema, circulatory collapse, CHD
Wernicke-Korsakoff Syndrome = “cerebral Beriberi” TRIAD→ ocular signs (nystagmus, ophthalmoplegia), ataxia, amnesia / confusion
228
Thiamine (B1)
Populations at risk of deficiency
```
alcoholics*
vomiting
elderly
chronic renal dialysis
refeeding after starvation
bariatric surgery
```
229
Riboflavin (B2)
function
Coenzyme = FAD, FMN → oxidation/reduction in TCA cycle and oxidative phosphorylation
AA and fatty acid metabolism
Metabolism of Vit K, Folate, B6, and Niacin
230
Riboflavin (B2)
Dietary sources (3)
dairy, eggs, meats
231
Riboflavin (B2)
Deficiency findings (3 areas)
oral-ocular-genital syndrome
Oral → cheilosis (cracked lips) angular stomatitis (sores in mouth corner)
Ocular → increased vascularization of conjunctiva, photophobia
Genital → seborrheic dermatitis and scrotal dermatitis
232
Niacin (B3)
Function
Nicotinamide in NAD and NADP - key for energy related pathways
233
Niacin (B3)
Dietary sources
what is a precursor for B3?
Preformed → meat, poultry, fish, peanut butter, legumes
TRYPTOPHAN = precursor → milk, eggs (rich in tryptophan)
234
Niacin (B3)
Deficiency findings
PELLAGRA 4 D’s
Dermatitis: symmetric pattern, aggravated by sun, heat exposure
Dementia: confusion, dizziness, hallucinations
Diarrhea
Death
235
Niacin (B3)
Risks for deficiency
Nutritional/dietary restriction
Malabsorption syndromes
Alcoholism
Metabolic “shunting” (carcinoid tumor → increased serotonin → decreased tryptophan)
236
Folate
Function
1-carbon transfers (especially in synthesis of nucleic acids and metabolism of AAs) and DNA methylation
Conversion of homocysteine → methionine
Methyl donor
Epigenetics
237
Folate
Dietary sources
foliage (deep green leaves, broccoli, orange juice, whole grains)
238
Folate
Deficiency findings (6)
1) *Macrocytic anemia
2) *hypersegmented neutrophils
3) *Glossitis
4) *Increased plasma homocysteine (homocysteinemia)
5) *Decreased plasma methionine
6) *Neural tube defects
239
Folate deficiency lab findings
- serum folate (shows recent intake)
- RBC folate (shows tissue stores / chronic status)
- increased homocysteine
- decreased methionine
- Macrocytic anemia
240
Risks for folate deficiency (5)
Inadequate intake or increased destruction in cooked foods
Alcoholics
Pregnancy - **Women of childbearing age advised to have intake of 400 ug/d to prevent neural tube defects (must begin supplementation before they know they are pregnant)
Hematopoietic conditions
Drug/nutrient interactions
241
Vitamin B12 (Cobalamin)
Function + name two key enzymes it is a cofactor for
1 carbon transfers, nucleic acid synthesis, protein synthesis
Metabolism of odd chain fatty acids (methylmalonyl CoA mutase)
Re-forms THF from methylfolate (homocysteine methyltransferase)
242
Vitamin B12 (Cobalamin)
Dietary sources
animal products only
243
Vitamin B12 (Cobalamin)
absorption and storage
- Takes years to develop deficiency (liver stores 1-10 mg)
- Excreted and recycled in bile
Absorption:
- Cleave vitamin from dietary protein in stomach
- Requires Intrinsic Factor from stomach
- Cobalamin-IF absorbed in distal ileum
- Transport in circulation by transcobalamin II
244
Vitamin B12 (Cobalamin)
Deficiency findings (5)
Macrocytic anemia with hypersegmented neutrophils
```
Neurologic disturbances (eventually IRREVERSIBLE)
*DO NOT treat macrocytic anemia with folate unless B12 deficiency ruled out (will correct anemia but NOT neuro sxs)
```
Increased plasma homocysteine
Decreased plasma methionine
Increased methylmalonic acid*
245
Vitamin B12 (Cobalamin)
Populations at risk for deficiency (5)
```
Pernicious anemia
Gastric atrophy
Resection of stomach or ileum (intrinsic factor secretion/absorption)
Strict vegan diet
Breastfed infant of B12 deficient mother
```
246
Vitamin B6 (Pyridoxine)
Function + two enzymes it is a cofactor for
amino acid metabolism, interconversions
Cofactor for cystathionine synthase (methionine/cysteine metabolism)
Cofactor for ALA synthase (first step in heme synthesis)
247
Vitamin B6 (Pyridoxine)
Dietary sources (3)
animal products, vegetables, whole grains
248
Vitamin B6 (Pyridoxine)
Deficiency findings (6)
```
Anemia
seizures
glossitis
+/- depression
-Increased serum homocysteine
-Increased serum methionine
```
NO MEGALOBLASTIC ANEMIA (differentiate with B12 and folate)
249
Vitamin B6 (Pyridoxine)
Risk for deficiency (3)
Isoniazid (INH)**
end stage renal disease
malabsorption
250
Vitamin B6 (Pyridoxine)
Toxicity
risk of toxicity at doses > 500 mg/d → sensory ataxia, impaired position/vibratory sensation
251
Vitamin C (Ascorbic Acid)
Function (4)
Antioxidant/reducing agent
Collagen synthesis
Reduction of Fe3+ → Fe2+
NE synthesis
252
Vitamin C (Ascorbic Acid)
Dietary sources
absorption maxes out → divide in <1g dose throughout day
Fruits, vegetables (broccoli, green pepper, citrus, potatoes)
253
Vitamin C (Ascorbic Acid)
Deficiency findings
Scurvy: defective collagen formation
- Painful joints**
- Hemorrhagic signs - bleeding gums, ecchymoses, petechiae
- Hyperkeratosis of hair follicles
254
Dietary sources of iron (5)
cellular animal protein (heme iron), legumes, nuts, whole grains, green leafy vegetables
255
More absorbable: heme iron (animal) or non heme iron?
Absorption of heme iron (animal protein) > nonheme iron
256
Main site of iron regulation
intestinal absorption
257
Things that decrease the absorption of iron (7)
1. Phytate (bran, oats, beans, rye)
2. Calcium
3. Polyphenols (tea, some vegetables)
4. Dietary fiber
5. Soy protein
6. Excessive Zn or Cu*
7. Inflammation
258
How does inglammation decrease absorption of iron?
Inflammation → increased hepcidin from liver → decrease absorption of Fe at enterocyte*
259
Increase absorption of iron (2)
1. Fe deficiency
| 2. Ascorbic acid (Vit C): Fe3+ → Fe2+ → more absorption of Fe2+
260
Who is the cutest dog ever?
Bosco
JK it's MUFFIN!
261
Transportation of iron
Transferrin → transport (iron does not travel freely)
262
Storage of iron
Ferritin
263
Hemosiderin
aggregated ferritin molecules
264
Most storage of iron in (3)
liver, bone marrow, spleen
265
Hepsidin
decreases iron uptake, present during times of inflammation
266
Function of iron (3)
oxygen transport in blood (Hgb) and muscle (myoglobin), electron transfer enzymes (cytochromes), CNS myelination
267
Severe iron deficiency--->
oxygen transport in blood (Hgb) and muscle (myoglobin), electron transfer enzymes (cytochromes), CNS myelination
268
Mild iron deficiency---->
anemia (microcytic, hypochromic, high RDW), **impaired cognitive development (can happen before anemia develops, and can have lifelong effects), decreased exercise tolerance, fatigue
269
8 risks for iron deficiency
1. Premature/SGA infants
2. Breastfed infants (> 6 months)
3. Young children - poor intake, increased requirements
4. Adolescent girls/young women - menstrual loss
5. Pregnant women → increased requirement
6. Blood loss
7. Obesity
8. Bariatric surgery
270
Iron deficiency pathophysiology
Iron is prioritized to erythrocytes because of role in O2 transport
Hepatic stores, skeletal muscles and intestine, cardiac iron, brain iron and finally erythrocyte iron depleted
271
Labs iron deficiency
Low serum Fe, high TIBC, low % saturation, low ferritin
Microcytic, hypochromic RBCs
Low Hb and Hct
272
Iron toxicity
Iron can act as PRO-OXIDANT
Deposition as hemosiderin in reticuloendothelial cells
Hereditary hemochromatosis
273
Dietary sources of zinc
animal products, whole grains, legumes, seeds
274
Bioavailability of zinc (3)
- Absorption impaired by phytate (corn, legumes, nuts)
- Absorption NOT increased with deficiency (unlike iron)
- Can absorb/secrete Zn in GI tract
275
Nutrition related 2015 Sustainable Development Goals (6):
1) Stunting - 40% reduction in number of children under five who are stunted
2) Anemia in women - 50% reduction of anemia in women of reproductive age
3) Low birthweight - 30% reduction of low birth weight
4) Overweight - no increase in childhood overweight
5) Exclusive breastfeeding - increase rate of breastfeeding in first 6 months up to at least 50%
6) Wasting - reduce and maintain childhood wasting to < 5%
276
Contextual factors that contribute to malnutrition
```
Lack of capital
Social, economic, political context
Poverty, food insecurity, unhealthy household, environment, inadequate care
Inadequate intake
Disease
Maternal and child undernutrition
```
277
Major nutrition problems in developing countries:
Undernutrition in pregnancy (maternal undernutrition, BMI < 18.5) → fetal growth and postnatal growth → stunting, obesity, non-communicable diseases in adulthood
Vit A and Zn deficiencies → death, largest disease burden among micronutrients
Iron and iodine (+stunting) → children fail to reach developmental potential
Maternal overweight and obesity → maternal morbidity, preterm birth increased infant mortality
278
Triple burden of poverty
diarrhea, stunting, chronic disease
279
4 approaches to improving nutritional status in vulnerable populations:
1) Country level - individual country nutrition strategies and programs
- Draw on international evidence of good practice
- Must be country “owned” and built on country’s specific needs/capacity
2) Scale up evidence based cost effective interventions to prevent and treat undernutrition
Priority to first “1000 days” crucial window or highest return on investment-1000 days between woman’s pregnancy and child’s 2nd bday
3) Multi-sectoral approach - integrate food security (agriculture), social protection (including emergency relief), and health (maternal and child health care, immunization, family planning)
4) Scale up domestic and external assistance for country-owned nutrition programs and capacity
280
BMI definitions:
normal
overweight
obese
severely obese
kg/m^2
BMI = 18.5-25.9 = Normal
BMI 25-29.9 = overweight → increased morbidity, but not mortality
BMI > 30 = obese
BMI > 40 or BMI > 35 + weight-related medical complications = Severe obesity
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BMI isn't an accurate measurement for who? (2)
BMI is not an accurate measurement for people that are very muscular, or people who have lost large amounts of muscle mass but have clinically important obesity (e.g. elderly, “sarcopenic obesity”)
282
Causes of malnutrition
protein malnutrition is the final common pathway, but energy requirements (president) trump ALL
Malnutrition secondary to chronic disease or due to acute effects of surgery, trauma, sepsis, etc. is estimated to occur in up to 50% of hospitalized patients
Anorexia nervosa
Poverty, ignorance, monotonous/restricted diets
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Consequences of malnutrition
- “Failure to Thrive” - infants/children with growth faltering
- Undernutrition
- Stunting
- Wasting
284
Cause of obesity
changes in environment for food and physical activity
Long term positive energy balance
Gene-environment interaction
285
Metabolic Syndrome
specific body phenotype of abdominal obesity associated with a group of metabolic disorders that are risk factors for CVD (CAD, stroke, CHF)
→ abdominal obesity, elevated BP, high TG, low HDL, impaired glucose tolerance
286
Metabolic Syndrome
requirements (5)
Definition using AHA/NCEP: ⅗ risk factors = dx of metabolic syndrome
1) Abdominal obesity: waist circumference
Men = > 40 inches)
Women = > 35 inches
2) Triglycerides FASTING, > 150 mg/dL or on drug tx for abnormal lipids
3) HDL cholesterol:
- Men < 40 mg/dL
- Women < 50 mg/dL
4) Blood pressure: > 130 mmHg systolic or > 85 mmHg diastolic or on anti-HTN drug
5) Fasting glucose: > 100 mg/dL or hypoglycemic drug
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Clinical evaluation of obese patient
1) Measure degree of adiposity
2) Assess other existing risk factors for CVD
3) Screen for complications of obesity
- Labs: TSH, diabetes screening (fasting glucose, A1c), lipid panel, LFTs
4) Rule out medical causes of obesity
5) Assess readiness for treatment
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Health problems associated with obesity:
huge list........
Cardiovascular: CAD, hyperlipidemia, HTN, CHF, stroke, venous thromboembolism
Pulmonary: obstructive sleep apnea, obesity-hypoventilation syndrome, asthma
Psychological: depression, social stigmatization, low self-esteem, distorted body image
Gastrointestinal: cholelithiasis, GERD, nonalcoholic fatty liver disease
Dermatological: acanthosis nigricans, cellulitis, striae, lymphedema, venous stasis
Orthopedic: osteoarthritis, restricted mobility, back pain
Genitourinary: PCOS, ED, BPH, menstrual abnormalities, infertility, pregnancy complications, stress incontinence
Metabolic: T2D, impaired glucose tolerance, gout, insulin resistance, metabolic syndrome, hyperuricemia, vit D deficiency, nephrolithiasis
Cancer: postmenopausal breast, colon, prostate, endometrial, kidney, gallbladder
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Function of zinc
regulation of gene expression (zinc fingers), zinc metalloenzymes,
structural role in membrane stability, metalloenzymes (>200!)
- Critical for growth, cellular tissue proliferation, and immune function
- Antioxidant
- Sexual maturation
290
Severe zinc deficiency
acro-orificial dermatitis, diarrhea
- Increased infections, poor wound healing
- Delayed sexual maturation
- Acrodermatitis enteropathica: mutation in enterocyte Zn transporter → fatal without high doses of Zn for life
291
Acrodermatitis enteropathica
mutation in enterocyte Zn transporter → fatal without high doses of Zn for life
292
Mild zinc deficiency
growth retardation, anorexia, increased infection
293
Zinc deficiency in fetus
intrauterine growth retardation, congenital malformations
294
High risk individuals for zinc deficiency (7)
- Infants, young children, breastfed infants (> 6 months)
- Zn in breast milk is independent of mom’s Zn status
- Pregnant women (high demand)
- Monotonous, plant based diets
- Bariatric surgery patients
- Elderly (low intake)
- GI illness/injury (diarrhea increases loss)
- Wounds, burns (increased requirement for synthesis of new tissue)
295
Zinc toxicity
impairs absorption of Fe and Cu, no real toxicity effects
296
Presentation of kwashiorkor (8)
higher mortality than marasmus
1. “Flaky paint” skin lesions
2. “Flag sign” hair texture and pigmentation changes
3. Generalized edema (“moon facies”)
4. Hypoalbuminemia + enlarged fatty liver (hepatomegaly) → edema
5. Increased permeability of biological membranes → edema
6. Impaired Na/K homeostasis (excess Na, K deficiency)
7. Hypotransferrinemia (anemia)
8. Impaired immune system (infection)
297
Consequences of malnutrition
- “Failure to Thrive” - infants/children with growth faltering
- Undernutrition
- Stunting
- Wasting
298
Stunting (like my daddy)
chronic malnutrition, harder to treat
https://www.youtube.com/watch?v=jSPa3c41Or4
299
Wasting
acute malnutrition - decreased weight relative to length
300
Determining percentile for a kid
take weight and length, divide by normal (e.g. severely wasted child wt/ht → 7, normal → 10 = 70% ideal body weight)
301
Short term events in starvation
decrease glucose, start kicking in with gluconeogenesis and fatty acid oxidation with ketone body formation → use fat stores, minimize muscle wasting → DECREASED basal metabolic rate
302
Short term starvation: Muscle
Increase utilization of TGs/FAs, decrease protein degradation
303
Short term starvation: Brain
increase utilization of ketones
304
Short term starvation: Liver
decreased gluconeogenesis
305
Short term starvation: Liver/Kidney
decreased urea production and excretion
306
Long term effects of starvation (4)
- Reduction in energy expenditure, decreased Na/K pump activity
- Decreased inflammatory response and impaired immune function
- Impaired function of GI tract
- EVENTUALLY → loss of functional reserve and loss of physiological responsiveness to stress = HALLMARKS of adaptation to severe PEM
307
Marasmus
severe wasting of fat and muscle mass due to energy deficiency (starvation)
- Slower onset, better adaptation
Aka severe acute malnutrition
308
Kwashiorkor
edematous PEM (with hypoalbuminemia), without wasting due to protein deficiency (not deficiency in total calories)
- Rapid onset, “maladaptation”
309
Pathophysiology of kwashiorkor
failure of normal adaptive response of protein sparing that is normally seen in fasting state
- Protein deficiency in face of adequate energy intake PLUS infectious stress, cytokine release, relative micronutrient deficiencies, free radical exposure
- Fat reserves and muscle mass unaltered (due to elevated insulin)
310
Presentation of kwashiorkor (8)
higher mortality than marasmus
1. “Flaky paint” skin lesions
2. “Flag sign” hair texture and pigmentation changes
3. Generalized edema (“moon facies”)
4. Hypoalbuminemia + enlarged fatty liver (hepatomegaly) → edema
5. Increased permeability of biological membranes → edema
6. Impaired Na/K homeostasis (excess Na, K deficiency)
7. Hypotransferrinemia (anemia)
8. Impaired immune system (infection)
311
Marasmic kwashiorkor
combination of chronic energy deficiency and chronic or acute protein deficiency
Presents with both wasting and edema
312
Treatment of severe PEM
GO SLOWLY
1) Resolve life threatening conditions
2) Restore nutritional status without abruptly disrupting homeostasis
3) Ensure nutritional rehabilitation
313
Resolving life threatening conditions in PEM (4)
- Enteral rehydration (avoid overhydration)
- K+ supplements +/- Mg2+ (avoid excessive Na+)
- Treat infections
- Avoid hypoglycemia with small, frequent, oral feeds
314
Restoring nutritional status without abruptly disrupting homeostasis in PEM
1. Small frequent feeds, liquid oral or nasogastric tube
- Goal is to maintain protein and energy requirements
- High protein, high fat
2. Replete specific micronutrient deficiencies
315
Ensuring nutritional rehabilitation in PEM (3)
1. Slowly advance energy intake to 1.5x normal and 3-4x protein
2. Begin AFTER resolution of edema
3. Emotional and physical stimulation
316
Refeeding syndrome
metabolic derangements due to acute shifts from ECF to ICD
317
4 metabolic derangements that occur with re-feeding syndrome
1. Potassium: increase insulin secretion → glucose and K+ IN to cells → decrease serum K+ → altered nerve/muscle function
2. Phosphorus: increased insulin secretion → P IN to cells → increase intracellular phosphorylated intermediates → P “trapped” in intracellular space
3. Magnesium: increased requirements with increased metabolic rate (cofactor for ATPase)
4. Thiamine: rapid depletion → cardiomyopathy +/- encephalopathy
