Lecture 25-Biochemical Metabolism Flashcards Preview

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Flashcards in Lecture 25-Biochemical Metabolism Deck (83):
1

Metabolic disease or IEMs represent one of the few diseases where prompt recognitino can ________

- significantly improve outcome and morbidity/mortality, particularly in intermediary metabolism

1

Sir Archibold Garrod

- characterized alkaptonuria in that it has familiar distribution, especially in consanguineous marriages
- found that lifelong diseases can arise due to an enzyme governing a single metabolic step that reduce activity or get rid of it altogether

2

IEMs predominately have what type of inheritance?

- autosomal recessive aside from the X-linked ones (like OTC)

3

Genetic changes can result in ____, _____, _____ or ______ defects.

- complete
- partial
- enhanced
- conditional

4

What are the different ways that genetic changes can impact metabolism? (2)

- when it affects a protein that is part of a complex so it's effect reaches beyond just that one enzyme (i.e., the enzyme itself being defective isnt as big of a deal as the fact that it disrupts the complex)
- some changes affect kinetics and wont show up until stress is applied (like chemo)

5

What is an example of the idea that the line between polymorphisms and mutations are not clear cut? That shows the environments role in promoting mutations...

- Hemachromatosis: Inborn error that affects iron metabolism. What once was advantageous now causes Fe levels in our american diet to lead to Fe accumulation to toxic levels in people of Irish descent

6

Why are newborns most vulnerable to IEMs?

- just came off of 9 mos of life support
- placenta and mom removed most of the harmful substances for the fetus
- newborn state highly catabolic!!!
- all sources of energy are used (carbs, fats, proteins) since energy use exceeds production in first few days
- most biochemical enzymes not at mature levels (ex: urea cycle at ~40% or <

7

GENERALLY speaking, how do these patients present?

- increased incidence of neurodevelopmental and behavioral problems (because the brain uses the most energy--25% while growing, 15% as adults)
- global delay

7

Why do patients with IEMs generally present with neurodevelopmental and behavioral problems?

- brain uses most of our energy
- these IEMs cause general neurotoxicity (although some can be highly specific-ex: gly)
- brain uses many intermediates of metabolism as NTs
- it is often the first place hit when things go awry

8

What are the top suspects in IEMs? (5)

- glycine
- ammonia
- lactate
- galactose
- organic acids

8

Why is glycine toxic?

- a commonly produced aa but also a NT so high levels disrupt normal neuronal firing

9

Why is ammonia toxic?

- affects aa transport
- ammonia has an inhibitory affect on AQPs

9

Why is lactate toxic?

- irritant to muscle even though it's a good energy source to neurons

10

Why is galactose toxic?

- galactose is NOT toxic, but it's converted into galacterol which is a neurotoxin that can build in the liver and lens of the eye to cause damage

10

Why are organic acids toxic?

- these biochemical intermediates should never be seen in the blood! They are immediately converted to their products so if they're there something is wrong. Also, these help point to where the issue is.

11

Describe when these problems usually manifest and why.

- normal at birth, stable
- metabolite needs time to build up or drop down (can be 24 hr to 1-2 weeks as the system is stressed)
- Kids are coming in with more toxic conditions because kids dont stay in the hospital as long as they use to an when they get home parents just think that they're tired (highly catabolic state!!)

11

IEMs generally look like what condition? Why is this dangerous?

- sepsis

- Because doctors will try to treat the sepsis and not look for underlying metabolic disease

12

How do these diseases normally affect the brain? (5)

- toxin destruction of neurons
- toxin disruption of neuron function
- over/under accumulation of metabolite that is also a NT
- not enough fuel
- unknown origin

12

What are 2 agents that can build up in IEMs that destroy neurons?

- phenylalanine
- phenylacetic acid

13

What agent can disrupt function of neurons?

- ammonia

13

What are the symptoms as the brain is increasingly affected by build up of toxins? (6 initial)

- anorexia
- sleepiness
- vomiting
- temperature instability
- hiccups
- hypotonia

14

What are the symptoms as the brain is increasingly affected by build up of toxins? (9-advanced)

- lethargy
- coma
- seizures
- respiratory arrest
- immune impairment
- hepatic dysfunction
- decorticate posturing
- cardiomyopathy
- death

14

What happens when ammonia inhibits aquaporins in the brain?

- brain swells because cells aren't releasing water
- puts pressure on the brainstem which slows blood flow as it pumps against the swollen brain
- decreased HR makes the brain think that the body is acidotic so it increases the respiratory rate actually making the body alkalotic (7.6-7.7)

15

What are the 3 NTs that could build up during a IEM and cause problems? Stimulatory or inhibitory?

- gly
- glu
- gln

- both stimulatory and inhibitory

16

Why can the lack of fuel caused by the IEM be a problem?

- the brain is already on the border of biochemical sufficiency so if glycolysis or the TCA are disrupted this causes lactic acid buildup and other alternative pathways become toxic

17

Give an example of a substance that for unknown reasons causes brain toxicity and how.

- homocysteinuria
- can cause schizophrenia in previously normal people

18

When people develop cerebral edema, once it starts to resolve it looks like _____.

a stroke

19

What are the common labs you should use to diagnose an IEM? (7)

- CBC
- Urinalysis
- blood gas
- electrolytes
- blood glu
- blood ammonia and BUN
- lactate and pyruvate

20

Why use CBC?

- detects pancytopenia (deficiency of all 3 cellular components: RBCs, WBCs, platelets)
from organic acids causing bone marrow suppression

21

Why use urinalysis?

- detects ketone bodies: indicative of function of FA oxidation
- reducing substances (galactose and fructose)

22

Why use blood gas test?

- detects acidosis (metabolic)/alkalosis

23

Why use Electrolyte test?

- detects anion gap: Na minus Cl minus CO2 which should normally be less than 15.

24

Why test blood glucose?

- detects defects in gluconeogenesis and energy substrate production (FA, etc.)--makes sure pathways are intact
- detects issues with substrate storage

25

Why test blood ammonia and BUN?

- detects 1º and 2º defects in urea cycle
- important for looking at N levels

26

Why test lactate and pyruvate levels? (5)

- detect defects in pyruvate metabolism
- and energy production/use
- and ETC
- detects inefficient metabolism
- detects stress

27

What are the 3 of the main specialty labs we should use to finalize our diagnosis? (3)

- Plasma AAs (PAAs)
- urine OAs (UOAs)
- ACP: acyl carnitine profiles

28

Why test for PAAs?

- detects breaks in normal AA metabolism or secondary affects on AA metabolism

29

Where do OAs come from?

- metabolites of protein and FA metabolism

30

Why test for UOAs?

- detects primary and secondary metabolites of unprocessed organic acids

31

Why test for ACP?

- detects organic acids in blood bound to carnitine
- detects unprocessed FA intermediates

32

What does carnitine do besides shuttle FAs into the mitochondria?

- solubilizes hydrophobic things and can carry them in the blood

33

PAAs (tested using HPLC) are best for testing for what enzyme deficiencies (3)? What disease and why?

- ASS
- ASA
- arginase

- MSUD: detects alloisoleucine as well as high Ile, Leu, Val

34

What are some of the main diagnoses you can make from UOAs? (4)

- MMA/PA
- IVA
- MSUD
- MCAD

35

In a UOA analysis using GC/MS, what would be diagnostic of MMA/PA?

- methylcitric acid
- 3OH-propionate

36

In a UOA analysis, what would be diagnostic of IVA?

- isovalerylglycine

37

In a UOA analysis, what would be diagnostic of MSUD?

- abnormal ketoacids

38

In a UOA analysis, what would be diagnostic of MCAD?

- Hexanoylglycine and others

39

ACP analysis using LC/MS/MS is best for detecting _____. What is it's caveat?

- organic acidemias
- may not be able to distinguish disease without UOAs

40

What are other diseases that may look like metabolic disease? (8)

- heart disease
- seizures
- code
- starvation
- liver disease
- valproate and other drugs
- TPN
- Penicillins

41

What diseases look like IEM because they cause lactic acidosis? (4)

- heart disease
- code
- seizures
- starvation

42

Why does starvation look like IEM? (3)

- ketosis
- varying aa levels
- lactic acidosis

43

Why do people on valproate and other drugs look like they may have an IEM? (2)

- elevated ammonia
- elevated gly

44

why may people on TPN look like they have an IEM?

- if IV is not cleaned before taking a blood sample it can show high aas

45

Why may people on antibiotics look like they have an IEM?

- false positive for reducing substances when normally they'd be looking for galactose and fructose. People who are in the hospital are probably on antibiotics already because these IEMs look like SEPSIS!!

46

Why do people with liver disease look like they may have an IEM?

- hypoglycemia
- AA elevations (Phe, Tyr, branched, Met, Homocysteine)

47

What are the main functions of the urea cycle?

- converts N (ammonia and aspartate) to urea
- generates arginine (and therefore NO)
- replenishes intermediates

48

Where is the urea cycle?

- in the liver
- proximal cycle (NAGS, CPS, OTC) in gut
- distal cycle (ASS, ASL, ARG) in kidney

49

Any block on the urea cycle makes ____ an essential aa.

arginine

50

if there is a block in the urea cycle, how does the level of ammonia change in our bodies?

- usually 30µM, but will rise to 2-3 mM in 24 hrs

51

How do urea cycle patients usually present?

- in newborn period (<7 days) with:
- hyperammonemia: acutely life-threatening if HA is not recognized and reversed
- vomiting (from increased ammonia)
- lethargy (remember: these kids are in highly catabolic state!!)
- respiratory ALKALOSIS with hyperventilation. pH normal to alkalotic

52

Patients with urea cycle defects are often mistaken for having _____. This is why it's important to check _______.

- overwhelming infection

- N levels

53

When will a urea cycle defect patient be acidotic?

- when there are in SEVERE respiratory depression

54

What are the steps to diagnosing someone with a UCD after you have found hyperammonemia? (2)

- check PAAs, ACP, UOAs
- check for sepsis, especially herpes

55

hyperammonemia is also seen in ______.

organic acidemias: proprionic acid interferes with NAGS

56

How would PAAs, ACP, and UOAs be if the patient has a UCD?

- ACP, UOAs are normal
- Characteristic changes in PAAs (note: PAA can detect changes in all urea cycle intermediates)

57

What is the most common urea cycle disruption? Inheritance?

- OTC

- X-linked

58

what are ways to reduce the amount of ammonia produced? (3)

- reduce input of protein
- dialysis
- ammonia trapping/scavenging
- reduce protein breakdown

59

When is reducing protein input a problem?

- in babies when they need the protein because they're growing
- also, because we can't make all the protein that we need our body will provoke the catabolic state to breakdown aas from other places in the body

60

What agents are ammonia trapping and what do they trap?

- sodium benzoate: glycine
- phenylacetate: glutamine

61

UCD patients will also have high blood ______. Why? What are the implications of this?

- Glutamine
- its acting as a final N acceptor
- causes lowering of Glu and because Gln is a NT in the brain the low Glu and high Gln can disrupt the brain

62

What are ways to reduce protein breakdown in patients with UCD?

- give excess calories
- can temporarily give insulin to induce an anabolic state

63

hyperammonemia is also seen in ______

organic acidemias

64

How would PAAs, ACP, and UOAs be if the patient has a UCD?

- ACP, UOAs are normal
- Characteristic changes in PAAs

65

What is the most common urea cycle disruption? Inheritance?

- OTC

- X-linked

66

what are ways to reduce the amount of ammonia produced? (3)

- reduce input of protein
- dialysis
- ammonia trapping/scavenging
- reduce protein breakdown

67

When is reducing protein input a problem?

- in babies when they need the protein because they're growing
- also, because we can't make all the protein that we need our body will provoke the catabolic state to breakdown aas from other places in the body

68

What agents are ammonia trapping and what do they trap?

- sodium benzoate: glycine
- phenylacetate: glutamine

69

UCD patients will also have high blood ______. Why? What are the implications of this?

- Glutamine
- its acting as a final N acceptor
- causes lowering of Glu and because Gln is a NT in the brain the low Glu and high Gln can disrupt the brain

70

What are ways to reduce protein breakdown in patients with UCD?

- give excess calories
- can temporarily give insulin to induce an anabolic state

71

Why are N scavenging agents helpful?

- they help alleviate the ammonia load but also can be excreted by the kidneys and pull loose N in

72

What is a common treatment for UCDs?

- liver transplant

73

In conclusion with UCDs what are the things that disrupt the urea cycle? (5)

- genetic enzyme defect
- damage to the liver: chemical toxins/infections
- drugs
- overloading the system: hemolysis and protein catabolism
- others: bariatric surgery, atkins diet

74

Note:

stopped on slide 34, page 12 of alana's notes