Choudhury CIS Flashcards

1
Q

Amino Acids in Metabolism- Fed State

A
Amino acids brought in by digestion
Travel to liver 
- Nitrogen to synthesize proteins
--- Particularly albumin
--- Amino acids released into blood for other tissues

Carbon converted to glucose, ketone bodies or triacylglycerols
- Stored or travel to other tissues

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2
Q

Amino Acids in Metabolism- fasting state

A

Amino acids released from protein breakdown

  • Some released into blood directly
  • Some lose the nitrogen to glutamine or alanine to be shuttled through the blood
  • – In the kidney, glutamine delivers ammonia into urine
  • – In the liver, alanine and other aa deliver nitrogen for urea
  • ——-Carbons are converted into glucose, etc.
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3
Q

Clay-colored stools mean

A

no bilirubin in the feces

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4
Q

tea colored urine

A

lacking bilirubin for coloration

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5
Q

clay-colored stools and tea colored urine indicate

A

blockage - tumor, stones, parasites- of hepatobiliary tract

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6
Q

types of hepatitis related to food

A

A or E

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7
Q

what should pts with liver issues avoid?

A

alcohol, NSAIDs, things that can increase hepatotoxicity

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8
Q

Hyper-ammonemia

A

In adults, caused by liver failure
Toxic effects of ammonia
- Brain swelling due to osmotic imbalance (High ammonia and glutamate in astrocytes)
- Astrocytes produce glutamine (From a-ketoglutarate and ammonia–> Exacerbates osmotic imbalance–> At high enough concentrations, opens mitochondrial permeability transition pore)

Decreases glutamate concentration
- An excitatory neurotransmitter

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9
Q

Glutamate

A

Central to urea production
Provides the two nitrogens Glutamate
- One in ammonium ion
—– From transamination of other amino acids followed by glutamate dehydrogenase reaction
- One in aspartate
—— Glutamate transaminates oxaloacetate (aspartate’s corresponding a-keto acid) to aspartate

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10
Q

Transamination: Removing the nitrogen

A

Nitrogen transferred to a-ketoglutarate
- Produces glutamate

The amino acid becomes its corresponding a-keto acid

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11
Q

Transamination: Production of Ammonia

A

Glutamate is deaminated by glutamate dehydrogenase:
a-ketoglutarate
Ammonium ion (NH4+)
reversible

Other sources of ammonia:
Deamination of other amino acids
Purine nucleotide cycle in brain and muscle
Bacteria in the gut

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12
Q

Glucose/Alanine Cycle

A

In muscle, glucose is metabolized via glycolysis
- Produces pyruvate
Pyruvate is transaminated by glutamate to
form alanine
Alanine is exported and used as one of two
main nitrogen carriers in the blood
Travels to the liver

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13
Q

transamination reactions

A

move an amine group.

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14
Q

Glutamine

A

The other main carrier (of nitrogen)

In somatic cells and liver

Glutamate can accept a second Nitrogen to
form glutamine

In liver:
- Reaction used to prevent any ammonia that escaped urea production from leaving liver

In somatic cells

  • Glutamine released into circulation to go to liver
  • Glutamine used to produce ammonia for urea cycle
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15
Q

Urea Cycle

A

In Liver Urea Cycle

Nitrogen enters as ammonium ion or aspartate

In mitochondria

  • Ammonium ion is used to form carbamoyl phosphate
  • Reacts with ornithine to produce citrulline
  • Transported to cytosol

In cytosol

  • Aspartate reacts with citrulline
  • Arginine is generated
  • Arginine is cleaved to release urea and regenerate ornithine
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16
Q

lactulose

A

a sugar, not well absorbed, inhibits bacterial transcription

can cause ostmotic diarrhea

17
Q

Urea Cycle Enzyme Defects

A

Accumulation of substrates or intermediates before the block
Changes extent of elevation of glutamine and ammonia

Low citrulline means defect before the step that produces citrulline, e.g.

18
Q

Carbamoyl phosphate syntetase deficiency

A

Urine orotate- low
blood citrulline- low
blood arginine- low
Blood NH3- High

19
Q

Ornithine transcarbamoylase defect

A

urine orotate- high
blood citrulline- low
blood arginine- low
blood NH3- high

20
Q

Argininosuccinate synthetase deficiency

A

blood citrulline- High (< 1000 microM),
blood arginine low,
blood NH3 high

21
Q

Argininosuccinate lyase deficiency

A

Blood citrulline- high (over 200 microM),
blood arginine low,
blood NH3 high

22
Q

ARginase defect

A

blood arginine high

blood NH3 moderately high

23
Q

Orotic Acid/Orotate

A

Carbamoyl phosphate Created in the mitochondria to allow ammonia to enter the urea cycle

Carbamoyl phosphate accumulation

  • When Ornithine transcarbamoylase is deficient
  • Excess carbamoyl phosphate enters the pathway for pyrimidine biosynthesis
  • Creates the intermediate, orotate or orotic acid
  • – Elevation in urine is indicative of urea cycle defect
24
Q

Degradation of Amino Acids

A

Glucogenic Carbons used to create glucose in the liver
- Produce intermediates of the TCA Cycle
- All non-essential amino acids can be used
to produce glucose

Ketogenic

  • Carbons used to create ketone bodies or their precursors
  • – Acetyl-CoA or acetoacetate
  • Lysine and leucine are strictly ketogenic

Can be categorized as both
- Tryptophan, isoleucine, threonine, phenylalanine and tyrosine

25
Q

Homocystinuria

A

Autosomal Recessive Deficiency:
Cystathione synthase

Presentation:
Cardiovascular disease
- Deep vein thrombosis
- Thromboembolism
- Stroke
Dislocation of the lens
Mental retardation
Marfanoid habitus
Accumulation of Substrates:
No cysteine
Elevated methionine
Elevated homocysteine
- Homocystine is the oxidized disulphide form

Can also arise from Vitamin Deficiency
B12 and Folate: Homocysteine methyltransferase
- Methylates homocysteine to methionine
Serum methionine levels low

26
Q

Coenzymes

A

Vitamin B12

Folate

Vitamin B6 (Pyridoxal Phosphate)

  • Key coenzyme for amino acid metabolism
  • Required for transamination reactions
  • – Enzyme bound pyridoxal phosphate
  • – Reacts with an amino acid
  • – Acquires the amino group and releases a-ketoacid
  • – Reacts with another a-ketoacid
  • – Releases the amino group to produce an amino acid
  • – Pyridoxal phosphate regenerated

Administered to treat homocystinuria (Free PLP catalysis)

27
Q

A diagnosis of type I homocystinuria was made (Cystathione synthase deficiency) based on elevated methionine levels:

A

Increased conversion of homocysteine to methionine due to increased availability of homocysteine.
In type II and III (deficiency in conversion of B12 and folate respectively) there is not increased methionine because these coenzymes are required for homocysteine methylation

28
Q

Treatment of homocystinuria

A

directed toward reduction of elevated homocysteine and methionine:
A diet low in methionine
Low-protein diet: vegetarian or vegan
Vit B12, L-cystine and choline (methyl-donor)
supplementation

Very high doses of oral Vitamin B6
Free PLP catalysis of homocysteine to cysteine
50% of type I patients are Vit B6 “responders”

29
Q

Alcoholic Hypoglycemia

A

Metabolism of Alcohol

  • Ethanol rapidly converted to acetaldehyde in liver–> Then converted to acetate
  • Both reactions require NAD+
  • – [NADH]/[NAD+] increases in the liver

NAD+ is required for gluconeogenesis
- Major precursors (lactate, alanine and glycerol) cannot enter pathway because the increased [NADH]/[NAD+] drives the reactions backwards

30
Q

Patient presentation in alcoholic hypoglycemia

A

Tremulous, sweating, increased HR

  • Adrenergic nervous system stimulation
    • Hormone release counter-regulatory to hypoglycemia
    • Glucagon, growth hormone, cortisol and epinephrine

Confused, combative, slurred speech, seizure
- “Neuroglycopenic symptoms”
– Insufficient glucose to brain tissue
- Wernicke encephalopathy (thiamine deficiency)
– Includes oculomotor dysfunction and
gait ataxia

31
Q

Maintenance of Blood Glucose Levels

A

Maintained by liver

Glycogenolysis

  • During fasting
  • Mostly depleted after more than 12 hours

Gluconeogenesis

  • During starvation
  • Increases as glycogen reserves decrease
  • Only source after 24 hours of fasting
32
Q

Gluconeogenesis

A

Most steps are a reverse of glycolysis

Major precursors:

  • Lactate
  • – Oxidized to pyruvate by lactate dehydrogenase
  • Alanine
  • – Converted to pyruvate by alanine aminotransferase
  • Glycerol-3-phosphate
  • – Oxidized to DHAP by glycerol-3-phosphate dehydrogenase
33
Q

4 reactions required to circumvent irreversible steps in glycolysis

A

The conversion of PEP to pyruvate is irreversible

Pyruvate carboxylase
- Reduces OAA to malate so it can leave the mitochondria and be converted back into OAA

Phosphoenolpyruvate carboxykinae (PEPCK)
- Converts OAA to PEP

NAD+ required to proceed

  • Conversion of OAA to Malate and back to OAA
  • Reduced due to alcohol metabolism

Kinases are not reversible in function:

  1. Fructose-1,6-bisphosphatase
    - - Hydrolyzes one phosphate to F-6-P
  2. Glucose-6-phosphatase
    - Hydrolyzes one phosphate to glucose
    - Occurs in ER so free glucose is transported out of cell
    - Only expressed in liver so only source of blood glucose through gluconeogenesis
34
Q

treatment of alcoholic hypoglycemia

A

Vitamin B1 (thiamine)!!!

Thiamine is converted to thiamine pyrophosphate (TPP) (requires magnesium)
3 important reactions in the body that require the following co-factors
TPP; Lipoic acid; Coenzyme A; FAD(H2) “Riboflavin”; NAD (H) “Niacin”
(Tender, Loving, Care, For, Nancy)

35
Q

So what are the 3 important reactions in the body that require the following co-factors ??
TPP; Lipoic acid; Coenzyme A; FAD(H2) “Riboflavin”; NAD (H) “Niacin”
(Tender, Loving, Care, For, Nancy)

A
  1. Pyruvate–>PDH –> Acetyl CoA
  2. a keto glutarate –> a ketoglutarate dehydrogenase –> succinyl CoA
  3. Leucine, Isoleucine, Valine –> branched chain ketoacid dehydrogenase –> Acetyl CoA, Propionyl CoA

In absence of the cofactors, the enzymes in the reactions either do not work or
Work very slowly.

Reactions 1 and 2 are important for glycolysis, TCA cycle and ETC to produce ATP

36
Q

In the absence of these critical reactions…

A

reactions 1 and 2 are important for glycolysis, TCA cycle and ETC to produce ATP
Without the enzymes functioning there will be NO ATP production
With i/v glucose, there will be a massive production of pyruvate then to lactate
As pyruvate cannot enter the TCA cycle
Huge amount of lactate will cause lactate acidois and eventual death
Glucose cannot enter hexose monophosphate shunt pathway and no production of NADPH, cell is not protected from stress due to increase reactive oxygen species, results in either cellular death or activation of apoptosis
Patient at risk of Wernicke-Korsakoff Syndrome, cerebellar degeneration and cardiovascular dysfunction

37
Q

Thiamine deficiency results in:

A

decreased ATP production
increased Lactic acid production will lead to acidosis
increased a-keto acids
increased NADH production will inhibit glycolysis
decreased NAD+ will inhibit glycolysis
decreased NADPH (via HMPS) production
increased Cell stress
increased Apoptosis/Cell death
Patient at risk of Wernicke-Korsakoff Syndrome,
cerebellar degeneration and cardiovascular dysfunction

38
Q

treatment of alcoholic hypoglycemia

A

give thiamine 100 mg i/v before administering glucose containing i/v fluids and then to continue this dose for several days. Severe hypoglycemia must be corrected within 6-10 hours to prevent permanent neurological damage.

The physician must also correct:
- Acidemia
Beta-hydroxybutyrate and acetoacetate to increase bicarbonate
- Ketoacidosis
Dextrose administration will increase insulin and decrease glucagon
Volume depletion
From vomiting/diarrhea or decreased intake; saline or isotonic electrolyte balanced solution administration
Deficiencies
Potassium and sodium (vomiting, diarrhea, urinary loss), magnesium (pancreatitis and diarrhea), phosphate (movement out of cells) and thiamine and vitamins (malabsorption and malnutrition)