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Endocrine Exam 2 > 25 - Porphyrin Metabolism > Flashcards

25 - Porphyrin Metabolism Flashcards

1
Q

What is heme?

A

A cofactor consisting of an Fe2+ (ferrous) ion contained in the center of a large heterocyclic organic ring called a porphyrin

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2
Q

What is the first step in the synthesis of heme?

A
  • Aminolevulinic acid synthase (ALA synthase) synthesizes ALA from succinyl-CoA and glycine
  • This happens in the mitochondria because that is where the succinyl-CoA is located *** KEY FACT
  • 2 molecules of ALA are joined to form porphobilinogen (PBG)
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3
Q

What steps occur next that form a heme molecule?

A
  • Four molecules of PBG are joined to form uroporphyrinogen (which is a ring formation (UPG III)
  • Modifications of the side-chains generate coporphyrinogen and protoporphyrinogen
  • At this point, the molecule goes back into the mitochondria
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4
Q

What happens in the mitochondria to form the final product?

A
  • Ferrochelatase inserts a Fe2+ into the protoporphyrinogen molecule to yield a heme
  • There NEEDS to be a Fe2+ from stored ferritin granules
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5
Q

How is the synthesis of heme regulated?

A

Low heme concentration activates ALA synthase

  • This is a negative feedback loop
  • Remember ALA synthase is the enzyme in the mitochondria in the first step of heme synthesis that combines glycine and succinyl-CoA to make ALA

Synthesis of heme-containing cytochrome p450 enzymes (EtOH barbiturates) induces heme synthesis

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6
Q

What happens if UPG absorbs light?

A
  • UPG III is important because it absorbs light (good in plants, bad in animals)
  • If this molecule catches a photon, it will start vibrating and therefore will shed electrons and can cause reactive oxygen species (ROS)
  • If people have a problem with this, they can have a disorder dealing with sun light
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7
Q

What is acute intermittent porphyria (AIP)?

A
  • A heme synthesis disorder caused by a deficiency in porphobilinogen deaminase (PBGD)
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8
Q

What happens to patients with AIP?

A
  • ALA and PBG accumulate in the circulation and in the urine

- This gives the urine a DARK RED color

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9
Q

Can AIP be life threatening?

A

Yes

  • AIP can be life-threatening and causes episodes of confusion and sharp abdominal pain
  • This can cause neurological damage
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10
Q

When will the urine be dark red in an AIP patient?

A

Only when they are having an “AIP attack”

  • Most of the time it will be “iced tea” colored
  • If it looks like red wine, they are having an attack
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11
Q

What triggers an AIP attack?

A

The trigger for an attack is anything that causes liver p450 to increase such as alcohol

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12
Q

What is porphyria cutanea tarda (PCT)?

A
  • A heme synthesis disorder that results from a deficiency of uroporphyrinogen decarboxylase
  • Remember that uroporphyrinogen decarboxylase is the enzyme that takes UPG III and makes CPG III
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13
Q

What does PCT cause in patients?

A
  • Leads to a buildup of porphyrins
  • Porphyrins can be detected in the urine and useful for diagnosis
  • Porphyrins are able to absorb visible and UV light
  • This is potentially harm-ful, as the absorbed light energy is discharged into the tissue and gen-erates reactive oxygen species (ROS)
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14
Q

What symptoms of PCT will you see?

A
  • Blistering of the skin
  • Skin sensitivity to UV light
  • Damaged skin and scarring
  • Photoactive urine that flouresces pink in UV light
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15
Q

What is the effect of lead poisoning?

A
  • Lead poisoning inhibits porphobilinogen synthase and ferrochelatase
  • There are two points of regulation that lead poisoning inhibits
  • Remember porphobilinogen synthase is the enzyme used to convert ALA into PBG and it is also called ALA dehydrogenase
  • Remember ferrochelatase is the enzyme that takes a Fe2+ in the mitochondria to form the final heme product
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16
Q

What does lead poisoning lead to?

A
  • The accumulation of ALA and other heme precursors in heme-producing tissues
  • Lead poisoning causes symptoms similar to the porphyrias (AIP and PCT)
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17
Q

Give a common patient presentation for acute intermittent porphyria (AIP)

A
  • A 15-year old boy was hospitalized with an episode of acute abdominal pain, cognition failure, hypertension, tachycardia and diffuse neurological symptoms.
  • This is an attack/crisis mode
  • Urinalysis revealed a very high concentration of aminolevulinic acid (ALA), porphobilinogen (PBG) and other porphyrin precursors.
  • Based on these findings, a diagnosis of acute intermittent porphyria was made.
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18
Q

What could have caused this AIP attack?

A

Alcohol, steak, infection can all cause this

19
Q

What happens when RBCs reach the end of their life?

A
  • The half-life of the red blood cells is about 120 days
  • Damaged cells are removed by the spleen and, to a lesser extent by the liver
  • After degradation of the RBCs by macrophages, the protein moiety of hemoglobin is hydrolyzed and the heme cofactors released
20
Q

What happens to heme in splenic macrophages?

A
  • The heme ring is cleaved into biliverdin, CO and Fe3+
  • NADPH-dependent reduction of biliverdin yields bilirubin
  • The iron released from heme is stored in ferritin globules and ca be recycled
21
Q

Describe the properties of bilirubin

A
  • Hydrophobic

- Needs to be bound to albumin to be transported in the circulation to the liver

22
Q

What happens after bilirubin reaches the liver?

A
  • In order to facilitate excretion, bilirubin is made more hydrophilic by the action of bilirubin-UDP glucuronyltransferase (UGT)
  • Bilirubin-UDP adds one or two glucuronic acid molecules to bilirubin
  • This generates a water soluble bilirubin monoglucuronide or bilirubin diglucuronides, respectively
23
Q

What do we call conjugated bilirubin?

A

Direct bilirubin

It is water soluble

24
Q

What do we call unconjugated bilirubin?

A

Indirect bilirubin

It is water insoluble

25
Q

How is bilirubin excreted?

A
  • Conjugated bilirubin is excreted by the liver into bile capillaries
  • It then exits through the gall duct into the gut and is excreted in the feces
26
Q

What happens once the bilirubin is in the gut?

A
  • There are some bacteria in the gut that digest bilirubin
  • They oxidize it to yield the color compount urobilin which is responsible for the color of feces
  • In contrast to bilirubin, urobilin is water soluble
27
Q

Does all bilirubin get excreted this way?

A

No

  • Minor fraction of urobilinogen is re-absorbed from the gut and can be re-excreted by the liver or the kidney
  • The re-absorbed urobilin-ogen also undergoes spontaneous conversion to urobilin
28
Q

What do you need to remember about the color of urine?

A

Remember: The yellow color of the urine comes from urobilins that were re-absorbed from the gut. ***

Under normal conditions, there is no detectable amount of bilirubin in the urine.

29
Q

What causes jaundice?

A

Hyperbilirubinemia

  • If the concentration of bilirubin in the serum exceeds 2-3 mg/dL, bilirubin will enter the tissues
  • This is what gives affected individuals the yellow-orange appearance
30
Q

What is the risk of uncontrolled jaundice?

A

Unconjugated bilirubin can diffuse across the blood-brain barrier and damage the brain (kernicterus).

31
Q

What are the three types of jaundice?

A
  • Pre-hepatic (hemolytic) jaundice
  • Hepatic jaundice
  • Post-hepatic jaundice
32
Q

Describe pre-hepatic jaundice

A
  • When there is elevated destruction of RBCs, it can exceed the liver’s capacity for glucuronation and excretion
  • This means that there will be high levels of indirect bilirubin (the bilirubin can’t get conjugated)
33
Q

What are some examples of pre-hepatic jaundice?

A
  • Neonatal physiological jaundice

- Hemolytic diseases

34
Q

What lab values will you find in pre-hepatic jaundice?

A
  • Bilirubin is usually only slightly elevated
  • No bilirubin is found in the urine
  • Blood analysis will show hemolysis (you know this because the reticulocyte count will be up)
  • Hemoglobin is low
35
Q

Describe hepatic jaundice

A
  • This occurs in patients with liver disease, which impairs the liver’s function to glucuronate bilirubin
  • The decreased glucuronation ability leads to a rise in indirect bilirubin in the plasma and tissues
  • This is often accompanied by tissue damage and cirrhosis
36
Q

Describe the patient presentation of hepatic jaundice

A
  • The condition can be recognized by pale color of the feces and urine
  • The bilirubin in serum and tissues is mostly unconjugated
37
Q

What are common causes of hepatic jaundice?

A
  • Most commonly hepatitis or acetaminophen poisoning
38
Q

What do you need to look for in a suspected case of hepatic jaundice?

A
  • Other markers of liver disease such as the presence of hepatic enzymes in serum (ALT and AST)
  • **
39
Q

What lab results would you see in hepatic jaundice?

A
  • Elevated bilirubin
  • Bilirubin in the urine
  • Markers of liver disease (ALT, AST)
40
Q

Describe post-hepatic jaundice

A

AKA cholestatic jaundice from an obstruction

  • This can be caused by gall stones or neoplasms which can obstruct the biliary duct
  • This imparis the liver’s ability to excrete conjugated bilirubin into the feces
  • The conjugated, water-soluble bilirubin is excreted through the kidneys
41
Q

What will you see in patients with post-hepatic jaundice?

A
  • This condition is recognized by the pale color of feces but the intense color of urine.
  • Bilirubin in tissues and urine is mostly conjugated
  • Causes: Gallstones, neoplasia, cirrhosis
42
Q

What else should you watch for in suspected cases of post-hepatic jaundice?

A
  • Other markers of blocked bile ducts such as the presence of alkaline phosphatase in the serum ***
43
Q

What lab values would you see with post-hepatic jaundice?

A
  • Bilirubin may be highly elevated
  • Bilirubin will be present in the urine
  • Markers of cholestasis are elevated (such as alkaline phosphatase)

Endocrine Exam 2 (18 decks)

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