25 - Porphyrin Metabolism Flashcards
What is heme?
A cofactor consisting of an Fe2+ (ferrous) ion contained in the center of a large heterocyclic organic ring called a porphyrin
What is the first step in the synthesis of heme?
- 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)
What steps occur next that form a heme molecule?
- 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
What happens in the mitochondria to form the final product?
- Ferrochelatase inserts a Fe2+ into the protoporphyrinogen molecule to yield a heme
- There NEEDS to be a Fe2+ from stored ferritin granules
How is the synthesis of heme regulated?
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
What happens if UPG absorbs light?
- 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
What is acute intermittent porphyria (AIP)?
- A heme synthesis disorder caused by a deficiency in porphobilinogen deaminase (PBGD)
What happens to patients with AIP?
- ALA and PBG accumulate in the circulation and in the urine
- This gives the urine a DARK RED color
Can AIP be life threatening?
Yes
- AIP can be life-threatening and causes episodes of confusion and sharp abdominal pain
- This can cause neurological damage
When will the urine be dark red in an AIP patient?
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
What triggers an AIP attack?
The trigger for an attack is anything that causes liver p450 to increase such as alcohol
What is porphyria cutanea tarda (PCT)?
- 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
What does PCT cause in patients?
- 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)
What symptoms of PCT will you see?
- Blistering of the skin
- Skin sensitivity to UV light
- Damaged skin and scarring
- Photoactive urine that flouresces pink in UV light
What is the effect of lead poisoning?
- 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
What does lead poisoning lead to?
- The accumulation of ALA and other heme precursors in heme-producing tissues
- Lead poisoning causes symptoms similar to the porphyrias (AIP and PCT)
Give a common patient presentation for acute intermittent porphyria (AIP)
- 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.
What could have caused this AIP attack?
Alcohol, steak, infection can all cause this
What happens when RBCs reach the end of their life?
- 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
What happens to heme in splenic macrophages?
- 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
Describe the properties of bilirubin
- Hydrophobic
- Needs to be bound to albumin to be transported in the circulation to the liver
What happens after bilirubin reaches the liver?
- 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
What do we call conjugated bilirubin?
Direct bilirubin
It is water soluble
What do we call unconjugated bilirubin?
Indirect bilirubin
It is water insoluble
How is bilirubin excreted?
- 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
What happens once the bilirubin is in the gut?
- 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
Does all bilirubin get excreted this way?
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
What do you need to remember about the color of urine?
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.
What causes jaundice?
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
What is the risk of uncontrolled jaundice?
Unconjugated bilirubin can diffuse across the blood-brain barrier and damage the brain (kernicterus).
What are the three types of jaundice?
- Pre-hepatic (hemolytic) jaundice
- Hepatic jaundice
- Post-hepatic jaundice
Describe pre-hepatic jaundice
- 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)
What are some examples of pre-hepatic jaundice?
- Neonatal physiological jaundice
- Hemolytic diseases
What lab values will you find in pre-hepatic jaundice?
- 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
Describe hepatic jaundice
- 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
Describe the patient presentation of hepatic jaundice
- The condition can be recognized by pale color of the feces and urine
- The bilirubin in serum and tissues is mostly unconjugated
What are common causes of hepatic jaundice?
- Most commonly hepatitis or acetaminophen poisoning
What do you need to look for in a suspected case of hepatic jaundice?
- Other markers of liver disease such as the presence of hepatic enzymes in serum (ALT and AST)
- **
What lab results would you see in hepatic jaundice?
- Elevated bilirubin
- Bilirubin in the urine
- Markers of liver disease (ALT, AST)
Describe post-hepatic jaundice
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
What will you see in patients with post-hepatic jaundice?
- 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
What else should you watch for in suspected cases of post-hepatic jaundice?
- Other markers of blocked bile ducts such as the presence of alkaline phosphatase in the serum ***
What lab values would you see with post-hepatic jaundice?
- Bilirubin may be highly elevated
- Bilirubin will be present in the urine
- Markers of cholestasis are elevated (such as alkaline phosphatase)
