Biochem: heme synthesis and jaundice part 2 (clinical correlates)

What porphyria and what step?

defective enzyme: Porphobilinogen deaminase

step 3

Acute intermittent porphyria

What porphyria and what step is affected?

painful abdomen, port-wine colored urine, polyneuropathy, psychological disturbances, and is precipitated by drugs (CYP inducers(, alcohol, and progesterone

step 3

acute intermittent porphyria

Photosensitivity (skin reactions) are seen with which porphyrias?

the ones after step 3; like porphyria cutanea tarda and erythropoietic protoporphyria

What prophyria and what step?

defective enzyme: uroprophyrinogen decarboxylase

step 5

porphyria cutanea tarda

What porphyria and what step?

clinical manifestation: red urine and chronic blistering skin lesions

step 5

porphyria cutanea tarda

What porphyria and what step?

defective enzyme: ferrochelatase

step 8

erythropoietic protoporphyria

What porphyria and what step?

clinical manifestation: acute non-blistering skin and photosensitivity

step 8

erythropoietic protoporphyria

What porphyrias are associated with photosensitivity?

the ones that occur after step 3 (think porphyria cutanea tarda and erythropoietic protoporphyria)

most of degraded heme comes from _____

senescent RBCs (dying/old RBCs)

what is the site of heme degradation?

macrophages

explain step 1 of heme degradation

heme is a ring so we bust open the ring and now the ring is a chain known as biliverdin (green pigment)

explain step 2 of heme degradation

biliverdin (the chain) gets reduced to bilirubin (red-orange pigment)

unconjugated bilirubin is ___ and is transported in the blood as ____

poorly soluble; bilirubin-albumin

what is the site and enzyme that converts UCB (unconjugated bilirubin) to CB (conjugated bilirubin)

hepatocytes; bilirubin UDP-glucuronosyl transferase

what is the major difference between UCB and CB?

UCB: less soluble in blood

CB: more soluble in blood

what is the rate limiting step of bilirubin production?

step 1 (where the heme ring is broken open by heme oxygenase) to make biliverdin

what is the rate limiting step of bilirubin degradation?

when the CB is secreted into the bile in the GI tract

what is urobilinogen?

when bilirubin is in the intestines it gets converted to urobilinogen that eventually leaves via feces (its a brown color)

What is this?

yellowish discoloration of the skin, mucous membranes, and sclera caused by deposition of bilirubin in the tissues

jaundice

what type of jaundice?

extensive hemolysis (like sickle cell anemia); leading to increased UCB in the blood and increased urobilinogen in the urine

hemolytic jaundice

what type of jaundice?

damaged liver (cirrhosis or hepatitis); leading to increased UCB in teh blood and increased urobilinogen in the urine

we see dark urine and pale, clay colored stools (they are pale because the urobilinogen is getting in the urine not the feces)

hepatocellular jaundice

what type of jaundice?

due to an obstruction in the common bile duct; leading to increased CB in the blood and urine, and urobilinogen is absent

dark urine (darken upon standing) and pale, clay colored stools

obstructive jaundice

what type of jaundice?

increased UCB in blood and increased urobilinogen in urine

vs

increased CB in blood and urine and absent urobilinogen

UCB and urobilinogen: either hemolytic or hepatocellular jaundice

CB increased and absent urobilinogen: obstructive jaundice

Which hereditary hyperbilirubinemia?

caused by changes in the ABCC2 gene which transports bilirubin out of the liver cells and into the bile; relatively benign

Dubin-Johnson syndrome

Which hereditary hyperbilirubinemia?

mild increase in UCB due to increased activity of conjugating enzyme UDP-glucuronosyltransferase (UGT) activity to around 30% of normal

Gilbert syndrome

Which hereditary hyperbilirubinemia?

mutations in UGT1A1 gene, resulting in reduced or absent function of the bilirubin-UGT enzyme → high UCB

Crigler-Najjar syndorme type I and II

Which hereditary hyperbilirubinemia?

buildup of both UCB and CB in the blood (mostly CB), due to multiple defects in hepatocyte uptake of bilirubin from the blood

rotor syndrome

why is jaundice at birth common? what can be a fatal consequence of this if not treated?

hepatic bilirubin UGT (enzyme) is low at birth and doesn’t reach adult levels until 4 weeks

tx the babies with phototherapy

persistently high UCB can diffuse into the basal ganglia and cause toxic encephalopathy (kernicterus)