00:01
Welcome.
00:02
In this talk, we're going to discuss four syndromes that are associated with hyperbilirubinemia.
00:08
These are hereditary causes.
Three of them are actually fairly benign,
other than being a little more yellow, it's not
a big deal, hence, the subtitle here, mellow yellow.
00:19
Crigler-Najjar of the four of these may
have the most severe symptomatology.
00:25
So, let's get into this.
00:28
The epidemiology of the hereditary hyperbilirubinemias can be broken into two potential defects.
00:36
Either the inability to conjugate bilirubin
as it's coming in from the bloodstream
or the ability to transport
conjugated material back out.
00:47
So, conjugation defects are going to be Gilbert syndrome
with the prevalence of about 5% of the population,
so, actually, fairly common.
Most cases are diagnosed around puberty.
00:58
When there may be elevations in the level
of bilirubins due to increased red cell turnover.
01:07
Crigler-Najjar syndrome, fortunately, is
much less common, about one in a million.
01:12
And again, remember, this is going to be the one
that's going to have more severe consequences.
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Transport defects.
So, you're conjugating just fine.
01:21
You are making the appropriate UDP
modified bilirubin, so, that you can excrete it.
01:30
But you just can't get it out of the liver.
And this is the Dubin-Johnson syndrome
with the variable prevalence, about one in a thousand.
In the Middle Eastern population,
less in other people's around the world.
And then, Rotor syndrome which is rare.
01:45
About one in a million again but also,
is not all that severe.
01:50
So, three of these, Gilbert, Dubin-Johnson
and Rotor, you live with happily ever after.
01:55
You're just a little yellow. Crigler-Najjar, more severe.
02:00
Let's go into the pathophysiology.
02:02
So, we have to understand again, how the
hepatocytes are metabolizing bilirubin as it comes in.
02:07
So, bilirubin that is coming from the
reticuloendothelial cell system,
that is to say, macrophages that have taken the heme,
converted it with various reduction stages into bilirubin,
send that bilirubin in the bloodstream
and the liver cells, hepatocytes take it up.
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It's going to be modified by UDP glucuronosyltransferases
that are in the endoplasmic reticulum.
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And that makes our conjugated, UDP
conjugated bilirubin now within the cytosol,
that is eventually accumulated
within the bile duct radicles,
the early stages of the biliary system, transported
out, and then, is excreted into the bile.
02:58
We can see that different defects along this
pathway will lead to the various syndromes.
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So, for Gilbert's and Crigler-Najjar,
this is either a partial loss of activity
of the UDP glucuronosyltransferase activity
or complete loss and that's in the Crigler-Najjar.
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So, in Gilbert's, you'll only have about 25% of the normal level of activity
because of mutations in the primary enzyme.
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In Crigler-Najjar, it is one in a million patients
have essentially, no enzymatic activity
and therefore, unable to conjugate the bilirubin
and it will accumulate to high levels.
03:37
So, that's those two and those are
the modification defects syndromes.
03:44
For the transport defects syndromes,
in order to store conjugated bilirubin
within the hepatocyte before it is
put into the bile system,
we have to have the activity of an organic
anion transport protein or OATP
and defects in that transport protein
will lead to the relative reduction in the inorganic or the organic ions necessary to store.
04:10
That's going to be the cause of Rotor's
syndrome, one in a million,
it has to do with the transport and storage
of the already conjugated bilirubin.
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On the other hand, being able to take
what's in the cytosol that's being stored
and put it into the biliary system
involves transport proteins
and defects in those transport proteins
are what cause Dubin-Johnson syndrome.
04:36
So, we kind of covered all of the territory.
04:39
How is this going to manifest?
How are these going to manifest?
So, the conjugation defect syndromes,
Gilbert and Crigler-Najjar, Gilbert is going to
be usually asymptomatic, very mild jaundice,
so, levels of three, four, five milligrams per deciliter.
And again, upper limits of normal or one to 1.5.
04:57
In Crigler-Najjar on the other hand, it's going to be
very early manifestations and much more severe disease
because you're not making any of the enzyme.
05:06
And in fact, babies with this will have
severe persistent neonatal jaundice
and will get to levels of 25 milligrams
per deciliter or more of bilirubin
which then will lead to kernicterus\which may lead to permanent CNS injury.
05:23
The transport defect syndromes
are Dubin-Johnson and Rotor.
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And again, Dubin-Johnson is the ability to take things out
of the cytosol and put them into the biliary system.
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That's a relatively mild to moderate jaundice.
The onset is during adolescence
when we are transiently having increased
levels of bilirubin formation.
05:44
It can worsen due to certain
medications or to pregnancy
or we may get more hemolysis or greater stress
on the erythrocytes and have greater turnover.
05:54
In Rotor's Syndrome, again, these are mutations
one in a million that have to do
with the organic anion transport protein,
OATP, usually, very low levels.
06:05
It's just your ability to kind of store the material.
It's usually asymptomatic and very mild.
06:11
It's non-itchy. It's just jaundice
at birth or early childhood,
which typically is well-tolerated
and in some cases, may even resolve.
06:21
The diagnosis overall is more
laboratory than anything else.
06:24
So, with the conjugation defects as you would
expect, you have increased indirect bilirubin.
06:30
You're not conjugating the bilirubin that's coming
in from the macrophages peripherally.
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In Gilbert syndrome, it's going to be three
or so milligrams per deciliter.
06:40
In Crigler-Najjar, it can be quite high because
you have none of the conjugation enzymes.
06:46
Overall, the rest of the liver function
is completely normal.
06:49
But again, in the neonatal period, if you get
above 25 milligrams per deciliter,
you may have permanent irreversible CNS damage.
So, Crigler-Najjar is not so benign. Gilbert's, very benign.
07:02
The transport defect syndromes, Dubin-Johnson
and Rotor are now direct hyperbilirubinemia.
07:10
Everything's been modified. It's been conjugated.
So, this is a direct bilirubin that's elevated.
07:16
The liver biopsy in Dubin-Johnson because
we are cumulating the conjugated bilirubin
within the cytosol, the liver hepatocytes
will be dark and very granular with pigmentation,
reflecting that
bilirubin that we're not putting into the bile system.
07:37
In contradistinction in the Rotor's syndrome,
although, it's a direct hyperbilirubinemia,
we're not really storing things.
07:44
The biopsy basically shows normal
absence of pigmentation
and this is because we're not able to store
the bilirubin in order to get it into the biliary system.
07:58
Normal function tests overall for the liver indicate
that the rest of the liver is doing its job just fine.
08:05
How do we manage this? So, for three out of the four,
for Gilbert's, Dubin-Johnson, and Rotor, don't do anything.
08:12
Tell the patient, they're going to be a little bit yellow.
Maybe they have to use a little makeup if this bothers them,
but overall, not anything that they need
to be worried about.
08:21
For Crigler-Najjar, you need to have support
for the fetus early on or for the neonate
and we'll do extensive phototherapy.
You may do plasmapheresis to remove circulating bilirubins
and the only curative therapy for
this is complete liver transplantation.
08:42
With that, the hyperbilirubinemic syndromes
and hopefully, you will feel a little mellow with your yellow.