Hereditary Hyperbilirubinemia Syndromes

by Richard Mitchell, MD, PhD

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    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.

    01:17 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.

    02:28 It's going to be modified by UDP glucuronosyltransferases that are in the endoplasmic reticulum.

    02:37 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.

    03:05 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.

    03:18 So, in Gilbert's, you'll only have about 25% of the normal level of activity because of mutations in the primary enzyme.

    03:26 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.

    04:21 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.

    05:26 And again, Dubin-Johnson is the ability to take things out of the cytosol and put them into the biliary system.

    05:33 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.

    06:35 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.

    About the Lecture

    The lecture Hereditary Hyperbilirubinemia Syndromes by Richard Mitchell, MD, PhD is from the course Disorders of the Biliary Tract.

    Included Quiz Questions

    1. UDP glucuronosyltransferase
    2. DNA polymerase I
    3. RNA polymerase III
    4. UDP amylase
    5. GTP isomerase
    1. Asymptomatic
    2. Adolescent jaundice
    3. Neonatal jaundice
    4. Jaundice during pregnancy
    5. Pruritic jaundice
    1. Persistent neonatal jaundice
    2. Jaundice during pregnancy
    3. Asymptomatic
    4. Adolescent jaundice
    5. Pruritic jaundice
    1. Crigler-Najjar syndrome
    2. Gilbert syndrome
    3. Dubin-Johnson syndrome
    4. Rotor syndrome

    Author of lecture Hereditary Hyperbilirubinemia Syndromes

     Richard Mitchell, MD, PhD

    Richard Mitchell, MD, PhD

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