Hyperbilirubinemia (Jaundice)

00:01 Welcome. With this talk, we're going to cover hyperbilirubinemia, elevated levels of bilirubin that will be manifest as jaundice.

00:10 Hyperbilirubinemia can be due to two basic processes, either we're making too much bilirubin due to altered hemoglobin metabolism and breakdown of the heme protein or it is a problem with not metabolizing it appropriately or excreting it.

00:33 And the major manifestation is jaundice. The pathophysiology of this.

00:36 So, this is getting back into basic biochemistry. Hopefully, this will be a pleasant review walking down memory lane.

00:43 There is normal red cell turnover about every 120 days, old red cells give up the ghost and die.

00:50 We release hemoglobin, so, that's the protein. And out of that hemoglobin, we will process the protein away and retain the heme and modify that in cells of the reticuloendothelial system, macrophages, and through heme oxygenase, we will convert the heme into biliverdin and then, through the biliverdin reductase, we'll convert it into unconjugated bilirubin.

01:14 As we'll see in a minute, unconjugated bilirubin is not particularly soluble in water.

01:20 So, we need to conjugate it. We need to modify it so that we can excrete it in the urine.

01:26 Or that it can circulate easily throughout the bloodstream and then, be removed.

01:31 That occurs in the liver and the hepatocytes have a UDP glucuronidase that's going to be responsible for conjugating the heme that's been already metabolized to biliverdin.

01:47 On the right-hand side, we're seeing that hemolysis will increase, obviously, the level of heme being released into the system.

01:55 And a variety of acquired or inherited disorders or ineffective erythropoiesis or abnormal vitamin supplementation, blood transfusions, reabsorption of hematomas will all increase the levels of heme that are coming into the system.

02:13 On the other hand, in the liver, if we don't conjugate, if we don't metabolize the biliverdin appropriately, then, we will end up with elevated levels of the intermediates which will be presenting as jaundice.

02:26 And there are a number of disorders that we'll talk about here, but also, in a subsequent talk that are involved in abnormal bilirubin or biliverdin conjugation.

02:37 Not only that, but the liver, once it's metabolized the bilirubin to something that can be excreted, it has to release it.

02:47 It has to get into the bloodstream or into the bile for release and injury to the biliary tree such as sclerosing cholangitis or primary biliary cirrhosis or tumors will diminish our ability to get the modified, the conjugated bilirubin out.

03:08 On this slide, we are looking at the actual chemical conformations of the various intermediates.

03:13 So, heme, as it gets released from hemoglobin as this planar array that gets clipped open with heme oxygenase.

03:20 That heme oxygenase then converts it to a linear polymer. That is our biliverdin.

03:26 Biliverdin then, will be further modified with biliverdin reductase to make a bilirubin.

03:33 And the bilirubin is what's going to be conjugated in the liver with the activity of UDP glucuronidase to add glucoronate or charged moieties that makes the whole thing water soluble.

03:46 From there, the hepatocytes have to release it into the biliary tree and it gets acted on in the gut.

03:55 So, it goes out the biliary tree into the common bile duct, into the duodenum and becomes part of the components within the stool.

04:05 Bacteria within the GI tract convert this further to urobilinogen and the vast majority of that is going to end up being excreted in the feces.

04:15 That excretion in the feces is what makes fecal material brown.

04:19 It's the metabolism or the metabolite of urobilinogen.

04:24 There will be a small amount that is excreted, about 2% in the urine and the remainder is actually reabsorbed.

04:32 So, there's an enterohepatic recirculation, so, you resorb it.

04:38 And about 20% or so, 18% goes back up to the liver to be recycled.

04:45 How will your patients present when they have hyperbilirubinemia and essentially, it's going to be as a result of jaundice.

04:53 It's going to be too much bilirubin in places you don't expect it.

04:58 So, with elevated levels of bilirubin, there will be in the whites of the eyes, scleral icterus, it's just jaundice.

05:07 And even in patients of color, you will still be able to see that the sclera has been discolored.

05:13 This occurs when bilirubin starts getting greater than two to three milligrams per deciliter.

05:18 Upper limits of normal for total bilirubin is about 1.5 milligrams per deciliter.

05:24 Cutaneous jaundice, so, in the skin, clearly, much more easily observed in Caucasian white individuals will become apparent when the bilirubin levels get greater than four to five milligrams per deciliter.

05:36 With chronically elevated bilirubins, you can get deposition of bile salts within the skin, it's intensely itchy or pruritic.

05:45 Remember that the brown color of stool is because of the urobilinogen, the modification the bacteria make to make a particular color that makes stool brown.

05:57 If you are not getting adequate delivery of conjugated bilirubin into the stool, they become very pale.

06:05 On the other hand, if you're not able to get the bilirubin into the stool because of obstruction or bile pathology, biliary tree pathology, then, a lot of that now water-soluble bilirubin conjugate will end up in the urine and the urine will become very dark.

06:28 So, clay colored stools, dark urine is also a sign of a bilirubin metabolism disease.

06:36 And then, in infants, when the blood brain barrier's immature, elevated levels of bilirubin, particularly, unconjugated bilirubin, can deposit and that will cause central nervous system damage, including hearing loss, learning disabilities, and symptoms that mimic cerebral palsy.

06:54 Making a diagnosis.

06:56 This is going to be fundamentally a laboratory exercise.

07:01 So, we want to look at the total bilirubin and then, we want to assess whether it's indirect which is unconjugated versus direct.

07:09 So, for pre-hepatic jaundice, that is to say because we have too much hemolysis or we're absorbing a huge hematoma, in that setting, we will have elevated indirect bilirubins.

07:21 So, we are loading up the system before it can get metabolized, so, indirect bilirubin, unconjugated will be more prevalent.

07:30 With intrahepatic jaundice due to primary hepatocyte injury or in some cases, to intrahepatic biliary pathology, we will have elevations of both indirect and direct.

07:44 So, we are not conjugating appropriately.

07:47 Or not able to release the conjugated bilirubin which is measured as the direct bilirubin.

07:53 And then, there's extrahepatic jaundice. And this will mean that the liver's working fine.

07:59 We're not overloading the system but we're just not able to excrete it and that will mean an elevation primarily in the direct or conjugated bilirubin.

08:07 So, when we talk about indirect, we're talking about unconjugated.

08:11 And when we talk about direct bilirubin, we're talking about conjugated.

08:15 Hope that makes sense.

08:19 Other markers that we can look for.

08:21 So, alkaline phosphatase is actually a reasonably sensitive marker for biliary obstruction within the liver, biliary tree damage.

08:29 And when that's elevated, we can say, "Oh, this is probably something happening within the bile system, not so much the hepatocytes." If on the other hand our transaminases, ALT, AST are way up, that says, "Oh, the hepatocytes are injured." Gamma-glutamyl transferase, GGT, is a marker of hepatocyte damage as well and will be elevated when it´s primary hepatocyte dysfunction.

08:52 When the hepatocytes aren't working, they're clearly not making coagulation factors and albumin.

08:56 So, that will be a marker of a hepatocyte injury.

08:59 And lactate dehydrogenase and haptoglobin levels are going to be markers of erythrocyte lysis.

09:05 So, LDH goes up, haptoglobin goes down.

09:08 The problem in that case with our hyperbilirubinemia is too much erythrocyte lysis.

09:17 Ultrasound's going to be an important modality by which we're going to assess whether we have extrahepatic cholestasis. So, we'll see big, dilated bile ducts.

09:25 We may even see a stone or a tumor or something within the extrahepatic biliary tree.

09:31 With intrahepatic cholestasis, the bile ducts won't be dilated.

09:36 So, ultrasound can be very helpful in deciding whether we have something outside the liver or inside the liver.

09:41 We can also do specific studies where we can, for example, an endoscopic retrograde cholangiopancreatography, ERCP or a magnetic resonance cholangiopancreatography and that's just looking specifically to see whether there's obstruction to the larger bile ducts.

10:00 And CT scan clearly can also be helpful helpful in trying to evaluate whether something is extrahepatic or intrahepatic.

10:07 How are we going to manage this? So, it depends on the level of elevated bilirubin.

10:14 In very low levels, two to three, even with a little bit of scleral icterus, very, very well tolerated even in infants.

10:23 But it also depends on the etiology of whether we want to go after, for example, hemolysis or whether we want to go after metabolism or we want to make sure that there's not some sort of obstruction due to say, a tumor.

10:36 So, the management will be specific to the cause. All those things that you see there.

10:41 With that, you have a very good, I think, foundation for thinking about hyperbilirubinemia.

10:47 And when your patient comes to you and they're yellow, you can think about it logically.