Well, my task today is to talk to you about some liver diseases in children. This is really a two part talk. First we are going to talk about acute and chronic hepatitis and then we are going to talk about obstructive jaundice beyond the neonatal period. Just by way of introduction, this is a little guy on the ventilator waiting for a liver transplant, with one of the causes of acute hepatitis in children; tyrosinemia. And we’ll come back to him in a little while.
Acute hepatitis is an acute inflammation of the liver marked by hepatocyte degeneration and necrosis. By definition the time course should be less than six months. Interestingly, it is a spectrum of disease, all the way from completely asymptomatic infection to fulminant liver failure, which is of course the most dreaded complication of any form of acute hepatitis at any age.
Now first let’s look at the neonatal period. Obviously, this is acute hepatitis within the first one month of life, by this definition. Far and away the most important reason is infectious etiologies. Of those infections, the viruses are preeminent. The TORCH viruses, you are very familiar what this stands for, generally present in the neonatal period with a slightly more chronic presentation, although these children can look acutely sick. The ones that you think about in a baby, and infant, presenting with full-blown fulminant liver failure are the adenoviruses, echovirus and the Coxsackie virus and also some of the herpes viruses. So these ones can be harder to diagnose and you must think about this in the newborn, in the first month of life, with fulminant liver failure.
Now, how do these infants look? Well, they present either at birth - particularly in the case of the TORCH infections - or within the first few days of life. Very often these babies are SGA and that may be one of your first tip-offs, and they present often as the generic septic infant. You have to put your thinking cap on to not miss the diagnosis.
So what are the clues? Well the first thing that might tip you off is on good old fashioned physical exam you may note that the liver is quite large as is the spleen, and these infants may have a variety of unusual rashes. Characteristically, on the laboratory findings, you are going to find an elevated AST and ALT, sometimes into the 5-600 range, or even into the 1,000 range. And this is going to be - sometimes, not always - associated with a conjugated hyperbilirubinemia. So this is conjugated as opposed to the physiologic jaundice of the newborn, which of course you know is unconjugated. Very often these children have low platelet counts but the white count may or may not be helpful. It might be up or down or normal. But look out for the low platelet count.
Apart from the infectious etiologies, the other main group to think about in the neonatal period are some of the metabolic diseases. And while these are rare, you certainly don’t want to miss this diagnosis. The three that classically spring to mind are of course fulminant liver failure in the neonatal period, tyrosinemia, galactosemia and fructosemia. And for each of these three there is a diagnostic clue. For galactosemia you are going to see reducing substances in the urine and these babies get sick very early, with their first intake of milk products. For fructosemia, the onset may be a little delayed. It may coincide with the introduction of fruit juices, which are obviously the source of fructose. Tyrosinemia, you need to think about and the clue is to order the succinylacetone in the urine.
The other major metabolic disease, which looks somewhat differently from the three that we’ve just talked about, but which may present in infancy, is alpha 1-antitrypsin deficiency. You may see an elevated conjugated bilirubin with increased transaminases. Interestingly, these babies are often jaundiced within the first weeks of life and this jaundice may completely resolve within the first six months. Generally speaking, alpha 1-antitrypsin deficiency does not cause significant decompensated liver disease in infancy. We’ll see later on where it tends to catch up with children when they are somewhat older. The key diagnostic test is to order an alpha 1-antitrypsin label in the serum and it’s going to be low.
This disease is worth thinking about, even it it’s just to remember where to look it up in the book. There’s probably a cadre of diseases that fall under the umbrella of neonatal iron-storage disease. This is an interesting group of diseases which we really haven’t defined very well yet. But the bottom line is that there is an abnormal iron deposition. Not only in the liver, but in other organs as well. These children can have a variety of presentations. The classic one is the very very sick newborn presenting with fetal hydrops, already profound cholestasis, and often these infants will die within the first days or weeks of life in the NICU. Interestingly, there is sometimes a family history but this is quite variable but something you should always inquire about. The way that you make the diagnosis is you test the iron and the ferritin in the peripheral blood. Both are elevated. If you get an MRI of the abdomen, you specifically ask the radiologist to do a T-2 weighted image and you will see increased iron deposition outside of the liver. And this is one of the classic ways of making the diagnosis.
Now lets move beyond infancy and into childhood, and talk about causes of acute hepatitis now in children. Far and away, again, the most common etiology is infection. And of the infections involving the liver in children, hepatitis A is by far the most common. The incidence is about 10 in 100,000 in the United States. But interestingly in California, it’s about double that. Now the hepatitis A virus is an RNA virus with a short incubation. About 1-2 weeks, or sometimes 2-3 weeks, 15-20 days. Spread fecal-oral and the risk factors, you are well familiar with; poor hygiene, contaminated food. The presentation can be highly variable, all the way from an anicteric maybe flu-like illness, maybe to no symptoms at all, or with fulminant liver failure at the end of the spectrum, and the jaundiced school child is the most common presentation in the middle. Peak incidence, 5-14 years of age. Now children actually tend to be asymptomatic more often than adults. Sometimes what you see happen is that the child is infected unknowingly and then infects the adult members of the household and they are the ones that get sick. If there are symptoms, they tend to be reasonably nonspecific. Although interestingly anorexia is often the most profound symptom of all and children may tell you - or their mothers may tell you - that their favorite food that they have always liked, they just can’t even bear the smell of it. If you hear that kind of profound story of anorexia along with maybe low grade fever, some right upper quadrant pain and a hint of jaundice, you should start thinking about hepatitis A. As I said, the jaundice doesn’t have to be there but very often the liver will be increased in size and often tender.
The key diagnostic tests: the AST and the ALT are going to be really elevated. They are going to be greater than 1,000. If those numbers are in the 200-300 range it’s very unlikely to be acute hepatitis A. As I have said, there may or may not be a conjugated hyperbilirubinemia. Now the two things you need to watch out for is the rare child who is going to really cause you problems and develop fulminant hepatitis. So if you are canny, on the first evaluation of that child it’s a very good idea to throw in a pro-time and maybe serum ammonia. Especially if you are the least bit concerned that their neurologic function may be very slightly off. That may help you identify early the 1% or so of children who will go on to fulminant liver failure. But in general, hepatitis A has an excellent outcome without chronic disease.
As you are probably aware, there is now a vaccine for hepatitis A. It’s a killed vaccine. It induces immunity to the hepatitis A virus in up to 95% of children, even with one shot. There is now an initiative that is certainly forming in California, and throughout the country, to mandate hepatitis A vaccination for preschoolers.
The serologic diagnosis: you are going to look for the antibody, this is the hepatitis A antibody, not an antigen, and you are going to look for the acute fraction, the IgM fraction. If you just order a total hepatitis A or the IgG you are not going to be able to differentiate acute from old infection. Treatment is generally just symptomatic. As I said, most of these children are going to do very well. As I have mentioned, there is the hepatitis A vaccine which has somewhat supplanted the use of pooled human immunoglobulin. The exception to that would in outbreaks when children are exposed to an index case and may have not been vaccinated. In which case, the current recommendations are to give both the vaccine and the immunoglobulin.
Just to show you in diagrammatic form what’s happening here, you can see here that this is the pattern of virus excretion in the stool and you can see this is where the symptoms begin. Around about here, but notice the bilirubin peak is coming right at the end of the fecal viral excretion. That’s why there is not much point in looking for the virus in the stool, and certainly not in the blood. But what you do see is this IgM fraction going up early and that’s where you make the diagnosis. The rise in the transaminases generally precedes that of the bilirubin by just a day or two. So the bottom line is; order a IgM antibody against hepatitis A. That’s the test.
Now what about hepatitis B? A very different kind of virus in all respects. First of all, it’s a DNA virus. The incubation period is much longer. It’s in the order of 2-3 months, not 2-3 weeks. And the spread is generally by blood, saliva, ***ual contact but there is also an incidence of intrafamily spread, particularly when there are small children in the family, and of course the worldwide problem of perinatal transmission. The risk factors are quite clear, particularly in pediatrics. It’s contaminated blood, and of course on the world stage, the asymptomatic carrier mother is by far the most important source of hepatitis B in children worldwide.
Presentation; again, all the way from anicteric asymptomatic disease to fulminant liver failure. The chronic carrier state is very often completely asymptomatic. So particularly in parts of the world where health care may not be as sophisticated as here, very often people don’t even know that they’ve got the virus and can transmit it. This is particularly a problem of course for women.
Symptoms; the same scenario. Malaise, low grade fever, maybe some right upper quadrant pain. But different to hepatitis A and may be a tip-off in terms of differentiating them is that there are more extrahepatic symptoms with hepatitis B, particularly arthralgias, myalgias and skin rashes.
The clinical course; a very interesting difference in the clinical course depending on age. If you are a neonate and you are infected with hepatitis B from your mother, 90% of these infants will not be able to clear hepatitis B. However, for you and I as healthy adults, if we acquire hepatitis B we have a 90% chance of clearing the virus. Only 10% of us will become chronic carriers. The chronic carrier state of course is something you don’t want to have because it leads to all kinds of unfortunate, and sometimes morbid, conditions even with associated mortality; chronic active hepatitis, cirrhosis, and of course hepatocellular carcinoma. In parts of the world where hepatitis B is endemic, death from HCC is one of the commonest causes of cancer death in adults, as opposed to in this country.
Serologic diagnosis of hepatitis B; this is where everybody needs to take a bit of a deep breath because it can get confusing. Acute infection is easy enough. You are going to see a rise in the hepatitis B surface antigen and you will initially see an E antigen as well. Now if you are going to clear the virus, you will develop hepatitis B surface antibody. Now the thing you’ve got to remember, if you remember nothing else about all this serologic diagnosis, is the surface antibody is the only protective antibody. If you don’t get this antibody, you are not protected. Hepatitis B core antibody rises early in the course of infection. The IgM component first and then the IgG component. Let’s take a look of this schematically. This is a picture, if you like, of somebody who is going to get acute hepatitis B and clear the virus. You can see that this is when the patient gets jaundiced. By the time they are jaundiced, hepatitis B surface antigen has already peaked, starting to fall. Hepatitis E antigen has come and actually gone. Remember, this is a person who is going to get better. The IgM core antibody has risen and is positive. Now, here’s our very important player. The anti-hepatitis B surface antibody is rising and if you could continue this line out for years you would see it go on being positive. So this is the pattern of somebody who is going to get better and clear the virus. Anti-hepatitis B surface antibody becoming positive, losing surface antigen, losing E antigen, maintaining the core antibody indefinitely.
Now what about the chronic carrier state? I know we are talking about acute hepatitis right now, but to understand the serologies it’s better to think of them together. The marker of the chronic carrier state is that you keep surface antigen but you never develop surface antibody. If you have an E antigen present that means the virus is actively replicating and this is not a particularly good prognostic sign. The hepatitis B core antibody IgG doesn’t tell you much, it just tells you that you have hepatitis B. Now let’s look at this on one of these diagrams. Okay, here we have the person - we are now interested in chronic infection - this is a person who is going to become a chronic carrier. You can see this surface antigen rises during the phase of acute infection, but it doesn’t go away. It keeps on going for years. Very importantly, you don’t see anywhere on this graph a hepatitis B surface antibody. Instead, what you see is that the core antibody does persist, doesn’t help you much. It’s not protective, it just happens to be there. The E antigen may persist or it may be negative. That’s an either/or. So again, the characteristics of the chronic carrier state; surface antigen persisting indefinitely, you see nothing on this graph that is labeled as hepatitis B surface antibody.
Okay, what about the treatment for hepatitis B? Well, largely it’s just symptomatic treatment. Of course the most important thing we can do nowadays is to vaccinate newborns with the hepatitis B vaccine, and also there is the passive immunization with hepatitis B immunoglobulin. If you have identified a carrier mother, the infant should receive both active immunization with the vaccine and passive immunization with the antibody. One of the sad comments, if you like, on the world scene is that we actually have the potential, if we had unlimited resources, to eradicate hepatitis B carriage from mothers to infants. Unfortunately, in the world scene, there isn’t enough money to pay for enough vaccine to be able to treat every newborn child, as in this country, with hepatitis B vaccine.
It’s a little bit like alphabet soup. We are up to hepatitis C. We’ve done A, B and now we are at C. Hepatitis C is a nasty little virus. It’s an RNA virus. It has a medium incubation period; somewhere between 1-2 months, 40-60 days, and we know for sure that it is spread by the parenteral route. But there are a lot of people who have hepatitis C who don’t seem to have any risk factor. About 50%. Increasingly we are aware that there is perinatal transmission, although not nearly of the same order as for hepatitis B. The risk factors; blood transfusions, IV drug abuse, the same risk factors really as for hepatitis B. But one of the things most perturbing is the number of people who we don’t know where they get the virus from. Hepatitis C almost always presents as chronic disease. It’s very seldom that you are actually going to see acute disease. It’s generally asymptomatic. The bad news about hepatitis C is that chronic disease occurs about 75% of the time after an acute infection, about half of which will progress interminably into chronic hepatitis over the course of several decades. Carrying with it the attendant risk of cirrhosis and hepatocellular carcinoma. Certainly from an epidemiologic standpoint, in this country the increasing incidence of hepatitis C is a real concern as we see more and more chronic disease in relatively young people; in their 20’s, 30’s and 40’s.
Symptoms; usually again of chronic liver disease, which we will come back to, but these people have little, small, shrunken up livers and may present for the first time with portal hypertension.
Serology; not particularly complicated. You can measure the viral antibody, you can’t measure the virus directly except by PCR techniques. But the antibody that is produced to the hepatitis C virus is not protective, so if you’ve got the antibody it doesn’t mean that you can’t have chronic disease or that you cannot transmit it. You are perfectly capable of transmitting hepatitis C even with a positive antibody. Because the hepatitis C virus has always been a very tricky virus and we can’t isolate it in a test tube, really the only way to directly measure antigen viremia is by PCR techniques, looking actually for the RNA of the virus.
Treatment for hepatitis C is again symptomatic. But more and more interest is being placed on the use of interferon, particularly combined with new antiviral agents such as ribavirin. But even with the most sophisticated combination therapy, which I should add has not been tested in children, the chances of being able to overcome the virus are probably well less than 20%.
Moving along the alphabet, delta hepatitis. The only thing you really have to remember about delta hepatitis is that it’s a funny little virus. It’s really like a parasite. It only exists in company with hepatitis B. So if you don’t have hepatitis B you can’t have delta hepatitis. There seems to be some geographic prevalence, particularly in Eastern European and Mediterranean populations. You make the diagnosis by sending off for the IgM antibody to the delta virus.
What about hepatitis E? You’ll be glad that we are coming to the end of this. We are not going to go all the way through to Z. Hepatitis E, if you have to remember anything about it, it’s a lot like hepatitis A in terms of its presentation. It’s an RNA virus, short incubation, spread by contaminated water, sometimes in epidemics, particularly in third world countries, there may be an endemic incidence particularly in the third world that you should be aware of, particularly if you have children visiting you from other countries, and clinically it looks a lot like hepatitis A and it does not lead to chronic disease. You get it, you get better or occasionally - very occasionally - you die from fulminant liver failure. Now interestingly, there is one other thing to remember about hepatitis E. It has a particularly bad prognosis if you happen to be pregnant and you contract hepatitis E. The diagnosis is again by detecting an antibody, but you have to send off to the CDC and go through a few phone calls before you are going to get the answer.
Now having gone through the alphabet soup, A, B, C, D, E, and I’m sure there are a whole lot of others out there, you should also keep in mind that some other viruses that we know quite a lot about can also infect the liver. By far and away the herpes viruses are the most important here. CMV, EBV, type I and type II and varicella. Remember, EBV virus can cause a big liver, big spleen. The tip-off there is that these children are going to have lots of big juicy lymph nodes. But they may even be jaundiced with elevated transaminases. So if you test for Epstein-Barr virus you may well find that as the cause of hepatitis. Now particularly in immunocompromised children you need to think about these other causes, the herpes viruses; CMV, herpes and varicella. Because these can cause quite severe hepatitis in an immunocompromised child.
What about some of the other causes of hepatitis in children? Well, there is a variety of toxic and metabolic diseases and I’m going to try to run through these to give you a vignette. This is not designed to be an exhaustive list or we’d be here all afternoon. Well, what about drug toxicities? Well, the one that we worry the most about because it is so commonly available is acetaminophen. There are basically two kinds of acetaminophen overdose in children. One is the teenager who takes a whole bunch of acetaminophen as a suicide gesture, or sometimes a very successful commitment of suicide, and then there is the problem in little children who are consistently and unknowingly overdosed by well-meaning parents. Giving the wrong dose of Tylenol over several days. And this may present as acute fulminant liver failure in a small child. A very important cause that you may miss if you don’t ask the question in the emergency room. There are some other drugs of the long long list that you should keep in mind. I have a long list which I look up and a short list which I keep in my head. Acetaminophen as I said is at the top but the other ones are INH. Sometimes children who are put on prophylactic INH will present three or four months later with hepatitis. Sometimes it is quite profound. The anticonvulsants, particularly sodium valproate, our old friend halothane, and of course some of the antineoplastic drugs may cause a quite severe hepatitis, such as methotrexate.
The presentation for drug toxicity is really very variable, and the key thing is to be suspicious and to ask the question. As I’ve already alluded to, acetaminophen may be particularly hard to diagnose if it’s the little person who has been inadvertently given too much Tylenol over several days. In the acetaminophen story you see very elevated transaminases, but interestingly the bilirubin may be normal or close to normal. By the time they present to you very often they have a prolonged pro-time and an elevated serum ammonia as they start the slippery slide down into fulminant liver failure. The reason for thinking of acetaminophen overdose very quickly is that there is a specific antidote, and that is N-acetylcysteine but if you don’t give it within the first 12, 24 - at the very very outside, 48 - hours it’s not going to do much to help your patient.
What about environmental toxins? Well this is kind of difficult because it seems like we are surrounded by environmental toxins, but certainly liver failure and hepatitis have been associated with glue sniffing, polyvinyl alcohol, carbon tetrachloride. Again, presentation very variable. Some may even develop fulminant liver failure. Others many have just a little bit of elevated transaminases with some cholestasis. Of the ingestion’s, the one that always stands out in our minds in a referral center is the family that goes on a little picnic, to do some mushroom gathering, and they decide that Amanita phylloides is such a pretty looking mushroom that they must take some home. That’s the one that has the red top and the little white flecks on it that looks like a mushroom out of a fairy tale. This is a highly, highly toxic mushroom. It can cause liver failure and of course sometimes you are in the position of needing to try to transplant three or four family members all at once.
Now I put up Reye’s syndrome, although maybe next year I really have to leave it off this slide because we’ve seen so little of it. But Reye’s syndrome causes a fulminant liver failure-type picture. It’s probably a mitochondrial defect. We are not really sure of its etiology. It also causes massive cerebral edema. We have associated it in the past with the use of aspirin in varicella. Since the campaigns to decrease aspirin use, particularly in children with varicella, we seem to be seeing very little Reye’s syndrome at all. However, I put it up there because maybe it’s going to rear its ugly head again. It was back in the 80’s a very worrying cause of fulminant liver failure, cerebral edema, and we lost a number of these children before we could ever transplant them.
Okay, what about chronic hepatitis in childhood? We are leaving behind acute and now we are going to chronic. And surprise, surprise, the definition is more than six months of duration and this chronic inflammation of the liver. Of the infections, again, the most common B and C are the ones to think about. The clinical features are very similar. The onset is often quite gradual and the histology may vary all the way from a relatively benign picture under the microscope, to full-blown cirrhosis.
The way these present is with the features of chronic liver disease, which are pretty generic. Patients are tired, they are usually jaundiced, they may not think so clearly, they may have already developed ascites with portal hypertension, maybe variceal bleeding, they lose weight. They often feel very lousy. However, having said all of that, you can have full-blown cirrhosis on a liver biopsy and no symptoms at all. Sometimes your patients, maybe in the older age group - the 17 or 18-year-old who was perhaps infected with hepatitis B at birth - may only be picked up because someone did liver tests because they had some other kind of illness and noticed they were elevated. So it can be a great masquerader. When you do do the laboratory tests you see the AST and the ALT are elevated but they are not super-high numbers. They are generally under 500 IU/ml. When the bilirubin is elevated it will be a conjugated type of bilirubinemia. And as I’ve said, even with full-blown cirrhosis not only can you be asymptomatic, you may have a completely normal bilirubin and you may have actually almost normal transaminases. But what you note, if you are astute, is that the serum albumin is on the low side and the pro-time may already be starting to prolong. These are the indicators of poor synthetic function. So in chronic liver disease you are really very interested in synthetic function rather than numbers, like what’s the AST?
Serology; well, we’ve gone through all of that with hepatitis B and C. What about the physical exam? These people in general have very small shrunken up livers, and you may only appreciate it if you take the time to percuss the liver span and you might hear a liver span of only 5 or 6 cm. Quite small. The spleen is very often enlarged. Some of these patients already have clubbing. As I said, they may have ascites, you may detect a fluid wave. You want to look for those little spider angiomata which are particularly seen on the chest and the back. Very often patients are quite malnourished and encephalopathy may be evident or at least it may be there but be quite subtle, and you may have to ask questions like, "Has school performance suffered?" "Has the child started to show some odd changes in personality?" It can be quite difficult to diagnose, particularly in children.
The management is largely symptomatic. You are going to restrict fluids and sodium. And you are going to treat encephalopathy, but generally you are often … these children may come all the way to needing transplant in their teen years, or sometimes even sooner. We have transplanted children with chronic hepatitis B who have already developed hepatocellular carcinoma as early as 12 years of age.
Acute hepatitis is an acute inflammation of the liver marked by hepatocyte degeneration and necrosis. By definition the time course should be less than six months. Interestingly, it is a spectrum of disease, all the way from completely asymptomatic infection to fulminant liver failure, which is of course the most dreaded complication of any form of acute hepatitis at any age.
Now first let’s look at the neonatal period. Obviously, this is acute hepatitis within the first one month of life, by this definition. Far and away the most important reason is infectious etiologies. Of those infections, the viruses are preeminent. The TORCH viruses, you are very familiar what this stands for, generally present in the neonatal period with a slightly more chronic presentation, although these children can look acutely sick. The ones that you think about in a baby, and infant, presenting with full-blown fulminant liver failure are the adenoviruses, echovirus and the Coxsackie virus and also some of the herpes viruses. So these ones can be harder to diagnose and you must think about this in the newborn, in the first month of life, with fulminant liver failure.
Now, how do these infants look? Well, they present either at birth - particularly in the case of the TORCH infections - or within the first few days of life. Very often these babies are SGA and that may be one of your first tip-offs, and they present often as the generic septic infant. You have to put your thinking cap on to not miss the diagnosis.
So what are the clues? Well the first thing that might tip you off is on good old fashioned physical exam you may note that the liver is quite large as is the spleen, and these infants may have a variety of unusual rashes. Characteristically, on the laboratory findings, you are going to find an elevated AST and ALT, sometimes into the 5-600 range, or even into the 1,000 range. And this is going to be - sometimes, not always - associated with a conjugated hyperbilirubinemia. So this is conjugated as opposed to the physiologic jaundice of the newborn, which of course you know is unconjugated. Very often these children have low platelet counts but the white count may or may not be helpful. It might be up or down or normal. But look out for the low platelet count.
Apart from the infectious etiologies, the other main group to think about in the neonatal period are some of the metabolic diseases. And while these are rare, you certainly don’t want to miss this diagnosis. The three that classically spring to mind are of course fulminant liver failure in the neonatal period, tyrosinemia, galactosemia and fructosemia. And for each of these three there is a diagnostic clue. For galactosemia you are going to see reducing substances in the urine and these babies get sick very early, with their first intake of milk products. For fructosemia, the onset may be a little delayed. It may coincide with the introduction of fruit juices, which are obviously the source of fructose. Tyrosinemia, you need to think about and the clue is to order the succinylacetone in the urine.
The other major metabolic disease, which looks somewhat differently from the three that we’ve just talked about, but which may present in infancy, is alpha 1-antitrypsin deficiency. You may see an elevated conjugated bilirubin with increased transaminases. Interestingly, these babies are often jaundiced within the first weeks of life and this jaundice may completely resolve within the first six months. Generally speaking, alpha 1-antitrypsin deficiency does not cause significant decompensated liver disease in infancy. We’ll see later on where it tends to catch up with children when they are somewhat older. The key diagnostic test is to order an alpha 1-antitrypsin label in the serum and it’s going to be low.
This disease is worth thinking about, even it it’s just to remember where to look it up in the book. There’s probably a cadre of diseases that fall under the umbrella of neonatal iron-storage disease. This is an interesting group of diseases which we really haven’t defined very well yet. But the bottom line is that there is an abnormal iron deposition. Not only in the liver, but in other organs as well. These children can have a variety of presentations. The classic one is the very very sick newborn presenting with fetal hydrops, already profound cholestasis, and often these infants will die within the first days or weeks of life in the NICU. Interestingly, there is sometimes a family history but this is quite variable but something you should always inquire about. The way that you make the diagnosis is you test the iron and the ferritin in the peripheral blood. Both are elevated. If you get an MRI of the abdomen, you specifically ask the radiologist to do a T-2 weighted image and you will see increased iron deposition outside of the liver. And this is one of the classic ways of making the diagnosis.
Now lets move beyond infancy and into childhood, and talk about causes of acute hepatitis now in children. Far and away, again, the most common etiology is infection. And of the infections involving the liver in children, hepatitis A is by far the most common. The incidence is about 10 in 100,000 in the United States. But interestingly in California, it’s about double that. Now the hepatitis A virus is an RNA virus with a short incubation. About 1-2 weeks, or sometimes 2-3 weeks, 15-20 days. Spread fecal-oral and the risk factors, you are well familiar with; poor hygiene, contaminated food. The presentation can be highly variable, all the way from an anicteric maybe flu-like illness, maybe to no symptoms at all, or with fulminant liver failure at the end of the spectrum, and the jaundiced school child is the most common presentation in the middle. Peak incidence, 5-14 years of age. Now children actually tend to be asymptomatic more often than adults. Sometimes what you see happen is that the child is infected unknowingly and then infects the adult members of the household and they are the ones that get sick. If there are symptoms, they tend to be reasonably nonspecific. Although interestingly anorexia is often the most profound symptom of all and children may tell you - or their mothers may tell you - that their favorite food that they have always liked, they just can’t even bear the smell of it. If you hear that kind of profound story of anorexia along with maybe low grade fever, some right upper quadrant pain and a hint of jaundice, you should start thinking about hepatitis A. As I said, the jaundice doesn’t have to be there but very often the liver will be increased in size and often tender.
The key diagnostic tests: the AST and the ALT are going to be really elevated. They are going to be greater than 1,000. If those numbers are in the 200-300 range it’s very unlikely to be acute hepatitis A. As I have said, there may or may not be a conjugated hyperbilirubinemia. Now the two things you need to watch out for is the rare child who is going to really cause you problems and develop fulminant hepatitis. So if you are canny, on the first evaluation of that child it’s a very good idea to throw in a pro-time and maybe serum ammonia. Especially if you are the least bit concerned that their neurologic function may be very slightly off. That may help you identify early the 1% or so of children who will go on to fulminant liver failure. But in general, hepatitis A has an excellent outcome without chronic disease.
As you are probably aware, there is now a vaccine for hepatitis A. It’s a killed vaccine. It induces immunity to the hepatitis A virus in up to 95% of children, even with one shot. There is now an initiative that is certainly forming in California, and throughout the country, to mandate hepatitis A vaccination for preschoolers.
The serologic diagnosis: you are going to look for the antibody, this is the hepatitis A antibody, not an antigen, and you are going to look for the acute fraction, the IgM fraction. If you just order a total hepatitis A or the IgG you are not going to be able to differentiate acute from old infection. Treatment is generally just symptomatic. As I said, most of these children are going to do very well. As I have mentioned, there is the hepatitis A vaccine which has somewhat supplanted the use of pooled human immunoglobulin. The exception to that would in outbreaks when children are exposed to an index case and may have not been vaccinated. In which case, the current recommendations are to give both the vaccine and the immunoglobulin.
Just to show you in diagrammatic form what’s happening here, you can see here that this is the pattern of virus excretion in the stool and you can see this is where the symptoms begin. Around about here, but notice the bilirubin peak is coming right at the end of the fecal viral excretion. That’s why there is not much point in looking for the virus in the stool, and certainly not in the blood. But what you do see is this IgM fraction going up early and that’s where you make the diagnosis. The rise in the transaminases generally precedes that of the bilirubin by just a day or two. So the bottom line is; order a IgM antibody against hepatitis A. That’s the test.
Now what about hepatitis B? A very different kind of virus in all respects. First of all, it’s a DNA virus. The incubation period is much longer. It’s in the order of 2-3 months, not 2-3 weeks. And the spread is generally by blood, saliva, ***ual contact but there is also an incidence of intrafamily spread, particularly when there are small children in the family, and of course the worldwide problem of perinatal transmission. The risk factors are quite clear, particularly in pediatrics. It’s contaminated blood, and of course on the world stage, the asymptomatic carrier mother is by far the most important source of hepatitis B in children worldwide.
Presentation; again, all the way from anicteric asymptomatic disease to fulminant liver failure. The chronic carrier state is very often completely asymptomatic. So particularly in parts of the world where health care may not be as sophisticated as here, very often people don’t even know that they’ve got the virus and can transmit it. This is particularly a problem of course for women.
Symptoms; the same scenario. Malaise, low grade fever, maybe some right upper quadrant pain. But different to hepatitis A and may be a tip-off in terms of differentiating them is that there are more extrahepatic symptoms with hepatitis B, particularly arthralgias, myalgias and skin rashes.
The clinical course; a very interesting difference in the clinical course depending on age. If you are a neonate and you are infected with hepatitis B from your mother, 90% of these infants will not be able to clear hepatitis B. However, for you and I as healthy adults, if we acquire hepatitis B we have a 90% chance of clearing the virus. Only 10% of us will become chronic carriers. The chronic carrier state of course is something you don’t want to have because it leads to all kinds of unfortunate, and sometimes morbid, conditions even with associated mortality; chronic active hepatitis, cirrhosis, and of course hepatocellular carcinoma. In parts of the world where hepatitis B is endemic, death from HCC is one of the commonest causes of cancer death in adults, as opposed to in this country.
Serologic diagnosis of hepatitis B; this is where everybody needs to take a bit of a deep breath because it can get confusing. Acute infection is easy enough. You are going to see a rise in the hepatitis B surface antigen and you will initially see an E antigen as well. Now if you are going to clear the virus, you will develop hepatitis B surface antibody. Now the thing you’ve got to remember, if you remember nothing else about all this serologic diagnosis, is the surface antibody is the only protective antibody. If you don’t get this antibody, you are not protected. Hepatitis B core antibody rises early in the course of infection. The IgM component first and then the IgG component. Let’s take a look of this schematically. This is a picture, if you like, of somebody who is going to get acute hepatitis B and clear the virus. You can see that this is when the patient gets jaundiced. By the time they are jaundiced, hepatitis B surface antigen has already peaked, starting to fall. Hepatitis E antigen has come and actually gone. Remember, this is a person who is going to get better. The IgM core antibody has risen and is positive. Now, here’s our very important player. The anti-hepatitis B surface antibody is rising and if you could continue this line out for years you would see it go on being positive. So this is the pattern of somebody who is going to get better and clear the virus. Anti-hepatitis B surface antibody becoming positive, losing surface antigen, losing E antigen, maintaining the core antibody indefinitely.
Now what about the chronic carrier state? I know we are talking about acute hepatitis right now, but to understand the serologies it’s better to think of them together. The marker of the chronic carrier state is that you keep surface antigen but you never develop surface antibody. If you have an E antigen present that means the virus is actively replicating and this is not a particularly good prognostic sign. The hepatitis B core antibody IgG doesn’t tell you much, it just tells you that you have hepatitis B. Now let’s look at this on one of these diagrams. Okay, here we have the person - we are now interested in chronic infection - this is a person who is going to become a chronic carrier. You can see this surface antigen rises during the phase of acute infection, but it doesn’t go away. It keeps on going for years. Very importantly, you don’t see anywhere on this graph a hepatitis B surface antibody. Instead, what you see is that the core antibody does persist, doesn’t help you much. It’s not protective, it just happens to be there. The E antigen may persist or it may be negative. That’s an either/or. So again, the characteristics of the chronic carrier state; surface antigen persisting indefinitely, you see nothing on this graph that is labeled as hepatitis B surface antibody.
Okay, what about the treatment for hepatitis B? Well, largely it’s just symptomatic treatment. Of course the most important thing we can do nowadays is to vaccinate newborns with the hepatitis B vaccine, and also there is the passive immunization with hepatitis B immunoglobulin. If you have identified a carrier mother, the infant should receive both active immunization with the vaccine and passive immunization with the antibody. One of the sad comments, if you like, on the world scene is that we actually have the potential, if we had unlimited resources, to eradicate hepatitis B carriage from mothers to infants. Unfortunately, in the world scene, there isn’t enough money to pay for enough vaccine to be able to treat every newborn child, as in this country, with hepatitis B vaccine.
It’s a little bit like alphabet soup. We are up to hepatitis C. We’ve done A, B and now we are at C. Hepatitis C is a nasty little virus. It’s an RNA virus. It has a medium incubation period; somewhere between 1-2 months, 40-60 days, and we know for sure that it is spread by the parenteral route. But there are a lot of people who have hepatitis C who don’t seem to have any risk factor. About 50%. Increasingly we are aware that there is perinatal transmission, although not nearly of the same order as for hepatitis B. The risk factors; blood transfusions, IV drug abuse, the same risk factors really as for hepatitis B. But one of the things most perturbing is the number of people who we don’t know where they get the virus from. Hepatitis C almost always presents as chronic disease. It’s very seldom that you are actually going to see acute disease. It’s generally asymptomatic. The bad news about hepatitis C is that chronic disease occurs about 75% of the time after an acute infection, about half of which will progress interminably into chronic hepatitis over the course of several decades. Carrying with it the attendant risk of cirrhosis and hepatocellular carcinoma. Certainly from an epidemiologic standpoint, in this country the increasing incidence of hepatitis C is a real concern as we see more and more chronic disease in relatively young people; in their 20’s, 30’s and 40’s.
Symptoms; usually again of chronic liver disease, which we will come back to, but these people have little, small, shrunken up livers and may present for the first time with portal hypertension.
Serology; not particularly complicated. You can measure the viral antibody, you can’t measure the virus directly except by PCR techniques. But the antibody that is produced to the hepatitis C virus is not protective, so if you’ve got the antibody it doesn’t mean that you can’t have chronic disease or that you cannot transmit it. You are perfectly capable of transmitting hepatitis C even with a positive antibody. Because the hepatitis C virus has always been a very tricky virus and we can’t isolate it in a test tube, really the only way to directly measure antigen viremia is by PCR techniques, looking actually for the RNA of the virus.
Treatment for hepatitis C is again symptomatic. But more and more interest is being placed on the use of interferon, particularly combined with new antiviral agents such as ribavirin. But even with the most sophisticated combination therapy, which I should add has not been tested in children, the chances of being able to overcome the virus are probably well less than 20%.
Moving along the alphabet, delta hepatitis. The only thing you really have to remember about delta hepatitis is that it’s a funny little virus. It’s really like a parasite. It only exists in company with hepatitis B. So if you don’t have hepatitis B you can’t have delta hepatitis. There seems to be some geographic prevalence, particularly in Eastern European and Mediterranean populations. You make the diagnosis by sending off for the IgM antibody to the delta virus.
What about hepatitis E? You’ll be glad that we are coming to the end of this. We are not going to go all the way through to Z. Hepatitis E, if you have to remember anything about it, it’s a lot like hepatitis A in terms of its presentation. It’s an RNA virus, short incubation, spread by contaminated water, sometimes in epidemics, particularly in third world countries, there may be an endemic incidence particularly in the third world that you should be aware of, particularly if you have children visiting you from other countries, and clinically it looks a lot like hepatitis A and it does not lead to chronic disease. You get it, you get better or occasionally - very occasionally - you die from fulminant liver failure. Now interestingly, there is one other thing to remember about hepatitis E. It has a particularly bad prognosis if you happen to be pregnant and you contract hepatitis E. The diagnosis is again by detecting an antibody, but you have to send off to the CDC and go through a few phone calls before you are going to get the answer.
Now having gone through the alphabet soup, A, B, C, D, E, and I’m sure there are a whole lot of others out there, you should also keep in mind that some other viruses that we know quite a lot about can also infect the liver. By far and away the herpes viruses are the most important here. CMV, EBV, type I and type II and varicella. Remember, EBV virus can cause a big liver, big spleen. The tip-off there is that these children are going to have lots of big juicy lymph nodes. But they may even be jaundiced with elevated transaminases. So if you test for Epstein-Barr virus you may well find that as the cause of hepatitis. Now particularly in immunocompromised children you need to think about these other causes, the herpes viruses; CMV, herpes and varicella. Because these can cause quite severe hepatitis in an immunocompromised child.
What about some of the other causes of hepatitis in children? Well, there is a variety of toxic and metabolic diseases and I’m going to try to run through these to give you a vignette. This is not designed to be an exhaustive list or we’d be here all afternoon. Well, what about drug toxicities? Well, the one that we worry the most about because it is so commonly available is acetaminophen. There are basically two kinds of acetaminophen overdose in children. One is the teenager who takes a whole bunch of acetaminophen as a suicide gesture, or sometimes a very successful commitment of suicide, and then there is the problem in little children who are consistently and unknowingly overdosed by well-meaning parents. Giving the wrong dose of Tylenol over several days. And this may present as acute fulminant liver failure in a small child. A very important cause that you may miss if you don’t ask the question in the emergency room. There are some other drugs of the long long list that you should keep in mind. I have a long list which I look up and a short list which I keep in my head. Acetaminophen as I said is at the top but the other ones are INH. Sometimes children who are put on prophylactic INH will present three or four months later with hepatitis. Sometimes it is quite profound. The anticonvulsants, particularly sodium valproate, our old friend halothane, and of course some of the antineoplastic drugs may cause a quite severe hepatitis, such as methotrexate.
The presentation for drug toxicity is really very variable, and the key thing is to be suspicious and to ask the question. As I’ve already alluded to, acetaminophen may be particularly hard to diagnose if it’s the little person who has been inadvertently given too much Tylenol over several days. In the acetaminophen story you see very elevated transaminases, but interestingly the bilirubin may be normal or close to normal. By the time they present to you very often they have a prolonged pro-time and an elevated serum ammonia as they start the slippery slide down into fulminant liver failure. The reason for thinking of acetaminophen overdose very quickly is that there is a specific antidote, and that is N-acetylcysteine but if you don’t give it within the first 12, 24 - at the very very outside, 48 - hours it’s not going to do much to help your patient.
What about environmental toxins? Well this is kind of difficult because it seems like we are surrounded by environmental toxins, but certainly liver failure and hepatitis have been associated with glue sniffing, polyvinyl alcohol, carbon tetrachloride. Again, presentation very variable. Some may even develop fulminant liver failure. Others many have just a little bit of elevated transaminases with some cholestasis. Of the ingestion’s, the one that always stands out in our minds in a referral center is the family that goes on a little picnic, to do some mushroom gathering, and they decide that Amanita phylloides is such a pretty looking mushroom that they must take some home. That’s the one that has the red top and the little white flecks on it that looks like a mushroom out of a fairy tale. This is a highly, highly toxic mushroom. It can cause liver failure and of course sometimes you are in the position of needing to try to transplant three or four family members all at once.
Now I put up Reye’s syndrome, although maybe next year I really have to leave it off this slide because we’ve seen so little of it. But Reye’s syndrome causes a fulminant liver failure-type picture. It’s probably a mitochondrial defect. We are not really sure of its etiology. It also causes massive cerebral edema. We have associated it in the past with the use of aspirin in varicella. Since the campaigns to decrease aspirin use, particularly in children with varicella, we seem to be seeing very little Reye’s syndrome at all. However, I put it up there because maybe it’s going to rear its ugly head again. It was back in the 80’s a very worrying cause of fulminant liver failure, cerebral edema, and we lost a number of these children before we could ever transplant them.
Okay, what about chronic hepatitis in childhood? We are leaving behind acute and now we are going to chronic. And surprise, surprise, the definition is more than six months of duration and this chronic inflammation of the liver. Of the infections, again, the most common B and C are the ones to think about. The clinical features are very similar. The onset is often quite gradual and the histology may vary all the way from a relatively benign picture under the microscope, to full-blown cirrhosis.
The way these present is with the features of chronic liver disease, which are pretty generic. Patients are tired, they are usually jaundiced, they may not think so clearly, they may have already developed ascites with portal hypertension, maybe variceal bleeding, they lose weight. They often feel very lousy. However, having said all of that, you can have full-blown cirrhosis on a liver biopsy and no symptoms at all. Sometimes your patients, maybe in the older age group - the 17 or 18-year-old who was perhaps infected with hepatitis B at birth - may only be picked up because someone did liver tests because they had some other kind of illness and noticed they were elevated. So it can be a great masquerader. When you do do the laboratory tests you see the AST and the ALT are elevated but they are not super-high numbers. They are generally under 500 IU/ml. When the bilirubin is elevated it will be a conjugated type of bilirubinemia. And as I’ve said, even with full-blown cirrhosis not only can you be asymptomatic, you may have a completely normal bilirubin and you may have actually almost normal transaminases. But what you note, if you are astute, is that the serum albumin is on the low side and the pro-time may already be starting to prolong. These are the indicators of poor synthetic function. So in chronic liver disease you are really very interested in synthetic function rather than numbers, like what’s the AST?
Serology; well, we’ve gone through all of that with hepatitis B and C. What about the physical exam? These people in general have very small shrunken up livers, and you may only appreciate it if you take the time to percuss the liver span and you might hear a liver span of only 5 or 6 cm. Quite small. The spleen is very often enlarged. Some of these patients already have clubbing. As I said, they may have ascites, you may detect a fluid wave. You want to look for those little spider angiomata which are particularly seen on the chest and the back. Very often patients are quite malnourished and encephalopathy may be evident or at least it may be there but be quite subtle, and you may have to ask questions like, "Has school performance suffered?" "Has the child started to show some odd changes in personality?" It can be quite difficult to diagnose, particularly in children.
The management is largely symptomatic. You are going to restrict fluids and sodium. And you are going to treat encephalopathy, but generally you are often … these children may come all the way to needing transplant in their teen years, or sometimes even sooner. We have transplanted children with chronic hepatitis B who have already developed hepatocellular carcinoma as early as 12 years of age.
