Crack the Case: Hepatitis, Adenovirus, and a Boy with Yellow Eyes

September 16, 2022

Transcript

Dr. Angela Kade Goepferd:  This is Talking Pediatrics, a clinical podcast by Children’s Minnesota, home to The Kid Experts, where the complex is our every day. Each week, we bring you intriguing stories and relevant pediatric health care information as we partner with you in the care of your patients. Our guests, data, ideas and practical tips will surprise, challenge and perhaps change how you care for kids.

Welcome to Talking Pediatrics. I’m your host, Dr. Angela Kade Goepferd. It’s time for another Crack the Case with Bryan Fate. Today’s episode features hepatitis, adenovirus, and a boy with yellow eyes. Many of you are familiar with the mysterious wave of acute hepatitis in children that is currently under investigation, spanning 43 states as well as international borders. These cases are unique, in that typical causes for liver injuries such as viral hepatitis have not been found. Worldwide, most children have recovered, though around 10% have needed liver transplant, and the vast majority have remained hospitalized. Listen in on the case today about a four-year-old who presents with signs and symptoms of possible hepatitis.

Dr. Bryan Fate: So welcome to Crack the Case, where we dive into real cases in our Minneapolis Continuity Clinic to highlight medical decision making, approaches to general pediatrics topics, and life in primary care. We’ll also incorporate music written by myself and friends at the end of every episode to highlight teaching points, and hopefully engage the emotive side of your brain.

I’m Dr. Bryan Fate, a primary care pediatrician at Children’s Minneapolis, and with me today is Dr. Rashedat Oshodi, one of our outstanding University of Minnesota residents. Dr. Oshodi grew up in Nigeria and did part of her training in Acra, Ghana before bringing her talents to the lakeside beaches of Minnesota. Dr. Oshidi brings a unique perspective to the hospital setting, in that in addition to caring for kids with special needs in the hospital, she also has an adorable five-year-old with more complex medical history at home.

So welcome, Dr. Oshodi, and our icebreaker question is, how has this experience shaped your perspective, being both a pediatrician and a mom of a child with complex special care needs?

Dr. Rashedat Oshodi: Oh, hi. Thanks for having me here. I will say it has made me acutely aware of my patients and their family situation. I guess more understanding, and more patient, and I always think about the family situation, what supports they have in place, and what resources, and how the mom, dad, or whoever the primary caregiver is coping and taking care of themselves and the child, who is my patient, because I live the same situation.

Dr. Bryan Fate: So today, as a introduction to our case, and we’re going to be talking about hepatitis, a mysterious wave of acute hepatitis in children is currently under investigation, spanning 43 states, as well as international borders. These cases are unique, in that typical causes for liver injury, such as the viral hepatitis A through E that we know and love, have not been found. Though the causal pathway for liver injury is unknown, association with a certain virus of gastroenteritis causing daycare fame has been demonstrated in more than half of cases. Adenovirus, particularly F type 41. Worldwide, most children have fully recovered, though around 10% have needed liver transplants, and the vast majority have been hospitalized. Today’s case explores a four-year-old who presented to our clinic with scleral icterus and hepatomegaly. So let’s start the case.

Dr. Rashedat Oshodi: So here we have a four-year-old who presented to clinic for complaints of a rash and yellowing of the eyes. The parents reported that two weeks prior, he had had non-bloody, non-bilious vomiting, and stomach pain, which lasted for a week, and then resolved. Of note, his older siblings also had the same symptoms, and again, symptoms resolved after a week. On further history, the abdominal pain was described as an intermittent pain, non-localized. And I said with vomiting, there was also a history of reduced appetites. Patients only wanted to drink lots of fluids, and was only taking small bite of food. The rash was noted a day prior to presenting at the clinic. Parents had reported that it started at the tip of his nose and then extended bilaterally to both cheeks.

Systemic review. There wasn’t any history of fever. No stool changes were noted. No diarrhea or constipation. No melena or haematochezia. Patient did not have painful urination, and there was no penile swelling noted.

Past medical history. So this was a pretty healthy kid. There wasn’t any past history of prior hospitalizations or surgeries. His vaccinations were all up to date. Social history, there wasn’t any history of a recent travel. No animal exposures. He was not on any medications prior to onset of any of the symptoms. No Tylenol use or exposures. No exposures to any [inaudible 00:05:38] preparations. There was not any family history of GI disease, or hemolytic blood diseases, or any liver failure. And of note, birth history was significant for him getting his hepatitis B vaccinations. Adequately vaccinated with hepatitis B.

Dr. Bryan Fate: That’s a wonderful review of the history of present illness, and let me bring forth a couple definitions first. So hepatitis being inflammation of the liver, segregating into two separate buckets. So infectious, which is the most common in kids, and noninfectious, as well as acute versus chronic. And this four-year-old’s symptoms sound pretty acute, so over the last week or two. He does, I think, teasing out symptoms of cholestasis, so that bile getting backed up in the bile ducts, and then that usually adds the color to our pee and our poop, which is a fun fact that parents like. But because that’s backed up, we think about those white stools that you talked about, which he doesn’t have. Dark urine. Jaundice. And I did see this patient, he was of Hispanic background, so his baseline skin tone was a little bit harder to tell, but definitely the yellow eyes with the bilirubin depositing there.

So birth history and travel you nailed wonderfully, because we want to see if there’s any risk factors for chronic hepatitis B in particular. If mom had any known history of that, if he had exposure neonatally, if he needed HBIG, or immunizations, and what his immunization history is for hepatitis A. Other things we think about, medications and toxins, which you went into. So Tylenol ingestion, would not want to miss that. He’s four, hopefully smart enough not to be guzzling Tylenol, but you never know. And then you mentioned the scleral icterus. So with other causes besides liver things you’ve totally tapped into, like hemolytic anemia, so thinking about his newborn screen, if he’s had CBCs done before, if there are any risk factors. If he has 26PD and eight smorgasbord of fava beans, that would be something. And then family history as well. So why don’t we move on to the physical exam.

Dr. Rashedat Oshodi: So physical exam, his vitals, he was afebrile. He had a normal heart rate and blood pressure. Patient was pretty playful and interactive in clinic on that day. He did have significant scleral icterus, and his abdominal exam was significant for palpated liver, which was about one cm below the costophrenic angle. It was, however, non-tender. There was no noted splenic enlargement at the time. No noted dilated abdominal veins, or any of the stigmata of liver disease that you would be looking out for. Patient had a facial rash. Facial rash was very fine papules, more on his right cheek and over his bridge of his nose. So bilaterally left and right, but more pronounced on the right cheek and the bridge of his nose.

Dr. Bryan Fate: Yeah. And I mentioned I did see this very cute four year old. He was jumping around. Looking at his eyes, I was very surprised that they were yellow, because he did not look like an acutely ill child. And spleen is always great to look at, just as a sign of portal hypertension. We see that back up to the spleen, which is usually more indicative of liver failure and end stage cirrhosis. So also looking out for those very scary signs of liver failure. So encephalopathy, if our ammonia is really high, and we’re confused or lethargic. Parents love using the word “lethargic,” though it doesn’t always apply to every patient. Also things like ascites, because that presents risk of infection, and then those very scary esophageal and gastric dilations that can cause life threatening bleeding, but he did not have those. And then the rash, I think, was interesting, because there is an association between Gianotti-Crosti, which is this non-specific, symmetric, papular vesicular rash that can happen with certain viruses like hepatitis EBV, hepatitis A. So I think that was coming into consideration, too.

So let’s move on to labs and imaging, and one of the tough parts about being a primary care doctor is things come back at different time periods. So there are times where you have to wait much longer for a certain diagnostic test to come back than you’d like. It doesn’t all come back at once. And so I think we will separate this into first the labs that came back right away for us in clinic, review those, and we’ll go into some of the diagnostic things that came back in the hospital later. So yeah, what was lab work and imaging notable for, Rashedat?

Dr. Rashedat Oshodi: Oh, so his liver enzymes were pretty elevated, showing some transaminitis. His ALT was high, at 3,840. His AST was 6,804. His GGT was elevated at 250, and ALP at 454. LDH was also high, at 1,223. We had checked bilirubin too, so total bilirubin was 8.2 milligrams per deciliter, and then direct was 6.2, which were both significantly high. And we had checked the factors to our [inaudible 00:11:22] studies. So his prothrombin time was high at 12.8 seconds, INR was 1.2, PTT was 35.1 seconds, and fibrinogen was low, at 187. A liver ultrasound was also done at the time, which revealed some mildly heterogeneous echo texture of the liver. There was mild prominence of the portal triads, and so this picture was described as a nonspecific appearance, but a picture that would be seen in acute hepatitis. So the CBC and inflammatory markers were all normal.

Dr. Bryan Fate: Excellent. So first tier, pretty standard liver function tests. So pointing out markedly elevated liver enzymes, indicative of damage. I’ll also say that muscle tissue also releases AST and ALT, so also thinking about sometimes getting a creatinine kinase or an aldolase to differentiate muscle versus liver injury. And then we saw signs of that biliary sludging, backing up, which are typically the GGT, alk phos, conjugated bili. So that was confirmed based on our exam as well. And then I think most alarmingly, we see signs that the liver is not making the things that it is supposed to make. So albumin is low.

Dr. Rashedat Oshodi: Is low.

Dr. Bryan Fate: And then our coagulation factors are off too, which presents risk of bleeding. We did not have any evidence of hemolysis on CBC, though the LDH was a little high, so question mark there. And so quite a few different tests were sent off for the causes. Given those abnormal labs for synthetic liver function, ultimately a decision was made to hospitalize this very cute four-year-old. Concerning lab value, so we’ll go into some of the causes, because it’s a good list, in the hospital, of course. So maybe some of the diagnostic workup they did there for infectious disease, you can go through, Dr. Oshodi.

Dr. Rashedat Oshodi: We did check at CMV, EBV titers and hepatitis testing. The EBV and hepatitis A did reveal some prior infection, but there wasn’t any notes of an acute infection from the serology. CMV was normal. Hepatitis B and C did show that patient was well immunized, and titers were normal. And then a viral screen, patient was found to be positive for norovirus.

Dr. Bryan Fate: So noting once again that infection is the number one cause of acute hepatitis in children, and then also from the beginning of this case, thinking about adenovirus, which was not found, that we’ve seen this kind of sweeping wave of cases associated with it, and then did test positive for norovirus.

Other things to point out, so the second bucket we think of, again, is non-infectious, which there are a few different categories. We did the liver ultrasound, which demonstrated some inflammation and potentially some fibrosis around the gallbladder. Did not show any masses or stones, or some of those other things on our differential that we think of. I was concerned about a mass when I first saw this kid too, but no evidence of cancer or things that kind of push on the biliary tree or the liver architecture itself.

One more note, with ultrasound, they actually did do a doppler to look for Budd-Chiari, which it was normal. So other causes, we think of autoimmune hepatitis. So these labs are typically elevated gamma globulins. Interestingly, even though your liver is not pumping enough albumin that it can actually cause a normal total protein, because there are so many inflammatory proteins coarsing around your body. So interesting lab interpretation note. But the workup for that, we also look at those auto antibodies for smooth muscle, anti-nuclear, anti-liver, kidney. Those were all normal.

Another subdivision, genetic causes. So celiac disease, which was negative. Wilson’s disease. Given his young age, they did not check copper levels. Cystic fibrosis can cause liver damage, though typically we would see earlier signs of pancreatic or pulmonary complications. And then alpha-1 antitrypsin is that effective protein that builds up in our liver, and that it was somewhat elevated during hospitalization, but was not thought to be the cause. And finally, inborn errors of metabolism, which were not found, and typically are picked up by newborn screens, so that’s not totally comprehensive. And finally, he was not getting into Tylenol, which is good. And nutritionally, there is non-alcoholic fatty liver disease, which can have fat deposits, but we would not expect it to present quite as acutely as it did.

So we went through some of the diagnostics that came back later in the hospital. And how was his overall course in the hospital, Dr. Oshodi?

Dr. Rashedat Oshodi: Like I said, right from the onset, he was pretty active. Did not want to be hospitalized. He was rehydrated on the day of admission. He did get some fluid resuscitation, and was given some local steroid cream for the rash. He began to have some good PO intake, and was having good urine outputs. So patient was discharged after two days of hospitalization, and he was followed closely in the GI clinic and primary care clinic for the next four weeks.

His synthetic liver function test improved before discharge. And then how about his overall pattern of liver injury that was tested over time, Dr. Oshodi?

Dr. Rashedat Oshodi: His liver enzymes over time eventually did normalize, continued to calm down. Same thing for his coagulation studies, too, and his appetite slowly was restored.

Dr. Bryan Fate: So that’s great. So he got better. They were quite concerned at the beginning, even thinking about liver transplant if it got a lot worse. But he was one of the many kids that made a full recovery.

Dr. Rashedat Oshodi: Yes.

Dr. Bryan Fate: So just to summarize for everyone, so we have a four-year-old who initially presented with scleral icterus, hepatomegaly, some fatigue, and decreased appetite, nonspecific abdominal pain, ultimately found to have acute cholestatic hepatitis of unknown etiology, given this very comprehensive diagnostic workup, though did test positive for norovirus. And given that we’ve seen this wave of hepatitis associated cases with adenovirus, most recently he did not test positive for adenovirus. So this has to be a consideration, given some of the associations we’ve seen in the last one or two years.

Dr. Rashedat Oshodi: The main take home points with that, so hepatitis has many causes, and management has to be different depending on the specific diagnosis. As we clinicians, we need to be aware of that, and also to perform an organized search to make sure we identify the responsible disease, and then initiate the appropriate treatment. In our case, a case of a viral hepatitis due to norovirus.

Dr. Bryan Fate: Presumed. Yeah.

Dr. Rashedat Oshodi: Presumed.

Dr. Bryan Fate: Yeah.

Dr. Rashedat Oshodi: The second take point is that in children, number one cause is viral. And even though there are a lot of viral causes that we might know about, there are a lot that are still unknown, and a lot that we’re unable to diagnose. And the third take home point is that there has been a recent increase in acute hepatitis in relation to adenovirus, so this warrants consideration in testing in patients with hepatitis of unknown etiology. However, the exact mechanism of liver injury associated with adenovirus is still being researched.

Dr. Bryan Fate: That’s the kind of cause and association question, is is the actual adenovirus, or in this case, the neurovirus, causing direct damage to the liver? Is there an association with something else, something autoimmune? We don’t really understand the mechanism, so at this time, I don’t think we can attribute it to the virus itself. More of an association-

Dr. Rashedat Oshodi: Association. Yeah.

Dr. Bryan Fate: … than a truly causal mechanism. I think there’s a lot that we’re still learning about this adenovirus association. Is it linked to COVID infections? We’re not quite sure. We have seen other cases of this. There was kind of a wave of acute disseminated encephalomyelitis cases with enterovirus in particular. So these kids that get confused, weakness, have spinal cord changes. So same picture is that we don’t really have a causal pathway for that. So at this point, it’s an association that is still being actively explored. But I think any kid who presents with acute hepatitis, we definitely need to think about adenovirus testing.

And as usual, an original musical number to solidify key concepts and hopefully tug at your heartstrings. Enjoy.

Dr. Angela Kade Goepferd: Thank you for joining us for Talking Pediatrics. Come back each week for a new episode with our caregivers and experts in pediatric health. Our executive producer and showrunner is Ilze Vogel. Episodes are engineered, produced, and edited by Jake Beaver. Amy Juba is our marketing representative. For more information and additional episodes, visit us at childrensmn.org/talkingpediatrics, and to rate and review our show, please go to childrensmn.org/survey.