This 14-year-old girl had a chief complaint of leg edema. She had been well until 2 weeks before this admission, when she began to develop increasing abdominal distention and pedal and ankle edema. One week before this visit, she started complaining of fatigue, abdominal pain, and nausea. There were no risk factors for Hepatitis A or B. Her medical history was remarkable for a diagnosis of attention-deficit/hyperactivity disorder (ADHD), for which she had been prescribed pemoline. In addition, she had been diagnosed as having depression and had been receiving sertraline. There was no family history of autoimmune disease. A paternal uncle had died of liver disease in his forties.
On physical examination, she was alert and communicative. Her vital signs and growth parameters were unremarkable. Skin exam was normal; there were no spider angiomata. HEENT examination revealed scleral icterus. There was no significant adenopathy. Lungs were clear. Sl and S 2 were normal without murmurs, gallops, or rubs.
The abdomen was distended. A fluid wave was appreciated. The liver was tender to palpation and palpable 5 cm below the right costal margin. A spleen tip was palpable. There was bilateral pitting pedal edema. On neurologic examination, she was fully oriented. There was no asterixis. She had normal gait, coordination, and deep tendon reflexes.
Laboratory evaluation revealed serum transaminases between 1,000 and 1,500 IU, a prothrombin time of 24 seconds, albumin 1.7 g/dL, total bilirubin 7.8 mg/dL, and direct bilirubin 5.7 mg/dL.
Douglas Nordli, MD, moderator: It's not a stretch to say that she has liver disease. My first question is how do we decide whether it's acute or chronic?
Estella Alonso, MD, pediatric hepatologist: The tender liver is more consistent with capsular distention and acute disease. Although we usually think of ascites as part of portal hypertension and chronic liver disease, there are acute conditions that can cause portal hypertension as well.
Budd-Chiari syndrome was our working diagnosis when she was transferred. Budd-Chiari syndrome is a result of thrombosis of the hepatic veins, which causes acute hepatic outflow obstruction. Pedal edema in combination with ascites is a very typical presentation of this condition. Children with chronic liver disease may have ascites but rarely develop pedal edema.
It's also possible that she has subacute hepatic injury. Some forms of acute hepatitis, such as drug injury or Wilson's disease, can cause just enough hepatic collapse to lead to portal hypertension.
Dr. Nordli: What are the causes of Budd-Chiari syndrome?
Dr. Alonso: Anything that leads to a hypercoagulable state such as Protein C or S deficiency or antiphospholipid syndrome.
Dr. Nordli: How does laboratory testing help in the differential diagnosis?
Dr. Alonso: The elevated transaminases don't help us significantly. Typically, serum albumin is not low unless the patient has albumin losses through the urine or the stool or the process has been going on for more 20 days, the half-life of albumin. Patients who have fulminant viral hepatitis should have a normal albumin. Patients with chronic liver disease generally have a prothrombin time between 1 8 and 20 seconds, unless there is concomitant vitamin K deficiency.
Dr. Nordli: Does the consistency of the liver on palpation offer any clues?
Dr. Alonso: In general, a full, rounded edge suggests an acute process which has caused edema and capsular distention. A nodular edge indicates cirrhosis. The bottom line in this case in that there were some features of acute liver injury and some indicating a more chronic process.
Dr. Nordli: Serologies for hepatitis A, B, and C were negative. The sedimentation rate was normal. The serum ceruloplasmin, copper, and alpha-one antitrypsin levels were normal; ophthalmologic exam for the presence of Kaiser-Fleischer rings was negative. The serum markers for autoimmune hepatitis (anti-smooth muscle antibody, antinuclear antibodies, and antibodies to liver/kidney microsome type 1) were all negative. A transjugular liver biopsy was performed.
Dr. Alonso: The transjugular approach was chosen for several reasons. First, this approach is safer in a patient with a coagulopathy. If the biopsy bleeds, the blood goes back into the blood vessel. Second, the presence of ascites is a relative contraindication to a percutaneous liver biopsy because ascitic fluid inhibits clot formation. Finally, this approach allows us to inject contrast into the hepatic veins to check for the presence of Budd-Chiari syndrome. Her hepatic veins were normal.
Hector Melin-Aldana, MD, pediatric pathologist: A liver biopsy may give the answer or it may provide useful information to help the physician interpret the clinical data, as it does in this case. The hepatocytes are pale and swollen, indicating some damage. There are scattered areas of inflammation (indicating acute, ongoing damage) and scarring with fibrosis (indicating chronic injury). There are areas of interface hepatitis where the inflammation involves the portal tracts initially and "spills over" into the parenchyma. Overall, this is a picture of chronic hepatitis. However, the findings don't point to a specific etiology. They could be seen in chronic viral hepatitis, autoimmune hepatitis, or even toxic hepatitis.
Dr. Nordli: Can you determine how long this has been going on?
Dr. Melin: While it's difficult, I'd guess that the injury has been occurring for weeks, not months or years.
Dr. Alonso: Our definition of acute fulminant hepatitis is evidence of hepatic synthetic dysfunction associated with encephalopathy within eight weeks of the onset of liver disease. This biopsy might be seen, for instance, in acute fulminant failure from autoimmune hepatitis.
Dr. Nordli: You mentioned toxic hepatitis. Could this have been due to pemoline?
Dr. Melin: The inflammatory infiltrate was generally lymphocytic with a few plasma cells. Usually, but not always, eosinophils are present in a drug-induced hepatitis.
Dr. Alonso: Pemoline hepatotoxicity can range from asymptomatic elevation of serum transaminases to fulminant hepatic failure. The pathophysiology of the hepatotoxicity is unknown. We interpreted the biopsy results as being inconsistent with a toxic hepatitis.
Dr. Nordli: How was she treated?
Dr. Alonso: We thought that the combination of findings was most consistent with an autoimmune hepatitis, even though her serology was negative. As such, we treated her with large doses of corticosteroids in an attempt to reverse the inflammatory process. Sometimes, this obviates the need for an immediate liver transplant. Unfortunately, she deteriorated rapidly and developed Grade IV hepatic encephalopathy. In this stage, the patient is unresponsive and may have decorticate or decerebrate posturing response to pain.
Denise Goodman, MD, pediatric intensive care physician: At this stage of encephalopathy, patients generally can't protect their airways, so she underwent endotracheal intubation. As part of the encephalopathy, intracranial pressure may become elevated. Intracranial pressure monitoring was considered. As opposed to traumatic head injury, I'm unaware of any study that documents the utility of intracranial pressure monitoring in this condition. On the one hand, coagulopathy makes the risk of intracranial hemorrhage substantial. On the other hand, we would like to prevent brain injury and irreversible brain dysfunction, which would preclude a liver transplant. It's impossible to titrate therapy for increased intracranial pressure without a monitor.
Dr. Nordli: What about following her vital signs?
Dr. Goodman: Cushing's triad - bradycardia, hypertension, and hypopnea - is a preterminal event. Once you're at that point, you've probably waited too long to intervene. Another criticism of ICP monitoring is that it only measures the pressure in one part of the brain, but it's the best we have.
Dr. Nordli: I noticed that she underwent plasmapheresis.
Dr. Alonso: Plasmapheresis and blood volume exchange have been in the literature for 20 years. While their efficacies hasn't been established, we're trying to stabilize these patients until a liver becomes available. I doubt that there will ever be a randomized, controlled study because the number of patients from a large number of liver centers needed would be daunting.
Dr. Nordli: Shortly thereafter, she received a liver transplant. I thought that the prognosis for patients with Stage IV encephalopathy was poor, perhaps suggesting that liver transplantation shouldn't be performed.
Dr. Alonso: There's no question that irreversible neurologic injury in acute liver failure generally is reserved to those patients who develop stage IV encephalopathy. However, there are certainly subgroups of patients within this stage. For instance, children without sustained elevations of intracranial pressure while being monitored may fare better. We also are reassured when neuroimaging shows little or no cerebral edema. Unless we feel beyond a reasonable doubt that the neurologic prognosis is dismal, we will proceed with liver transplantation.
Leon Epstein, MD, pediatric neurologist: Those of us who lived through the era of Reye syndrome all took care of children who looked terrible, had high intracranial pressure measured by monitoring, yet who woke up and were neurologically normal at the end of therapy. The only point is that it's very difficult to prognosticate with certainty in these situations.
Dr. Nordli: Did the histology of the explanted liver help confirm the etiology?
Dr. Melin: Unfortunately, it just showed an advanced cirrhotic liver.
Dr. Alonso: Our best guess was that she had autoimmune hepatitis, probably chronic with an acute exacerbation. This could have taken place over a few months' time.
Dr. Nordli: Following the liver transplant, she recovered nicely and had normal mental status 8 days later. However on day 8 post-transplant, she started hallucinating, speaking strangely, and imagining that bugs were crawling on her. She was seen by the psychiatrists and diagnosed as having delirium. Haloperidol was started and an attempt was made to treat the delirium by reducing the external stimuli in the intensive care unit. Initially, she improved but then she developed "tremulousness" including strange movements of her mouth and tongue, and seizures were suspected. Video EEG recording clearly demonstrated that she was having non-convulsive status epilepticus. The ictal activity stopped with lorazepam. She proceeded to talk to her mother for the first time in 3 days.
Dr. Epstein: This girl developed limbic encephalitis, a combination of confusion, apparent insomnia, and tremors. This was first described in adults following stem cell transplantation and found to be a result of reactivated human herpes virus 6 (HHV-6) in the hippocampus. Several of these patients were found to have HHV-6 DNA in the cerebrospinal fluid. One patient died and HHV-6 protein was found in the hippocampus, indicating active infection.
Dr. Nordli: What is the role of HHV-6 in the genesis of febrile seizures?
Dr. Epstein: More than 50% of simple febrile seizures have been found to be due to HHV-6.
Dr. Nordli: Does HHV-6 infection have any long-lasting effects?
Dr. Epstein: We know that a significant percentage of children with temporal lobe seizures who have evidence of hippocampal injury on magnetic resonance scanning, termed mesial temporal sclerosis, have a history of prolonged febrile seizures in childhood. However, we don't know the role of HHV-6 and HHV-7 infection, if any, in the development of mesial temporal sclerosis and subsequent epilepsy. At the present, there is a large multicenter study which will hopefully answer this question. Our theory is that those children who develop mesial temporal sclerosis and temporal lobe epilepsy are those who have had HHV-6 and HHV-7 infections.
Ben Katz, MD, pediatric infectious disease specialist: We all know that HHV-6 is a cause of roseola in immunocompetent patients. These data on its role as a pathogen in immunocompromised patients are relatively new. It's interesting to speculate on potential therapies for this girl's encephalitis. First, lowering her level of immuno-suppression a bit might allow her own immune system to control this generally benign virus. Alternately, some antiviral agents such as acyclovir and cidofovir may have some activity against HHV-6. Before their use, I would try identifying HHV-6 DNA by polymerase chain reaction on cerebrospinal fluid.
One more comment. I have no idea as to the role of pemoline in this child's liver failure. However, I believe that it is important that it get reported to the drug company as a possible adverse reaction. Rare reactions to drugs may go unnoticed unless these incidents are reported.
Dr. Nordli: It was reported. Her seizures first were controlled by valproic acid. Because this drug may be hepatotoxic as well, she was switched to levetiracetam. She ultimately did very well and was discharged from the hospital several days later. HHV-6 DNA was not detected in the cerebrospinal fluid but was ultimately identified in the liver. Thank you, everybody.