The Quarterly Consult is a quarterly supplement to the Bulletin highlighting pediatric clinical expertise. If you have an item of interest to include in the Quarterly Consult, contact Dr. Steve Dassel at 206-625-7373, mailbox 8588.

By Steve Dassel, MD

In more than 20 years doing the Consult, I don't remember an interview that focused on liver disease. I had the opportunity to talk with Simon Horslen, MD, professor of pediatrics, Division of Gastroenterology, and medical director of the Liver and Intestine Transplant Service at Children's Hospital. A hepatologist, Dr. Horslen has been with Children's Hospital for three years. He is also the director of the Intestinal Rehabilitation Program.

Q: What are some of the causes of acute liver disease that may wind up resulting in a liver that needs to be transplanted?

A: Fulminant viral hepatitis is one of the main causes. Hepatitis A causes only about 0.1% to 0.5% of cases in the United States, although throughout the world it causes many more. A few cases are caused by Epstein-Barr virus, but the vast majority are idiopathic, and therefore may not be viral at all. Some cases of acute liver failure are due to metabolic diseases, such as Wilson disease; others may be autoimmune, and some are from drug hepatotoxins such as acetaminophen and nondrug hepatotoxins. The best recognized of these is from mushroom (amanita) poisoning.

Q: What about the chronics?

A: The most common by far is biliary atresia. In fact, this is the major indication for liver transplants constituting about 45% to 50% of pediatric liver transplants. Other examples would be alpha-1 antitrypsin deficiency, cystic fibrosis and some of the biliary transport defects. In addition to acute and chronic etiologies, there are also hepatocellular abnormalities that present with normal liver architecture. Examples are disorders of the urea cycle, the organic acidemias, porphyria and hemophilia A and B.

Q: So, what were the diseases contributing to hepatic transplant at Children's Hospital in the past 3 years?

A: That would be 37 transplants - 25% due to biliary atresia, 20% fulminant hepatitis, and the rest a mix of the chronic and metabolic liver diseases. There were also four to five patients with unresectable hepatoblastoma.

Q: What can we generalists do to get liver transplant candidates in to see you faster?

A: There is good evidence that early recognition leads to improved outcomes. A good example is early recognition of the infant with biliary atresia.

Q: What are the red flags?

A: Elevated direct or conjugated bilirubin levels. This may be complicated in the infant with a mixed hyperbilirubinemia, and, in those cases, it is important for you to know which assay your lab is doing. If the lab is assaying for direct bilirubin, then the values should be less than 20% of the total and should certainly not be greater than 4 or 5 mg/dL. If they are assaying for conjugated bilirubin, the values should be less than 2 mg/dL. You should also be alert to the red flag of a bilirubin which had been dropping, that begins to increase, and you should look carefully at any infant with a persistent (greater than 10 days) elevated bilirubin. The danger of following only total bilirubin is that you will miss the elevated conjugated bilirubin levels. So, at least the last bilirubin level you are going to get in any particular follow-up of neonatal jaundice should include a conjugated bilirubin.

Q: Anything else?

A: Yes, yellow urine is a red flag. Babies who are taking enough fluid to maintain hydration should have almost colorless urine. A breast-fed baby also can have a fairly light yellow-colored stool, but it should not be white or gray.

Q: Those are certainly pits we may fall into. Any others?

A: With the epidemic of childhood obesity, we are seeing more fatty liver disease, which mildly elevates liver function tests. There really is little we have to offer these patients other than general nutritional advice.

Q: What should be our work-up of an abnormal liver function test before we refer them on to you?

A: Rule out autoimmune liver disease with antinuclear antibody and smooth muscle antibody. Rule out Wilson disease with a serum ceruloplasmin and get a viral hepatitis panel. Finally, a fasting insulin, fasting glucose A1c hemoglobin and lipid profile may reveal evidence of deranged glucose homeostasis.

Q: What about an abdominal ultrasound?

A: That is probably standard procedure when looking at abnormal liver function tests, but is likely only to show increased echogenicity compatible with steatosis.

Q: What is the history behind the liver transplant unit at Children's Hospital?

A: Liver transplants were begun here in the early 1990s. The institution made a major commitment to enlarge the program in 2004. We did 17 liver transplants last year.

Q: How does that rank with other large programs such as Stanford, UCLA, etc.?

A: Very few pediatric liver transplant programs in the United States do 20 or more transplants a year, but the largest centers, such as UCLA and Stanford, do about 25-30 pediatric liver transplants a year.

Q: What is your catchment area?

A: The United Network for Organ Sharing (UNOS), the federally appointed program that is in charge of organ distribution in the United States, has partitioned the country into 11 regions. We are in Region 6, which comprises Washington, Oregon, Idaho, Alaska, Montana and Hawaii. The majority of referrals will come from within Region 6, but we are also reaching out further, and some families from other parts of the country also choose to come to Seattle for evaluation and transplantation.

Q: What percent of Region 6 transplants do you do?

A: About 60% currently, but it is our aim to offer our services to all regional patients, since there are no other pediatric liver transplant teams in Region 6.

Q: How many pediatric liver transplants take place a year in the United States?

A: 500 to 600.

Q: How is the size of a region decided?

A: Both by population and geography.

Q: What is your capacity?

A: We expect to do about 20 to 25 isolated liver transplants a year over the coming years. With the growth of our intestine transplant program, we will also be doing combined liver and intestine transplants.

Q: Is that what it takes to maintain proficiency?

A: This is not an easy question to answer as such data does not exist, but I would suggest that one liver transplant a month is probably the level needed to maintain a top program.

Q: Although all of the liver recipients in Region 6 do not come to Children's Hospital, does your team have first choice on all of the liver donors in Region 6?

A: There is a degree of severity of hepatic failure, and the most severe must be served first. So yes, we have first choice on all our patients who are in the highest order of severity.

Q: Do all kids who need a new liver get one in time?

A: As a rule, and in our experience, the answer is yes; however, a number of children do die in the United States awaiting liver transplants each year. The addition of children to the liver transplantation waiting list each year in the United States is a fairly constant number, unlike the adult list, which is growing every year. This is due to a number of factors, including the recognition that an increasing number of patients with end-stage liver disease, particularly in older age groups, can still benefit from liver transplantation.

Q: Are there enough pediatric livers to cover the demand?

A: Well, adult livers can be cut down to as much as one-fifth their original volume and transplanted, but the pediatric population contributes far more livers to the pool than it takes from the pool.

Q: Tell me about the severity scale. How is that determined?

A: Group 1A is the most severe. They are made up of the fulminant hepatic failures, judged to have a significant risk of dying within a few days without transplantation. Nationally, about 70% of these kids get their livers before death. In recent years, we have not had a death of such a child while waiting for a liver, due to the ability of our team to utilize a number of innovations such as reduced size organs, living donors and ABO incompatible allografts. The liver transplant team in a region gets the first offer of an available liver for their 1A patients.

Q: What is a 1B severity?

A: 1B is a purely pediatric category and enables the sickest children with chronic liver disease a chance to receive an organ offer as soon as possible. A potential recipient is required to be in an ICU with advanced end-stage liver disease and have significant ongoing blood loss or be on respiratory or renal support. The average wait for a liver here at Children's, for this group, is about 2 weeks.

Q: If a child is on the waiting list, but not eligible for either of the Status 1 categories, what determines their likelihood of receiving an organ offer?

A: The ranking of candidates depends on their PELD (Pediatric End-Stage Liver Disease) score if they are younger than 12 years or on their MELD (Model of End-Stage Liver Disease) score for adolescents and adults.

Q: What are the factors that determine these severity scores?

A: They are based on objective parameters that have been shown to be associated with an increased incidence of death in patients with chronic liver disease. For the PELD score, these are presence of a coagulopathic state, reduced serum albumin levels, conjugated bilirubin and growth failure. Increased severity is also awarded if the patient is less than a year old. For MELD score, the calculation is based on coagulopathy, serum bilirubin and creatinine level. Although prediction of mortality on the waiting list varies somewhat between MELD and PELD, low scores, for example, below 6, are associated with less than 1% mortality, whereas scores of 40 are associated with 50% or greater mortality by 90 days.

Q: What is the donor-to-recipient ratio for kids?

A: As I mentioned, there are 500 to 600 pediatric recipients a year, and there are 900 to 1,000 pediatric donors every year. So, obviously some kids' livers, principally livers from older kids and adolescents, go to adults.

Q: This has certainly been an education for me. What telephone numbers do we call to refer a patient?

A: Routine referral through Gastroenterology or Transplant Clinics. But I am happy to take direct calls to answer questions pediatricians may have concerning any aspect of liver disease or transplantation or to expedite their patient's visit. To do this, page me at (206) 469-0841 or call (206) 987-7777 and ask the physician operator to page me for you.

Q: What information should we have on hand for you?

A: Most important is the general clinical information; however, recent liver function tests and a conjugated bilirubin level would be appreciated.

Q: Thank you Dr. Horslen.