Although we are making headway in understanding and treating people living with Alagille Syndrome (ALGS) — a rare genetic disorder that manifests in a variety of ways — several questions remain. Here, Henry C. Lin, MD, pediatric gastroenterologist in the Division of Gastroenterology at Doernbecher Children’s Hospital, Oregon Health & Science University, shares his perspective on the state and direction of Alagille research and what that research means for patients going forward.
“While we have come a long way in understanding what ALGS is and why it occurs, we do not have a deep understanding of how the genetic mutations that cause the syndrome lead to the symptoms that arise in these patients,” Dr. Lin says. “The broad range of symptoms and symptom severity complicates the picture. It is difficult to pinpoint why people with the same genetic abnormalities may experience very different symptoms that affect entirely separate organ systems.”
Liver and Heart Involvement Pose Challenges in ALGS
While ALGS can affect the kidneys, eyes, skeleton, and other parts of the body, there is a lot of focus on liver and heart involvement. Dr. Lin is particularly interested in what drives liver dysfunction in ALGS. He says: “It is not entirely clear whether it is the liver cells themselves or bile cells that make the liver vulnerable to ALGS. Because there is no ideal animal model, researchers have been limited in their ability to study the relevant processes and mechanisms.”
Liver involvement varies significantly from patient to patient, with some people with ALGS showing only a mild elevation of liver enzymes that may go unrecognized without testing. Others have severe liver involvement, and we don’t fully understand why. Even within individual patients, the severity of liver involvement often varies within the first few years of life.
However, we do know that the severity of liver involvement in the first few years of life can help predict how involved the liver will be going forward. According to Dr. Lin, “By the time you’re 4 or 5 years old, your liver severity is a good indicator of your liver involvement as you age.”
Another major challenge in ALGS is pulmonary stenosis, in which the blood vessels that carry blood away from the heart and to the lungs are narrower than they should be. This condition can lead to more problems as people with ALGS age. Unfortunately, though we know that pulmonary stenosis often occurs in ALGS, we do not know exactly why. This knowledge gap prevents us from developing highly effective treatments that specifically target the type of pulmonary stenosis that these patients experience. For now, we generally treat it by adding a stent to open the narrow vessels so that blood can flow freely.
Nutritional Difficulties in ALGS
One of the frequent effects of changes in the liver in people with ALGS is a paucity of bile ducts, which means bile flow from the liver becomes blocked. This blockage leads to 2 major problems: there is not enough bile to aid with the normal digestion and absorption of certain nutrients, and cholesterol and toxins can build up in the body because bile levels aren’t high enough to sufficiently eliminate them.
“We want to ensure that people with ALGS are growing in as healthy a way as possible — both in terms of their weight and their height — and that they are getting the vitamins they need for normal health and development,” Dr. Lin says. “It can be difficult to maintain adequate vitamin levels in these patients, even when more vitamins are introduced through the diet because bile is required to absorb critical vitamins including vitamins A, D, E, and K.”
A specific challenge related to vitamin K is that low levels of the vitamin can lead to clotting difficulties, but problems with clotting are also associated with liver failure. “When we see that patients are having trouble clotting, we are not sure whether that clotting is due to low vitamin K levels or a failing liver,” Dr. Lin says. “Because it is hard to measure vitamin K directly, management in these patients is a challenge.”
People With ALGS Often Struggle to Grow
A few significant challenges in people with ALGS can pose threats to normal growth. These may be addressed by using a feeding tube to introduce more calories and nutrients. The more severe one’s liver disease, the more energy they will need.
One of the challenges is patients may simply feel too sick to consume the calories advised for healthy growth. In cases where the spleen is enlarged, they may experience abdominal competition, where there is not enough space to accommodate an increase in stomach volume that would come with increased consumption. In severe cases, fluid can enter the stomach, further reducing the capacity for more intake.
There are studies working toward creating growth curves for people with ALGS to make it easier for clinicians to understand normal growth in these patients. Knowing how ALGS affects growth is important because failing to grow can also be indicative of chronic liver disease, which would require different interventions.
Severe Itching Is Common in ALGS
Pruritus, or severe itching, is the ALGS symptom we can most address therapeutically. Itching in ALGS is thought to occur in part because the dysfunction in bile acid flow leads to the accumulation of bile acids that often end up deposited in the skin.
Management for itching usually begins with antihistamines as a first-line treatment. If antihistamines are not effective in significantly reducing the itching sensation, antibiotics that can help break down bile acids are usually the next choice. Other pharmacological options for itching in ALGS are cholestyramine and naltrexone. In severe cases, biliary diversion surgeries may be used to prevent bile acids from being reabsorbed.
A newer and potentially more promising pharmacological approach to itching in ALGS is the use of bile transport inhibitors, which block the reuptake of bile acids. “These drugs have been used in pediatric cholestatic disease and are being applied more in ALGS as we have gained more of an understanding for the mechanisms mediating pruritus,” Dr. Lin says.
Ongoing clinical trials may bring more knowledge and relief to the ALGS community.
Through innovative research programs, we have learned that it is the bile ducts rather than liver cells that appear to drive liver disease in ALGS.
“What we don’t know yet is how the genetic mutations that lead to ALGS affect bile ducts and how those changes to bile ducts cause liver disease,” says Dr. Lin. “And why it is that there is so much variety in terms of the organs that are involved in the disease is still a bit of a mystery.”
According to Dr. Lin, most of the clinical trials in ALGS are currently focused on itching symptoms because those are the most recent innovations from a medical management standpoint. However, there is also ongoing research into understanding the mechanisms by which cells of the biliary tract impact liver function. Potential stem cell applications are also being investigated. “It is very important to have these trials open and accessible so that we can collect as much information as possible on this syndrome and develop therapies that can help people with ALGS,” he says.