Calming the Itch of Liver Disease

KEY TAKEAWAYS:

• A hidden side effect of liver disease can be itchiness that may not detected by medical tests
• Itchiness caused by liver malfunction can cause discomfort and scratching, and interfere with sleep and eating, even in children too young to talk
• A new class of medications can ease the itch  

A surprising yet miserable side effect of liver disease can be severe itchiness. Children with inherited cholestatic liver diseases can experience intermittent itching that doesn’t show up on standard tests but interferes with their lives, sleep, and ability to concentrate. Children too young to talk may be unable to explain their discomfort. This itching, called pruritis, is an effect of cholestasis, an inherited condition that affects about 1 in every 2,500 people, in which bile ducts become blocked, causing excessive bile to circulate in the body. “It's extremely debilitating,” says Rohit Kohli, MBBS, MS, Chief, Division of Gastroenterology, Hepatology, and Nutrition at Children’s Hospital Los Angeles. “Children come in who have scratched themselves to the point of bleeding. And if you are itching constantly, you cannot concentrate in school and don't feel like eating either, so growth and development is impaired.”

A variety of rare childhood liver conditions can come with cholestasis-induced itchiness, including:

• Progressive familial intrahepatic cholestasis (PFIC), a set of progressive genetic disorders in which bile builds up in liver cells and damages the liver
• Alagille syndrome, in which a child has underdeveloped bile ducts or too few bile ducts
• Biliary atresia, a condition where bile ducts are blocked or damaged
• Cystic fibrosis, which causes thick bile and secretions that can block the bile ducts

What happens when the liver doesn’t do its job

The liver removes toxins from the blood and produces nearly all the proteins found in the blood. It also produces bile, which absorbs fats and fat-soluble vitamins and nutrients from food. Normally bile flows out of the liver through the bile ducts into the small intestine. When bile flow is blocked, bile acids can build up in the liver and blood—leading to jaundice and itching.

The itchiness of cholestatic liver diseases is not detectable by a medical test. Children too young to talk may show symptoms including fretfulness, scratching, abraded skin, poor sleep, and general failure to thrive. Previous drugs meant to treat these symptoms did not work well for many children. Only a liver transplant would end the itching.

A new set of medications offers relief—and may do more

As a part of the National Institutes of Health-funded Childhood Liver Disease Research Network, a consortium of 14 children’s hospitals with clinical sites and research labs in the U.S., Canada, and London, CHLA researchers are involved in ongoing clinical studies that resulted in the FDA approval of a new category of medications for cholestatic pruritis: Livmarli (maralixibat) and Bylvay (odevixibat).

“We use these drugs now as first-line treatments,” says Dr. Kohli. “We have anecdotally seen an improvement in growth. We've definitely seen improvement in itching.” The drugs may also offer an improvement in the liver disease itself, but that is not yet proven.

How these drugs work

These intestinally active medications block the reabsorption of bile acids that are typically reabsorbed at the far end of the small intestines—the area called the Ilium. Normally, the body recycles bile acids eight to 10 times a day. Bile acids are important in the absorption of fat-soluble vitamins and other metabolic signaling. Using medications to block reabsorption helps the body eliminate excess bile acids. "After prescribing these medications, we observed that the children who were previously having a lot of pruritus caused by high levels of bile acids didn't itch anymore,” says Dr. Kohli. The drugs would be used as a chronic treatment for itching unless patients get a liver transplant.

But there is a bigger goal in mind. “The hope is that the liver disease is either stalled or reversed because the toxic bile acids are no longer recirculating back to the liver and damaging it,” says Dr. Kohli. “With these medications, in the future, we may not need liver transplantation, except for maybe some patients we’re just reaching too late.” He cautions that some elevation of liver enzymes was also associated with these medications, so it will be important to collect Phase 4 data for these potential side effects.

CHLA is one of the top pediatric liver transplant centers in the U.S. Juliet Emamaullee, MD, PhD, FRSC, FACS, Research Director, Division of Abdominal Organ Transplantation and a transplant surgeon on the team, also hopes that these medications will mean fewer transplants, but she cautions that the disease has a spectrum of intensity in patients. “Some patients may do very well with these medications in general, and some patients might progress quickly to needing a liver transplant. Having these as a tool can make it a bit easier to figure out their trajectory.”

It can also make their wait for a transplant a little more bearable.